Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a ...few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial.
Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR<3) versus high (NLR≥3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution.
NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) hazard ratio (HR) 1.27 (95% CI 1.05–1.55), P=0.017 and overall survival (OS) HR 1.56 (95% CI 1.25–1.95), P<0.001 than patients with low NLR. In the multivariable model, NLR retained a significant association with OS HR 1.44 (95% CI 1.14–1.82), P=0.014 but not with PFS HR 1.18 (95% CI 0.95–1.46), P=0.375. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction=0.536) or OS (P for interaction=0.831). Patients with low HR 0.84 (95% CI 0.64–1.08) and high HR 0.73 (95% CI 0.54–0.97) NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS HR 0.83 (95% CI 0.62–1.12) for low NLR; HR 0.82 (95% CI 0.59–1.12) for high NLR.
This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.
The BEBYP trial is a prospective, randomized, open-label, multicenter, phase III study evaluating the continuation or reintroduction of bevacizumab with second-line chemotherapy in mCRC patients ...progressed to a first-line therapy containing bevacizumab. The primary end point was PFS. Despite some limitations, mainly due to the premature interruption, the study met its primary end point.
The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy.
In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with anα andβ error of 0.05 and 0.20, respectively, 262 patients were required.
In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group adjusted HR = 0.70; 95% confidence interval (CI) 0.52–0.95; stratified log-rankP = 0.010. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56–1.06; stratified log-rankP = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%;P = 0.573). Toxicity profile was consistent with previously reported data.
This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC.
NCT00720512.
Abstract Background BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4–6 months with first-line ...conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding. Patients and methods This phase II trial was designed to detect an increase in 6 month-Progression Free Rate (6 m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618. Results Two-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7 months, 6 m-PFR was 73%. Median PFS and OS were 9.2 and 24.1 months, respectively. In the pooled population, at a median follow up of 40.4 months, 6 m-PFR was 84%. Median PFS and OS were 11.8 and 24.1 months, respectively. Overall RR and disease control rate were 72% and 88%, respectively. Conclusion Lacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.
KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. ...Additional KRAS mutations are described in CRC.
We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients.
Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients.
Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.
Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II ...prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy.
We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy.
Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P=0.01).
Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options.
Astronomy. ASASSN-15lh: A highly super-luminous supernova Dong, Subo; Shappee, B J; Prieto, J L ...
Science (American Association for the Advancement of Science),
2016-Jan-15, 20160115, Letnik:
351, Številka:
6270
Journal Article
Recenzirano
We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± ...0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.
•Data on rotations of 46 binary and triple asteroid systems were collected.•An anti-correlation of secondary synchroneity with orbital eccentricity observed.•Libration angles of synchronous ...secondaries are less than 20° on most epochs.•A paucity of chaotic rotations among asynchronous secondaries is apparent.•An upper limit on the secondary equatorial axis ratios of 1.5 was found.
We collected data on rotations and elongations of 46 secondaries of binary and triple systems among near-Earth, Mars-crossing and small main belt asteroids. 24 were found or are strongly suspected to be synchronous (in 1:1 spin–orbit resonance), and the other 22, generally on more distant and/or eccentric orbits, were found or are suggested to have asynchronous rotations. For 18 of the synchronous secondaries, we constrained their librational angles, finding that their long axes pointed to within 20° of the primary on most epochs. The observed anti-correlation of secondary synchroneity with orbital eccentricity and the limited librational angles agree with the theories by Ćuk and Nesvorný (Ćuk, M., Nesvorný, D. 2010. Icarus 207, 732–743) and Naidu and Margot (Naidu, S.P., Margot, J.-L. 2015. Astron. J. 149, 80). A reason for the asynchronous secondaries being on wider orbits than synchronous ones may be longer tidal circularization time scales at larger semi-major axes. The asynchronous secondaries show relatively fast spins; their rotation periods are typically <10 h. An intriguing observation is a paucity of chaotic secondary rotations; with an exception of (35107) 1991 VH, the secondary rotations are single-periodic with no signs of chaotic rotation and their periods are constant on timescales from weeks to years. The secondary equatorial elongations show an upper limit of a2/b2∼1.5. The lack of synchronous secondaries with greater elongations appears consistent, considering uncertainties of the axis ratio estimates, with the theory by Ćuk and Nesvorný that predicts large regions of chaotic rotation in the phase space for a2/b2≳2. Alternatively, secondaries may not form or stay very elongated in gravitational (tidal) field of the primary. It could be due to the secondary fission mechanism suggested by Jacobson and Scheeres (Jacobson, S.A., Scheeres, D.J. 2011. Icarus 214, 161–178), as its efficiency is correlated with the secondary elongation. Sharma (Sharma, I. 2014. Icarus 229, 278–294) found that rubble-pile satellites with a2/b2≲1.5 are more stable to finite structural perturbations than more elongated ones. It appears that more elongated secondaries, if they originally formed in spin fission of parent asteroid, are less likely to survive intact and they more frequently fail or fission.
The ASAS-SN bright supernova catalogue – II. 2015 Holoien, T. W.-S; Brown, J. S; Stanek, K. Z ...
Monthly Notices of the Royal Astronomical Society,
05/2017, Letnik:
467, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
This manuscript presents information for all supernovae discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN) during 2015, its second full year of operations. The same ...information is presented for bright (mV ≤ 17), spectroscopically confirmed supernovae discovered by other sources in 2015. As with the first ASAS-SN bright supernova catalogue, we also present redshifts and near-ultraviolet through infrared magnitudes for all supernova host galaxies in both samples. Combined with our previous catalogue, this work comprises a complete catalogue of 455 supernovae from multiple professional and amateur sources, allowing for population studies that were previously impossible. This is the second of a series of yearly papers on bright supernovae and their hosts from the ASAS-SN team.
Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, ...we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status.
Patients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status.
Information about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N=173) presented shorter OS 23.7 versus 31.0months, HR=1.42 (95% CI 1.09–1.84), P=0.010 and a trend toward shorter PFS 10.2 versus 11.5months, HR=1.24 (95% CI: 0.98–1.56), P=0.083 than those with left-sided tumors (N=185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR=0.59 versus 0.89, P for interaction=0.099) and OS (HR=0.56 versus 0.99, P for interaction=0.030) and this advantage was independent of their RAS and BRAF status.
FOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.
The phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a ...significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS=0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender.
Subgroup analyses according to age (<70 versus 70–75years) and gender were carried out for overall response rate (ORR), progression-free survival (PFS), and AE rates.
Of 1187 patients, 1005 (85%) were aged <70years and 182 (15%) 70–75years; 693 (58%) were males and 494 (42%) females. There was no evidence of interaction between age or gender and the benefit provided by the intensification of the upfront chemotherapy in terms of ORR and PFS, or the increased risk of experiencing G3/4 AEs. Elderly patients and females experienced higher rates of overall G3/4 AEs (73% versus 60%, P<0.01 and 69% versus 57%, P<0.01, respectively). Notably, in the FOLFOXIRI/bevacizumab subgroup, G3/4 diarrhea and febrile neutropenia occurred in 27% and 16% of elderly patients, respectively, while females reported high incidences of any grade nausea (67%) and vomiting (50%).
The improvements in terms of ORR and PFS of FOLFOXIRI/bevacizumab versus doublets/bevacizumab are independent of gender and age, with a similar relative increase in AEs among elderly patients and females. Initial dose reductions and possibly primary G-CSF prophylaxis should be recommended for patients between 70 and 75years old treated with FOLFOXIRI/bevacizumab, and a careful management of antiemetic prophylaxis should be considered among females.
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