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.
Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. ...Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of β1-integrin (Itgβ1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted β1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl(-) gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
Activation of nuclear factor E2-related factor-2 (Nrf2), a sensor of oxidative stress, is neuroprotective in animal models of cerebral ischemia, traumatic brain injury, subarachnoid hemorrhage, and ...spinal cord injury. We show here that Nrf2 activation with sulforaphane (SFN) in vivo or in vitro increases expression and transport activity of three ATP-driven drug efflux pumps at the blood-brain barrier P-glycoprotein, ATP binding cassette b1 (Abcb1); multidrug resistance-associated protein-2 (Mrp2), Abcc2; and breast cancer resistance protein (Bcrp), Abcg2. Dosing rats with SFN increased protein expression of all three transporters in brain capillaries and decreased by 50% brain accumulation of the P-glycoprotein substrate verapamil. Exposing rat or mouse brain capillaries to SFN increased P-glycoprotein, Bcrp, and Mrp2 transport activity and protein expression; SFN increased P-glycoprotein activity in mouse spinal cord capillaries. Inhibiting transcription or translation abolished upregulation of P-glycoprotein activity. No such effects were seen in brain capillaries from Nrf2-null mice, indicating Nrf2 dependence. Nrf2 signaled indirectly to increase transporter activity/expression. The p53 inhibitor pifithrin abolished the SFN-induced increase in transporter activity/expression, and the p53-activator nutlin-3 increased P-glycoprotein activity. SFN did not alter P-glycoprotein transport activity in brain and spinal cord capillaries from p53-null mice. Inhibitors of p38 MAPK and nuclear factor κB (NF-κB) blocked the effects of SFN and nutlin-3 on P-glycoprotein activity. These results implicate Nrf2, p53, and NF-κB in the upregulation of P-glycoprotein, Bcrp, and Mrp2 at blood-CNS barriers. They imply that the barriers are tightened selectively (efflux transporter upregulation) by oxidative stress, providing increased neuroprotection, but also reduced penetration of many therapeutic drugs.
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 study investigates fatigue growth and shape evolution of a corner crack in a pin-loaded hole by means of three-dimensional FE analyses. The constraint factor/plasticity-induced crack closure ...strategy was tuned to reproduce experimentally measured crack front shapes. The study quantitatively determines the LEFM acceptability regions using elastic–plastic simulations. It also assesses the sensitivity of crack propagation and shape evolution to the stress distribution along the front, to the relationship between J-integral and stress intensity factor, and to changing propagation rates along different directions. The proposed approach produces very accurate results in terms of crack propagation rate and shape evolution.
•Fatigue crack growth of a pin-loaded hole corner crack is investigated.•Constraint factor/plasticity-induced crack closure is tuned to capture crack shapes.•Elastic–plastic simulations are used to determine the constraint factor distribution.•Sensitivity to changing propagation rates along different directions is assessed.
Indocyanine green (ICG) fluorescence-guided surgery is a modality of intra-operative navigation that might support the surgeon with enhanced visualization of anatomical structures in real time. Over ...the last years, it has emerged as one of the most promising and rapidly developing technical innovations in surgery. The most popular current clinical applications include fluorescence cholangiography, bowel anastomotic perfusion assessment, fluorescence-guided lymphography for sentinel lymph-node identification and guided lymphadenectomy and the possible use in oncological surgery for the identification and localization of tumors and the diagnosis and treatment of peritoneal carcinosis. This paper provides an overview of the multiple fields of applications of ICG fluorescence-guided surgery in visceral and oncological surgery, discussing indications summarizing most recent and significative available literature and giving technical notes of use.
Subjects increasing sperm DNA fragmentation (sDF) during Density Gradient Centrifugation (DGC), a common sperm selection procedure in Assisted Reproduction Techniques (ARTs), experience a 50% lower ...probability of pregnancy. Hence, identification of these subjects is of clinical importance. Here, we investigated whether such subjects are identified with higher accuracy detecting DNA fragmentation in viable (viable sDF) instead of total spermatozoa (total sDF) and whether swim up, an alternative procedure to DGC, does not increase sDF. With DGC, we identified 10/20 subjects increasing total sDF, and 2 more subjects using viable sDF. With swim up, we identified 8/40 subjects increasing total sDF, and 8 more subjects using viable sDF. In addition, viable sDF reveals more accurately the increase of the damage when it occurs. Finally, a multivariate analysis demonstrated that the proportional increase of sDF was higher after DGC respect to swim up. In conclusion, viable sDF is a more accurate parameter to reveal the increase of the damage by selection both with swim up and DGC. Swim up increases sDF in some samples, although at a lesser extent than DGC, suggesting that it should be used to select spermatozoa for ARTs when possible.
Aim
Altered mitochondrial function across various tissues is a key determinant of spaceflight‐induced physical deconditioning. In comparison to tissue biopsies, blood cell bioenergetics holds promise ...as a systemic and more readily accessible biomarker, which was evaluated during head‐down tilt bed rest (HDTBR), an established ground‐based analog for spaceflight‐induced physiological changes in humans. More specifically, this study explored the effects of HDTBR and an exercise countermeasure on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs).
Methods
We subjected 24 healthy participants to a strict 30‐day HDTBR protocol. The control group (n = 12) underwent HDTBR only, while the countermeasure group (n = 12) engaged in regular supine cycling exercise followed by veno‐occlusive thigh cuffs post‐exercise for 6 h. We assessed routine blood parameters 14 days before bed rest, the respiratory capacity of PBMCs via high‐resolution respirometry, and citrate synthase activity 2 days before and at day 30 of bed rest. We confirmed PBMC composition by flow cytometry.
Results
The change of the PBMC maximal oxidative phosphorylation capacity (OXPHOS) amounted to an 11% increase in the countermeasure group, while it decreased by 10% in the control group (p = 0.04). The limitation of OXPHOS increased in control only while other respiratory states were not affected by either intervention. Correlation analysis revealed positive associations between white blood cells, lymphocytes, and basophils with PBMC bioenergetics in both groups.
Conclusion
This study reveals that a regular exercise countermeasure has a positive impact on PBMC mitochondrial function, confirming the potential application of blood cell bioenergetics for human spaceflight.
Objective
We compared demographic and clinic-pathological variables related to the number of surgeries for thyroid conditions or for cancer, morbidity, and fine needle aspiration (FNA) practices ...among Covid19 pandemic phases I, II, III and the same seasonal periods in 2019.
Methods
The prospective database of the Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, China was used for this study. Covid19 emergency levels were stratified according to the World Health Organization: phase I (January 25–February 25, 2020), phase II (February 26–March 19), phase III (March 20–April 20).
Results
There were fewer outpatient FNAs and surgeries in 2020 than in 2019. There were no thyroid surgeries during phase I. There were also fewer surgeries for cancer with a significant reduction of advanced stage cancer treatments, mainly stage T1b N1a in phase II and T3bN1b in phase III. Operative times and postoperative stays were significantly shorter during the pandemic compared to our institutional baseline. In phase III, vocal cord paralysis (VCP) increased to 4.3% of our baseline numbers (
P
= 0.001). There were no cases of Covid19-related complications during the perioperative period. No patients required re-admission to the hospital.
Conclusion
The Covid19 outbreak reduced thyroid surgery patient volumes. The decrease of Covid19 emergency plans contributed to unexpected outcomes (reduction of early stage cancer treatment, decreased operative times and hospital stays, increased VCP rate).
Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy ± anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). ...These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev.
A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index.
A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS ≥20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response.
FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation.
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