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.
In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, ...and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI).
From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups.
Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.
Purpose:
The Medtronic CareLink allows remote implantable device follow‐up. In this first European experience with CareLink, we assessed the ease of use of the system, the acceptance, and ...satisfaction of patients and clinicians.
Methods:
Patients implanted with biventricular defibrillators for more than 6 months received the CareLink monitor and were trained to perform home device interrogation and transmission. Patient and clinician experience and preference were evaluated through specific questionnaires.
Results:
Sixty‐seven patients were enrolled and were able to perform data transmissions during the 3‐month study duration. The overall duration of interrogation procedure was 7 ± 5 minutes, and frequently the procedure did not require the assistance of a caregiver. Patients reported a general preference for remote versus in‐clinic follow‐up and described a sense of reassurance created by the remote monitoring capability.
In the centers, the review procedure was successful; its mean duration was 5 ± 2 minutes per transmission and the users indicated that the access and navigation of the review website were easy. At the end of the evaluation, the data available for remote review were judged complete and adequate to provide almost the same standard of care as that offered in traditional in‐clinic visit. In general, the remote monitoring was seen as a potential tool to improve the clinical management of patients with device.
Conclusions:
The ease of use, satisfaction, and acceptance of the CareLink Network in European clinical practice appears elevated both for patients and for clinicians.
We investigated the effectiveness and safety of intravesical resiniferatoxin (Sigma Chemical Co., St. Louis, Missouri) and botulinum-A toxin injections into the detrusor muscle in a group of spinal ...cord injured patients with neurogenic detrusor overactivity unresponsive to conventional anticholinergic therapy.
A total of 25 patients were randomly assigned to receive intravesically 0.6 μM resiniferatoxin in 50 ml of 0.9% NaCl or injections into the detrusor muscle of 300 units botulinum A-toxin diluted in 30 ml 0.9% NaCl. Clinical evaluation and urodynamics were performed at baseline, and at 6, 12 and 18 months after treatment.
In both arms there was a significant decrease in catheterization and incontinent episodes, and a significant increase in first detrusor contraction and maximum bladder capacity at 6, 12 and 18-month followup. There were no local side effects with either treatment. Botulinum-A toxin induced a significant decrease in the frequency of daily incontinence episodes (p <0.05), a significant increase in first uninhibited detrusor contraction (p <0.01) in maximum bladder capacity (p <0.01), and a significant decrease in maximum pressure of uninhibited detrusor contractions (p <0.01) compared to resiniferatoxin at 6, 12 and 18-month followup.
In spinal cord injured patients with refractory neurogenic detrusor overactivity, intravesical resiniferatoxin and botulinum-A toxin injections into the detrusor muscle provided beneficial clinical and urodynamic results with decreases in detrusor overactivity and restoration of urinary continence in a large proportion of patients. Botulinum-A toxin injections provided superior clinical and urodynamic benefits compared to those of intravesical resiniferatoxin.
In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm ...the REGOMA data in a real-world setting.
The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status Eastern Cooperative Oncology Group performance status (ECOG PS 0-1) and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs).
From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years interquartile range (IQR) 53-67 years, 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months (95% confidence interval (CI) 6.5-9.2 months and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs.
This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.
•This is the largest prospective study to evaluate the activity and safety of regorafenib in the real-world setting.•In this study, the survival was very similar to the REGOMA trial with a better controlled toxicity profile.•Molecular predictors of regorafenib efficacy need to be investigated to provide more personalized treatment.
Uncontrolled studies with intraplaque electromotive administration of verapamil and dexamethasone have demonstrated objective improvements in Peyronie’s disease. We performed a prospective controlled ...study to assess the efficacy of intraplaque electromotive verapamil/dexamethasone vs electromotive lidocaine.
Patients with Peyronie’s disease were randomized into a study group (47 patients) and a control group (49 patients). For each treatment session an electrode receptacle was sited over the plaque and filled with either 5 mg verapamil and 8 mg dexamethasone (study group) or 2% lidocaine (control group), and a 2.4 mA electric current was applied for 20 minutes. All patients were scheduled for 4 sessions per week for 6 weeks. Assessment before and after treatment included measurements of plaque volume and penile curvature, and pain on erection (from questionnaire).
A total of 37 patients in the study group and 36 in the control group completed treatment courses. In the study group there were significant decreases in median plaque volume from 824 to 348 mm
3, and in penile curvature from 43 to 21 degrees. In the control group median volume and curvature were unchanged. The difference in results after treatment between the 2 groups was also significant. Significant pain relief occurred in both groups, transient in the control group and permanent in the study group. All patients experienced temporary erythema at the electrode site. There were no other side effects.
Intraplaque electromotive verapamil and dexamethasone induce substantial objective improvement in Peyronie’s disease compared to electromotive lidocaine administration.
Our eyes are always in motion. Even during periods of relative fixation we produce so‐called ‘fixational eye movements’, which include microsaccades, drift and tremor. Mental fatigue can modulate ...saccade dynamics, but its effects on microsaccades and drift are unknown. Here we asked human subjects to perform a prolonged and demanding visual search task (a simplified air traffic control task), with two difficulty levels, under both free‐viewing and fixation conditions. Saccadic and microsaccadic velocity decreased with time‐on‐task whereas drift velocity increased, suggesting that ocular instability increases with mental fatigue. Task difficulty did not influence eye movements despite affecting reaction times, performance errors and subjective complexity ratings. We propose that variations in eye movement dynamics with time‐on‐task are consistent with the activation of the brain's sleep centers in correlation with mental fatigue. Covariation of saccadic and microsaccadic parameters moreover supports the hypothesis of a common generator for microsaccades and saccades. We conclude that changes in fixational and saccadic dynamics can indicate mental fatigue due to time‐on‐task, irrespective of task complexity. These findings suggest that fixational eye movement dynamics have the potential to signal the nervous system's activation state.
Participants performed a simulated air traffic control task for two hours, while their eye movements were measured. Microsaccadic velocity decreased with time‐on‐task, whereas drift velocity increased, suggesting that ocular instability increases with mental fatigue.
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