As significant numbers of acute myeloid leukemia (AML) patients are still refractory to conventional therapies or experience relapse, immunotherapy using T cells expressing chimeric antigen receptors ...(CARs) might represent a valid treatment option. AML cells frequently overexpress the myeloid antigens CD33 and CD123, for which specific CARs can be generated. However, CD33 is also expressed on normal hematopoietic stem/progenitor cells (HSPCs), and its targeting could potentially impair normal hematopoiesis. In contrast, CD123 is widely expressed by AML, while low expression is detected on HSPCs, making it a much more attractive target. In this study we describe the in vivo efficacy and safety of using cytokine-induced killer (CIK) cells genetically modified to express anti-CD33 or anti-CD123 CAR to target AML. We show that both these modified T cells are very efficient in reducing leukemia burden in vivo, but only the anti-CD123 CAR has limited killing on normal HSPCs, thus making it a very attractive immunotherapeutic tool for AML treatment.
FD stent placement is a promising therapy for challenging intracranial aneurysms. Long-term evaluations about angiographic and morphologic results are still missing. This is the aim of this ...multicenter series.
We report our experience and 1-year FU in a retrospective chart review of 65 consecutive subjects with 77 unruptured or recanalized aneurysms that were treated with Silk FD stents at 6 centers in France. Both angiographic and clinical results were recorded before treatment and at 6 and 12 months after treatment. At the 12-month FU, relationships between angiographic aneurysm occlusion and shrinkage of the thrombosed aneurysm sac were evaluated.
Stent deployment was achieved in 64 cases (98.5%) and failed in 1 case (1.5%). Seven misdeployments of the Silk stent caused the occlusion of 6 parent arteries. Overall acute/subacute procedural morbidity was 7.7%, and mortality was zero. Delayed complications were observed in 10.9% of subjects. At the 6-month FU, permanent morbidity was 7.8% and mortality was 3%. Complete occlusion occurred within 6 months in 68% of aneurysms and within 12 months after treatment in 84.5% of aneurysms. At the 12-month FU, in angiographically complete occluded aneurysms, MR imaging/CT analysis showed the complete disappearance of the thrombosed aneurysm in 30% of cases and partial shrinkage in 52%; furthermore, thrombosed aneurysms were stable in 11% of cases and enlarged in 7%.
The Silk stent is an effective tool for the treatment of challenging aneurysms because it allows complete occlusion in most cases 1 year after treatment. Permanent morbidity was 7.8%, and mortality was 3%.
Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance ...is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls.
TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons.
Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50–160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220–560 ms; 190–420 ms). Patients showed a reduction of both early (50–110 ms) gamma increase and later (180–230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms.
Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics.
•Transcranial magnetic stimulation (TMS) revealed cortical inhibition deficit in schizophrenia.•This tool has recently been combined with electroencephalography (TMS-EEG).•TMS-EEG may shed more light into the pathophysiology of schizophrenia.•TMS-EEG biometrics showed altered excitation/inhibition balance in schizophrenia.•TMS-EEG fingerprints may provide a marker of diagnosis and treatment response.
Introduction: Acute lymphoblastic leukemia (ALL) is the first neoplasm where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has proven to be a fundamental ...tool for guiding therapeutic choices. In recent years, thanks to real-time quantitative PCR (qPCR), MRD monitoring has further achieved higher levels of sensitivity and standardization. However, some outstanding issues still remain to be addressed and emerging technologies hold the promise of improving MRD detection in ALL patients.
Areas covered: Through a comprehensive review of the literature, we analyze the state-of-the-art of molecular MRD assessment in ALL to better understand how, in the upcoming years, some of its limitations could be tackled by emerging molecular technologies. Furthermore, we highlight the future role of molecular MRD monitoring in the context of personalized protocols, taking into account the growing genetic complexity in ALL.
Expert commentary: Although new molecular technologies are promising tools for MRD assessment, qPCR still remains the gold standard for evaluating MRD in ALL. High-throughput sequencing and droplet digital PCR allow to identify new prognostic factors and/or MRD targets at diagnosis and to perform earlier MRD evaluations, thereby optimizing patient stratification and earlier MRD-based clinical intervention to improve ALL patient outcomes.
Incomplete occlusion and recanalization of large and wide-neck brain aneurysms treated by endovascular therapy remains a challenge. We present preliminary clinical and angiographic results of an ...experimentally optimized Surpass flow diverter for treatment of intracranial aneurysms in a prospective, multicenter, nonrandomized, single-arm study.
At 24 centers, 165 patients with 190 intracranial aneurysms of the anterior and posterior circulations were enrolled. The primary efficacy end point was the percentage of intracranial aneurysms with 100% occlusion on 6-month DSA. The primary safety end point was neurologic death and any stroke through a minimum follow-up of 6 months.
Successful flow-diverter delivery was achieved in 161 patients with 186 aneurysms (98%); the mean number of devices used per aneurysm was 1.05. Clinical follow-up (median, 6 months) of 150 patients (93.2%), showed that the primary safety end point occurred in 18 subjects. Permanent neurologic morbidity and mortality were 6% and 2.7%, respectively. Morbidity occurred in 4% and 7.4% of patients treated for aneurysms of the anterior and posterior circulation, respectively. Neurologic death during follow-up was observed in 1.6% and 7.4% of patients with treated intracranial aneurysms of the anterior and posterior circulation, respectively. Ischemic stroke at ≤30 days, SAH at ≤7 days, and intraparenchymal hemorrhage at ≤7 days were encountered in 3.7%, 2.5%, and 2.5% of subjects, respectively. No disabling ischemic strokes at >30 days or SAH at >7 days occurred. New or worsening cranial nerve deficit was observed in 2.7%. Follow-up angiography available in 158 (86.8%) intracranial aneurysms showed 100% occlusion in 75%.
Clinical outcomes of the Surpass flow diverter in the treatment of intracranial aneurysms show a safety profile that is comparable with that of stent-assisted coil embolization. Angiographic results showed a high rate of intracranial aneurysm occlusion.
Flow cytometric quantification of minimal residual disease (MRD) in acute leukemia (AL) represents an indispensable tool to guide modern therapeutic protocols toward a precision medicine approach, ...being a powerful predictor of the overall response to treatment. This review covers the most challenging aspects and developments of this method, aiming at supporting further its implementation in clinical practices. Area covered: Flow cytometric MRD is based on the discrimination of leukemia cells from their physiological counterparts by the recognition of the leukemia-associated immunophenotypes. Technical and standardization advances along the last decades have been implemented allowing flow cytometric MRD to consolidate its role in modern therapeutic protocols for ALs. However, gaps in sensitivity and data interpretation are still present together with the need for further optimization of MRD-based clinical protocols. In this review, we critically analyze and discuss the most relevant and representative contributions in the field by accurate selection of the literature available in PubMed. Expert commentary: Further research in flow cytometric MRD can bring this technology toward wider and consistent applications in multiple acute leukemia settings rendering this tool a future golden standard and providing clinicians with more reliable and accurate tools for clinical decisions.
•In a cohort of “device naïve” patients, participants were able to set-up and operate the system effectively•A score system, the Wearable technology Self-management Score (WSS), was strongly ...associated with seizure capture rate.•The identification of a cut-off WSS value helped at differentiating optimal self-management from poor self-management.•Technology self-management did not differ according to age, level of education or presence of psychiatric comorbidities.•Digital inequalities may extend to variations in how individuals feel about their own disease and manage the technology.
wearable devices aimed at detecting seizures are rapidly emerging. Continuous collection and optimal data quality are paramount to guarantee the acquisition of clinically meaningful data. It is still unknown how successfully patients can self-manage new technologies and which factors have an impact on this. We assessed the performance of patients managing a wrist-worn device.
patients wearing a wrist-worn device received a single training session to perform 5 tasks: (1) fitting the device correctly; (2) switching the device on and off; (3) charging the device on a daily basis; (4) pairing the device with a phone or tablet; (5) seeking assistance. Participants were then reviewed every 24 h and, at the end of the study, a Wearable technology Self-management Score (WSS) was calculated according to their performance in the different tasks (0–12). The association between WSS, seizure capture, demographics and clinical characteristics was analysed.
Thirty patients were included. The mean WSS score was 9.4 ± 2.1 points. The task more often performed inaccurately was pairing the device with a phone or tablet, followed by performing charging procedures. A strong association was found between WSS and seizure capture (p = 0.019), with higher scores strongly associated with more seizures captured. A WSS of ≥9 was the minimum value of WSS that allowed the device to record all the seizures. Number of AEDs and illness-perception related factors (perceived disease timeline and personal control) were significantly associated with WSS.
Overall, participants demonstrated good performances in self-managing a wrist-worn device. Digital inequalities may extend to variations in how different individuals feel about their own disease and, consequently, manage the technology. These aspects should be addressed when technological solutions are delivered to users.
Background
Laparoscopic right hemicolectomy is a commonly performed procedure. Little is known on how to perform the enterotomy closure after stapled side-to-side intracorporeal anastomosis.
Method
A ...multicentric case-controlled study has been designed to compare different ways to fashion enterotomy closure: double layer versus single layer, sewn versus stapled, and robotic versus laparoscopic approach. Furthermore, additional characteristics including sutures’ materials, interrupted versus running suture and the presence of deep corner suture has been investigated.
Results
We collected data for 1092 patients who underwent right hemicolectomy at ten centers. We analyzed 176 robotic against 916 laparoscopic anastomosis: no significant differences were found in terms of bleedings (
p
= 0.455) and anastomotic leak (
p
= 0.405). We collected data from 126 laparoscopic sewn single-layer versus 641 laparoscopic sewn double-layer anastomosis: a significant reduction was recorded in terms of leaks in double-layer group (
p
= 0.02). About double-layer characteristics, we found a significant reduction of bleedings (
p
= 0.008) and leaks (
p
= 0.017) with a running suture; similarly, a reduction of bleedings (
p
= 0.001) and leaks (
p
= 0.005) was observed with the usage of deep corner closure. The presence of a barbed suture thread seemed to significantly reduce both bleedings (
p
= 0.001) and leaks (
p
= 0.001). We found no significant differences in terms of bleedings (
p
= 0.245) and anastomotic leak (
p
= 0.660) comparing sewn versus stapled anastomosis.
Conclusions
Fashioning a stapled ileocolic intracorporeal anastomosis, we can recommend the adoption of a double-layer enterotomy closure using a running barbed suture in the first layer. Totally, stapled closure and robotic assistance have to be considered a non-inferior alternative.
When treatment fails, the clinical outcome of acute leukemia patients is usually very poor, particularly when failure occurs after transplantation. A second allogeneic stem cell transplant could be ...envisaged as an effective and feasible salvage option in younger patients having a late relapse and an available donor. Unmanipulated or minimally manipulated donor T cells may also be effective in a minority of patients but the main limit remains the induction of severe graft-versus-host disease. This clinical complication has brought about a huge research effort that led to the development of leukemia-specific T-cell therapy aiming at the direct recognition of leukemia-specific rather than minor histocompatibility antigens. Despite a great scientific interest, the clinical feasibility of such an approach has proven to be quite problematic. To overcome this limitation, more research has moved toward the choice of targeting commonly expressed hematopoietic specific antigens by the genetic modification of unselected T cells. The best example of this is represented by the anti-CD19 chimeric antigen receptor (CD19.CAR) T cells. As a possible alternative to the genetic manipulation of unselected T cells, specific T-cell subpopulations with in vivo favorable homing and long-term survival properties have been genetically modified by CAR molecules. Finally, the use of naturally cytotoxic effector cells such as natural killer and cytokine-induced killer cells has been proposed in several clinical trials. The clinical development of these latter cells could also be further expanded by additional genetic modifications using the CAR technology.
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