Search

Replacement of damaged neuronal population by fetal tissue transplantation represents a potential treatment for neurodegenerative diseases. Consistent success has been achieved with fetal striatal transplantation in Huntington's disease animal models and patients. We report the neo-generation of metabolically active tissue with striatum-like imaging features after transplantation of striatal primordia in a patient with Huntington's disease. This study represents the first "in vivo" demonstration that a human striatal anlagen, transplanted into the adult human brain, is able to progress in its development and to generate a new anatomical structure in the host, without evidence of neoplasia or teratoma.

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Objective: To assess the agreement between patients and relatives concerning the formers’ quality of life (QOL) before intensive care unit (ICU) admission.¶Design: Prospective study involving direct interviews of patients and relatives during ICU stay.¶Setting: Two four-bed surgical-medical ICUs in a 960-bed teaching hospital.¶Patients and methods: A hundred seventy-two adult, co-operative patients consecutively admitted to ICU for more than 24 h, and their relatives were interviewed. The instruments used were two questionnaires suitable for ICU patients: QOL-IT and QOL-SP. Interobserver reproducibility was investigated in 36 patients.¶Results: Interobserver reproducibility was nearly perfect (weighted Kappa 0.99 for QOL-IT and QOL-SP). Considering global scores, weighted Kappa was 0.78 for QOL-IT and 0.82 for QOL-SP, with the mean difference between patients and relatives lower than 0.3 for both scores but with limits of agreement wider than 4. Among the items, concordance was excellent in the areas of physical activity and social life for both questionnaires. Gender, living together with the patient and the degree of relationship of relatives did not influence the agreement.¶Conclusions: The relatives give global scores for both instruments which can be regarded as acceptable substitutes for those given by patients. However, the wide limits of agreement should make investigators cautious in analysing together scores generated by patients and by relatives. The emotional dimension seems to be assessed less accurately by relatives than the physical one.

To investigate the comfort and satisfaction of patients with trauma of the upper limb during two different techniques of axillary brachial plexus block, electrical nerve stimulation and fascial pop.Randomized-prospective, observational study.University surgical center.100 ASA physical status I and II patients undergoing surgery for trauma of the hand and forearm.Patients received axillary brachial plexus block with a mixture of 0.5% bupivacaine and 2% lidocaine. They were then allocated to one of two groups to receive either electrical nerve stimulation (Group 1, n = 50), or fascial pop technique (Group 2, n = 50) for nerve location.Data were collected on patient demographics, surgery, frequency of complications, and sedation required during the block. Discomfort during the block and surgical comfort were quantified by visual analog scale (0-10). Satisfaction was determined by the following scale: very satisfied, satisfied, dissatisfied, and very dissatisfied. Patients also indicated if in the future they would like to receive the same method of anesthesia.No differences in demographic or surgical data were found. No serious complications were observed. Eighteen Group 1 patients (36%) and none in Group 2 needed sedation during the blocks. Discomfort during the procedures was greater in Group 1 than Group 2 (4.5 +/- 1.2 vs 1.5 +/- 1, P0.05), while patients reported good surgical comfort with both techniques (2.4 +/- 2.9 vs 2.2 +/- 2.1, NS). Eighteen patients in Group 1 and 48 patients in Group 2 would accept the same block for future surgery.In trauma patients, the fascial pop technique is effective, reduces sedation during axillary brachial plexus block, and has a higher patient acceptance rate than the electrical nerve stimulation technique.

In this multicenter prospective study, we identified factors associated with satisfaction with anesthesia in patients staying in hospital at least 24 h after surgery.The study was performed in six centers. Inpatients aged more than 18 yr, who underwent a wide range of common surgical procedures, were asked to answer a 10-item instrument to measure patient satisfaction with anesthesia (mean score range, 0-10) and some specific questions, and to rate their perceived health (score, 0-10). Anesthesia staff members were invited to self-compile a Maslach Burnout Inventory.The satisfaction evaluation questionnaire was returned by 1290 patients (mean age, 61 +/- 16 yr; males, 54.4%). The mean global satisfaction score was 8.7 (95% CI: 8.7-8.8), being9 in 632 (49%) andor =9 in 658 (51%) patients. The Maslach Burnout Inventory was returned by 55 anesthesiologists and 68 nurses. Multivariate regression identified five variables as significant predictors of a mean global satisfaction of/=9: 1) having been treated in a service with perioperative nurses specifically dedicated only to anesthesia; 2) having been treated where anesthesia information leaflets were provided preoperatively; 3) having received more than two anesthesiologist visits after surgery; 4) having a perceived health score8.5; and 5) being older that 70 yr. No relationship was found between staff burnout and patient satisfaction.Inpatient satisfaction can be improved by an organization in which surgical suite nurses are dedicated only to anesthesia, a written anesthesia information leaflet is given during the preoperative visit and postoperative visits are enhanced.

Elective abdominal aneurysm repair can be performed by using the transperitoneal or the retroperitoneal approach. The latter has been described as having a better outcome, reducing the impairment of respiratory function or the incidence of lung complications. Hence, the retroperitoneal approach has been proposed for treatment of medically high-risk patients. However, the superiority of one technique or the other in preserving pulmonary function has not been conclusively demonstrated. The aim of this study was to ascertain whether the retroperitoneal and the transperitoneal approaches affect respiratory function differently. A prospective randomized study. Two four-bed surgical-medical ICUs of a University hospital. Twenty-three consecutive patients undergoing abdominal aortic aneurysm repair were randomized to the retroperitoneal (12 patients) and transperitoneal approach (11 patients). They were studied: a) within 30 min the end of surgery; b) 8 h after the end of surgery; and c) during a T-piece tube-weaning trial. The comparison between the two groups was based on respiratory mechanics, partitioned between lung and chest wall components, basic spirometry, tension-time index of the inspiratory muscle, weaning indexes, and length of stay both in ICU and hospital. The two surgical techniques do not differ in their impact on either respiratory mechanics or inspiratory muscle function or weaning indexes. However, there was a tendency for retroperitoneal patients to stay for less time both in ICU and in the hospital. During the first 24 h after surgery, the postoperative impairment of respiratory function is independent of the surgical approach.

Purpose: The purpose of this article was to investigate the relationship between analgesia, sedation, and memory of intensive care. Patients and Methods: One hundred fifty-two adult, cooperative intensive care unit (ICU) patients were interviewed 6 months after hospital discharge about their memory of intensive care. The patient was considered to be cooperative when he/she was aware of self and environment at the interview. The patients were grouped as follows: A (45 patients) substantially no sedation, B (85) morphine, and C (22) morphine and other sedatives. Results: The patients having no memory of intensive care were 38%, 34%, and 23% respectively, in the three groups. They were less ill, according to SAPS II (P < .05), and had a shorter ICU stay (P < .01). Group C patients were more seriously ill according to SAPS II, duration of mechanical ventilation, and length of stay in ICU and in hospital (P < .001). The incidence of factual, sensation, and emotional memories was not different among the three groups. Females reported at least one emotional memory more frequently than males (odds ratio 4.17; 95% CI 10.97-1.59). Conclusions: The patients receiving sedatives in the ICU are not comparable with those receiving only opiates or nothing, due to the different clinical condition. The lack of memory of intensive care is present in one third of patients and is influenced more by length of stay in ICU than by the sedation received. Sedation does not influence the incidence of factual, sensation, and emotional memories of ICU admitted patients. Females have higher incidences of emotional memories than males. Copyright © 2001 by W.B. Saunders Company

To evaluate plasma dopamine concentration and the effects of low doses infusion on urinary output after abdominal vascular surgery in patients with renal function impairment we performed a prospective clinical study. Twenty hemodynamically stable patients (mean age 66.6 years), with serum creatinine concentration2 mg %, who undergoing general anesthesia for major vascular surgery participated. A low dose of dopamine (3 micrograms/kg/min) was administrated to patients with postoperative protracted urinary output0.5 ml/kg/hr for at least eight hours. Plasmatic determinations were taken at T0 (no dopamine administration), when urinary output began to increase, or if not, after two hours (T1), at eight (T2), and 24 (T3) hours after the beginning of infusion. After 24 hours the dopamine infusion was stopped and the patient's plasmatic level was measured four hours later (T4). Dopamine plasma concentrations were measured using high-performance liquid chromatography. Plasma dopamine concentration increased in all patients and reached a steady state at T2 (T2 = 76.41 +/- 16.84 ng/ml). Dopamine induced a concentration-dependent increase in urinary output (T0 = 0.45 +/- 0.14; T1 = 1.49 +/- 1.11; T2 = 2.34 +/- 1.44; T3 = 1.57 +/- 0.57; T4 = 0.85 +/- 0.7 ml/kg/hr). Three patients did not have an enhanced urinary output after dopamine infusion; they did have a prolonged clamping time and operation time (162 +/- 24 and 570 +/ 30 min, respectively). We conclude that low dose dopamine induces a dose-dependent increase of urinary output. This phenomenon also has been found in patients when their plasma concentration had not yet reached the steady-state. Lack of responsiveness to dopamine suggests a renal function impairment probably due to the prolonged aortic clamping time.

BACKGROUND: Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. METHODS: We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells. RESULTS: The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3(+) lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD(–)). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. CONCLUSION: SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities. TRIAL REGISTRATION: ClinicalTrials.gov NCT03389035. FUNDING: This study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).

Highlights • Narsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage, reducing thrombotic risk. • All patients treated with narsoplimab, a lectin-pathway inhibitor, improved and survived without any drug-related adverse events., In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway’s effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.

Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

This open-label phase 2 study (CONTRALTO) assessed the safety and efficacy of BCL-2 inhibitor venetoclax (VEN) plus rituximab (R), and VEN plus bendamustine (B) and R, vs B + R (BR) alone in relapsed/refractory (R/R) follicular lymphoma. Patients in the chemotherapy-free arm (arm A: VEN + R) received VEN 800 mg/d plus R 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, 10, and 12. After a safety run-in with VEN 600 mg, patients in the chemotherapy-containing cohort were randomized to either VEN + BR (arm B; VEN 800 mg/d for 1 year + 6 cycles of BR [B 90 mg/m2 on days 1 and 2 and R 375 mg/m2 on day 1]) or 6 cycles of BR (arm C). Overall, 163 patients were analyzed (9 in the safety run-in and 52, 51, and 51 in arms A, B, and C, respectively). Complete metabolic/complete response rates were 17% (arm A), 75% (arm B), and 69% (arm C). Of patients in arm B, only 61% received ≥90% of the planned B dose vs 96% of patients in arm C. More frequent hematologic toxicity resulted in more reduced dosing/treatment discontinuation in arm B vs arm C. Rates of grade 3/4 adverse events were 51.9%, 93.9%, and 60.0% in arms A, B, and C, respectively. VEN + BR led to increased toxicity and lower dose intensity of BR than in arm C, but efficacy was similar. Optimizing dose and schedule to maintain BR dose intensity may improve efficacy and tolerability of VEN + BR, while VEN + R data warrant further study. This study was registered at www.clinicaltrials.gov as #NCT02187861. Key Points: • Chemotherapy-free VEN + R had modest efficacy and acceptable toxicity in relapsed/refractory disease warranting further study. • VEN + BR led to increased toxicity; optimized chemotherapeutic dosing and/or combinations remain to be explored.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m 2) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features. © 2014 Macmillan Publishers Limited.

SummaryMalignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of ‘in vivo’ clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients’ hemostatic parameters were evaluated before entry into the study and after starting chemotherapy ± prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p

Alemtuzumab has been shown to be effective in poor-prognosis chronic lymphocytic leukemia (CLL); treatment, however, has been associated with significant toxicity. With the aim of seeking better tolerability, we treated 39 patients with fludarabine-refractory CLL subcutaneous alemtuzumab 10 mg three times a week, for 18 weeks. In 18 randomly selected patients, after obtaining lymphocyte count reduction by 1 Log, the antibody was administered once weekly at the dose of 30 mg. Overall response rate was 44%, including 8% complete remissions. Median overall survival and progression free survival were 29.1 and 10.3 months, respectively. Treatment was well tolerated, severe non-CMV infection occurred in 7% of the patients. CMV reactivation was detected in 27% of the patients, with only one case of CMV disease. No deaths occurred during therapy. In conclusion, low-dose alemtuzumab shows a promising safety profile coupled with satisfactory effectiveness in this category of poor prognosis CLL patients. © 2012 Informa UK, Ltd.