Summary
Background
Chimeric antigen receptor (CAR) T cells targeted to the CD19 B‐cell antigen form an approved treatment for patients with relapsed/refractory diffuse large B‐cell lymphoma (r/r ...DLBCL). However, since this therapy is administered after multiple lines of treatment and exposure to lymphotoxic agents, there is an urgent need to optimize this modality of treatment.
Methods
To circumvent the difficulties of harvesting adequate and optimal T cells from DLBCL patients and improve CART therapy, we suggest an earlier lymphopheresis (i.e. at first relapse, before salvage treatment). We conducted a prospective study and evaluated the potential benefit of an earlier lymphopheresis (early group, n = 22) on the clinical outcome of CD19‐CART infused DLBCL patients, in comparison with standard lymphopheresis (i.e. at second relapse and beyond; standard group, n = 23).
Results
An increased percentage of naïve T cells and increased in vitro T‐cell functionality were observed in the early group. Additionally, these cells exhibit a lower exhaustion profile than T cells collected in the standard group.
Conclusion
While improved T‐cell phenotype and function in the lymphopheresis product did not translate into significantly improved clinical outcomes, a trend towards better overall survival (OS) and progression‐free survival (PFS) was observed. Early lymphopheresis maximizes the potential of salvage therapies, without compromising CAR T‐cell quality.
Background
A growing number of severely ill patients require long-term care in non-hospital residential facilities (RFs). Despite the magnitude of this development, longitudinal studies surveying ...fairly large resident samples and yielding important information on this population have been very few.
Aims
The aims of the study were (1) to describe the socio-demographic, clinical, and treatment-related characteristics of RF patients during an index period in 2010; (2) to identify predictors and characteristics associated with discharge at the 1-year follow-up; (3) to evaluate clinicians’ predictions about each patient’s likelihood of home discharge (HD).
Methods
A prospective observational cohort study was conducted involving all patients staying in 23 medium-long-term RFs of the St John of God Order with a primary psychiatric diagnosis. A comprehensive set of socio-demographic, clinical, and treatment-related information was gathered and standardized assessments (BPRS, HONOS, PSP, PHI, SLOF, RBANS) were administered to each participant. Logistic regression analyses were run to identify independent discharge predictors.
Results
The study involved 403 patients (66.7 % male), with a mean age of 49 years (SD = 10). The participants’ average illness duration was 23 years; median value for length of stay in the RF was 2.2 years. The most frequent diagnosis was schizophrenia (67.5 %). 104 (25.8 %) were discharged: 13.6 % to home, 8.2 % to other RFs, 2.2 % to supported housing, and 1.5 % to prison. Clinicians’ predictions about HD were generally erroneous.
Conclusions
Very few patients were discharged to independent accommodations after 1 year. The main variables associated with a higher HD likelihood were: illness duration of <15 years and effective social support during the previous year. Lower severity of psychopathology and higher working skill levels were also associated with a significantly greater HD likelihood.
Purpose
Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, ...especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients.
Methods
Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5–5 mg/kg/day in children and 3–6 million international units (IU) in adults, adjusted to renal function) during the period 2008–2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease).
Results
Twenty-nine children and adults received 38 courses of intravenous colistin (2.5–5 mg/kg/day in children and 3–6 × 10
6
IU in adults, adjusted to renal function) allogeneic HSCT (22 courses) and HM (16 courses) for 3–28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5 %) courses. In 32 (84 %) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18 %) died while on colistin therapy. No death was attributed to an adverse effect of colistin.
Conclusions
Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.
Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, ...and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.
PERDOVE study is a prospective observational cohort study, which providing follow-up at one year, aims to investigate the socio-demographic and clinical characteristics of patients in the 23 ...medium-long term RFs of the St John of God Order.
Objective
Daratumumab is a promising new antimyeloma agent. We report a single center “real‐world” series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab.
Methods
...Forty‐one patients were included: 7 second‐line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL.
Results
Second‐line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression‐free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti‐CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab.
Conclusions
Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short‐lived, stressing the administration of this agent should be early in the course of the disease.
Online track processor for the CDF upgrade Thomson, E.J.; Ciobanu, C.; Chung, J.Y. ...
IEEE transactions on nuclear science,
06/2002, Letnik:
49, Številka:
3
Journal Article
Recenzirano
Odprti dostop
A trigger track processor, called the eXtremely Fast Tracker (XFT), has been designed for the Collider Detector at Fermilab (CDF) upgrade. This processor identifies high-transverse-momentum (> 1.5 ...GeV/c) charged particles in the new central outer tracking chamber for CDF II. The XFT design is highly parallel to handle the input rate of 183 Gb/s and the output rate of 44 Gb/s. The processor is pipelined and reports the result for a new event every 132 ns. The processor uses three stages: hit classification, segment finding, and segment linking. The pattern recognition algorithms for the three stages are implemented in programmable logic devices (PLDs) which allow in situ modification of the algorithm at any time. The PLDs reside on three different types of modules. The complete system has been installed and commissioned at CDF II. An overview of the track processor and performance in CDF Run II are presented.
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk ...stratification are lacking.
To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions.
Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in
-related genes (
,
, and
) and identified novel SVs facilitating immune evasion (
and
). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg,
,
, and
) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact.
mutations (31%) showed the strongest association with worse PFS (hazard ratio HR, 2.52 95% CI, 1.50 to 4.21;
< .001) and overall survival (HR, 2.33 95% CI, 1.14 to 4.76;
= .02). IPI high-risk patients with mutated
demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the
mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast,
-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 95% CI, 0.07 to 0.55;
= .002) and prolonged OS (HR, 0.11 95% CI, 0.01 to 0.78;
= .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively.
This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification.
and
mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.
Abstract
BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials ...in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials.
MATERIAL AND METHODS
We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in 5 referral centers in Israel between 2001-2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation.
RESULTS
Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5gr/m2 (range 1.14-6 gr/m2) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median PFS and OS were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS:12.5 vs. 34.2 p=0.006 and OS:19.9 vs 77.3 p=0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and ECOG performance status.
CONCLUSION
The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX- based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the
INTRODUCTION
of HDC-ASCT.
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