Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

A phase I trial of bortezomib in combination with epirubicin, carboplatin and capecitabine (ECarboX) in advanced oesophagogastric adenocarcinoma.

PURPOSE: The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy. DESIGN: A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m(-2) on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m(-2) intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m(-2) BD days 1-21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. RESULTS: 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m(-2) (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m(-2) BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. CONCLUSIONS: The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy.

The reliability and characteristics of the brief syntactic analysis.

BACKGROUND: Linguistic analysis is of great potential benefit to psychiatry as a research and assessment tool, but the skill and time it demands means that it has not been widely used. This paper describes a much simplified form of syntactic analysis. METHOD: A detailed protocol for the Brief Syntactic Analysis (BSA) was written, based on earlier work by Morice and Ingram. Three psychiatrists were trained in its use, and inter-rater reliability established through independent ratings of 12 transcripts taken from a mixed group of psychiatric patients and a group of non-psychiatric controls. Concurrent reliability of the BSA against the Morice and Ingram analysis was established by comparing measures from the two methods on 16 transcripts of mixed patients. RESULTS: There were high levels of agreement between the three psychiatrists and between the BSA and the Morice and Ingram analysis, although one-way ANOVA indicated that for some variables there were small but statistically significant absolute differences between the two. The reasons for this were discussed. A principal components analysis confirmed the presence of three factors corresponding closely to the three families of linguistic variables. CONCLUSIONS: The results indicate that psychiatrists can be trained to use a syntactic analysis with high levels of agreement. The BSA, which takes much less time to complete, produces measures that are comparable with the original analysis from which it was derived.

Speech and language in first onset psychosis differences between people with schizophrenia, mania, and controls.

BACKGROUND: Several studies have revealed linguistic differences between diagnostic groups. This study investigates the extent to which these differences are accounted for by factors such as chronicity, or disturbances in cognition associated with acute psychosis. METHOD: Transcripts of interviews with patients suffering from RDC schizophrenia (n=38), mania (n=11) and controls (n=16) were examined using the Brief Syntactic Analysis (BSA). Patients were within two years of first onset of psychotic symptoms, and received tests of working memory and attention. RESULTS: The speech of patients with schizophrenia was syntactically less complex than that of controls. Patients with schizophrenia and mania made more errors than controls. These differences were, to some extent, related to group differences in social class, working memory and attention, although significant group differences in language persisted after the effects of covariates were removed. CONCLUSIONS: The study confirms the existence of differences in the speech of psychiatric patients. Low complexity appears to be a particular feature of speech in schizophrenia, even in the earliest stages of the condition. The importance of this finding is discussed in relation to two recent theories of schizophrenia: Crow's evolutionary model, and Frith's neuro-psychological model.

Erotomania and Fregoli-like state in Down's syndrome: dynamic and developmental aspects.

The present authors report the case of a 42-year-old female with Down's syndrome who developed a misidentification syndrome, erotomanic delusions towards her Bible instructor, and increasing grandiosity following the death of her father. The authors believe that her symptoms may be formulated in developmental and dynamic terms.

Uptake and metabolism of myo-inositol by L1210 leukaemia cells.

The initial rate of uptake of [3H]myo-inositol by L1210 murine leukaemia cells is directly proportional to the extracellular concentration and unaffected by several analogues of myo-inositol even at millimolar concentrations. Scyllitol, a geometric isomer of myo-inositol, partially inhibited the uptake of myo-inositol (40% at 0.1 mM). A portion of the uptake of myo-inositol was not inhibited even at 5 mM-scyllitol. At steady-state the intracellular concentration of [3H]myo-inositol is directly proportional to the extracellular concentration. Addition of myo-inositol to medium does not enhance the growth of L1210 cells; these cells can maintain an extracellular concentration of 20 microM-myo-inositol even when grown in myo-inositol-free medium. Synthesis of myo-inositol from glucose by L1210 cells was demonstrated by use of [13C]glucose and m.s. L1210 cells maintain myo-inositol pools by a combination of synthesis de novo and uptake of exogenous myo-inositol by either passive diffusion or a low affinity carrier.

Stimulation of uracil nucleotide synthesis in mouse liver, intestine and kidney by ammonium chloride infusion.

De novo pyrimidine synthesis was studied in mouse liver, intestine, and kidney by intraperitoneal infusion of 15NH4Cl and analysis of 15N incorporation into uracil nucleotide pools. When the dose of a 1-h infusion of 15NH4Cl was increased from 50 mumol to 250 mumol the fraction of the total uracil nucleotide pool formed by de novo synthesis increased 4.0-fold in liver to 8.4% and 2.3-fold in intestine to 13.7%. The increase in intestine was independent of the increase in liver as evidenced by the lack of correlation between the increase observed in the intestine and liver of the same animal and the different distributions of label in the uracil ring nitrogens. A 2.4-fold increase in newly formed uracil nucleotides was observed in kidney when the infusion dose was raised from 150 mumol to 250 mumol. The increase in kidney was correlated with the increase in liver in the same animal and the distribution of label in the uracil ring nitrogens was similar to the distribution in liver. These results suggest that the increase in newly formed uracil nucleotides in intestine is due to increased de novo synthesis of pyrimidines in the intestine, while the increase in the kidney is due to increased salvage synthesis of uracil nucleotides from uridine synthesized in the liver and output to the circulation.

G1499-2, a new quinoline compound isolated from the fermentation broth of Cytophaga johnsonii.

A new quinoline compound, G1499-2[C18H21NO(I)] is produced by Cytophaga johnsonii. G1499-2 has an unusual structure containing a cyclopropylidene radical. The compound has limited antibiotic activity against a few bacteria. It is not toxic to mice.

Childhood deafness in Cape Town.

An aetiological survey of a Cape Peninsula school for the deaf, in which 366 Cape Coloured and Asiatic children were examined, is reported. The relevant hereditary factors and the abnormal clinical findings are documented, and the more important of these are discussed. In 20% (74) of the children, the deafness was genetic; in 36% (132) it was acquired, and in 44% (160) it was cryptogenic.

Properties and metabolism of 2alkylalkanoates. 3. absorption of methyl and ethyl 2-methylpalmitate.

The recovery from rat and rabbit tissues of fed methyl-(14)C and ethyl-2-(14)C 2-methylpalmitate with unaltered specific activity has demonstrated the existence of mechanisms for the absorption and deposition of both methyl and ethyl esters of fatty acids, at least for 2-methylpalmitate. In thoracic duct-cannulated rats, approximately 9% of the fed compounds was recovered from the lymph during the first 24 hr, the rate of recovery reaching a maximum between 6 and 8 hr. In the rabbit, the fed, unaltered esters in plasma were transported principally by means of the low density lipoproteins. Only trace amounts of the unaltered esters were subsequently detected in the blood and tissue lipids after feeding, however, even during the period of maximal absorption; moreover, in contrast to at least one report by others, further analyses for methyl or ethyl esters of other fatty acids has shown that such esters of short-chain alcohols constitute no more than a trace amount (0.004-1.03%) of the lipids extracted from a wide variety of mammalian tissues. The possibility remains that even these trace amounts of esters arose as artifacts of autolysis, extraction, or assay.