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PubMed2026

Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial.

BACKGROUND: High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS: ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS: 36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION: The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING: National Cancer Institute of the National Institutes of Health.

Humans↗

PubMed1979

Combined reversed-phase and normal-phase high-performance liquid chromatography in the purification and identification of 7,12-dimethylbenz[a]anthracene metabolites.

A total of 37 compounds have been identified as rat liver microsomal metabolites of the potent carcinogen 7,12-dimethylbenz[a]anthracene and its hydroxymethyl derivatives 7-methyl-12-hydroxymethylbenz[a]anthracene, 7-hydroxymethyl-12-methylben[a]anthracene and 7,12-dihydroxymethylbenz[a]anthracene. The metabolites were characterized by: (i) retention times on reversed-phase (with a C18 column) and normal-phase (with a silica gel column) high-performance liquid chromatography (HPLC); (ii) ultraviolet absorption and fluorescence spectra; (iii) mass spectral analysis; (iv) optical activity; and (v) comparison of the physicochemical properties of the metabolites with those of some available synthetic standards. The 37 identified metabolites include four trans-3,4-dihydrodiols, four trans-5,6-dihydrodiols, four trans-8,9-dihydrodiols, four trans-10,11-dihydrodiols, two methyl carboxylic acids, two methyl aldehydes, two hydroxymethyl aldehydes, four 2-phenols, four 3-phenols, four 4-phenols and three hydroxymethyl derivatives. The trans configuration of the dihydrodiols was determined by their inability to form vicinal cisacetonides. Seven dihydrodiol metabolites were found to be optically active. Detailed physicochemical properties, such as ultraviolet absorption spectra, fluorescence spectra measured in methanol and in 0.1 N NaOH, major mass ions from mass spectral analysis and the retention times on two HPLC systems, are presented in support of the structural assignments.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1976

Evidence for phase boundary lipid. Permeability of Tempo-choline into dimyristoylphosphatidylcholine vesicles at the phase transition.

The existence of distinct regions of mismatch in molecular packing at the interfaces of the fluid and ordered domains during the phase transition of dimyristoylphosphatidylcholine vesicles has been demonstrated by measuring the temperature dependence of the permeability to a spin-label cation and comparing this with a statistical mechanical calculation of the fraction of interfacial lipid. The kinetics of uptake and release of the 2,2,6,6-tetramethylpiperidinyl-1-oxycholine (Tempo-choline) spin label by single-bilayer dimyristoylphosphatidylcholine vesicles were measured using electron spin resonance spectroscopy to quantitate the amount of spin label present within the vesicles after removal of the external spin-label by ascorbate at 0 degrees C. Both the uptake and release experiments show that the Tempo-choline permeability peaks to a sharp maximum at the lipid-phase transition, the vesicles being almost impermeable to Tempo-choline below the transition and having a much reduced permeability above. The temperature profile of the permeability is in reasonable quantitative agreement with calculations of the fraction of interfacial boundary lipid from the Zimm and Bragg theory of cooperative transitions, which use independent spin-label measurements of the degree of transition to determine the cooperativity parameter. The relatively high intrinsic permeability of the interfacial regions (P approximately 0.2-1.0 X 10(-8) cm/s) is attributed to the mismatch in molecular packing of the lipid molecules at the ordered-fluid boundaries, which could have important implications not only for permeability in natural membranes (e.g., in transmitter release), but also for the function of membrane-bound enzymes and transport proteins.

Binding Sites↗

PubMed1978

Measurement of acetate in aqueous solutions and plasma by gas phase chromatography using a porous polymer stationary phase.

A method of acetate determination by gas phase chromatography using a porous polymer stationary phase is reported that is suitable for use with aqueous and plasma samples. It is linear up to 100 mmol/l and has a coefficient of variation of less than 4% for acetate values of greater than 1 mmol/l. The recovery of acetate from plasma is 92% and sample retention time is 3 minutes. The reference range of plasma acetate in a group of 40 apparently healthy subjects was from less than 0.1 to 0.35 mmol/l. The frequently encountered problem of absorption and ghosting of volatile fatty acids is overcome without the addition of formic acid vapour to the carrier gas.

Acetates↗

PubMed1975

Rhinosporidium seeberi. An ultrastructural study of its endosporulation phase and trophocyte phase.

The endosporulation phase of Rhinosporidium seeberi is the part of the life cycle most vulnerable to drug therapy. The laminated body formed from the precleavage sporangium has double-membraned tubular and vesicular structures within concentric layers. Similar tubular structures are also found in the developing sporoblast. The development of trophocytes involves three distinct phases. The early trophocyte retains many of the characteristics of the sporoblast as well as endoplasmic reticulum and other radiating filamentous structures in the cell wall. The itermediate tropocyte is larger (20 mug to 30mug m) and contains lipid bodies and microbodies, whereas the mature trophocyte is smaller (7mug m to9mug m) and microbodies are sparse or absent.

Cell Nucleus↗

PubMed1978

Phase I and preliminary phase II study of neocarzinostatin.

Neocarzinostatin is a protein antitumor antibiotic isolated from cultures of Streptomyces carzinostaticus var.F41. The drug has undergone extensive clinical trial in Japan, and has been reported active against a variety of human tumors. A phase I and preliminary phase II evaluation of the drug has been performed, using an iv bolus daily x 5 schedule. Ninety-six patients have been treated at doses from 500 to 2250 units/m2/day. Courses were repeated at 4-week intervals if allowed by bone marrow recovery. Dose-limiting toxicity was myelosupppression, which occurred late (median nadir, Day 27). Myelosuppression was more pronounced in patients who had received previous chemotherapy. In nine patients (9%) thrombocytopenia was prolonged (greater than or equal to 45 days) or irreversible. Acute administration of the drug was associated with rigors in approximately half the patients. Gastrointestinal side effects were mild. Three patients had a severe acute reaction resembling anaphylaxis. The maximally tolerated dose for this dose schedule is approximately 2250 units/m2/day. Antitumor activity has been seen in hepatoma and hematologic malignancies. Activity in lung and colorectal carcinoma appears limited with this dose schedule.

Adolescent↗

PubMed1979

Novel 125I-labeled nortriptyline derivatives and their use in liquid-phase or magnetizable solid-phase second-antibody radioimmunoassays.

Nortriptyline derivatives prepared by reaction with fluorescein isothiocyanate or conjugation to N-acetyl-L-histidine were radioiodinated and the products purified with Sephadex LH-20 columns to obtain two novel nortriptyline radioligands. Antisera were raised in rabbits by immunization with nortriptyline conjugated to succinylated ovine albumin. By use of the iodinated fluorescein derivative we developed a liquid-phase second-antibody radioimmunoassay that gives results correlating closely (r = 0.98) with those by an established radioimmunoassay of similar specificity in the assay of apparent total amitriptyline and its metabolite nortriptyline in serum or plasma from patients being treated with these drugs. With the iodinated N-acetyl-L-histidine derivative we developed a magnetizable solid-phase second-antibody radioimmunoassay. The cross reactivities of amitriptyline and nortriptyline could be made equal by performing the assay at pH 9.0, which makes it possible to measure true total active drug concentrations in patients receiving amitriptyline.

Amitriptyline↗

PubMed1976

Amphotericin B plus 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU-NSC no. 409962) in advanced cancer. Phase I and preliminary phase II results.

Twenty-one patients with advanced metastatic cancer received amphotericin B (AmB) plus BNUC in a Phase I chemotherapy trial. Of 11 patients with measurable metastases from bronchogenic carcinoma, five had partial antitumor responses lasting 1.5 to 12+ months, and one had objective improvement. Only two of six patients with other types of tumors had objective improvement of short duration. No consistent evidence of immunologic stimulation was observed in eight patients studied. These results suggest that amphotericin B may increase the therapeutic ratio of BCNU, and further trials of this new concept in chemotherapy of advanced tumors are in progress. The dose-limiting toxicity was myelosuppression, usually thrombocytopenia. No enhancement of BCNU toxicity by the addition of AmB was observed. The recommended dose for future studies is: AmB, 7.5 mg/m2 on day 1, 15 mg/m2 on day 1, 30 mg/m2 on days 3 and 4; plus BCNU, 250 mg/m3 on day 4. The regimen is repeated every 6 to 8 weeks.

Amphotericin B↗

PubMed1979

A theoretical model for lipid mixtures, phase transitions, and phase diagrams.

We present a new model for the thermodynamic properties of lipid bilayers. The model consists of a system of hard cylinders of varying radii that correspond to the different molecular radii of lipids having different numbers of gauche rotations in their chains. Scaled particle theory is used to provide an accurate estimate of the entropy of packing of the cylinders. To apply the model to bilayers we introduce a semiempirical attractive potential energy. Once the form of this potential is chosen, we adjust one parameter, the interaction strength, so that the model fits the transition temperatures and entropies for various phospholipids. The model then agrees quite well with other published data for these systems. We also directly generalize our model to lipid mixtures, and we obtain phase diagrams that we compare to existing data for these systems. We use the model to describe lipid protein interactions in bilayers as well.

Lipid Bilayers↗

PubMed1978

[Preliminary results of polychemiotherapy and immunostimulant treatment with Corynebacterium parvum in tumors of the breast in the postoperative phase and advanced phase].

Difficulties still encountered in the coordinated interdisciplinary management of solid tumours in hospitals are discussed. Preliminary results obtained with a polychemical and immunostimulating protocol based on Corynebacterium parvum (introduced in 1973) in breast tumours immediately after surgery and in the advanced stage are presented. Two out of eight subjects with advanced forms died. Partial regression or a steady state were noted in the remainder. No locoregional recurrences or metastases were observed from 1 to 2 yr after the commencement of treatment in 22 patients treated in the immediate post-operative phase. These results are considered satisfactory, though a final evaluation would be premature. Stress is laid on the importance of immunostimulating management in the avoiding the immunodepression caused by the administration of drugs.

Adult↗

PubMed1979