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Background: Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia., Methods: We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m 2 , days 1-3), cyclophosphamide (250 mg/m 2 , days 1-3), and rituximab (375 mg/m 2 day 1 of cycle 1; 500 mg/m 2 day 1 of cycles 2-6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT02251548) and is ongoing., Findings: Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50-58). At data cutoff, median follow-up was 16·5 months (IQR 10·6-34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23-0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%)., Interpretation: The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients., Funding: Pharmacyclics and the Leukemia & Lymphoma Society., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or mantle cell lymphoma often do not derive durable benefit from ibrutinib monotherapy. We hypothesised that dual B-cell receptor pathway blockade would be tolerable and efficacious. We investigated a next-generation phosphoinositide-3-kinase-δ inhibitor (PI3K-δi), umbralisib, plus a Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma., Methods: We did an investigator-initiated, multicentre, phase 1-1b study of patients from five sites in the USA (academic and community sites). Patients were 18 years and older with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma, with an Eastern Cooperative Oncology Group performance status of 2 or less, and were given umbralisib orally once daily (400 mg, 600 mg, or 800 mg) and ibrutinib orally once daily (420 mg for chronic lymphocytic leukaemia or 560 mg for mantle cell lymphoma) until disease progression or unacceptable toxicity. The phase 1 dose-escalation cohorts for each histology escalated independently in a standard 3 × 3 design. The primary endpoints were intention-to-treat assessment of maximum-tolerated dose, safety, and dose-limiting toxicities. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02268851., Findings: Between Dec 5, 2014, and March 7, 2018, we enrolled 44 patients, of which 42 were given at least one dose of study drug (chronic lymphocytic leukaemia, n=21; mantle cell lymphoma, n=21). Patients had a median age of 68 years (range 48-85) and had a median of two (IQR 1-3) previous therapies. No dose-limiting toxicities were observed and the maximum-tolerated dose of umbralisib was not reached. The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily. The most frequent adverse events included diarrhoea (22 [52%] patients, 10% of whom had grade 3), infection (21 [50%], 17% grade 3-4), and transaminitis (ten [24%], 2% grade 3). Serious adverse events occurred in 12 (29%) patients and included lipase elevation, atrial fibrillation, hypophosphataemia, adrenal insufficiency, transaminitis, and infections., Interpretation: Umbralisib plus ibrutinib is well tolerated and active in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma, with a recommended phase 2 dose of umbralisib 800 mg once daily. To the best of our knowledge, these are the first clinical data on a BTKi and PI3K-δi doublet in B-cell malignancies, and the results suggest that this approach is feasible and worthy of further study., Funding: TG Therapeutics, Leukemia and Lymphoma Society Therapy Accelerator Program., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Four experiments were conducted to examine the development of castration-induced behavioral changes, the effects of castration age on pig weight gain, and the efficacy of common analgesics for use in castrated pigs. In Exp. 1, behavioral changes associated with castration of pigs at 1, 5, 10, 15, or 20 d of age were evaluated. Castration caused measurable changes (reduced suckling, reduced standing, and increased lying times, P < .05) in the behavior of young pigs compared with that of intact pigs at all ages tested. Effects of age and interactions between age and castration treatment were not significant (P > .10) for any behaviors evaluated. In Exp. 2, the performance of pigs castrated at 1 d of age was compared with the performance of those castrated on d 14 and female littermates. Birth weights, weaning weights, and mortality were recorded. Pigs that were castrated on d 14 were heavier (P = .05) at weaning and had a higher (P < .05) weight gain during lactation compared to pigs castrated on d 1 of age. Pig mortality was similar among the treatments. In Exp. 3 and 4, the efficacies of pain-reducing drugs (non-narcotic analgesics) were evaluated for effectiveness in reducing castration-induced behavioral changes in 8-wk-old pigs. Although castration reduced (P < .05) feeding time and weight gain, neither aspirin nor butorphanol influenced behavioral changes associated with castration. We conclude that pigs show similar behavioral changes (and probably pain perception) when castrated from 1 to 20 d of age. However, pig performance data favored castration at 14 d rather than at 1 d of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Effective treatment of the alcohol-abusing borderline patient involves knowledge of two pathological processes. Alcoholism treatment methods and theory can have a profound effect upon the approach used with such patients, helping the therapist deal with the patient in a way that is respectful of his strengths and weaknesses. This paper describes how a knowledge of alcoholism treatment can be used in psychoanalytic psychotherapy, which is defined as the application of analytically-derived insights into motivations and resistances. Treatment of the alcoholism and the psychiatric disorder are best begun together at the outset of therapy, each method assisting the other.

This study was done in an attempt to elucidate some of the properties of bovine IFNs. Maximum levels of both fibroblast and leukocyte IFNs occurred prior to 24 h whereas maximum levels of immune IFN were not reached until after 72 h. The latter species of IFN was unstable at either pH 2 or 56 degrees C whereas both the fibroblast and leukocyte IFNs were more stable under these conditions. Studies of cross-species protection between fibroblast and leukocyte IFNs indicate that the former was more protective for other species than the latter.

Four experiments were conducted to examine the effects of general and local anesthetics given prior to castration on piglet behavior and weight gain. The first experiment showed that use of general anesthesia by xylazine, ketamine hydrochloride and glyceryl guaiacolate for 2-wk-old piglets resulted in the death of 28% of the piglets and, for those that survived, suppressed nursing behavior. In the second experiment, using 2-wk-old piglets, local anesthesia by lidocaine hydrochloride prevented the slight (30 min) castration-induced nursing behavior suppression. In the third and fourth studies, using 7-wk-old pigs, local or general anesthetic did not overcome castration-induced changes in behavior. Castration affected behavior of 7-wk-old pigs for 6 to 8 h. None of the treatments in any of the studies influenced weight gain. We conclude that castration is painful for 2-wk-old and 7-wk-old pigs. The 2-wk-old pig seems behaviorally less affected by castration than does the 7-wk-old pig. Local anesthetic prevented pain-induced behavior changes for 2-wk-old, but not for 7-wk-old, pigs. At present, the FDA does not permit use of these anesthetics in meat-producing animals.