Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Age dependence of the radiosensitivity of glial progenitors for In vivo fission-neutron and X irradiation.

O-2A progenitor cells are the stem cells of the myelin-forming oligodendrocytes in the central nervous system. In the epithermal reactor beams used for boron neutron capture therapy (BNCT) for treatment of brain tumors, fission neutrons are a contaminating component. To estimate the radiosensitivity of the O-2A progenitors for fission neutrons, an in vivo-in vitro clonogenic assay was used. Radiosensitivity of progenitors obtained from the spinal cord of 1- or 5-day-old rats or the optic nerve of 2- or 12-week-old rats for 1 MeV fission neutrons was compared to that for 300 kVp X rays. Dose-survival curves were fitted according to the linear-quadratic model. The resulting beta component was very small to negligible. Progenitor cells obtained from rats of different ages show differences in radiosensitivity, characterized by different alpha values. RBE values for fission neutrons were 3.5 for 1-day-old spinal cord, 3.2 for 5-day-old spinal cord, 3.0 for 2-week-old optic nerve, and 4.3 for 12-week-old optic nerve. These high RBE values indicate the importance of minimizing the fast-neutron component in the epithermal neutron beams used for BNCT.

Relationship between attitudes to health, body weight and physical activity and level of physical activity in a nationally representative sample in the European Union.

OBJECTIVE: To explore the factors that influence attitudes and beliefs about the effects of body weight and physical activity on health. DESIGN: Cross-sectional survey using a face-to-face interview-assisted questionnaire. SETTING: The survey was conducted between March and April 1997 in the 15 member states of the EU. SUBJECTS: Approximately 1000 adults aged 15 years plus from each country were selected by quota-controlled sampling; the total sample was of 15,239 persons (7162 males and 8077 females). Data were weighted by population size for each country and by age, gender and regional distribution within countries. RESULTS: Overall 27% of men and 35% of women reported not engaging in any form of recreational activity; rates were highest in those with a primary-level education (37% men, 43% women) compared with tertiary-level education (20% men, 25% women). Recreational activity levels declined with age and tended to be lowest in those who were more physically active at work. Eighteen per cent of respondents believed that physical activity was one of the two greatest influences on health; 13% mentioned body weight, 38% mentioned food, 41% mentioned smoking and 33% mentioned stress. Logistic regression was used to assess for the effects of gender, age, educational level, body mass index (BMI), smoking status, activity level and country on beliefs that body weight and physical activity influenced health. Primary-educated, overweight, ex- and non-smoking women were most likely to mention body weight as an influence; young tertiary-educated, thinner, non-smoking and active males were most likely to mention physical activity. There was wide variation across Europe in reported behaviour and beliefs, which persisted after taking account of all of the other factors in the regression model. CONCLUSIONS: Relatively few people in some countries believed body weight and physical activity were important influences on health. Many people mentioned stress and it might be possible to use this interest to motivate changes in physical activity to relieve stress. It may be important to take a more integrated approach to activity patterns that consider the role of work and recreation. Although social and demographic factors were important, after adjusting for these factors there was still wide between-country variation in reported attitudes, beliefs and behaviour. This will need to be taken into account in any activity promotion campaigns.

Perceived benefits and barriers to physical activity in a nationally representative sample in the European Union.

OBJECTIVE: To examine the attitudes of consumers, in particular their perceived benefits and barriers to physical activity from all EU member states, and having a measure of prevailing levels of activity, inactivity and self-reported body weight and body shape. DESIGN: Cross-sectional survey using an interview-assisted face-to-face questionnaire. SETTING: The survey was conducted between March and April 1997 in the 15 member states of the EU. SUBJECTS: Overall, 15,239 EU subjects, classified according to sex, age (six levels) and highest level of education attained (primary, secondary or tertiary), completed the survey. Sample selection of subjects in each EU member state was quota-controlled to ensure they were nationally representative. RESULTS: The most important motivation for people to participate in physical activity is to maintain good health (42%), to release tension (30%) and to get fit (30%). The importance of the health argument is highest in older persons and in subjects with a primary education level. Only 13% of the EU population (16% of women, 10% of men) perceived losing weight as a benefit of physical exercise. The most important barriers to increase physical activity are work or study commitments (28%) and the subjects' belief that they are not 'the sporty type' (25%). There is considerable between-country variation in the answering pattern within the EU.

Medical management of perianal Crohn's disease.

Perianal disease is a frequent complication necessitating both medical and surgical management in Crohn's disease. Fissures, fistulae, or abscesses are found in approximately 36% of patients; occur more often in the ileocolonic and colonic disease; and may precede the onset of intestinal symptoms (Farmer et al, Gastroenterology 68:627-635, 1975; Rankin et al, Gastroenterology 77:914-920, 1979; Gray et al, Gut 6:515-524, 1965; and Homan et al, Arch Surg 111:1333-1335, 1976). To approach perianal manifestations, the physician must identify the anatomic location of the disease, treat the suppurative complications, and consider a long-term approach to palliation of chronic inflammatory sequelae. This article will review the medical management of perianal Crohn's disease and indications for surgery.

Healing of transsphincteric perianal fistulas in Crohn's disease using a new technique.

OBJECTIVES: Transsphincteric perianal fistulas in Crohn's disease are often refractory to medical therapy and difficult to treat surgically. Our objective was to determine whether a new method of anal fistulotomy was effective in healing these fistulas. METHODS: In this new method, the internal opening of the fistula tract was displaced distally to the region of the anal mucosa in 26 patients with Crohn's disease. RESULTS: Healing was achieved within 5 weeks of surgery in 45/49 (92%) of the fistulas and was not influenced by perioperative medication, site of preexisting Crohn's disease, or condition of the rectum. There has been no alteration of preoperative continence. CONCLUSIONS: We conclude that this method is highly effective in treating transsphincteric perianal fistulas in Crohn's disease.

Regulation of a hevein-like gene in Arabidopsis.

An Arabidopisis cDNA clone was isolated that encodes a protein similar to the antifungal chitin-binding protein hevein from rubber tree latex. This hevein-like (HEL) mRNA was inducible by either turnip crinkle virus infection or ethylene treatment. In addition, expression was moderately inducible by treatment with the resistance-inducing compounds salicylic acid and 2,6-dichlorisonicotinic acid. The 786-bp cDNA contains an open reading frame of 212 codons. The deduced amino acid sequence contains a putative signal sequence of 21 amino acids followed by a 43-amino-acid cysteine-rich lectin domain and a 129-amino-acid carboxy-terminal domain. The predicted protein is approximately 70% identical to hevein, to the wound-inducible WIN1 and WIN2 proteins from potato, and to PR-4, a pathogenesis-related protein from tobacco.