Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.

We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

Factor VII deficiency and the FVII mutation database.

Factor VII (FVII) is a zymogen for a vitamin K-dependent serine protease essential for the initiation of blood coagulation. It is synthesized primarily in the liver and circulates in plasma at a concentration of approximately 0.5 microg/ml (10 nmol/L). The FVII gene (F7) is located on chromosome 13 (13q34), consists of 9 exons, and spans approximately 12kb. It encodes a mature protein of 406 amino acids, which has an N-terminal domain (Gla) post-translationally modified by gamma-carboxylation of glutamic acid residues, two domains with homology to epidermal growth factor (EGF1 and 2), and a C-terminal serine protease domain. The single chain zymogen is activated by proteolytic cleavage at Arg152-Ile153. There are 238 individuals described in the world literature with mutations in their F7 genes (FVII mutation database; europium.csc. mrc.ac.uk). Complete absence of FVII activity in plasma is usually incompatible with life, and individuals die shortly after birth due to severe hemorrhage. The majority of individuals with mutations in their F7 gene(s), however, are either asymptomatic or the clinical phenotype is unknown. In general, a severe bleeding phenotype is only observed in individuals homozygous for a mutation in their F7 genes with FVII activities (FVII:C) below 2% of normal, however, a considerable proportion of individuals with a mild-moderate bleeding phenotype have similar FVII:C by in vitro assay. The failure of in vitro tests to differentiate between these groups may be due to lack of sensitivity in the assays to the very low amounts of FVII:C, which are sufficient to initiate coagulation in vivo. A number of polymorphisms have been identified in the F7 gene and some have been shown to influence plasma FVII antigen levels.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.

3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.

Exclusion of the first EGF domain of factor VII by a splice site mutation causes lethal factor VII deficiency.

We have studied a family with homozygous lethal, blood coagulation factor VII (FVII) deficiency. To identify the mutation responsible for the deficiency, exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by polymerase chain reaction and screened by single-strand conformational polymorphism analysis. The fragment showing aberrant mobility was cloned and sequenced. We detected a single point mutation, a homozygous G to A substitution at nucleotide position 6070, in the invariant GT dinucleotide at the 5' splice site of intron 4. Homozygosity was confirmed by loss of a site for the restriction endonuclease Mlu I. Analysis of the splicing pattern of ectopic transcripts in lymphocytes in the parents revealed that this mutation is associated with skipping of exon 4, which produces an mRNA encoding FVII with an in-frame deletion of the first epidermal growth factor-like domain (EGF 1). Transient transfection of COS-7 cells with an expression vector containing the triangle upEGF 1 FVII cDNA shows that this mutant protein is not expressed. The identification of the molecular basis of the FVII deficiency in this family allowed mutation-specific prenatal diagnosis to be performed in a subsequent pregnancy. In this family complete FVII deficiency is associated with a severe bleeding diathesis but no developmental abnormalities, lending weight to the hypothesis that fetal FVII is not required for the putative angiogenic functions of tissue factor in humans.

Major depression in the primary care setting.

This article has provided a brief overview of the prevalence, differential diagnosis, and clinical manifestations of depression in the primary care setting. While the high prevalence of depression is well documented, another body of evidence is accruing that demonstrates that depression not only increases over utilization of medical resources, but may worsen the long-term prognosis of certain medical conditions such as MI. Evidence also suggests that the diagnostic and management skills of primary care physicians--who comprise the "front line" and may offer the only line of care for these patients--is in need of improvement. This series of articles focusing on the diagnosis and treatment of depression in primary care will hopefully contribute to that effort.

Evaluation of a patient teaching skills course disseminated through staff developers.

Effective Patient Teaching (EPT), a course designed to improve health professionals' and health professions students' teaching skills, reliably produces gains in participants' skills when presented by its developers. The objective of this dissemination research study was to investigate whether, using a 'training of trainers' approach, seven nurses with staff development responsibilities in five different sites could teach EPT with similar effectiveness. The evaluation included pre- and post-course analysis of audiotaped patient education sessions conducted by 48 health professional participants who took EPT from one of the trainers in their home institutions. Post-course participant satisfaction surveys were also administered. EPT resulted in teaching skill improvements in four of five sites, and overall teaching skills scores improved significantly (P < 0.01). EPT can improve participants' teaching skills when taught by health professional trainers with staff development responsibilities who have recently received EPT training.

Evaluation of a training program for improving adherence promotion skills.

A workshop for improving the adherence counseling skills of health professionals was developed and evaluated. Target audiences have included medical students, nursing students, dietetic interns, and practising nurses and dietitians. Four categories of skills are taught: relationship building, interviewing, problem diagnosis, and behavioral intervention. Teaching methods include faculty demonstration, participant rehearsal, and group and individual feedback. The Adherence Promotion Training (APT) workshop has been offered as a 3- to 5-day intensive course and as a semester-long elective. A reliable coding system was developed to assess these skills from videotaped provider-patient interactions. A standardized patient task was given to 60 subjects before and after participation in the adherence counseling skills workshop. Videotapes were coded by trained raters, who were masked to whether the tape came from before or after the workshop. Significant short-term improvements were observed in all four core skills. This uncontrolled evaluation suggests that the Adherence Promotion Training program is a promising way to enhance the ability of health professionals to care for nonadherent patients.

Problem solving anchored instruction about sick days for adolescents with diabetes.

This study's hypotheses were that both shortly after instruction and after an 8-month follow-up, diabetic children taught via anchored instruction (AI), a format for problem solving, would outperform controls. Subjects were 81 9-15-year-old campers with insulin dependent diabetes who were randomly assigned to AI or control groups for two 45-min small group teaching sessions. Als viewed a video about a girl who mismanages her diabetes during intercurrent illness, and they were challenged to identify, define and solve her errors. Controls learned sick-day management via conventional direct instruction. At the end of the 2-week camp, AI and control groups' scores on factual knowledge were equal. AIs were more likely than controls at the end of the camp (0.75 vs. 0.54, P < 0.05) and 8 months later (0.59 vs. 0.38, P < 0.02) to provide a rationale for the use of remembered guidelines. Across all campers, this ability to link guidelines and their rationales was significantly correlated (r = 0.55, P < 0.01) with the number of self-management practices employed by campers who suffered an illness between the end of camp and the 8-month follow-up. Only one long-term behavioral difference between groups emerged: Als' parents shared in making most diabetes decisions on sick days, while controls' parents left more decision making to their children. AI appears at least as good as conventional teaching, and may better 'link' rules and reasons, perhaps aiding daily real-life problem solving.

Continuing education on teaching skills for health professionals. Evaluation of training the trainers.

Effective Patient Teaching (EPT), a health professions continuing education course, improves educators' teaching skills when presented by its developers. This study aimed to determine whether others could teach EPT with similar effectiveness. Four nurse managers who provide staff training and supervision for multiple hospital diabetes care units presented EPT to health care professionals at seven such sites; another seven served as controls. The evaluation included observations of trainers conducting EPT programs in the field, teaching skills ratings of health professionals in both groups, and knowledge test administered to patients. Six months after training, teaching skills scores of health professional EPT participants were better (p < .05) than controls. The EPT program improves participants' teaching skills and maintains these effects in field settings, when presented by faculty not involved in its development.

Improving dietitians' teaching skills.

Many health professionals lack important teaching skills, perhaps adding to patient difficulties in understanding and adopting therapeutic diets. Research suggests that teaching skills improved after dietitians took a continuing education course entitled "Effective Patient Teaching." Our study tested whether dietitians' new skills would persist in the field and whether selected patient outcomes would differ as a result. Thirty staff dietitians from six urban hospitals were videotaped teaching patients, then randomly assigned to take the Effective Patient Teaching course or not (control group). Follow-up videotapes were made after 1 week, 1 month, and 3 months. After each teaching session, patient satisfaction and recall were assessed. Two judges rated 20 teaching skills, which were divided into four subsets for analysis. Repeated measures analyses of variance showed overall gains only for the group that took the Effective Patient Teaching course, which scored higher than the control group at 1 week and 1 month, but not at baseline or 3 months. Gains occurred in presentation skills and essential teaching functions. Throughout the study, interpersonal skills were high and adherence promotion skills were low for dietitians in both groups. Groups did not differ on patient satisfaction or recall. Improvements in dietitians' teaching skills translated to the field immediately after they completed the continuing education program, but not all gains were sustained after 3 months. We recommend that dietitians assess their teaching and adherence promotion skills, obtain training where warranted, and periodically reassess the application of those skills during patient teaching sessions.

Registered dietitians' teaching and adherence promotion skills during routine patient education.

Even following education sessions, dietary adherence among medical patients is generally poor. One contributor to this problem may be the quality of teaching and adherence promotion skills employed by Registered Dietitians, whose behavior during routine patient interactions was evaluated in this observational study. Thirty dietitians were videotaped with one of their patients. Twenty operationally defined skills were rated on a scale from 0 (skill absent) to 3 (excellent). Dietitians' interpersonal skills were good (mean = 2.1, S.D. = 0.35), but all other skills were performed significantly less well (mean scores less than 1.0). Adherence promotion skills were rarely observed. Dietitians need supplemental training to improve teaching and adherence promotion skills.

Training health care professionals to enhance their patient teaching skills.

Lack of training interferes with health-care professionals' ability to teach effectively. Nursing staff development educators are seeking strategies to overcome teaching-skill deficits. A 30-hour program was designed to improve teaching skills. Evaluation was based on operationally defined teaching skills. Sixty-six course participants' teaching skills improved from the beginning to the end of the course. Further research is needed to determine whether effects persist in practice, whether patients benefit, and whether "training of trainers" is feasible.