Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.

PURPOSE: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. METHODS: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. RESULTS: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). CONCLUSION: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Atypical neurofibromatosis type 1 with unilateral limb hypertrophy mimicking overgrowth syndrome.

Neurofibromatosis type 1 (NF1; OMIM 162200), a dominantly inherited multitumor syndrome, results from mutations in the Neurofibromin 1 (NF1) gene. We present the case of a Hungarian woman with the clinical phenotype of NF1 over her whole body and the clinical features of unilateral overgrowth involving her entire left leg. This unusual phenotype suggested either the atypical form of NF1 or the coexistence of NF1 and overgrowth syndrome. Direct sequencing of the genomic DNA isolated from peripheral blood revealed a novel frameshift mutation (c.5727insT, p.V1909fsX1912) in the NF1 gene. Next-generation sequencing of 50 oncogenes and tumour suppressor genes, performed on the genomic DNAs isolated from tissue samples and peripheral blood, detected only wild-type sequences. Based on these results, we concluded that the patient is affected by an unusual phenotype of NF1, and that the observed unilateral overgrowth of the left leg might be a rare consequence of the identified c.5727insT mutation.

Mechanistic insights into insulin resistance in the genetic era.

Sir Harold Himsworth first observed and articulated the phenomenon of insulin resistance in the late 1930s. Although a long delay followed before his observations were acknowledged and enshrined in formal diagnostic classifications of diabetes mellitus, insulin resistance-related pathology in the early 21st century poses one of the major global healthcare challenges for contemporary physicians. Whilst insulin resistance is closely related to obesity and decreased physical fitness, despite intensive investigation it has proved extremely challenging to discriminate key events in its causation from epiphenomena, many related to compensation for the primary defect. Thus, a complete account of the molecular pathogenesis of insulin resistance-related diseases remains elusive. One approach circumventing such problems is the study of patients with single gene defects causing severe insulin resistance. In such patients the primary defect is known, and thus lessons may be learned about human physiology from detailed physiological study allied to knowledge of the function of the mutated protein. This review discusses developments in understanding of monogenic severe insulin resistance since discovery of the first insulin receptor mutations in 1988 and reviews the physiological lessons learnt, including the critical role of adipose tissue in human metabolic health and the meaning and importance of 'partial' insulin resistance for major human disease.

Isolation and characterisation of a linked cluster of genes from Agrobacterium tumefaciens encoding proteins involved in flagellar basal-body structure.

We report the DNA sequence of 7205 bp of the Agrobacterium tumefaciens chromosome. This contains a putative operon encoding homologues of the flagellar rod and associated proteins FlgBCG and FliE, the L and P ring proteins (FlgHI) a possible flagellum-specific export protein FliP, and two proteins of unknown function, FlgA and FliL. Several of these genes have overlapping stop and start codons. Three non-flagellate Tn5-induced mutations map to this operon: fla-11 to the first gene, encoding the rod protein FlgB; fla-15 to flgA; and fla-12 to fliL. A site-specific mutation introduced into the final gene in this cluster, fliP, also resulted in a non-flagellate phenotype. This indicates that the operon is expressed, and that at least FlgB, FlgA, FliL and FliP are required for flagellar assembly in A. tumefaciens. The bulk of this operon is conserved in the same order in Rhizobium meliloti.

Comparative dosing and efficacy of continuous-release nifedipine versus standard nifedipine for angina pectoris: clinical response, exercise performance, and plasma nifedipine levels.

To assess the dosing equivalency and the early and late antianginal efficacy of a gastrointestinal therapeutic system for once-daily, continuous-release nifedipine (N-GITS), 10 patients with stable angina pectoris, who were previously receiving chronic treatment with nifedipine, completed a 12-week trial comparing N-GITS with standard nifedipine. All patients (nine men and one woman; mean age 54 +/- 2 [SEM] years) who were receiving standard nifedipine (mean dose 40 +/- 5 mg/24 hr) for more than 2 weeks (mean 8 +/- 2 months, range 2 to 36 months) were switched to an equivalent once-daily dose (39 +/- 5 mg/24 hr) of N-GITS. Standard nifedipine and N-GITS were compared by symptom-limited exercise treadmill tests with a baseline test (A) performed 3 hours after a standard dose of nifedipine. Exercise tests were also performed after 2 weeks of treatment with N-GITS 3 hours (B) and 24 hours (C) after the drug was given, and after 12 weeks of treatment with N-GITS, 24 hours after dosing (D). Results of exercise tests showed no significant difference in mean exercise time--(A) 422 +/- 25 vs (B) 426 +/- 36 vs (C) 438 +/- 35 vs (D) 487 +/- 37 seconds. Likewise, there was no significant mean difference in peak double product, resting heart rate, peak exercise heart rate, or resting or maximal systolic blood pressure for any of the exercise test points. Furthermore, five patients (50%) reported side effects with standard nifedipine (all vasodilator-flushing, dizziness, or both), which resolved after treatment with N-GITS (p +/- 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nifedipine gastrointestinal therapeutic system in stable angina pectoris. Results of a multicenter open-label crossover comparison with standard nifedipine.

To compare the clinical efficacy and dose equivalency of standard nifedipine versus a new gastrointestinal therapeutic system (GITS) formulation of nifedipine, 98 patients with chronic stable angina pectoris participated in a 14-week, multicenter, open-label, crossover trial. All patients were administered nifedipine capsules for one month prior to study entry and continued receiving other antianginal, non-calcium blocker medications. Ninety-one patients (93 percent), 80 men and 11 women, mean age 62 +/- 1 years, completed the trial, which included two weeks receiving standard nifedipine followed by 12 weeks receiving nifedipine GITS starting at a dosage equal to the 24-hour total dose of nifedipine capsules and titrated upward as necessary. However, throughout the trial, mean nifedipine dosage was similar on nifedipine GITS compared with standard nifedipine. Angina frequency was significantly less with nifedipine GITS at Weeks 6, 10, and 14 (0.8 episodes/week) compared with baseline with standard nifedipine (1.3 episodes/week, p less than 0.05). Likewise, nitroglycerin consumption was also less at Weeks 6, 10, and 14, but only significantly less at Week 6 (nifedipine 1.2/week versus nifedipine GITS at six weeks, 0.7/week; p less than 0.05). Resting hemodynamic parameters, including systolic and diastolic blood pressure and heart rate, were not significantly different with standard nifedipine versus nifedipine GITS during the 12-week study. Total incidences of side effects were similar for both treatments (standard nifedipine, 16; nifedipine GITS, 17). However, incidence of vasodilator side effects (flushing, dizziness, and light-headedness) was significantly less frequent with nifedipine GITS (standard nifedipine, 12; nifedipine GITS, six; p less than 0.05). Thus, results from this open-label, crossover trial suggest that nifedipine GITS dosing is similar to multidose standard nifedipine with equivalent 24-hour efficacy for nifedipine GITS.

Alternative medical treatment for patients with angina pectoris and adverse reactions to beta blockers. Usefulness of nifedipine.

Although beta blockers are effective for the treatment of angina pectoris, chronic adverse effects produced by these agents--including lethargy, fatigue, and male impotence--can adversely affect patient acceptance and treatment compliance. To assess the clinical effects of switching from anti-anginal treatment with beta blocker only (phase I) to half-dose beta blocker plus the calcium blocker nifedipine (phase II) or nifedipine alone (phase III), 18 patients with chronic stable angina pectoris and side effects to beta blockers were evaluated in a 12-week, open-label trial. Three patients did not complete the study, one secondary to new unstable angina and two secondary to nifedipine side effects. Of the 15 patients completing the trial (13 men and two women; mean age, 54 +/- 5 [SEM] years), all sequentially participated in the one-month phases. Weekly angina frequency assessed from patient diaries was significantly less for treatment with nifedipine only (phase III) as compared with beta blocker (phase I) (1.7 +/- 1 versus 3.9 +/- 1 episodes per week), while phase II was not significantly different. Exercise test time was maintained throughout all phases (phase I, 457 +/- 39; phase II, 458 +/- 40; and phase III, 498 +/- 48 seconds, p not significant). All 15 patients in phase I (100 percent) had side effects to beta blockers, but these side effects were lessened in 12 patients (80 percent) in phase II and 13 patients (86 percent) in phase III, with total alleviation of symptoms in two patients (13 percent) in phase II, and eight patients (53 percent) in phase III. Thus, in patients with side effects to beta blockers, switching to nifedipine is associated with a significant reduction in beta blocker adverse symptoms and equal anti-anginal efficacy.

Acute electrophysiologic, hemodynamic and left ventricular effects of nifedipine and beta-blocker interactions. Maintenance of global and regional left ventricular wall motion.

To assess potential cardiac effects of nifedipine and beta-blocker interactions, 10 men receiving chronic beta-blocker therapy for angina underwent hemodynamic, electrophysiologic and left ventricular (LV) functional analyses at the time of cardiac catheterization before and after buccal administration of 10 mg of nifedipine. Although this combination is usually well tolerated, there have been occasional reports suggesting that the combination of nifedipine and beta-blocking agents may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina. All patients had class II or III stable angina pectoris and were receiving at least 160 to 240 mg/day of propranolol or equivalent doses of beta-blocker therapy. Nifedipine produced no acute electrophysiologic changes, including heart rate, PR interval, AH interval, HV interval, sinus node recovery time or heart rate at which atrioventricular nodal block occurred. Hemodynamic effects included no significant change in mean right atrial pressure (7 +/- 1 vs 5 +/- 1 mm Hg), while mean pulmonary artery pressure decreased significantly (20 +/- 2 vs 17 +/- 1 mm Hg, p less than or equal to 0.05). In addition, LV end-diastolic pressure decreased significantly from 16 +/- 2 to 10 +/- 1 mm Hg (p less than or equal to 0.05), with a nonsignificant decrease in mean aortic pressure from 93 +/- 5 to 86 +/- 4 mm Hg. Likewise, no significant change occurred in cardiac index (3.2 +/- 0.4 vs 3.0 +/- 0.4 liters/min/m2) or systemic vascular resistance (1,157 +/- 247 vs 1,170 +/- 236 dynes/s/cm-5). Left ventricular ejection fraction (EF) was the same before and after nifedipine (73 +/- 2% vs 74 +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)