Treatment regimens in patients over 64 years with acute myeloid leukaemia: a retrospective single-institution, multi-site analysis.

OBJECTIVES: The aim of this study is to investigate the effect of treatment choice on survival, transfusion needs and hospitalizations in patients > 64 years old with newly diagnosed acute myeloid leukaemia (AML). MATERIAL AND METHODS: This study retrospectively analysed patients over 64 years with AML diagnosed at a regional healthcare network in Switzerland between 2017 and 2020. Patients underwent four therapy groups: intensive chemotherapy (IC), hypomethylating agent in combination with the BCL2-Inhibitor venetoclax (HMA + VEN), hypomethylating agents alone (HMA) or best supportive care (BSC). RESULTS: Of 54 patients 12 (22%) were selected for IC, 13 (24%) for HMA + VEN, 17 (32%) for HMA and 12 (22%) for BSC. The median overall survival of the patients was 76 days, with a significant difference in the four therapy groups (IC 119 days, HMA + VEN 732 days, HMA monotherapy 73 days and BSC 12 days Log-Rank Test Chi2(2): p < 0.001). Patients with HMA + VEN spent significantly less time in the hospital 6.8 days/month compared to IC (19.5 days/month), HMA (20.5 days/month) and BSC (10.5 days/month) (p = 0.005). Transfusion needs were the highest in IC (7.0 RBC/month, 8.0 PC/month) (p = 0.023), whereas there was no difference between HMA + VEN (2.5 RBC/month, 3.2 PC/month), HMA monotherapy (5.3 RBC/month, 6.2 PC/month) and BSC (3.0 RBC/month, 1.4 PC/month). CONCLUSION: Our real-world data demonstrate superior OS rates of HMA + VEN when compared to IC, HMC or BSC, with a favourable side effect profile with regard to transfusion needs or hospitalization days.Abbreviations: AML, acute myeloid leukaemia; BCL2, B-cell leukaemia/lymphoma-2; BSC, best supportive care; CR, complete response; Cri, complete response with incomplete haematologic regeneration; FLT3, Fms Related Receptor Tyrosine Kinase 3; EKOS, Ethikkomission Ostschweiz; ELN, European Leukaemia Net; HMA, hypomethylating agent; IC, intensive chemotherapy; IDH, Isocitratdehydrogenase; LDAC, low-dose Cytarabine; NCCN, National Comprehensive Cancer Network; OS, overall survival; PC, platelet concentrate; RBC, red blood cell; RCT, randomized controlled trials; t-AML, therapy relative acute myeloid leukaemia'; VEN, venetoclax.

Sirolimus-Coated Balloon Angioplasty of Infra-popliteal Lesions for the Treatment of Chronic Limb-Threatening Ischemia: Study Protocol for the Randomized Controlled LIMES Study.

PURPOSE: Evidence on efficacy and long-term safety of paclitaxel-coated devices is still conflicting. Therefore, this study aims to assess whether sirolimus-coated balloon angioplasty is safe and effective for the treatment of infra-popliteal occlusions in patients with chronic limb-threatening ischemia (CLTI). STUDY DESIGN: The randomized controlled, single-blinded, multicentre, investigator-initiated study aims to enrol 230 participants with CLTI and infra-popliteal occlusions at up to 25 centres. Patients will be randomized in a 1:1 ratio to either sirolimus-coated balloon angioplasty or to plain old balloon angioplasty (POBA). Bailout stenting in case of flow-limiting dissection or ≥ 50% residual diameter stenosis is permitted. OUTCOME MEASURES: Primary outcome is the Kaplan-Meier estimate of primary patency at 6 months, defined as the absence of target lesion occlusion with restoration of in-line flow to the ankle. Key secondary outcome is non-inferiority in the proportionate occurrence of major adverse limb events and perioperative all-cause death at 30 days. Overall, participants will be followed for 36 months to assess further secondary efficacy and safety outcomes. ASSUMED GAIN OF KNOWLEDGE: If sirolimus-coated balloon angioplasty turns out to be superior to uncoated-balloon angioplasty regarding patency of infra-popliteal lesions without safety signals, it could become a welcome treatment option for patients with CLTI. Trial Registration ClinicalTrial.gov Identifier: NCT04772300, German Clinical Trials Register: DRKS00024629. Level of Evidence Level 2a, randomized controlled trial.

Study protocol: multimodal physiotherapy as an add-on treatment to botulinum neurotoxin type A therapy for patients with cervical dystonia: DysPT-multi-a prospective, multicentre, single-blind, randomized, controlled study.

BACKGROUND: Botulinum neurotoxin (BoNT) is currently the best therapeutic option in the treatment for cervical dystonia (CD). Additional treatments like physiotherapy (PT) may even improve the results of the BoNT injection with type A (BoNT-A), but there are no definite recommendations. In the last few years, some studies showed tendencies for PT as an adjuvant therapy to benefit. However, high-quality studies are required. METHODS: This study is a multicentre, randomized, single-blind, controlled trial to demonstrate the effectiveness of a multimodal PT program compared to a nonspecific cupping therapy, additionally to the BoNT-A therapy. Two hundred participants will be assigned into the multimodal PT plus BoNT intervention arm or the BoNT plus cupping arm using randomization. Primary endpoint is the total Score of Toronto Western Spasmodic Rating Scale (TWSTRS). Secondary endpoints are the mobility of the cervical spine (range of motion, ROM), the TWSTRS subscales, and the quality of life (measured by questionnaires: CDQ-24 and SF-36). Patients will be single-blind assessed every 3 months according to their BoNT injection treatment over a period of 9 months. DISCUSSION: The study aims to determine the effectiveness and therefore potential benefit of an additional multimodal physiotherapy for standardized treatment with BoNT-A in patients with CD, towards the BoNT-therapy alone. This largest randomized controlled trial in this field to date is intended to generate missing evidence for therapy guidelines. TRIAL REGISTRATION: The study was registered in the German Clinical Study Register before the start of the patient recruitment ( DRKS00020411 ; date: 21.01.2020).

Head-to-head comparison of sirolimus- versus paclitaxel-coated balloon angioplasty in the femoropopliteal artery: study protocol for the randomized controlled SIRONA trial.

BACKGROUND: Endovascular revascularization has established as the first-line therapy of femoropopliteal artery disease. Paclitaxel-coated balloon angioplasty proved to be superior to plain old balloon angioplasty (POBA) regarding prevention of restenosis and need for recurrent revascularization. Over the past years, paclitaxel was the only active drug to inhibit neointimal proliferation which could be processed to an appropriate balloon coating. The purpose of this study is to assess whether efficacy and safety of sirolimus-coated balloon angioplasty is noninferior to paclitaxel-coated balloon angioplasty. METHODS: This randomized controlled, single-blinded, multicentre, investigator-initiated noninferiority trial aims to enrol a total of 478 participants with symptomatic femoropopliteal artery disease of Rutherford category 2 to 4 due to de novo stenosis or restenosis. After pre-dilation, participants will be allocated in a 1:1 ratio to either sirolimus- or paclitaxel-coated balloon angioplasty. Post-dilation with the drug-coated balloon (DCB) used or standard balloon is mandatory in case ≥ 50%, and optional in case of ≥ 30% residual diameter stenosis. Bailout stenting with bare-metal nitinol stents should be conducted in case of flow-limiting dissection. Primary noninferiority endpoints are primary patency and the composite of all-cause mortality, major target limb amputation, and clinically driven target lesion revascularization at 12 months. Secondary outcomes are clinical and hemodynamic improvement, change in health-related quality of life, and safety throughout 60 months. DISCUSSION: Although concerns about long-term safety of paclitaxel-coated devices were not confirmed by recent patient-level data analyses, conflicting evidence contributed to a loss of confidence among patients and physicians. Therefore, sirolimus, known for a broader therapeutic range than paclitaxel, may serve as a welcome alternative. This will be justified if noninferiority of sirolimus-coated balloon angioplasty against the current standard of paclitaxel-coated balloon angioplasty can be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04475783 . Registered on 17 July 2020 EUDAMED No. CIV-20-11-035172, DRKS00022452.

Surface electrical stimulation for facial paralysis is not harmful.

INTRODUCTION: Does electrical stimulation (ES) of denervated muscles delay or prevent reinnervation, or increase synkinesis? In this retrospective study we evaluate the outcome, with and without ES, of patients with acutely denervated facial muscles. METHODS: The effect of ES was analyzed in two experiments. In the first experiment, 39 patients (6 with home-based ES, median 17.5 months) underwent facial nerve reconstruction surgery. Time to recovery of volitional movements was analyzed. The second experiment involved 13 patients (7 with ES, median 19 months) during spontaneous reinnervation. Sunnybrook and eFACE scores provided functional outcome measures. RESULTS: No difference in time of reinnervation after facial nerve reconstruction surgery was seen between the patients with and without ES (median [interquartile range]: 4.5 [3.0-5.25] vs 5.7 [3.5-9.5] months; P = .2). After spontaneous reinnervation, less synkinesis was noted (Sunnybrook synkinesis score: 3.0 [2.0-3.0] vs 5.5 [4.75-7.0]; P = .02) with ES. DISCUSSION: We find no evidence that ES prevents or delays reinnervation or increases synkinesis in facial paralysis.

Hyperpolarization-activated cation currents in human epileptogenic neocortex.

PURPOSE: Hyperpolarization-activated cation currents (I(H)) play a pivotal role in the control of neuronal excitability. In animal models of epilepsy both increases and decreases of I(H) have been reported. We, therefore, characterized properties of I(H) in human epileptogenic neocortex. METHODS: Layer II/III neurons in slices from epilepsy surgery tissues and rat cortex were investigated with whole-cell patch-clamp recordings. RESULTS: A total of 484 neurons from 96 temporal lobe epilepsy (TLE) tissues and 32 neurons from 8 frontal lobe epilepsy (FLE) tissues were recorded. Voltage-clamp recordings revealed on hyperpolarizing command steps two time- and voltage-dependent inward currents, namely a fast, Ba(2+)-sensitive current (K(IR)) and a slowly activating current, namely consisting of two kinetically distinct components sensitive to the established I(H) blocker ZD7288. Only, the fast component (I(H)(fast)) of TLE neurons was on average smaller and activated more slowly (density 2.7 +/- 1.6 pA/pF; tau 38.4 +/- 34.0 ms) than in FLE neurons (4.7 +/- 2.3 pA/pF; 16.6 +/- 7.9 ms; p < 0.001 for both). Within the TLE tissues the I(H)(fast) density (averaged per patient) was smaller in cases with numerous annual grand mal seizures (GM; 2.2 +/- 0.6 pA/pF) compared to those with few GM (2.8 +/- 1.0 pA/pF; p = 0.0184). A similar difference was obtained in the case of complex partial seizures (CPS; many CPS 2.2 +/- 0.6 pA/pF; few CPS 2.9 +/- 1.0 pA/pF, p = 0.0037). DISCUSSION: The biophysical properties of I(H) in cortices from TLE, FLE, and rat tissue suggest a deficit of HCN1 subunits in the human epileptogenic neocortex, which in turn may increase excitability and probability of seizure activity.

Reduction of safrole and methyleugenol in Asari radix et rhizoma by decoction.

INTRODUCTION: Asari radix et rhizoma (Xixin, Manchurian Wildginger, Asarum spp) is a herbal drug commonly used as an ingredient in traditional Chinese medicine (TCM). Many species of Asarum contain safrole and methyleugenol as the main components of their volatile oils. However, toxicological studies have shown that safrole and methyleugenol may be a hepatocarcinogen and/or genotoxic leading to concerns regarding the habitual consumption of this herbal drug. MATERIALS AND METHODS: An HPLC method was established to assess the levels of safrole and methyleugenol in five batches of Asari radix et rhizoma and two TCM formulae containing this herbal drug as an ingredient. Analyses showed that the content of safrole in the dried herbal drugs tested ranged from 0.14-2.78 mg/ g whilst the content of methyleugenol ranged from 1.94-16.04 mg/g. RESULTS: The present study demonstrated that following a 1-hour decoction, the amount of safrole was decreased by more than 92% resulting in the equivalent of no more than 0.20 mg/g safrole remaining in the aqueous extract. Similarly, the content of methyleugenol was decreased to the equivalent of 0.30-2.70 mg/g. Furthermore, both TCM formulae, after decoction, showed negligible amounts of safrole (maximum, the equivalent of 0.06 mg/ g), and only 1.38-2.71 mg/g of methyleugenol. CONCLUSIONS: The present study shows that a decoction procedure, similar to that traditionally used for Chinese herbal preparations, is able to effectively reduce the amount of safrole and methyleugenol effectively. Such a reduction in the content of safrole should be acceptable for therapeutic use.

Negative regulation of RANKL-induced osteoclastic differentiation in RAW264.7 Cells by estrogen and phytoestrogens.

We studied estrogen effects on osteoclastic differentiation using RAW264.7, a murine monocytic cell line. Differentiation, in response to RANKL and colony-stimulating factor 1, was evaluated while varying estrogen receptor (ER) stimulation by estradiol or nonsteroidal ER agonists was performed. The RAW264.7 cells were found to express ERalpha but not ERbeta. In contrast to RANKL, which decreased ERalpha expression and induced osteoclast differentiation, 10 nm estradiol, 3 microm genistein, or 3 microm daidzein all increased ERalpha expression, stimulated cell proliferation, and decreased multinucleation, with the effects of estrogen > or = daidzein > genistein. However, no estrogen agonist reduced RANKL stimulation of osteoclast differentiation markers or its down-regulation of ERalpha expression by more than approximately 50%. Genistein is also an Src kinase antagonist in vitro, but it did not decrease Src phosphorylation in RAW264.7 cells relative to other estrogen agonists. However, both phytoestrogens and estrogen inhibited RANKL-induced IkappaB degradation and NF-kappaB nuclear localization with the same relative potency as seen in proliferation and differentiation assays. This study demonstrates, for the first time, the direct effects of estrogen on osteoclast precursor differentiation and shows that, in addition to effecting osteoblasts, estrogen may protect bone by reducing osteoclast production. Genistein, which activates ERs selectively, inhibited osteoclastogenesis less effectively than the nonselective phytoestrogen daidzein, which effectively reproduced effects of estrogen.

Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte cultures.

St. John's wort extract (SJW) (Hypericum perforatum L.) is among the most commonly used herbal medications in the United States. The predominance of clinical reports indicates that SJW increases the activity of cytochrome P450 3A4 (CYP3A4) enzyme and reduces plasma concentrations of certain drugs. Although the inductive effect of SJW on CYP3A4 is clear, other reports indicate that SJW constituents may have, to a small degree, some enzyme inhibitory effects. Therefore, we sought to study the induction and inhibition effects of the constituents of SJW on CYP3A4 in the human hepatocyte model. Moreover, most research has focused on the induction of CYP3A4 by SJW with little attention paid to other prominent drug-metabolizing enzymes such as CYP1A2, CYP2C9, and CYP2D6. To examine the effects of SJW on CYP1A2, CYP2C9, CYP2D6, as well as CYP3A4, hepatocytes were exposed to hyperforin and hypericin, the primary constituents of SJW extract. Hepatocytes treated with hypericin or hyperforin were exposed to probe substrates to determine enzyme activity and protein and RNA harvested. Hyperforin treatment resulted in significant increases in mRNA, protein, and activity of CYP3A4 and CYP2C9, but had no effect on CYP1A2 or CYP2D6. Acute administration of hyperforin at 5 and 10 microM 1 h before and along with probe substrate inhibited CYP3A4 activity. Hypericin had no effect on any of the enzymes tested. These results demonstrate that with chronic exposure, the inductive effect of SJW on drug-metabolizing enzymes predominates, and human hepatocyte cultures are a versatile in vitro tool for screening the effect of herbal products on cytochrome P450 enzymes.

The effectiveness of psychological interventions for the rehabilitation of low back pain: a randomized controlled trial evaluation.

Forty-five low back pain patients were randomly assigned to either a standard inpatient rehabilitation program or the standard program with additional psychological components. The standard program emphasized education, support, and physical reconditioning through exercise. Patients receiving the psychological program were given additional training in relaxation and other coping skills and received contingent reinforcement for exercise. Both programs included reduction of medication intake and an emphasis on family involvement after discharge. Measures of functional status were taken prior to the program, at discharge from the 3-week inpatient program, and at a 6-month follow-up appointment. These data revealed that patients improved their overall functioning at discharge and maintained these gains at the follow-up assessment. A similar pattern of findings was obtained for self-reported pain and interference. Furthermore, 81% of the patients had returned to work or were engaged in active job retraining by the follow-up. Using a conservative measure of full-time return to the same or an equivalent job, 57% were employed by the follow-up. Patient improvement, however, was not differentially affected by treatment group assignment, suggesting that the psychological treatment failed to add to the effectiveness obtained by the standard rehabilitation program. Results are discussed in the context of improving patient outcomes from rehabilitation for low back pain.

Efficacy of electroacupuncture and TENS in the rehabilitation of chronic low back pain patients.

Fifty-four patients treated in a 3-week inpatient rehabilitation program were randomly assigned to and accepted treatment with electroacupuncture (n = 17), TENS (low intensity transcutaneous nerve stimulation, n = 18), and TENS dead-battery (placebo, n = 18). Outcome measures included estimates of pain (on a Visual Analogue Scale) and disability by both physician and patient, physical measures of trunk strength and spine range of motion, as well as the patient's perceptions of the relative contribution of the education, exercise training, and the electrical stimulation. Analyses of variance were utilized to determine effects of treatment (electroacupuncture, TENS, placebo) across time (admission, discharge, and return) for the outcome measures. There were no significant differences between treatment groups with respect to their overall rehabilitation. All 3 treatment groups ranked the contribution of the education as being greater than the electrical stimulation. However, the electroacupuncture group consistently demonstrated greater improvement on the outcome measures than the other treatment groups. For the visual analogue scale measure of average pain, there was a statistical trend at the return visit suggesting that the acupuncture group was experiencing less pain.