PAD Therapy Research Articles

#6037 VALUE OF ARTERIAL CALCIFICATION DETECTED BY UPPER LIMB DOPPLER ULTRASOUND IN ADVANCED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Vascular calcification is a common complication of chronic kidney disease (CKD), particularly in end-stage-renal disease (ESRD) and is predictive of subsequent cardiovascular disease and mortality. The aim of the present study was to evaluate the relationship between arterial calcification assessed by doppler ultrasound (DUS) performed by the same observer and biochemical parameters of CKD-MBD as well as the standard-of-care therapy for CKD-MBD. Method We present a retrospective study of 454 patients who were evaluated by DUS for pre-surgical vascular mapping from 2018 to 2021. Both arms brachial, radial and cubital arteries were analyzed, and vascular calcification was classified as absent, mild or moderate/severe (presence of acoustic shadowing). Laboratory serum analysis of PTH, serum Calcium (sCa), serum phosphorous (sPi) and serum magnesium (sMg) were collected (with a maximum interval of 6 months from DUS evaluation). Mortality was also registered during follow-up period. Results The demographics and biochemistry of the study population are summarized in Table 1. Arterial calcification was observed in 91.6% (n = 416) of the patients, 62.3% (n = 259) had mild calcification and 37.7% (n = 157) presented moderate/severe calcification. In univariate analysis, male gender (OR 2.2, p < 0.023), age (OR 1.03, p < 0.003), phosphate binders (OR 0.55, p value < 0.03) and cinacalcet use (OR 0.28, p < 0.019) were independently associated with the presence of arterial vascular calcification. Presence of vascular calcification on DUS was associated to mortality. In patients with vascular calcifications, moderate/severe calcification was associated with diabetes mellitus (OR 2.85, p<0.000), male gender (OR 1.69, p < 0.012), PAD (OR 2.43, p <0.001) and hemodialysis therapy for more than 5 years (OR 3.00, p< 0.010). Cinacalcet, phosphate binders, serum calcium, phosphorous, PTH and mortality did not correlate with calcification severity. In the multivariate logistic regression analysis adjusted to age, gender, PAD and serum calcium and magnesium, we found that serum PTHi (OR 1.00, p<0.040), hemodialysis for more than one year (OR 4.44, p< 0.040) and diabetes mellitus (OR 3.95, p< 0.001) were associated with moderate/severe vascular disease. Conclusion Concerning CKD-MBD related markers our study showed that only phosphate binders and cinacalcet use were predictive of absence of vascular calcifications, however no causality could be advanced with these data. For serious calcification, in our multivariable model, only PTH had statistical significance. It is widely recognized the importance of monitoring serum PTH, calcium and Pi to reduce the adverse clinical events associated with CKB-MBD. Widespread implementation of DUS in pre-surgical mapping for VA construction is also an opportunity for vascular study and features as calcifications can be a surrogate of CKD-MBD and cardiovascular burden.

Pharyngeal tongue base augmentation for dysphagia therapy: A prospective case series in patients post head and neck cancer treatment.

Dysphagia post head and neck cancer (HNC) multimodality treatment is attributed to reduced pharyngeal strength. We hypothesized that pharyngeal tongue base augmentation for dysphagia (PAD therapy) would increase pharyngeal pressures during swallowing thereby improving swallow symptoms. Adults with moderate-severe dysphagia post-HNC treatment had PAD therapy using a temporary filler (hyaluronic acid [HA]), with follow-up long-lasting lipofilling. Swallowing preprocedure and postprocedure was assessed with the Sydney Swallow Questionnaire (SSQ), High-Resolution Pharyngeal Manometry (HRPM), and Videofluoroscopic Swallowing Study (VFSS). Statistical comparison utilized paired tests. Six participants (all male; median age 64 years [IQR 56, 71]) underwent PAD therapy at a median of 47 [IQR 8, 95] months post-treatment. SSQ scores reduced from baseline (mean 1069 [95%CI 703, 1434]) to post-HA (mean 579 [76, 1081], p > 0.05), and post-lipofilling (491 [95%CI 913, 789], p=0.003, n=4). Individual participants demonstrated reduced Swallow Risk Index, Bolus Presence Time, and increased Upper Esophageal Sphincter opening, but mesopharyngeal contractile pressures were unchanged. VFSS measures of aspiration, residue, and severity were unchanged. Novel PAD therapy is safe and improves dysphagia symptoms. Biomechanical swallowing changes are suggestive of more efficacious bolus propulsion with conservative filler volume, but this was unable to resolve residue or aspiration measures.

Care for perineal tears in vaginal delivery: An update for midwife

ObjectiveThe purpose of this study will be to review several studies regarding the repair or treatment of perineal tears after vaginal delivery. This is expected to be an update for a midwife in daily caring. MethodsTwo electronic databases (PubMed and Sciencedirect) were searched to locate relevant literature about perineal tears/wound/laceration/trauma that is published in 2016–2021. 124 Pubmed articles and 452 ScienceDirect articles filtered successfully. The articles that have been obtained will be evaluated based on the inclusion criteria in this study. We summarize place and date, objective, design, samples, the measurement used, and research results. Results9 articles were found that matched the inclusion criteria. Three articles examined the effect of the type of suture on perineal pain, and another 6 discussed therapy to reduce the adverse effects of perineal tears. The therapies used are far-infrared radiation therapy, capacitive-resistive radiofrequency therapy, pelvic floor muscle training in early postpartum, cold therapy, and treatment with TheresienOl (natural oil). ConclusionSutures and technique/suturing second-degree perineal tears or a postpartum episiotomy can affect perineal pain. Cold gel pad therapy and treatment with natural oil on perineal wounds can affect perineal pain and wound healing.

Peripheral arterial disease has a strong impact on cardiovascular outcome in patients with acute coronary syndromes: from the START Antiplatelet registry

BackgroundPeripheral arterial disease (PAD) was reported to increase the risk of new cardiovascular events in patients with acute coronary syndromes (ACS). However, most of the evidence comes from randomized clinical trials. We aimed to assess the impact of PAD on cardiovascular outcome and treatment decisions in ACS patients in a current real-life setting. MethodsSTART-ANTIPLATELET is a multicenter registry enrolling ACS patient. Baseline clinical characteristics and treatment at discharge were recorded and follow-up was repeated at 6-months and 1-year. PAD was defined as intermittent claudication and/or previous revascularization. ResultsAmong 1442 patients enrolled, 103 (7.1%) had PAD. PAD patients were older (71.8 ± 10.6vs66.2 ± 12.6 yrs., p < 0.0001), more frequently hypertensive (90.3vs68.6%, p< 0.0001), hypercholesterolemic (66vs52%, p= 0.037), diabetic (51.5vs24%, p= 0.0001), obese (28.2vs19.3%, p= 0.029) and with previous TIA (7.8vs2.8%, p= 0.005) or stroke (11.7vs3.1%, p< 0.0001). Clinical presentation and acute treatment were similar in non-PAD and PAD patients, but the latter were discharged significantly less frequently on dual antiplatelet therapy (DAPT) (68.9vs85%, p= 0.005). After a median follow-up time of 11.1 months, major cardio/cerebrovascular event-free survival [MACCE, including cardiovascular death, MI, TIA and stroke, target-vessel revascularization (TVR) and major arterial ischemic events] was significantly shorter (9.0vs11.2 months, p= 0.02; HR 3.2, 2.4–8.4) in PAD patients and net adverse cardiovascular events (NACE = MACCE plus major hemorrhages) were significantly more frequent (19.1%vs10.5%, p = 0.049). ConclusionsPAD identifies a subgroup of ACS patients at significantly increased cardiovascular risk, but these patients tend to be undertreated. Patients admitted for ACS should be screened for PAD and optimal medical therapy at discharge should be implemented.

Meta-analysis of efficacy of pressure therapy in treating patients with hypertrophic scars

Objective: To systematically evaluate the efficacy of pressure therapy in treating patients with hypertrophic scars by meta-analysis. Methods: Databases including PubMed, Embase, Web of Science, and Cochrane Library were retrieved with the search terms"hypertrophic scar, hyperplastic scar, HTS, pressure therapy, pressure treatment, and the Chinese Journals Full-text Database was retrieved with the search terms in Chinese version",,,,"to obtain the publicly published randomized controlled trials about pressure therapy in the treatment of patients with hypertrophic scar from the establishment of each database to July 2017. The measurement indexes included the effective ratio, Vancouver Scar Scale (VSS) score, scar vascularity, scar hardness, scar pigment, scar thickness, and value of scar color (brightness, red, and yellow). RevMan 5.3 and Stata 12.0 statistical software were used to conduct a meta-analysis of eligible studies. Results: A total of 667 hypertrophic scar patients were enrolled in 11 articles, including 362 patients in pressure therapy group who received pressure treatment and 305 patients in untreated group who received no treatment. The bias risks of the 11 studies included were uncertain. Compared with those of untreated group, the effective ratio of patients in pressure therapy group was significantly increased, with the relative risk of 5.98 (95% confidence interval=1.83-19.46, P<0.01); the VSS score and scar vascularity of patients in pressure therapy group were obviously decreased, with weighted mean differences of -2.24 and -0.66 respectively (95% confidence interval=-4.16--0.33, -1.21--0.12, P<0.05); the scar hardness, scar pigment, scar thickness, and value of scar color (brightness, red, and yellow) of patients in pressure therapy group were not changed obviously (P≥0.05). Significant heterogeneity existed in the included studies of the effective ratio, VSS score, scar vascularity, scar hardness, scar pigment, and scar thickness, P<0.01, I(2)=90%, 87%, 80%, 93%, 86%, 94%. Pressure range might be the heterogeneity source of effective ratio, and pressure clothing combined with pressure pad therapy might be a heterogeneous source of VSS score. Sensitivity analysis showed that the combined effect size results were stable in the effective ratio and scar pigment, but not stable in the VSS score, scar thickness, scar hardness, and scar vascularity. There was no publication bias in the effective ratio, VSS score, scar hardness, scar pigment, and scar vascularity (P>0.1), while there was publication bias in the scar thickness (95% confidence interval=-19.77--3.30, P<0.1). Conclusions: Compared with patients without treatment, in the treatment of hypertrophic scars, pressure therapy can obviously increase the effective ratio, reduce the VSS score and scar vascularity, but can not obviously improve the scar hardness, scar pigment, scar thickness, and value of scar color (brightness, red, and yellow).

RNA Sequencing of Newly Diagnosed Multiple Myeloma to Identify a Predictive Signature for Proteasome Inhibitor-Based Therapy

A major challenge in modern myeloma management is the selection of the best initial treatment from a plethora of available therapies. PAD (bortezomib, doxorubicin, and dexamethasone) is a highly effective regimen which may obviate the need for an upfront high-dose melphalan stem cell transplant (HDSCT). However, it is not clear a priori which patients will benefit from this treatment. In the phase 2 PADIMAC trial, patients with newly diagnosed myeloma were treated with six cycles of PAD and stratified to receive HDSCT in partial remission (PR) or watch and wait in very good partial remission (VGPR) or better. To identify predictive biomarkers, we extracted somatic RNA prior to treatment and performed massively parallel RNA sequencing (RNAseq).Basic quality control metrics suggested a high-quality RNAseq dataset. Furthermore, spiked expression of IgH fusion partners was consistent with fluorescent in situ hybridization (FISH) data for each sample. All t(4;14) and t(4;16) cases were correctly identified by RNAseq on the basis of the relevant fusion transcript. As a final quality control measure, recurrent variants (e.g. NRAS, KRAS, TP53, FAM46C, DIS3) were identified in the expected proportions.We performed a pre-planned analysis of differential gene expression between those patients achieving a VGPR or better, sustained for at least 12 months without HDSCT (excellent responders), and those patients who achieved less than a PR (poor responders). 85 genes were upregulated in poor responders and 225 in excellent responders. Interestingly, there was no significant overlap between our PAD-predictive signature and the Arkansas 70 gene poor prognosis signature, the Arkansas 17 gene poor prognosis signature, or the EMC92 prognostic signature. This is likely to reflect in part, the greater sensitivity of RNAseq for gene expression compared to microarrays. However, it also implies that there is a selective signature for PAD responsiveness.We employed the Gage and Pathview packages to identify non-redundant pathways associated with PAD responsiveness. Significantly upregulated genes in poor responders were those involved in: DNA replication, base excision repair, and the Fanconi anaemia pathway. Genes upregulated in excellent responders included those involved in: several signalling pathways (including RAS, NF-Kappa B, FOXO and JAK-STAT pathways); chemokine and cell adhesion; protein processing in the endoplasmic reticulum; and immune activation pathways such as T-cell receptor signalling and natural killer cell-mediated cytotoxicity.Finally, we investigated the ability of expression signatures to stratify patients on the basis of PAD responsiveness. Our analysis suggests that RNASeq-defined transcriptional profiles could aid in the selection of patients for PAD therapy (leading to an increase in overall response rate from 70% to 86%), as well as the stratification of patients in CR to a non-HDSCT protocol. We anticipate that our current analysis could easily incorporate specific response signatures for other regimens and could make personalized therapy for myeloma a reality in the foreseeable future. DisclosuresYong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Streetly:Guys and St. Thomas’ NHS Trust: Honoraria. Schey:Celgene, Takeda: Honoraria; Celgene: Consultancy; Celgene, Johnson & Johnson: Speakers Bureau. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria. Cook:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees.

Evaluation the effects of led photo-activated disinfection on periodontal clinical parameters in patients with chronic periodontitis

The purpose of the study was to assess the effects of LED-PAD and tolonium chloride on periodontal clinical parameters in chronic periodontitis. Materials and Methods: The study was conducted on patients with chronic periodontitis, divided in 2 groups (study group and control group of patients who, besides the conventional therapy measures, also received PAD therapy). The periodontal clinical parameters were registered at baseline and after 3 months. Results and Discussions: The post-therapy evaluation revealed significantly improved results of periodontal clinical parameters in the study group, when compared to the control group. Our results support the literature studies conducted on chronic periodontitis patients but without any systemic diseases. Conclusion: The PAD disinfection determined a significant improvement for the periodontal clinical parameters in patients with periodontal disease.

Minor Variations in Electrode Pad Placement Impact Defibrillation Success

Defibrillation is essential for resuscitating patients with ventricular fibrillation (VF), but shocks often fail to defibrillate. We hypothesized that small variations in pad placement affect shock success, and that defibrillation waveform and shock dose could compensate for suboptimal pad placement. In 10 swine experiments, electrode pads were attached at 3 adjacent anterolateral positions, less than 3 centimeters apart. At each position, 24 episodes of VF were induced and shocked, 8 episodes for each of 3 defibrillation therapies. This resulted in 9 tested combinations of pad position and defibrillation therapy, with 80 episodes of VF for each combination. An episode consisted of 15 seconds of untreated VF, followed by a first shock and, if necessary, a repeat shock. Episodes were separated by four minutes of recovery. Both electrode pad position and therapy order were randomized by experiment. Primary outcome was defined as successful VF termination after the first shock; secondary outcome was the cumulative success of the first and second shocks. First shock efficacy varied widely across the 9 tested combinations of pad position and defibrillation therapy, ranging from 11.3% to 86.3%. When grouped by therapy, first shock efficacy varied significantly between the 3 pad positions: 38.3%, 48.3%, 36.7% (p = 0.02, ANOVA), and, when grouped by pad position, it varied significantly between therapies: 15.0%, 32.5%, 75.8% (p < 0.001, ANOVA). Cumulative 2-shock success varied significantly with therapy (p < 0.001, ANOVA) but not with pad position (p = 0.30, ANOVA). The lowest first shock success was at one position in 6 of 10 animals, at another position in 4 of 10 animals, and never at the third position. Small variations in pad placement can significantly affect defibrillation shock efficacy. However, anatomical variation between individuals and the challenging conditions of real-world resuscitations make optimal pad placement impractical. Suboptimal pad placement can be overcome with defibrillation waveform and shock dose.

Computational Network Model Prediction of Hemodynamic Alterations Due to Arteriolar Rarefaction and Estimation of Skeletal Muscle Perfusion in Peripheral Arterial Disease.

To estimate the relative influence of input pressure and arteriole rarefaction on gastrocnemius muscle perfusion in patients with PAD after exercise and/or percutaneous interventions. A computational network model of the gastrocnemius muscle microcirculation was adapted to reflect rarefaction based on arteriolar density measurements from PAD patients, with and without exercise. A normalized input pressure was applied at the feeder artery to simulate both reduced and restored ABI in the PAD condition. In simulations of arteriolar rarefaction, resistance increased non-linearly with rarefaction, leading to a disproportionally large drop in perfusion. In addition, perfusion was less sensitive to changes in input pressure as the degree of rarefaction increased. Reduced arteriolar density was observed in PAD patients and improved 33.8% after three months of exercise. In model simulations of PAD, ABI restoration yielded perfusion recovery to only 66% of baseline. When exercise training was simulated by reducing rarefaction, ABI restoration increased perfusion to 80% of baseline. Microvascular resistance increases non-linearly with increasing arteriole rarefaction. Therefore, muscle perfusion becomes disproportionally less sensitive to ABI restoration as arteriole rarefaction increases. These results highlight the importance of restoring both microvascular structure and upstream input pressure in PAD therapy.

A Second Autologous Stem Cell Transplant (ASCT2) Induces Superior Durability Of Response (DuR) Following Bortezomib-Containing Re-Induction Therapy For Relapsed Multiple Myeloma (MM): Final Results From The BSBMT/Ukmf Myeloma X (Intensive) Trial

▪ IntroductionAlthough ASCT in MM is standard consolidative therapy in first line treatment definitive evidence for its use in salvage therapy is lacking. The principal aim of this multi-centre phase III randomised controlled trial was to evaluate the durability of response (DuR) of a second ASCT compared with a less intensive alkylating agent consolidation, after a bortezomib-containing re-induction strategy. Patients and MethodsEligible patients with MM relapsing after a prior ASCT were enrolled. All patients were re-induced with PAD therapy (Bortezomib 1.3mg/m2 iv D1, 4, 8 & 11; Doxorubicin 9mg/m2/day iv D1-4; Dexamethasone 40mg/day PO D1-4: additionally D8-11 & D15-18 on cycle 1 only) delivered in 4-6 21-day cycles before 1:1 randomization to either a second ASCT (Melphalan 200mg/m2 iv; ASCT2 supported by either stored stem cells or remobilized stem cells) or low dose consolidation with weekly cyclophosphamide 400mg/m2 PO for 12 weeks (C-weekly). Response assessment (by IMWG criteria) was analyzed after re-induction and 100 days post-randomization and time-to-disease progression (TTP) determined. Patients were stratified by β2microglobulin (β2M) at trial entry and response to re-induction and analyzed according to cytogenetic abnormalities by iFISH (unfavorable: t(4,14), t(14,16) and del17p). The primary endpoint was Time-to-progression (TTP) with secondary endpoints of OS, overall response rate (to PAD and randomized intervention), feasibility of stem cell mobilization in salvage therapy, safety & quality of life. ResultsThe Data and Safety Monitoring Board (DSMB) recommended randomization closure and early result release owing to the primary end-point having been met. 297 patients were entered into the study and 174 randomized from April 2008 to November 2012: ASCT2 n = 89, C-weekly n = 85. Median age was 61 (range 38 -75) with 73.6% of patients relapsing more than 24 months from first ASCT. ORR to re-induction therapy was 79.4%% with 16.0% sCR/CR rate. Post-randomization, sCR/CR was significantly higher in ASCT2 (39.3%, 95% CI 29.1, 50.3) than C-weekly (22.4%, 95% CI 14.0, 32.7) cohorts with more patients upgrading response to sCR/CR in the ASCT2 (n = 22) than C-weekly (n = 7) cohorts. At the time of analysis, 125 of 174 patients have progressed, 57 in the ASCT2 (64%) and 68 in the C-weekly (80%) cohorts. Median TTP was 19 months (95% CI 16, 25) for ASCT2 compared with 11 months (95% CI 9, 12) for C-weekly (HR 0.36 95% CI 0.25, 0.53; Cox regression analysis p<0.0001). Response to re-induction therapy (HR 2.90, 95% CI 1.45, 5.63; p = 0.0017) and DuR from ASCT1 (HR 3.49, 95% CI 1.07, 11.45; p = 0.039) had a significant impact on TTP. The median β2M level at registration was 2.7mg/L (range 1.3- 11.6) with a trend to improved TTP in patients undergoing ASCT2 when a β2M was <3.5 vs ≥ 3.5mg/L (HR 0.48, 95%CI 0.21, 1.08; p = 0.077). The presence of unfavorable iFISH did not impact on TTP in the C-weekly cohort but had a significant impact on TTP in the ASCT2 cohort (interaction HR 0.08, 95% CI 0.02, 0.41; p = 0.0024). TTP in patients with unfavorable iFISH was similar in the ASCT2 and C-weekly cohorts. Overall, 15 (17%) in the ASCT2 and 17 (20%) in the C-weekly arms have died with PD accounting for 8 and 9 deaths, respectively. Currently, there is no impact of the post-randomization intervention on OS (HR 0.62, 95%CI 0.3, 1.3; p = 0.193), though interpretation is limited by the current short follow-up and patients in the C-weekly cohort who received a second ASCT after reaching the primary end-point. ConclusionThe final analysis demonstrates a clear advantage in terms of durability of response when a second high dose Melphalan-conditioned ASCT consolidates re-induction therapy with a bortezomib-containing regimen in myeloma patients at first relapse. The impact on overall survival and quality of life remains to be clarified. Disclosures:Cook:Janssen: Honoraria, Research Funding, Speakers Bureau. Williams:Janssen: Honoraria, Speakers Bureau. Snowden:Janssen: Honoraria, Research Funding, Speakers Bureau. Cavet:Janssen: Research Funding.

PAD Induction Therapy Followed by Autologous Peripheral Blood Stem Cell Transplant (APBSCT) as Upfront Treatment for Myeloma (MM) in Chinese Patients.

Abstract 4367 IntroductionThe anti-myeloma effect of bortezomib, used as a single agent or in combination chemotherapy, is well recognized in various clinical studies. The aim of this study is to determine the feasibility of using the PAD combination (bortezomib, doxorubicin and dexamethasone) as upfront treatment in Chinese patients with newly diagnosed MM, followed by APBSCT. MethodPatients between the ages of 18 to 65 year-old with newly diagnosed MM were recruited. PAD (bortezomib 1.3 mg/m2 on days 1, 4, 8 & 11; doxorubicin 9 mg/m2 on days 1 & 4; dexamethasone 40 mg on days 1-4, 8-11 & 15-18 during cycle 1 and days 1-4 during cycles 2-4) induction therapy was administered for four 28-days cycles, followed by autologous peripheral blood stem cell mobilization with cyclophosphamide 3 g/m2 plus G-CSF 5 mg/kg/BD. Subsequently, APBSCT was performed with high dose melphalan 200 mg/m2 conditioning. ResultsA total of 25 patients has been recruited so far (male:female = 14:11). The age ranged from 44 to 65 year-old (median 53). Eleven patients were of IgG subtype, 6 were IgD, 4 were IgA and 4 were kappa light chain disease. By Durie-Salmon staging, 22 were stage III, 2 were stage II and 1 was stage I. Seventeen (68%) patients have completed the four cycles of PAD induction therapy, while 3 (12%) are still having on-going PAD induction. Five (20%) patients withdrew from the PAD therapy. One patient developed disease progression after 2 cycles of PAD, while the other 4 developed serious adverse events with the first cycle of PAD, including 1 patient each with severe bradycardia, atrial fibrillation, severe sensory neuropathy and pulmonary haemorrhage. Of the 18 patients who had evaluable response to PAD (i.e. 17 patients who completed four cycles of PAD and 1 who progressed on PAD induction), the results were 3 CR, 7 VGPR, 5 PR and 3 NR. Fourteen of the patients with at least PR received APBSCT. Post-APBSCT responses were so far evaluable in 11 patients with 6 CR, 4 VGPR and 1 PR. Hence, PAD is a feasible and effective upfront induction therapy for Chinese patients with MM resulting in a satisfactory response rate. Nevertheless, significant adverse events may occur even early on with the treatment. Subsequent APBSCT further improved the response rate but long-term survival rate remains to be established. Disclosures:No relevant conflicts of interest to declare.

Effects of Far Infrared Acupoint Stimulation on Autonomic Activity and Quality of Life in Hemodialysis Patients

Patients receiving regular hemodialysis sessions have been known to suffer from fatigue and depression. This experiment was designed to determine the effects of far infrared ray (FIR) stimulation on acupoints of patients suffering from renal failure who are receiving regular hemodialysis. Patients receiving long-term and regular hemodialysis who volunteered for this procedure were randomly selected to undergo either FIR or heat pad (HP) therapy to determine the impact of FIR treatment on these patients. Both the activities of the autonomic nervous system and changes in quality of life were measured before and after treatment to determine the effectiveness of the FIR treatment. Results from this study show that FIR therapy decreases both stress and fatigue levels of these patients. It also stimulates autonomic nervous system (ANS) activity in patients who are diagnosed with end-stage renal disease (ESRD) and are receiving regular hemodialysis (HD). Therefore, benefits of FIR stimulation on these patients are clearly demonstrated in this preliminary study.

Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy Followed by Thalidomide and Dexamethasone (TD) as a Salvage Treatment for Relapsed Multiple Myeloma (MM): Analysis of Efficacy and Safety

Introduction: PAD was reported to be highly effective regimen as an induction therapy before high dose therapy. TD is an another effective regimen with no cross resistance. We conducted a phase II study with PAD followed by TD in relapsed MM to test effectiveness of this combination.Method: Patients were planned to receive 6 cycles of PAD, (bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, doxorubicin 4.5 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, every 21 days). Responders following 6 cylces of PAD received 12 cycles of TD (thalidomide 100 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days). In patients with progression during PAD therapy, regimen was changed to 12 cycles of thalidomide 200 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days. Response was assessed by EBMT criteria, with additional categories of nCR and VGPR. Adverse events were graded by the NCI-CTC, Version 3.0.Result: This study aimed to enroll 40 patients till Oct 2007 and we are reporting the result with 40 patients. Efficacy could be assessed in 34 patients. After two cycles of PAD, 34 patients showed response with 6 CR. Overall response rate to 6 cylces of PAD was 90.9% with 36.4% CR. Seven of total 24 patients with TD showed further improvement of response status with 7 additional CR. Overall response to PAD followed by TD was 94%: CR 57.6%, nCR 15.2%, VGPR 6%, PR 15.2%, SD 3%, PD 3%. There was no prognostic factor for CR+nCR achieving in the univariate analysis. The median follow-up was 16.2 months with 2 year OS 54.5%. The median PFS time from study treatment was 18 mon (95% CI, 11.0~24.9 mon), median OS was not reached. The median OS time from first diagnosis was 112.9 mon (95% CI, 24.6~201.1 mon). One hundred seventy-eight PAD cycles (median 6, range 1–6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3/4 in 39.5%. Grade 3/4 neutropenia was observed in 10.5%. Sensory neuropathy occurred with grade 2 in 26.3% and grade 3 in 13.2%. The median dose intensity was 1.35 mg/m2/week for bortezomib and 5.21 mg/m2/week for doxorubicin, which correspond 78% and 86.8% of the planned dose intensities, respectively. A total of 185 TD treatment cycles (median 2, range 0–12 cycles) was administered. One patient die by the pneumonia.Conclusion: PAD followed by TD in patients with relapsed multiple myeloma is very active and tolerable.

PAD Given at Relapse Is More Effective Than VAD Given as Induction Therapy - Results of a Phase II Study.

Introduction: The combination of Vincristine, Adriamycin and Dexamethasone (VAD) followed by autologous transplantation has been a standard of care for patients with Myeloma for a number of years. Recently, it has been shown that a combination of Bortezomib with Adriamycin/Dexamethasone (PAD) is a highly effective induction agent with response rates of up to 95% (Oakervee et al, BJH 2005; 129: 755–62). We postulated that the superior efficacy of PAD chemotherapy could be demonstrated by studying patients who have been previously treated with VAD or a VAD-like regimen (VAMP, C-VAMP, Z-DEX etc.) by comparing the response to PAD given following relapse to the response previously obtained with the VAD or VAD-like regimen, in terms of both relative and absolute changes in the paraprotein or light chains and the degree of remission obtained by the standard EBMT criteria.Materials and Methods: A Phase II study was developed with three cohorts, each planned to recruit 23 patients. Cohort 1; patients treated with VAD or VAD-like regimen who previously had an autologous transplant; Cohort 2 - similar patients but without previous transplant and Cohort 3 - patients refractory to VAD. Patients in groups 1 and 2 were allowed to have received one further line of treatment following VAD but patients in group 3 would proceed directly to PAD. A total of 42 patients have been recruited and as recruitment to cohort 1 is now complete, this report will focus on these 23 patients.Results: 23 patients in Cohort 1 (9 females, 14 males) had a median age of 60 years (range 41–73). 8 patients had received thalidomide-based regimens following relapse after transplantation and had relapsed again. 15 patients were in first relapse. The time from diagnosis to PAD chemotherapy was 46 months (18–179 months). Previous treatment given was VAD 13, C-VAMP 5, C-VAD 3, Z-DEX 2. Patients received a median of four cycles of PAD. 8 patients achieved CR following PAD compared to 3 post-VAD p=0.013 using McNemar's Chi-squared test with continuity correction. Comparison of the fall in paraprotein showed a median fall of 89% post-PAD compared to 60% post-VAD. This difference was significant by the Wilcoxon Matched Pairs Rank Test (p<0.003). There were no reports of increased cardiotoxicity. A number of patients proceeded on to second transplant following their response to PAD therapy.Conclusion: PAD is a highly active therapy for patients with myeloma in relapse, even if they have received a prior VAD or VAD-like regimen the differences are statistically significant despite the fact the patients have all experienced at least one relapse. PAD therapy will be incorporated into the NCRI (UK) Myeloma X regimen as an induction therapy in patients who have relapsed post autologous transplantation, with patients randomised to consolidation with a second autologous transplant or conventional dose cyclophosphamide.

Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy Followed by Thalidomide and Dexamethasone (TD) as a Salvage Treatment for Relapsed Multiple Myeloma (MM): Preliminary Analysis of Efficacy and Safety.

Introduction: PAD was reported to be highly effective regimen as an induction therapy before high dose therapy. TD is an another effective regimen with no cross resistance. We conducted a phase II study with PAD followed by TD in relapsed MM to test effectiveness of this combination.Method: Patients were planned to receive 6 cycles of PAD, (bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, doxorubicin 4.5 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, every 21 days). Responders following 6 cylces of PAD received 12 cycles of TD (thalidomide 100 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days). In patients with progression during PAD therapy, regimen was changed to 12 cycles of thalidomide 200 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days.Result: This study aimed to enroll 40 patients till Oct 2007 and we are reporting preliminary result with 35 patients. Efficacy could be assessed in 29 patients. After two cycles of PAD, 29 patients showed response with 5 CR. Overall response rate to 6 cylces of PAD was 96.4% with 39.3% CR. Six of total 13 patients with TD showed further improvement of response status with 5 additional CR. Overall response to PAD followed by TD was 92.8%: CR 57.1%, nCR 10.7%, VGPR 7.1%, PR 17.9%, SD 3.6%, PD 3.6%. There was no prognostic factor for CR+nCR achieving in the univariate analysis. The median follow-up was 8.4 months with 1 year PFS 66.8% and 1 year OS 59.4%. One hundred fourty-six PAD cycles (median 5, range 1–6) in 35 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3/4 in 37.1%. Grade 3/4 neutropenia was observed in 5.8%. Sensory neuropathy occurred with grade 2 in 31.4% and grade 3 in 8.6%. The median dose intensity was 1.44 mg/m2/week for bortezomib and 5.25 mg/m2/week for doxorubicin, which correspond 83.2% and 87.5% of the planned dose intensities, respectively. A total of 112 TD treatment cycles (median 0, range 0–12 cycles) was administered. Two patients developed grade 3 neutropenia. One patient die by the pneumonia.Conclusion: PAD followed by TD in patients with relapsed multiple myeloma is very active and tolerable. Updated results will be presented at the meeting.*Protocol Number: KMM55-NCT00319865

Bortezomib, Adriamycin Dexamethasone (PAD) Combination Therapies or Patients with Relapsed or Refractory Myeloma Previously Treated with VAD or VAD like Therapy.

Background: Although active as a single agent Bortezomib has been shown to be highly effective in combination therapy and particularly high rates of response have been obtained in newly diagnosed patients with the PAD combination. This combination has not been studied before now in patients with relapsed or refractory disease. We have chosen to study this combination in patients who have received a VAD (Vincristine Adriamycin and Dexamethasone) or VAD like therapy (VAMP, Z-DEX, etc) as initial treatment for their myeloma as there is therefore an opportunity to compare the response of their initial disease to VAD or VAD like therapy with the response obtained upon relapse with PAD, each patient acting as their own “control”.Aims and primary objectives: This phase II study was to assess the feasibility and potential efficacy of PAD therapy patients who had previously received VAD or VAD like therapy. Three cohorts were identified:patients who had received VAD and a subsequent autologous transplantpatients who had received VAD but had not been transplantedpatients who were refractory to VAD (less than partial response)In Cohorts 1 and 2, one additional treatment could be given after their initial line of therapy; patients in group 3 would proceed directly to PAD therapy. In view of patients previous exposure to Anthracycline additional echocadiograms were reviewed after each two cycles of PAD Chemotherapy. Twenty three patients will be entered in each cohort.Methods: Eligible patients received up to six twenty one day cycles of PAD comprising Bortezomib 1.3mgm2, days 1,4,8 and 11, Adriamycin 9mgm2 by IV infusion days 1 – 4 and Dexamethasone 40mg orally given on days 1 – 4, 8 – 11 and 15 – 18 in cycle one and days 1 – 4 during subsequent cycles. Patients were permitted to proceed to autologous transplant (or second autologous transplant) at the end of therapy if blood stem cells were harvested or available from previously harvest patients. Patients on PAD were given antiviral and pneumocystitis prophylaxis and vitamin supplementation as per unit protocol; early Bortezomib reduction for neuropathy was encouraged.Results: To date fifteen patients have been enrolled, seven in cohort 1, two in cohort 2 and six in cohort 3; ten male and five female age, 35–65 years, of the six relapsed patients (cohorts 1 & 2) evaluable for response all six have achieved at least a very good partial response (VGPR) and all six have had a better response to PAD than their original VAD like therapy. Of the three refractory patients, all three have had some reduction in paraprotein level and one patient has achieved a partial response and has proceeded to successful stem cell harvest.Conclusions: PAD therapy appears to be a very promising line of therapy for relapsed and refractory myeloma, obtaining better responses than their previous VAD or VAD like therapy.

Innovations in PAD therapy

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PAD therapy (bortezomib, doxorubicin and dexamethasone) for untreated multiple myeloma (MM)

6550 Background: Bortezomib (Velcade, formerly PS341) (P) shows encouraging clinical results in patients (pts) with relapsed MM with dexamethasone showing additive benefit. In vitro, P demonstrates potent synergy with cytotoxics including anthracyclines. Therefore, a Phase I/II study of PAD combination was undertaken in patients with previously untreated MM. The study objectives were: feasibility of peripheral blood stem cell (PBSC) collection and support for high dose melphalan (HDM); safety, toxicity and response rate. Methods: Pts with previously untreated MM were eligible. Pts received 4x21 day cycles of PAD. All pts received P 1.3mg/m2 on days 1,4,8,11 and oral D 40mg days 1–4, 8–11, 15–18 Cycle 1 (day 1–4 only cycles 2–4). Level 1 pts received no doxorubicin [Adriamycin (A)], level 2 pts received 4.5mg/m2 d1–4, level 3 received 9mg/m2 d1–4. Following PBSC harvesting, HDM with PBSC rescue was given. In vitro testing included gene expression analysis on purified plasma cells to identify gene expression profiles associated with response and known prognostic factors. Results: Fifteen pts are enrolled (1F; median age 52 [37–64] yrs) and all have completed at least 1 cycle (Level 1 –3 pts; level 2 –4 pts; level 3 –8 pts). All pts have achieved at least a partial response with 2 achieving a complete response by immunofixation (1 at level 1; 1 at level 3). In 8/8 pts PBSC collection was successful (median 3.13 x106 CD34+ cells/kg (1.92–7.4). 6 pts have completed HDM with PBSCs. Median time to neutrophil (>0.5) and platelet (>20) engraftment was 18 days (13–23) and 12.5 days (10–33). Most adverse events were NCI-CTC Grade 1–2. Of 6 serious adverse events only 2 were considered to be possibly study drug related. There were no deaths on study. Conclusion: PAD is well tolerated, highly effective and does not prejudice PBSC collection or subsequent engraftment. PAD warrants further evaluation in prospective clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc.; Ortho Biotech

PAD therapy (bortezomib, doxorubicin and dexamethasone) for untreated multiple myeloma (MM)

6550 Background: Bortezomib (Velcade, formerly PS341) (P) shows encouraging clinical results in patients (pts) with relapsed MM with dexamethasone showing additive benefit. In vitro, P demonstrates potent synergy with cytotoxics including anthracyclines. Therefore, a Phase I/II study of PAD combination was undertaken in patients with previously untreated MM. The study objectives were: feasibility of peripheral blood stem cell (PBSC) collection and support for high dose melphalan (HDM); safety, toxicity and response rate. Methods: Pts with previously untreated MM were eligible. Pts received 4x21 day cycles of PAD. All pts received P 1.3mg/m2 on days 1,4,8,11 and oral D 40mg days 1–4, 8–11, 15–18 Cycle 1 (day 1–4 only cycles 2–4). Level 1 pts received no doxorubicin [Adriamycin (A)], level 2 pts received 4.5mg/m2 d1–4, level 3 received 9mg/m2 d1–4. Following PBSC harvesting, HDM with PBSC rescue was given. In vitro testing included gene expression analysis on purified plasma cells to identify gene expression profiles associated with response and known prognostic factors. Results: Fifteen pts are enrolled (1F; median age 52 [37–64] yrs) and all have completed at least 1 cycle (Level 1 –3 pts; level 2 –4 pts; level 3 –8 pts). All pts have achieved at least a partial response with 2 achieving a complete response by immunofixation (1 at level 1; 1 at level 3). In 8/8 pts PBSC collection was successful (median 3.13 x106 CD34+ cells/kg (1.92–7.4). 6 pts have completed HDM with PBSCs. Median time to neutrophil (>0.5) and platelet (>20) engraftment was 18 days (13–23) and 12.5 days (10–33). Most adverse events were NCI-CTC Grade 1–2. Of 6 serious adverse events only 2 were considered to be possibly study drug related. There were no deaths on study. Conclusion: PAD is well tolerated, highly effective and does not prejudice PBSC collection or subsequent engraftment. PAD warrants further evaluation in prospective clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc.; Ortho Biotech