First-Line Rituximab Efficacy and Safety in Patients with Acquired Idiopathic Thrombotic Thrombocytopenic Purpura Experiencing a Non Optimal Response to Therapeutical Plasma Exchange: Results of a Prospective Multicenter Phase 2 Study From the French Reference Center for the Management of Thrombotic Microangiopathies.

Abstract Abstract 890 Background: Acquired idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) resulting from an autoantibody-mediated defect in the von Willebrand factor-cleaving protease ADAMTS13. Therapeutical monoclonal antibodies directed against B-lymphocytes (rituximab) provided interesting results on preliminary studies. Objectives: We assessed rituximab efficacy and safety in adult patients with acquired idiopathic TTP who experienced a non optimal response to daily TPE, as defined by a refractory disease at day 5 or a flare-up of the disease within the first 15 days of standard intensive TPE treatment. Design: We conducted a prospective multicenter open-label single arm phase 2 trial. Patients with a non optimal response received 4 rituximab infusions at days 1, 4, 8 and 15, along with daily TPE continuation (R+ group). Peripheral blood B-lymphocyte count was evaluated before each rituximab administration, and then at 3, 6, 9 and 12 months. Outcome from the first TPE session was compared to this of 57 historical patients (R- group) treated by TPE alone (36 cases) or associated with vincristine (21 cases) for the same indication. ADAMTS13 activity was assessed at 3, 6, 9 and 12 months in both groups. Results: Both groups had comparable features on admission. Twenty-two patients were included to receive rituximab. All received 4 rituximab infusions. One patient died in a context of refractory disease, whereas the 21 others achieved durable remission. The median time to durable platelet count recovery was 20 days (extremes: 14-33), which required a median plasma volume of 950 mL/kg (extremes: 310-1940). The median time from the first rituximab infusion to durable platelet count recovery was 10 days (extremes: 5-27). All patients recovered platelet count before day-35. No relapse was observed during the first year. However, 3 (14.3%) patients relapsed after a mean follow-up of 21.2±13.8 months. In R- group, 4 patients died beyond day-5. The mean time to platelet count recovery and the mean plasma volume required to achieve remission did not significantly differ between survivors in R+ and R- groups (p=0.28 and 0.67, respectively). However, 13 (21.6%) patients of R- group were still thrombocytopenic at day-35 (p=0.01). Rituximab allowed a profound and sustained peripheral blood B-cell depletion as early as day day-4 despite associated daily plasmapheresis. Peripheral blood B-cells were undetectable from day-8 to the 6th or 9th month, and recovered at 1 year. Consistently, ADAMTS13 activity was significantly higher at 3, 6 and 9 months in R+ patients (85% [0-150], 90% [42-150], and 89% [92-125], respectively) when compared to R- patients (49% [0-150], 54% [0-130] and 40% [0-90], respectively, p<0.01, <0.05 and <0.001, respectively), which correlated with significantly lower levels of serum anti-ADAMTS13 antibodies (16 [0-77], 8 [0-18] and 10 [0-25] U/L, respectively, in R+ group and 44 [7-100], 33 [12-100] and 34 [10-130] U/L, respectively, in R- group; p=0.003, 0.007 and 0.04, respectively). However, these differences vanished at 12 months. Neither patient experienced side effects related to rituximab during infusions. No patient developed hypogammaglobulinemia. No significant infectious complications occurred during follow-up. Conclusion: In patients with acquired idiopathic TTP, rituximab allows to shorten treatment duration in slow responders and prevents 1-year relapses by allowing a higher increase in ADAMTS13 activity. However, rituximab does not prevent long term relapses. Whether rituximab should be introduced systematically on diagnosis or only in patients identified as being slow responders with standard treatment remains a matter of debate which should be accurately assessed through larger, randomized trials. Disclosures: No relevant conflicts of interest to declare.

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Efficacy and safety of radiofrequency ablation for benign thyroid nodules in patients with previous thyroid lobectomy

BMC Medical Imaging ◽

10.1186/s12880-021-00577-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lin Yan ◽

Mingbo Zhang ◽

Fang Xie ◽

Jun Ma ◽

Jing Xiao ◽

...

Keyword(s):

Radiofrequency Ablation ◽

Symptom Score ◽

Thyroid Function ◽

Thyroid Nodules ◽

Efficacy And Safety ◽

Thyroid Lobectomy ◽

The Mean ◽

Benign Thyroid Nodules ◽

Benign Thyroid

Abstract Background Radiofrequency ablation (RFA) is recommended for the treatment of benign thyroid nodules. However, data on the clinical role of RFA for benign thyroid nodules in patients with history of thyroid lobectomy are insufficient. The purpose of this study was to evaluate the efficacy and safety of radiofrequency ablation (RFA) for benign thyroid nodules in patients who had previously undergoing thyroid lobectomy. Methods From May 2015 to October 2018, a total of 20 patients (19 females, 1 male, mean age 49.50 ± 14.26 years, range 22–74 years) with 20 benign thyroid nodules (mean volume 15.04 ± 21.17 ml, range 0.40–69.67 ml) who had undergone previous thyroid lobectomy were included in this retrospective study. Patients were followed up at 3, 6, 12 months after RFA and every 12 months thereafter by ultrasound, clinical evaluation and thyroid function. Volume, volume reduction rate (VRR), symptom score and cosmetic score were evaluated. Results During the mean follow-up time of 21.24 ± 16.41 months, the mean nodule volume decreased significantly from 15.04 ± 21.17 ml to 1.29 ± 1.17 ml (P = 0.018) with a mean VRR of 85.41 ± 12.17%. Therapeutic success was achieved in a single session for all thyroid nodules. The symptom score (P = 0.001) and cosmetic score (P = 0.001) were both significantly reduced at the last follow-up. The levels of free triiodothyronine (fT3), free thyroxine (fT4) and thyroid stimulating hormone were not significantly different at the last follow-up from those prior to treatment (all P > 0.05). No life-threatening complications or sequelae occurred after RFA. Conclusions As a minimally invasive modality, RFA was a safe, effective, and thyroid function-preserving option for patients with symptomatic benign thyroid nodules after a previous lobectomy.

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MP09: Canadian Community Utilization of Stroke Prevention Pilot Study-Emergency Department (C-CUSP ED)

CJEM ◽

10.1017/cem.2017.175 ◽

2017 ◽

Vol 19 (S1) ◽

pp. S68 ◽

Cited By ~ 1

Author(s):

R. Parkash ◽

K. Magee ◽

M. McMullen ◽

M.B. Clory ◽

M. D’Astous ◽

...

Keyword(s):

Stroke Prevention ◽

Phase 1 ◽

Retrospective Chart Review ◽

Phase 2 ◽

Phase 3 ◽

Three Phase ◽

Rigorous Study ◽

The Mean ◽

Prior Risk

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia affecting 1-2% of the population. Oral anticoagulation (OAC) reduces stroke risk by 60-80% in AF patients, but only 50% of indicated patients receive OAC. Many patients present to the ED with AF due to arrhythmia symptoms, however; lack of OAC prescription in the ED has been identified as a significant gap in the care of AF patients. Methods: This was a multi-center, pragmatic, three-phase before-after study, in three Canadian sites. Patients who presented to the ED with electrocardiographically (ECG) documented, nonvalvular AF and were discharged home were included. Phase 1 was a retrospective chart review to determine OAC prescription of AF patients in each ED; Phase 2 was a low-intensity knowledge translation intervention where a simple OAC-prescription tool for ED physicians with subsequent short-term OAC prescription was used, as well as an AF patient education package and a letter to family physicians; phase 3 incorporated Phase 2 interventions, but added immediate follow-up in a community AF clinic. The primary outcome of the study was the rate of new OAC prescriptions at ED discharge in AF patients who were OAC eligible and were not on OAC at presentation. Results: A total of 632 patients were included from June, 2015-November, 2016. ED census ranged from 30000-68000 annual visits. Mean age was 71±15, 67±12, 67±13 years, respectively. 47.5% were women, most responsible ED diagnosis was AF in 75.8%. The mean CHA2DS2-VASc score was 2.6±1.8, with no difference amongst groups. There were 266 patients eligible for OAC and were not on this at presentation. In this group, the prescription of new OAC was 15.8% in Phase 1 as compared to 54% and 47%, in Phases 2 and 3, respectively. After adjustment for center, components of the CHA2DS2-VASc score, prior risk of bleeding and most responsible ED diagnosis, the odds ratio for new OAC prescription was 8.0 (95%CI (3.5,18.3) p<0.001) for Phase 3 vs 1, and 10.0 (95%CI (4.4,22.9) p<0.001), for Phase 2 vs 1). No difference in OAC prescription was seen between Phases 2 and 3. Conclusion: Use of a simple OAC-prescription tool was associated with an increase in new OAC prescription in the ED for eligible patients with AF. Further testing in a rigorous study design to assess the effect of this practice on stroke prevention in the AF patients who present to the ED is indicated.

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ADAMS-TS13 Inhibitor Level and Risk of Relapse in Acquired Idiopathic Thrombotic Thrombocytopenic Purpura

Blood ◽

10.1182/blood-2021-149338 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1012-1012

Author(s):

Annum Faisal ◽

Darla Liles ◽

Yara Park ◽

Meera Sridharan

Keyword(s):

North Carolina ◽

Platelet Count ◽

Thrombotic Microangiopathy ◽

Final Analysis ◽

Refractory Disease ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Inhibitor Level ◽

Inhibitor Titer ◽

Risk Of Relapse

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to reduced activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13). This disorder can be due to a congenital deficiency state or be acquired (immune TTP (iTTP)) due to an antibody which either inhibits or causes clearance of ADAMTS13. The aim of our study was to determine whether ADAMTS13 inhibitor titer at initial presentation could serve as a predictor of refractory disease and relapse in iTTP. We also measured clinical outcomes across different gender and racial subgroups. Methods: The United States Thrombotic Microangiopathy (USTMA) iTTP registry was used to extract patient information for two academic institutions in Eastern North Carolina. Descriptive statistics were used to analyze the data. The first iTTP episode recorded in the data base was used as the index episode. All patients included in the final analysis had an ADAMTS13 activity of <10%. An inhibitor level of 5 Bethesda units was arbitrarily chosen as the cutoff between low (<5) and high (>/5) inhibitor level. Response time was defined as the number of days of plasma exchange (PEX) required to achieve a platelet count of 150,000 for two consecutive days. Relapse was defined as occurrence of a new episode of iTTP 30 days after achievement of response. Refractory disease was defined as persistence of thrombocytopenia or absence of a sustained platelet count increment or platelet counts of < 50,000 despite 4-7 days of plasma exchanges and steroid treatment. Rituximab resistance was defined as lack of platelet recovery to more than 150,000 within 11 to 14 days of administration of the first dose of Rituximab. Results: A total of 161 patients with iTTP were identified. Ten patients had ADAMTS13 activity >10% and 15 patients did not have a reported inhibitor level. These subjects were not included in the final analysis. The cohort had 28% male (n =38/136) and 72% (n=98/136) female patients. There were more African American patients 73% (n=99/136) than Caucasians 24% (n=32/136). There were also 2 Hispanic, 1 Native American and 2 patients with unidentified race. Median ADAMTS3 inhibitor titer was 1.05 (Range 0-87). Forty three patients with ADAMTS13 activity <10 % had an inhibitor level of 0 (i.e undetectable).They were included in the low inhibitor group. Overall, 88% patients (n=120/136) had low inhibitor level and only 12% (n=16/136) had a high inhibitor. Thirteen percent females (n=13/98) and 8% (n=3/38) males had a high inhibitor level (p=0.387). Fourteen percent (n=14/99) African Americans and 6 % (n=2/32) Caucasians had a high inhibitor, p=0.23. In the low inhibitor group 30% (n=36/120) patients suffered at least one episode of relapse whereas 31% (n=5/16) had relapsed in the high inhibitor group. The median time to response was 6 days (range 1-76) in the low inhibitor group and 7 days (range 4-20) in the high inhibitor group (p=0.61). While looking at the various subgroups, median time to response for males was 6 days (range 4-21), females 6 days (range 1-76) , African Americans 6 days (range 3-29) , and Caucasians 6 days (range 1-76). The frequency of refractory disease was 31 % (n=5/16) in the high inhibitor group and 29% (n=34/119) in the low inhibitor group. At the time of enrollment in the registry, Rituximab was not a part of first line therapy. Only 26 out of 136 patients had received Rituximab. In the low inhibitor group 5 patients displayed Rituximab resistance whereas there were no patients in the high inhibitor group with Rituximab resistance. Conclusion: When evaluating patients presenting with iTTP in two centers in North Carolina, no correlation was found between a high inhibitor levels of >/ 5 Bethesda units and risk of relapse or refractory disease. A larger study is needed to evaluate this further. Disclosures No relevant conflicts of interest to declare.

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Venetoclax and Azacitidine for Older Newly Diagnosed Patients with Acute Myeloid Leukemia: A Single-Institution Pilot Study Using Measurable Residual Disease to Guide Therapy

Blood ◽

10.1182/blood-2019-122120 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2638-2638 ◽

Cited By ~ 1

Author(s):

Amanda Winters ◽

Jonathan A Gutman ◽

Enkhtsetseg Purev ◽

Brett M. Stevens ◽

Shanshan Pei ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Ras Pathway ◽

Measurable Residual Disease ◽

Count Recovery

Background: Venetoclax (ven) was approved for older untreated acute myeloid leukemia (AML) patients due to high response rates and durable remissions. As a participating site in the dose escalation study, we observed deeper/more durable responses in some who received >400mg ven. We also noted 16/33 discontinued azacitidine (aza) after achieving a response; 9 relapsed and 7 remained in long term remission on ven only. Based on these observations, we designed a study that hypothesized: A)Higher initial doses of ven would allow deeper/more durable responses, and B)Multi modality high sensitivity measurable residual disease (MRD) testing could identify patients able to discontinue aza and remain on maintenance ven. Methods: This is an ongoing phase 2 study (NCT03466294) of 42 untreated AML patients ≥60 who decline/are ineligible for induction. Patients have adequate organ function and white blood cell counts <25x109/L (hydrea permitted). In cycle 1, patients receive aza 75mg/m2 on days (d) 1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d 1-4. Ven continues at 600mg d 5-28 and bone marrow biopsies (BMBXs) are performed on d 8 and 28. Patients who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles, with growth factor support; "upgraded" responses are recorded if count recovery occurs. Non responders discontinue or receive up to two additional cycles of aza and ven 600mg. Responders who remain MRD+ by multiparameter flow cytometry (MPFC, Hematologics) and/or digital droplet PCR (ddPCR) for as many identifiable diagnostic genes as possible also receive up to 2 additional cycles of aza and ven 600mg. MRD+ responders after 3 cycles continue aza and ven 400mg until toxicity/progression. Patients who experience MRD- responses at any time stop aza and continue ven 400mg daily (Fig 1). Results: 30 patients enrolled between May 2018 and July 2019; median age is 71 (60-88), 10% evolved from MDS and 10% and 73% had intermediate and unfavorable risk disease by ELN, respectively (Table 1). 732 adverse events (AEs) occurred; 46 (6%) were serious, the most common were neutropenic fever (37%) and pneumonia (13%). The most common >grade 2 related AEs were leukopenia (53%), thrombocytopenia (44%) and neutropenia (35%); there were no related grade 5 AEs. The overall response rate was 70% (21/30; CR=19, MLFS=2). Median number of cycles to achieve best response was 1. Significant blast reductions were seen on day 8; of the 28 with interpretable day 8 BMBXs, 10 achieved MLFS on day 8. 4 completed ≥1 cycle and were refractory. An additional 4 did not complete cycle 1: 1 died of disease and 3 elected to come off therapy (all subsequently died of disease). Four (19%) responders relapsed, after a median 180 days (27-279). With median follow up of 214 days, median response duration has not been reached. 10 patients died, after a median 65 days (29-256); 1/30 died within 30 days. Median overall survival has not been reached. Of the 26 who completed ≥1 cycle, 19 were MRD- by MPFC, including 18/19 who achieved CR. Of these 26, 3 were not monitored by ddPCR: for 2 patients this was due to the absence of detectable baseline mutations and for 1 patient it was due to refractory disease. The remaining 23 had ddPCR monitoring; 3 became MRD- by this modality (Fig 2). All 3 were also MRD- by MPFC and per protocol discontinued aza and initiated ven maintenance (Fig 1). MRD negativity by both parameters occurred after cycles 1, 2 and 3, respectively. One MRD- patient relapsed after 216 days; two remain in remission after 301 and 124 days. An additional 4 who achieved MRD+ responses discontinued aza at their insistence (and in violation of the protocol); 1 relapsed after 279 days, and 3 remain in ongoing remission. Univariate predictors of refractory disease were FAB M0/M1 (OR 0.070, p=0.02) and RAS pathway mutations (OR 14.25, p=0.02). Conclusions: Higher initial doses of ven are tolerated in this population. Blast reduction occurs quickly in many patients (day 8), for this low intensity regimen. Response rates are consistent with lower doses of ven. Very deep responses, as measured by highly sensitive MRD methods (MPFC and ddPCR are capable of sensitivity up to 0.02%), are attainable. Longer follow up time will determine if higher ven doses and MRD-driven decisions related to continuation of aza result in more durable responses. Increased maturation of blasts and RAS pathway mutations are predictors for refractory disease. Disclosures Lyle: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pollyea:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Comparison of the efficacy and safety of bimatoprost (0.03 %) and travoprost (0.004 %) in patients with primary open angle glaucoma

Nepalese Journal of Ophthalmology ◽

10.3126/nepjoph.v5i1.7831 ◽

2013 ◽

Vol 5 (1) ◽

pp. 75-80 ◽

Cited By ~ 5

Author(s):

Ashish Chander ◽

H Kapoor ◽

S Thomas

Keyword(s):

Intraocular Pressure ◽

Side Effect ◽

Primary Open Angle Glaucoma ◽

Open Angle Glaucoma ◽

Open Angle ◽

Efficacy And Safety ◽

Once Daily ◽

The Mean ◽

To Receive

Purpose: To compare the efficacy and safety of bimatoprost (0.03 %) and travoprost (0.004 %) in patients with primary open angle glaucoma (POAG). Subjects and methods: Patients with POAG were randomized to receive either bimatoprost or travoprost once daily. Detailed ocular examination was done and intraocular pressure (IOP) was measured at 9.00 am, 1.00 pm and 4.00 pm at the baseline and at 1, 2, 4, 6 and 12 weeks of therapy. Results: A total of 31 patients were analysed. The patients were randomly divided into two groups (Bimatoprost group = 16; Travoprost group = 15). Both the groups had a statistically significant reduction from the baseline IOP at all follow up visits at 9.00 am, 1.00 pm and 4.00 pm. The mean IOP decreased from a baseline of 25 ± 2.32 mm Hg to 15.93 ± 1.79 mm Hg after 12 weeks in the bimatoprost group (p < 0.001), and from 24.2 ± 1.60 mm Hg to 16.53 ± 1.56 mm Hg in the travoprost group (p < 0.001). A better mean reduction of IOP was obtained with bimatoprost than with travoprost at the end of the study at 12 weeks (p = 0.03). Mild ocular redness was the commonest side effect in both the groups but was not significant in either group. Conclusion: Both drugs lowered IOP effectively but bimatoprost showed a greater reduction in the mean IOP than did travoprost at 12 weeks and both are safe for ocular use. Nepal J Ophthalmol 2013; 5(9):75-80 DOI: http://dx.doi.org/10.3126/nepjoph.v5i1.7831

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Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa196 ◽

2020 ◽

Author(s):

Toshihiro Kudo ◽

Yoshiyuki Murai ◽

Yoshitsugu Kojima ◽

Kenji Uehara ◽

Taroh Satoh

Keyword(s):

Body Weight ◽

Ascitic Fluid ◽

Dose Escalation ◽

Urine Volume ◽

Fluid Volume ◽

Phase 2 ◽

Efficacy And Safety ◽

Open Label ◽

Dose Escalation Study ◽

The Mean

Abstract Objective This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. Methods In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5–7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. Results The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: −2304.3 ml, minimum: −27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). Conclusions Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75–30 mg/day.

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Ilizarov technique combined with limited adjunctive surgical procedures for correction of relapsed talipes equinovarus in children

Journal of International Medical Research ◽

10.1177/0300060517724710 ◽

2017 ◽

Vol 46 (2) ◽

pp. 802-810 ◽

Cited By ~ 2

Author(s):

Xiao-Jian Wang ◽

Feng Chang ◽

Yun-Xing Su ◽

Xiao-Chun Wei ◽

Lei Wei

Keyword(s):

Study Group ◽

Ilizarov Technique ◽

Efficacy And Safety ◽

Limited Surgery ◽

Talipes Equinovarus ◽

Before And After ◽

Lateral Plane ◽

The Mean ◽

Surgical Operations

Objective To evaluate the efficacy and safety of using the Ilizarov invasive distraction technique combined with limited surgical operations in the treatment of relapsed talipes equinovarus in children. Methods This retrospective study analysed the outcomes of paediatric patients with relapsed talipes equinovarus who were treated with the Ilizarov technique with moderate open limited soft tissue or bony operations. The International Clubfoot Study Group (ICFSG) classification system score was used to evaluate the deformities before and after surgery. Results The study evaluated 16 feet in 14 patients (nine boys). The correction time ranged from 6 to 12 weeks. The mean duration of frame application was 5.9 months. The gait was improved significantly in all patients. At final follow-up, the mean ankle dorsiflexion and plantarflexion ranges were 8.3° and 34.6°, respectively. The talocalcaneal angle improved from 10.0° preoperatively to 28.3° postoperatively in the anteroposterior plane; and from 4.1° preoperatively to 42.1° postoperatively in the lateral plane. The differences in the angle of plantarflexion, dorsiflexion, range of motion of the ankle joint and talocalcaneal angles pre- and postoperation were significant. Conclusions These current findings suggest that the Ilizarov technique combined with limited surgery effectively corrects relapsed talipes equinovarus in children.

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Recovery of Donor Peripheral Blood Platelet Count Following Platelet Apheresis.

Blood ◽

10.1182/blood.v110.11.2892.2892 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2892-2892

Author(s):

Larry J. Dumont ◽

L. Lassahn ◽

Peter A. Tomasulo ◽

Dennis Harpool ◽

S. Pinkard ◽

...

Keyword(s):

Platelet Count ◽

Regression Model ◽

Peripheral Blood ◽

De Novo ◽

Blood Platelet ◽

Platelet Recovery ◽

Platelet Release ◽

Kinetics Of ◽

Blood Platelet Count

Abstract BACKGROUND: Apheresis platelet collection from healthy normal blood donors can reduce the donor peripheral blood platelet concentration by 50% or more. The kinetics of peripheral blood platelet count (PLT) recovery in the apheresis donors over the first 24 hours has not been described. The objective of this study was to determine the recovery kinetics of the donor peripheral blood platelet count following apheresis platelet donation. METHODS: Healthy apheresis platelet donors were enrolled following informed consent. The apheresis platelet collection was performed using the Gambro Trima system (Gambro BCT, Lakewood, CO) following local SOP and manufacturer’s directions for use. The minimum predicted post-count was configured in the Trima to no less than 78K plt/μL. PLT was determined pre-procedure (Pre), immediately post procedure (Post), 4–11 h (FU1) and 11–41 h (FU2) post-donation using standard methods. The PLT recovery was evaluated as the increase in PLT following the donation (Delta). The effects of study site, time of sample, and the fraction of platelets collected (Fpc) at donation on Delta were evaluated using a random effects generalized linear regression model. A full regression model of Delta as a function of study site, follow-up period and Fpc with all main and interaction effects was used to test hypotheses. RESULTS: 548 subjects were entered into the study at 3 study sites; Pre-PLT 276±59 × 103 plt/μL, Post-PLT 205±47 × 103 plt/μL, Fpc 25±10%. No adverse events were reported by any subjects. Recovery of platelet count following apheresis platelet donation is variable between subjects; and the independent variables of study site, follow-period and Fpc accounted for 25% of the total variation in Delta. PLT increased 12.4±0.9 × 103 plt/μL by the time of follow-up sampling (p=0.01), although there was no difference between PLT at FU1 (214±49 × 103 plt/μL) and FU2 (212±47 × 103 plt/μL; p=0.15). None of the donors reached their pre-donation platelet count during the follow-up period. There was no difference in Delta between centers (p=0.23). Fpc had a significant affect on Delta (p<0.0001); with estimated Delta of 5.2±0.9 × 103 plt/μL at Fpc=15% and 16.0±.8 × 103 plt/μL at Fpc=30%. CONCLUSION: Platelet recovery following apheresis platelet donation was observed to be dependent on the fraction of platelets donated. Surprisingly, the recovery observed within the first 11 h was equivalent to that observed between 11–42 h, averaging 17.5% of the drop observed during apheresis. Recovery was not complete when observed for up to 41 h following donation in this study. Additional investigation of PLT recovery following apheresis donation is indicated to describe and differentiate the potential roles of de novo production, early pro-platelet release and platelet release from peripheral pools over the early post-donation period.

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A Phase 2 Open-Label, Sequential-Cohort, Dose-Escalation Study of AMG 531 in Japanese Patients with Chronic Immune Thrombocytopenic Purpura (ITP).

Blood ◽

10.1182/blood.v110.11.1308.1308 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1308-1308

Author(s):

Yukari Shirasugi ◽

Kiyoshi Ando ◽

Satoshi Hashino ◽

Toshiro Nagasawa ◽

Yoshiyuki Kurata ◽

...

Keyword(s):

Platelet Count ◽

Dose Escalation ◽

Japanese Patients ◽

Phase 2 ◽

Platelet Response ◽

Phase 3 ◽

Continuation Phase ◽

Platelet Counts ◽

Starting Dose ◽

The Mean

Abstract AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. Key Measures of Platelet Response

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The Immature Platelet Fraction in HIV Patients with Thrombocytopenia.

Blood ◽

10.1182/blood.v110.11.2095.2095 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2095-2095

Author(s):

Brian T. Garibaldi ◽

Rupal B. Malani ◽

Hsin-Chieh Yeh ◽

Deborah Michell ◽

Evan J. Lipson ◽

...

Keyword(s):

Diabetes Mellitus ◽

Bone Marrow ◽

Platelet Count ◽

Peripheral Blood ◽

Reticulocyte Count ◽

Control Group ◽

P Value ◽

Hiv Patients ◽

Immature Platelet Fraction ◽

The Mean

Abstract Thrombocytopenia is a common clinical feature of HIV infection. Given the number of possible etiologies of thrombocytopenia in a patient with known HIV, a peripheral blood test effective in determining the likely pathophysiologic basis of the thrombocytopenia would be a valuable clinical tool. Immature platelets are released early from the bone marrow in response to increased platelet turnover. These platelets contain residual megakaryocyte mRNA and have been termed reticulated platelets. A new assay, the Immature Platelet Fraction (IPF), measures the reticulated platelet count in peripheral blood. Patients with increased destruction of platelets from such conditions as ITP consistently have a higher IPF percent, while patients with decreased platelet production have a low or normal IPF percent. The goal of our study was to determine the performance characteristics of the IPF assay in HIV patients with thrombocytopenia and to see if the IPF percent could be used to help elucidate the etiology of low platelet counts in this group of patients. All adult patients admitted to the Johns Hopkins Hospital with a diagnosis of HIV and a platelet count less than 150,000 were eligible for enrollment. 62 patients were identified from February 2007 to June 2007. 34 control samples were obtained from inpatients with HIV who were not thrombocytopenic. In addition, 81 samples were available from non-HIV historical controls with normal platelet counts. The mean platelet count in the HIV thrombocytopenic group was 92,000 while the mean platelet count in the HIV control group was 254,000 (p value <.001). The mean platelet count in the non-HIV historical control group was 274 (p=.34 when compared to the HIV control group). The mean IPF percent in the HIV thrombocytopenic group was 10.2% as compared to 6.8% in the HIV control group (p=.001). The mean IPF in historical non-HIV controls was 3.1% (p<.001 for both the HIV thrombocytopenic and the HIV control group). Univariate analyses were conducted to identify potential individual predictors of a high IPF percent. Backward selection was then performed using multivariate linear models with a threshold Wald test p-value of 0.05. ITP, diabetes mellitus and cirrhosis were significantly associated with a higher IPF percent with a co-efficient (95% confidence interval) of 6.98 (3.05–10.91), 4.73 (1.39–8.06), and 14.18 (9.7–18.66), respectively. CD4 count, HIV viral load, hepatitis C and reticulocyte count were not correlated with IPF percent. Our results suggest that patients with HIV have increased platelet turnover as compared to patients without HIV. Thrombocytopenic patients with HIV have increased platelet turnover relative to both non-thrombocytopenic HIV patients and to historical non-HIV controls. History of ITP, diabetes mellitus, and cirrhosis are predictive of an elevated IPF percent. Reticulocyte count is not correlated to IPF percent, suggesting that a low reticulocyte count is not a reliable marker for decreased bone marrow production in HIV thrombocytopenia. It is unlikely that the IPF assay alone can be used to determine the pathophysiologic basis of thrombocytopenia in any single patient with HIV. Further work needs to be done to clarify the utility of the IPF assay in this group of patients.

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