Publications by authors named "Frank Hsieh"

41 Publications

Musculoseptocutaneous Perforator of Anterolateral Thigh Flap: A Clinical Study.

Plast Reconstr Surg 2021 01;147(1):103e-110e

From the Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital; and the Department of Plastic and Reconstructive Surgery, Bankstown-Lidcombe Hospital.

Background: The anterolateral thigh flap is one of the most useful workhorse flaps for microsurgical reconstruction. However, it can pose a great challenge to surgeons because of its anatomical variability. As the technology advances, not only septocutaneous or musculocutaneous courses of anterolateral thigh perforators but also a hybrid musculoseptocutaneous perforator pattern have been identified on computerized imaging and on cadaveric study. However, there is a paucity of clinical study in the literature. The aim of this investigation was to identify the features of this pattern.

Methods: All patients undergoing anterolateral thigh flap harvest between September of 2017 and May of 2018 performed by a single surgeon are included. Every pulsatile perforator was dissected to document its location on the thigh, emerging location (septum/muscle), size, course, and origin.

Results: Thirty-seven patients with 115 perforators were identified. Ten percent of perforators were septocutaneous, 37 percent were musculoseptocutaneous, and 52 percent were musculocutaneous. Forty-seven percent of perforators emerged on the septum between the rectus femoris and the vastus lateralis. Eighty-one percent of patients had one or more perforators in the "hot zone." Medium and large perforators were more frequently located in the proximal and hot zones. All perforators originated from the vascular tree of the lateral circumflex femoral artery, with 10 percent originating from the transverse branch, 28 percent originating from the oblique branch, and 62 percent originating from the descending branch.

Conclusions: A high proportion of musculoseptocutaneous perforators were identified. The clinical relevance of this is to be very cautious on the skin paddle design while harvesting the flap.
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http://dx.doi.org/10.1097/PRS.0000000000007471DOI Listing
January 2021

Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development.

Mov Disord 2020 01 10;35(1):134-141. Epub 2019 Sep 10.

TransThera Consulting Co, Portland, Oregon, USA.

Background: LRRK2 mutations are a common cause of dominantly inherited PD. Previous studies showed decreases in urine levels of didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate in LRRK2-knockout mice and in non-human primates treated with LRRK2 kinase inhibitors. We hypothesized that urine levels of bis(monoacylglycerol)phosphate isoforms will be higher in individuals with a PD-causing gain-of-kinase function mutation, LRRK2 G2019S. The objective of this study was to investigate alterations in urinary phospholipids as biomarkers of LRRK2 mutations and Parkinson's disease status/phenotypes.

Methods: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to assess 54 bioactive phospholipids in urine from the LRRK2 Cohort Consortium (n = 80). To confirm and extend the findings, urine from an independent LRRK2 cohort from Columbia University Irving Medical Center (n = 116) was used. Both cohorts were composed of LRRK2 G2019S carriers and non-carriers with and without PD.

Results: In each cohort, 4 bis(monoacylglycerol)phosphate isoforms (di-18:1-bis[monoacylglycerol]phosphate, didocohexaenoyl [22:6] bis[monoacylglycerol] phosphate, 2,2'-di-22:6-bis[monoacylglycerol]phosphate, and 2,2'-di-18:1-bis[monoacylglycerol]phosphate) were significantly higher (2.5- to 4.3-fold) in G2019S carriers compared with non-carriers. Interestingly, 2,2'-di-18:1-bis(monoacylglycerol)phosphate levels were marginally higher in LRRK2 carriers with PD than in those without PD (P = 0.045). Moreover, increased 2,2' and total di-22:6-bis(monoacylglycerol)phosphate were associated with worse cognitive status assessed by the Montreal Cognitive Assessment (P = 0.0033 and 0.0144, respectively).

Conclusions: The observed association of bis(monoacylglycerol)phosphate isoforms with LRRK2 G2019S mutation, PD status among G2019S carriers, and correlation with cognitive decline suggest the potential use of urinary bis(monoacylglycerol)phosphate isoforms as biomarkers for clinical trials of LRRK2-targeted therapies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981003PMC
January 2020

Clinical features, microbiological epidemiology and recommendations for management of cellulitis in extremity lymphedema.

J Surg Oncol 2020 Jan 2;121(1):25-36. Epub 2019 Jul 2.

Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Background: This high volume, single center study investigated the prevalence, bacterial epidemiology, and responsiveness to antibiotic therapy of cellulitis in extremity lymphedema.

Methods: From 2003 to 2018, cellulitis events from a cohort of 420 patients with extremity lymphedema were reviewed. Demographics, lymphedema grading, symptoms, inflammatory markers, cultures and antibiotic therapy regimens were compiled from cellulitis episodes data. Univariate and multivariate analyses were performed for detailed analysis.

Results: A total of 131 separate episodes of cellulitis were recorded from 43 (81.1%) lower limb and 10 (19.9%) upper limb lymphedema patients. The prevalence and recurrence rates for cellulitis in lymphedema patients were 12.6% (53 of 420) and 56.6% (30 of 53), respectively. The most common findings were increased limb circumference (127 of 131; 96.9%) and abnormal C-reactive protein (CRP) level (86 of 113; 76.1%). Blood cultures were obtained in 79 (60.3%) incidents, with 9 (11.4%) returning positive. Streptococcus agalactiae was the most isolated bacterium (5 of 9; 55.5%).

Conclusions: The cellulitis prevalence and recurrence rate in extremity lymphedema were 12.6%, and 56.6%, respectively. Strongest indicators of cellulitis were increased affected limb circumference and elevated CRP level. Empiric antibiotic therapy began with coverage for Steptococcus species before broadening to anti-Methicillin-resistant Staphylococcus aureus and anti-Gram negatives if needed for effective treatment of extremity lymphedema cellulitis.
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http://dx.doi.org/10.1002/jso.25525DOI Listing
January 2020

The Correlation of Age and Patterns of Maxillofacial Bone Fractures and Severity of Associated Injuries Caused by Motorcycle Accidents.

Ann Plast Surg 2019 12;83(6):e28-e34

Division of Traumatic Plasty, Craniofacial Research Center, Department of Plastic and Reconstructive Surgery.

Background: Every year, there are significant numbers of motorcycle accident casualties in Taiwan. These accidents are the leading cause of maxillofacial trauma. Age should be an important factor of maxillofacial fracture patterns yet there is limited literature on the topic. Therefore, this study aims to evaluate the correlation of age with maxillofacial fracture in motorcycle accidents.

Methods: This is a retrospective descriptive analysis conducted over 2-year period at Linkou Chang Gung Memorial Hospital. We focused on the population of maxillofacial injury caused by motorcycle accidents. Data, including demographics, age, fracture patterns of facial bones, and other associated injuries, were collected.

Results: Among 881 admissions, there were 179 patients in the minor group, 644 patients in the adult group, and 58 patients in the geriatric group. With patterns of maxillofacial fracture, midface fracture was the most common type. The minor group had higher incidence of mandibular fracture. The geriatric group sustained more midface fracture. Associated injuries, such as severe head injuries and c-spine injury, were more likely to occur with the old age victims. The overall mortality rate was 3.1%.

Conclusions: Our study presents the different trends of fracture patterns in different age groups, which is associated with different types of treatment required. We summarized all these data in the hope of providing further assistance to trauma doctor dealing with motorcycle accidents.
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http://dx.doi.org/10.1097/SAP.0000000000001943DOI Listing
December 2019

Validation of a multiplexed LC-MS/MS clinical assay to quantify insulin-like growth factor-binding proteins in human serum and its application in a clinical study.

Toxicol Appl Pharmacol 2019 05 26;371:74-83. Epub 2019 Mar 26.

Nextcea Inc., 500 West Cummings Park #4550, Woburn, MA 01801, USA. Electronic address:

Circulating insulin-like growth factor-binding proteins (IGFBPs) continue to gain attention as biomarkers of drug activities on insulin like growth factor (IGF)/IGF receptor signaling pathways. A multiplexed LC-MS/MS method was validated for the absolute quantitation of IGFBPs in human serum. The method was used to measure screening concentrations of IGFBPs in spinal and bulbar muscular atrophy (SBMA) patients in a phase 2 clinical trial. Concentrations of IGFBP 1, 2, 3, and 5 were simultaneously determined based on representative signature peptides derived from an optimized trypsin digestion procedure. Signature peptide levels were absolutely quantitated using a sensitive/specific targeted LC-MS/MS method. Corresponding mass-shifted, stable isotope-labeled peptides were employed as internal standards. A true blank matrix for the quantitation of IGFBPs was not available since they are endogenous proteins in human serum. In this method, calibration standards/curves were prepared using authentic synthetic peptides spiked into a surrogate matrix. The surrogate matrix was generated from human serum treated in the same way as the study samples, but using iodoacetic acid instead of iodoacetamide as the alkylation reagent. This surrogate matrix approach allowed for the direct and sensitive/specific quantification of IGFBP 1, 2, 3, and 5 due to the lack of any endogenous background. Equivalent matrix effect and recovery of analytes was achieved for the authentic and surrogate matrices. The fully validated LC-MS/MS assay will allow further evaluation of the utility of IGFBP biomarkers in clinical trials.
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http://dx.doi.org/10.1016/j.taap.2019.03.024DOI Listing
May 2019

Immediate and Long-term Complications of Direct-to-implant Breast Reconstruction after Nipple- or Skin-sparing Mastectomy.

Plast Reconstr Surg Glob Open 2018 Nov 5;6(11):e1977. Epub 2018 Nov 5.

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.

Background: Traditionally, breast reconstruction options after mastectomy comprise an autologous flap or staged expander/implant reconstruction, or a combination of both. Recent introduction of skin or nipple-sparing mastectomies have led to much interest in direct-to-implant immediate breast reconstructions. We performed a retrospective review of our initial experience.

Methods: Between June 1998 and December 2010, 31 of 671 patients (4.6%) who received implant-only breast reconstruction underwent direct-to-implant immediate breast reconstruction after mastectomy for primary or recurrent cancers, or risk reduction. Their files were audited, and the primary factor examined was the failure of reconstruction with loss of prosthesis. Other complications, revision surgery, and aesthetic result are also recorded.

Results: The mean follow-up period for the 31 patients was 49.5 months. A total of 45 mastectomies were performed for 21 primary and 4 recurrent breast cancers after previous conservation surgery and radiotherapy (RT), and 20 for risk reduction. Ten patients received RT (4 before mastectomy and 6 afterward). Average size of implants was 380.0 g (range, 205-620 g). The most common postoperative complications were seromas (20%); only 1 implant was lost (2.22%). Nineteen breasts required revision surgery after 6 months with 1 more implant lost. Despite the high revision rate, 28 (90.3%) had excellent or good aesthetic result.

Conclusions: Immediate single-stage direct-to-implant breast reconstruction has a high rate of both immediate postoperative complications and revisions after 6 months, especially after RT. However, most complications are manageable and do not necessarily result in implant loss. Most cases can have a successful outcome without implant loss with excellent or good cosmetic results.
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http://dx.doi.org/10.1097/GOX.0000000000001977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414105PMC
November 2018

A multiplexed UPLC-MS/MS assay for the simultaneous measurement of urinary safety biomarkers of drug-induced kidney injury and phospholipidosis.

Toxicol Appl Pharmacol 2019 03 15;366:54-63. Epub 2019 Jan 15.

Nextcea Inc., 500 West Cummings Park #4550, Woburn, MA 01801, USA. Electronic address:

Drug-induced kidney injury (DIKI) is a major concern in drug risk assessment given its clinical importance and the absence of a sensitive/specific method of diagnosis. Pharmaceutical regulatory agencies have qualified and issued letters of support for new biomarkers to better evaluate DIKI in nonclinical toxicity and clinical studies. Additional efforts have focused on drug-induced phospholipidosis (DIPL) and its potential link with collateral renal damage. The combined use of urinary biomarkers is an efficient way to evaluate renal safety in nonclinical and clinical studies. Eight FDA/EMA/PMDA qualified (or supported) urinary biomarkers, including kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), clusterin (CLU), cystatin C (CysC), trefoil factor 3 (TFF3), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and alpha-glutathione S-transferase (α-GST), were quantified by multiplex UPLC-MS/MS in a repeat dose study of gentamicin in rats. Rats administered gentamicin at 100 mg/kg/day for 2 weeks developed renal lesions detected by histopathology. Biomarkers of tubular damage (CLU, KIM-1, OPN) increased 9.8, 34.7, and 35.6-fold (relative to concurrent controls), respectively, after 2 weeks of dosing. Biomarkers of glomerular damage and/or impairment of tubular reabsorption (CysC, B2M) increased 11.7 and 22.6-fold. NGAL and α-GST increased <3-fold after 2 weeks of dosing. TFF3 was comparable to concurrent controls. The elevated biomarker concentrations met PSTC threshold criteria and were consistent with mechanisms of gentamicin nephrotoxicity. Increased urinary di-22:6-BMP indicated concomitant DIPL as confirmed by TEM. This work provides evidence supporting the combined use of the DIKI biomarker panel and di-22:6-BMP as a biomarker of DIPL in drug risk assessment.
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http://dx.doi.org/10.1016/j.taap.2019.01.012DOI Listing
March 2019

Aggressive Angiomyxoma-Report of a Rare Male Buttock Lesion.

Plast Reconstr Surg Glob Open 2018 Aug 8;6(8):e1879. Epub 2018 Aug 8.

Department of Plastic & Reconstructive Surgery, Chiayi Chang Gung Memorial Hospital, Chang Gung University, Taiwan.

Aggressive angiomyxoma is a very rare benign tumor for male population with fewer than 50 cases reported since the description of this tumor. Most documented cases of aggressive angiomyxomas were found in genital, perineal, and pelvic regions in women of child bearing age. We report a case of a massive (> 20 cm) aggressive angiomyxomas in a man who presented with perineal swellings. Macroscopically the mass was highly vascular and lobulated with high similarity to plexiform neurofibroma. Microscopic examination revealed a hypocellular tumor comprising bland oval and spindle-shaped cells along with vessels of varying calibre. The accompanying stroma was myxocollagenous. Immunohistochemical staining showed CD34 and focal estrogen receptors positivity and negative staining for S100, actin, desmin, and progesterone receptors. The histologic and immunohistochemical features favored the diagnosis of aggressive angiomyxoma. Despite the rarity of such tumor in the male population, aggressive angiomyxoma should be considered in the differential diagnosis when encountering chronic para-perineal lesions.
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http://dx.doi.org/10.1097/GOX.0000000000001879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181506PMC
August 2018

Immediate Two-Stage Prosthetic Breast Reconstruction Failure: Radiation Is Not the Only Culprit.

Plast Reconstr Surg 2018 06;141(6):1315-1324

Sydney, New South Wales, Australia; and Auckland, New Zealand.

Background: Immediate prosthetic breast reconstruction produces a satisfactory aesthetic result with high levels of patient satisfaction. However, with the broader indication for postmastectomy adjuvant radiation therapy, many patients are advised against immediate breast reconstruction because of concerns of implant loss and infection, particularly as most patients also require chemotherapy. This retrospective cohort study examines outcomes for patients who underwent immediate two-stage prosthetic breast reconstruction after mastectomy with or without adjuvant chemotherapy or radiotherapy.

Methods: Between 1998 and 2010, 452 patients undergoing immediate two-stage prosthetic breast reconstruction involving a total of 562 breasts were included in this study. Stage 1 was defined as insertion of the temporary expander, and stage 2 was defined as insertion of the final silicone implant. Postoperative adjuvant radiotherapy was recommended with a tissue expander in situ for 114 patients. Complications, including loss of prosthesis, seroma, and infection, were recorded and analyzed. Cosmetic result was assessed using a four-point scale.

Results: Postoperative prosthesis loss was 2.7 percent, 5.3 percent for patients undergoing adjuvant chemotherapy and increasing to 11.3 percent for patients receiving chemotherapy plus radiotherapy. Chemotherapy and radiotherapy independently were the main, statistically significant risk factors for expander or implant loss [incidence rate ratio, 13.85 (p = 0.012) and 2.23 (p = 0.027), respectively]. Prosthesis loss for patients undergoing combination chemotherapy plus radiotherapy was also significant [incidence rate ratio, 4.791 (p < 0.001)].

Conclusions: These findings serve to better inform patients on risk in weighing treatment options. Postmastectomy radiation therapy doubles the risk of prosthesis loss over and above adjuvant chemotherapy but is an acceptable option following immediate two-stage prosthetic breast reconstruction in a multidisciplinary setting.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0000000000004358DOI Listing
June 2018

Social media mediate the education of the global microsurgeons: The experience from International Microsurgery Club.

Microsurgery 2018 Jul 23;38(5):596-597. Epub 2018 Feb 23.

Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung, Medical College and Chang Gung University, Taoyuan, Taiwan.

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http://dx.doi.org/10.1002/micr.30312DOI Listing
July 2018

Two-Stage Prosthetic Breast Reconstruction after Mastectomy with or without Prior Postmastectomy Radiotherapy.

Plast Reconstr Surg Glob Open 2017 Sep 21;5(9):e1489. Epub 2017 Sep 21.

Department of Plastic and Reconstructive Surgery, Westmead Hospital, Sydney, NSW, Australia; and Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.

Background: Two-stage prosthetic breast reconstruction with initial insertion of a tissue expander followed by an implant after a period of inflation is a well-established breast reconstruction option. Most of the current literature concentrates on the immediate setting, and there are only a few reports into delayed cases, especially after postmastectomy radiotherapy (RT). We performed a retrospective review of our experience over a 12.5-year period.

Methods: Between June 1998 and December 2010, a total of 671 patients received prosthetic-only breast reconstruction. Of these, 170 (25.3%) underwent delayed 2-stage prosthetic breast reconstruction after mastectomy for cancer. Patients were divided into group A, no postmastectomy RT (n = 150), and group B, postmastectomy RT (n = 20). The primary factor examined was the failure of the reconstruction from loss of prosthesis with or without smoking. Other complications, as well as rates of revisional surgery were also recorded.

Results: Expander or implant loss occurred in 3 of 150 patients in group A (2.0%) and 3 of 20 patients in group B (15%; = 0.02). For nonsmokers, implant loss was 1.6% and 5.6%, respectively ( = NS). Smoking was associated with 1 of the 3 losses in group A and 2 of the 3 in group B (smokers, n = 2; < 0.01). There was no significant difference in other complications such as seromas or minor wound infections.

Conclusions: Delayed 2-stage prosthetic breast reconstruction has a low failure rate. It can also be successfully completed in selected patients after postmastectomy RT, but care must be taken with patients who smoke.
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http://dx.doi.org/10.1097/GOX.0000000000001489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640361PMC
September 2017

Breast Augmentation after Conservation Surgery and Radiation Therapy.

Plast Reconstr Surg Glob Open 2016 Jul 12;4(7):e796. Epub 2016 Jul 12.

Department of Plastic and Reconstructive Surgery, Westmead Hospital, Sydney, New South Wales, Australia; and Faculty of Medicine and Health Sciences, Macquarie University Hospital, Sydney, New South Wales, Australia.

Background: There is a paucity of data regarding outcomes for patients undergoing breast augmentation with implants after breast conservation surgery (BCS) and radiotherapy. This retrospective study examined outcomes for patients with breast implant-only augmentation after BCS and radiotherapy.

Methods: Between June 1998 and December 2010, 671 women underwent prosthetic breast reconstruction. Nineteen patients (2.8%) underwent an augmentation after BCS and radiotherapy. The mean age was 55.8 years (range, 40-69 years). Sixteen of these patients underwent one-stage implant-only breast augmentation, whereas 3 patients underwent two-stage expander and then implant augmentation.

Results: All surgeries were successful. The average size of breast implant used was 258.7 g. Seven patients also received contralateral augmentation with an average implant size of 232.2 g. One patient received oral antibiotics for minor wound infection. Patients were judged to have an excellent (14/19; 73.7%), good (3/19; 15.8%), or fair (2/19; 10.5%) cosmetic result.

Conclusion: The breasts of selected patients with breast cancer after BCS and radiotherapy. with asymmetry can be adequately augmented with breast implants alone.
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http://dx.doi.org/10.1097/GOX.0000000000000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977124PMC
July 2016

Unusual Vascular Supply to Extensor Digitorum Brevis.

Plast Reconstr Surg Glob Open 2016 Apr 6;4(4):e673. Epub 2016 Apr 6.

University of New South Wales, Randwick, New South Wales, Australia; and Department of Plastic and Reconstructive Surgery, Prince of Wales Hospital, Randwick, New South Wales, Australia.

Lower limb reconstruction after a traumatic event has always been a challenge for plastic surgeons. The reliability of vessel integrity postinjury often drives us away from a local reconstructive option. With the advancement of computed tomography angiogram, it can not only demonstrate the continuation of major vessels but also helps to map the vascular supply at a perforator level. We hereby report an incidentally identified anatomical variant with dual dominant blood supply to the extensor digitorum brevis muscle from an extra branch of anterior tibial artery originated at midtibial level. This variant was picked up preoperatively by computed tomography angiogram and confirmed intraoperatively to be one of the dominant supply. We took advantage of this unusual anatomy by basing our reconstruction on this branch and hence spared the need to terminalize distal dorsalis pedis artery.
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http://dx.doi.org/10.1097/GOX.0000000000000608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859232PMC
April 2016

Evaluation of AirXpanders for Breast Reconstruction: Early Experience from Sydney.

Plast Reconstr Surg Glob Open 2015 Aug 27;3(8):e495. Epub 2015 Aug 27.

Department of Plastic and Reconstructive Surgery, Westmead Hospital, University of Sydney, Westmead, New South Wales, Australia.

Aim: Two-staged prosthetic breast reconstruction has become a popular option involving a series of saline injections to expanders to create a pocket large enough for a permanent implant. This, however, requires frequent visits to the surgeon and numerous needle pricks with potential infection risk. A new form of tissue expander, the AirXpanders, has recently been trialed in Perth and the United States. It uses a remote-controlled release of compressed CO2 where needle punctures are avoided.

Methodology: Prospective data were collected on the first 10 patients to have the AirXpanders implant inserted for breast reconstruction at Western Sydney. The implants were inserted subpectorally as the saline expanders, and patients were instructed how to use the remote 4 weeks postoperation.

Results: Ten patients (4 immediate and 6 delayed) aged between 30 and 65 (mean, 48.3 years) underwent 14 AirXpanders insertions. One patient passed away due to metastatic malignancy. With the remaining patients, the average period of active expansion was 15.8 days (r, 6-21). The average size of final implant used was 451 g (r, 195-685). The only complications were 2 seromas.

Conclusion: Our early results are consistent with the Perth trial. The new AirXpanders is safe to use and able to achieve satisfactory tissue expansion faster than saline expander. It also has the advantage of patient self-controlled without the need for multiple medical reviews and needle punctures.
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http://dx.doi.org/10.1097/GOX.0000000000000471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560228PMC
August 2015

Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study).

Arthritis Res Ther 2014 Oct 30;16(5):467. Epub 2014 Oct 30.

Introduction: Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).

Methods: Patients (n = 214) with active RA (≥ 6 swollen and tender joints, C-reactive protein ≥ 10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed.

Results: Pateclizumab reduced the DAS28(4)-ESR response (-1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (-1.54), while adalimumab (-2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients.

Conclusions: Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.

Trial Registration: ClinicalTrials.gov NCT01225393, Registered 18 October 2010.
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http://dx.doi.org/10.1186/s13075-014-0467-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243296PMC
October 2014

Silicone breast implants are thicker than water.

Plast Reconstr Surg Glob Open 2013 Sep 7;1(6):e43. Epub 2013 Oct 7.

Department of Plastic and Reconstructive Surgery University of Sydney Westmead Hospital Westmead, NSW, Australia.

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http://dx.doi.org/10.1097/GOX.0b013e3182a85b49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174160PMC
September 2013

Intrathoracic defects-a reconstructive approach.

Eplasty 2014 26;14:ic22. Epub 2014 Jul 26.

Burns, Plastic, Reconstructive and Maxillofacial Surgery, Royal North Shore Hospital, St Leonards, Sydney, Australia.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117206PMC
September 2014

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment.

Toxicol Appl Pharmacol 2014 Sep 23;279(3):467-476. Epub 2014 Jun 23.

Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA. Electronic address:

The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann-Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings.
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http://dx.doi.org/10.1016/j.taap.2014.06.014DOI Listing
September 2014

The effects of postmastectomy adjuvant radiotherapy on immediate two-stage prosthetic breast reconstruction: a systematic review.

Plast Reconstr Surg 2013 Sep;132(3):511-518

Westmead and Sydney, New South Wales, Australia From the Department of Plastic and Reconstructive Surgery and the NSW Breast Cancer Institute, Westmead Hospital, and the Macquarie University Cancer Institute, Australian School of Advanced Medicine, Macquarie University.

Background: The authors performed a systematic review of the literature on the outcome of therapy for patients with breast cancer who underwent adjuvant radiotherapy after an immediate two-stage prosthetic breast reconstruction, either following tissue expansion (stage 1) or after removal of the tissue expander and insertion of a final breast implant (stage 2). Their outcomes were compared to those of patients who had reconstruction without postmastectomy irradiation.

Methods: Electronic database searches were supplemented by a full-text review of possible relevant articles on two-stage prosthetic immediate breast reconstruction and radiotherapy. Delayed or one-stage prosthetic or nonprosthetic breast reconstruction studies were excluded. The primary outcome measured was the reconstruction failure rate with prosthesis loss. Secondary endpoints were capsular contracture and aesthetic outcome.

Results: No randomized controlled trials were identified, and only one prospective, nonrandomized, multicenter trial was found. Reports with more than 15 patients were included; 12 studies had a total of 1853 patients (715 irradiated and 1138 nonirradiated). Adjuvant radiotherapy resulted in a significantly higher reconstruction failure rate in immediate two-stage prosthetic breast reconstruction compared with controls (18.6 percent versus 3.1 percent, p < 0.00001). Radiotherapy particularly increased the failure rate when given after stage 1 (expander) (29.7 percent versus 5 percent, p < 0.00001) but also stage 2 (permanent implant) (7.7 percent versus 1.5 percent, p = 0.0003). There was also an increase in severe capsular contractures and an inferior cosmetic result in the irradiated patients.

Conclusion: Nonrandomized studies suggest that adjuvant radiotherapy results in a higher risk of reconstruction failure.
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http://dx.doi.org/10.1097/PRS.0b013e31829acc41DOI Listing
September 2013

Previous multiple abdominal surgeries: a valid contraindication to abdominal free flap breast reconstruction?

Eplasty 2012 23;12:e31. Epub 2012 Jul 23.

Unlabelled: PRESENTED IN PART AT THE FOLLOWING ACADEMIC MEETINGS: 57th Meeting of the Italian Society of Plastic, Reconstructive and Aesthetic Surgery, September 24-27, 2008, Naples, Italy.45th Congress of the European Society for Surgical Research (ESSR), June 9-12, 2010, Geneva, Switzerland.British Association of Plastic Reconstructive and Aesthetic Surgeons Summer Scientific Meeting, June 30-July 2, 2010, Sheffield Hallam University, Sheffield, UK.

Background: Patients with previous multiple abdominal surgeries are often denied abdominal free flap breast reconstruction because of concerns about flap viability and abdominal wall integrity. We therefore studied their flap and donor site outcomes and compared them to patients with no previous abdominal surgery to find out whether this is a valid contraindication to the use of abdominal tissue.

Patients And Methods: Twenty patients with multiple previous abdominal operations who underwent abdominal free flap breast reconstruction by a single surgeon (C.M.M., 2000-2009) were identified and retrospectively compared with a cohort of similar patients without previous abdominal surgery (sequential allocation control group, n = 20).

Results: The index and control groups were comparable in age, body mass index, comorbidities, previous chemotherapy, and RT exposure. The index patients had a mean age of 54 years (r, 42-63) and an average body mass index of 27.5 kg/m(2) (r, 22-38). The main previous surgeries were Caesarean sections (19), hysterectomies (8), and cholecystectomies (6). They underwent immediate (n = 9) or delayed (n = 11) reconstructions either unilaterally (n = 18) or bilaterally (n = 2) and comprising 9 muscle-sparing free transverse rectus abdominis muscle and 13 deep inferior epigastric perforator flaps. All flaps were successful, and there were no significant differences in flap and donor site outcomes between the 2 groups after an average follow up of 26 months (r, 10-36).

Conclusion: Multiple previous abdominal surgeries did not predispose to increased flap or donor site morbidity. On the basis of our experience, we have proposed some recommendations for successful abdominal free flap breast reconstruction in patients with previous multiple scars. Careful preoperative planning and the use of some intraoperative adaptations can allow abdominal free flap breast reconstruction to be reliably undertaken in such patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403601PMC
August 2012

Bis(monoacylglycerol)phosphate as a non-invasive biomarker to monitor the onset and time-course of phospholipidosis with drug-induced toxicities.

Expert Opin Drug Metab Toxicol 2010 May;6(5):555-70

Nextcea, Inc., 600 West Cummings Park, #6375, Woburn, MA 01801, USA.

Importance To The Field: Drug-induced phospholipidosis (PL) is a phospholipid storage disorder characterized by the accumulation of multi-lamellar bodies (myeloid bodies) in tissues. A major unanswered question is whether PL represents a benign adaptive response, symptom or early event in drug toxicity. The absence of a non-invasive biomarker to monitor tissue PL has made it difficult to determine the prevalence and implications of PL in the clinic. As a result, the interpretation of PL in risk assessment remains uncertain in preclinical and clinical drug development.

Areas Covered In This Review: This review describes the rationale for bis(monoacylglycerol)phosphate (BMP) as a biomarker of PL and explores the potential links between PL and the toxicities of drugs.

What The Reader Will Gain: The similarities between the hypothesized roles of BMP in PL and Niemann-Pick type C disease are discussed. The potential implications of PL for cellular function are described in the context of drug-induced QT prolongation, myopathy and renal toxicity.

Take Home Message: A specific species of BMP, di-docosahexaenoyl-BMP, should be investigated further as a non-invasive biomarker to monitor the onset and time course of PL and to better understand the functional consequences which could contribute to the toxicities of drugs.
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http://dx.doi.org/10.1517/17425251003601961DOI Listing
May 2010

A new approach to preexisting vertical midline abdominal scars with crossover DIEP flap breast reconstruction.

Microsurgery 2010 ;30(2):151-5

Department of Plastic and Reconstructive Surgery and NSW Breast Cancer Institute, University of Sydney Westmead Hospital, Westmead, New South Wales, Australia.

Breast reconstruction using a free transverse rectus abdominis myocutaneous flap or a deep inferior epigastric perforator (DIEP) flap is a challenge in patients with a vertical midline abdominal scar due to the poor perfusion of the lower abdominal skin ellipse across the midline. In such patients, only one half of the abdominal skin ellipse can be used with certainty, and this limits the amount of tissue available for reconstructing the breast. Two cases of breast reconstruction in patients with a lower midline abdominal scar are presented using the DIEP flap, in which the poor perfusion across the midline scar was overcome by a technique of crossover anastomoses between the two deep inferior epigastric pedicles. Reliable perfusion of the entire lower abdominal skin ellipse was achieved. This crossover anastomoses technique overcomes the poor perfusion imposed by the vertical midline abdominal scar and enables DIEP flap breast reconstruction to be offered to women with midline abdominal scars.
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http://dx.doi.org/10.1002/micr.20705DOI Listing
July 2010

Experience with the Mentor Contour Profile Becker-35 expandable implants in reconstructive breast surgery.

J Plast Reconstr Aesthet Surg 2010 Jul 27;63(7):1124-30. Epub 2009 Jun 27.

Department of Plastic and Reconstructive Surgery, Cambridge Breast Unit, Addenbrooke's University Hospital, Cambridge, UK.

Introduction: Round expander-implants (Beckers 25 and 50) and anatomical expander-prostheses filled with firm cohesive gel (McGhan Style 150) are established choices for single-stage expander breast reconstruction. Because of their drawbacks we selectively adopted the anatomical Becker-35 expander-implant filled with soft cohesive gel from January 2005.

Patients And Methods: All patients undergoing reconstructive breast surgery using the Contour Profile Becker-35 expandable implant over a two-year period were retrospectively reviewed with respect to indication, implant sizes, inflation details, complications and outcomes.

Results: 36 patients, mean age 48.9 years (r=14-69), received 39 anatomical Becker-35 expanders (three bilaterally). Three quarters of these implants (29) were used for immediate breast reconstruction while the remainder were equally divided between delayed postmastectomy reconstruction (5) and correction of congenital breast asymmetry (5). Half of the patients had simultaneous latissimus dorsi myocutaneous flap coverage of the implants. The median numbers of inflations and deflations needed to achieve the target expansion size and shape were 3 (r=0-7) and 0 (r=0-4), respectively. The mean time from expander insertion to completion of reconstruction was 4.6 months (r=0-13 months). Four patients required surgical intervention for haematoma, implant infection, severe capsular contracture, and palpable rippling. Additionally there were three injection port adjustments, giving a 20% overall revisional surgery rate (8/39 breasts) after a median follow-up of 20 months (r=6-38 months). Four implants (10%) developed significant but asymptomatic rippling. The significant capsular contracture rate was 21% (8/39 breasts), which was related to chest wall radiotherapy.

Conclusion: In this short-term study, the Becker-35 expander was successfully used for single-stage prosthetic breast reconstruction with an incidence of early complications comparable to alternative prostheses. Although it has expanded the range of implants available to the breast surgeon, its exact role in reconstructive breast surgery has yet to be established.
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http://dx.doi.org/10.1016/j.bjps.2009.05.043DOI Listing
July 2010

Elucidation of potential bortezomib response markers in mutliple myeloma patients.

J Pharm Biomed Anal 2009 Jan 17;49(1):115-22. Epub 2008 Oct 17.

Nextcea, Inc., 600 West Cummings Park, #6375, Woburn, MA 01801, United States.

Liquid chromatography coupled to mass spectrometry (LC/MS) was used to elucidate early biomarkers of bortezomib response in multiple myeloma patients. The change in serum myeloma M-protein level, maintained for a minimum of 6 weeks, is used as one of the main criteria to evaluate patient clinical response to therapy. The objective of this study was to identify biomarkers using LC/MS in order to predict patient response to bortezomib sooner and more accurately compared to serum M-protein levels. The plasma LC/MS biomolecular/biochemical profiles, comprised of thousands of endogenous small molecules, peptides and proteins, were determined for 10 multiple myeloma patients at predose and 24 h after initial dosing with bortezomib. The comparative analysis of the metabolic profiles of non-responders and partial responders provided an opportunity to investigate mechanisms related to disease progression and identify biomarkers related to drug response. The plasma levels of two potential efficacy response markers were significantly more abundant in the non-responsive patients compared to the responders at 24-h postdose. The potential response biomarkers, apolipoprotein C-I and apolipoprotein C-I', were identified by mass spectral analyses and confirmed by authentic protein standards based on MALDI-TOF MS/MS sequencing of proteolytic peptides.
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http://dx.doi.org/10.1016/j.jpba.2008.09.053DOI Listing
January 2009

An algorithmic approach to abdominal flap breast reconstruction in patients with pre-existing scars--results from a single surgeon's experience.

J Plast Reconstr Aesthet Surg 2009 Dec 26;62(12):1650-60. Epub 2008 Nov 26.

Department of Plastic and Reconstructive Surgery, Addenbrooke's University Hospital, Cambridge, UK.

Background: Breast reconstruction using the TRAM flap and its variations in patients with pre-existing abdominal scars is controversial. In our practice, abdominal scars are considered not to be a contraindication for such reconstruction. We therefore reviewed our experience and reconstructive strategies adopted in such patients over a 7-year period.

Methods: Patients with previous abdominal scars undergoing abdominal flap breast reconstruction performed by a single surgeon (Jan 2000-Dec 2006) were retrospectively reviewed with respect to scar types, reconstructive approach, flap outcomes and donor-site complications.

Results: Thirty patients (mean age=52 years) with pre-existing scars (midline, Pfannenstiel, subcostal, appendicectomy, etc.) underwent unilateral (n=24) or bilateral (n=6) breast reconstruction (36 flaps). The flap design strategies employed included splitting the flap (hemi-TRAM), skewing it to avoid abdominal scars, minimal abdominoplasty flap undermining and selective use of DIEP, SIEA, free and pedicled TRAM flaps. There were no free flap failures (0/30), except for one pedicled TRAM flap failure (one out of six). One bilateral DIEP reconstruction patient developed an abdominal bulge requiring mesh repair. No significant wound dehiscence or frank abdominal hernias were recorded.

Conclusion: Pre-existing scars are not an absolute contraindication to abdominal flap breast reconstruction. With careful preoperative planning and adoption of appropriate reconstructive strategies, it is possible to achieve satisfactory results comparable to patients without abdominal scars. An algorithmic approach to the selection of the relevant techniques is presented.
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http://dx.doi.org/10.1016/j.bjps.2008.08.009DOI Listing
December 2009

Toxicological protein biomarker analysis--an investigative one-week single dose intravenous infusion toxicity and toxicokinetic study in cynomolgus monkeys using an antibody-cytotoxic conjugate against ovarian cancer.

Pharm Res 2008 Jun;25(6):1309-17

Nextcea, Inc., 110 Hartwell Avenue, Lexington, Massachusetts 02421, USA.

Introduction: Antibody-cytotoxic conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify toxicological markers in serum that correlate with MLN8866 (an antibody-cytotoxic conjugate) exposure and related pathological events in monkeys.

Materials And Methods: Cynomolgus monkeys were treated once with 5, 15, or 30 mg/kg MLN8866 via a 20 min intravenous infusion. MLN8866 exposure (Cmax and AUCO-4 day) was determined by quantifying MLN8866 levels in serum.

Results: The increase in MLN8866 exposure was approximately dose proportional. Two acute phase proteins in serum (serum amyloid A and haptoglobin) were correlated with MLN8866 exposure and toxicological outcomes (e.g., erythropoiesis and leucopoiesis).
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http://dx.doi.org/10.1007/s11095-007-9485-zDOI Listing
June 2008

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance.

Proc Natl Acad Sci U S A 2007 Sep 14;104(39):15448-53. Epub 2007 Sep 14.

Institut National de la Santé et de la Recherche Médicale, U643, Centre Hospitalier Universitaire de Nantes, Institut de Transplantation et de Recherche en Transplantation, and Université de Nantes, Faculte de Medicine, F-44000 Nantes, France.

Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a "tolerant footprint" of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted.
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http://dx.doi.org/10.1073/pnas.0705834104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000539PMC
September 2007

Transplant reno-vascular stenoses associated with early erythropoietin use.

Clin Transplant 2007 Sep-Oct;21(5):597-608

Department of Pediatrics (Nephrology) Stanford University, Palo Alto, CA 94305-5208, USA.

Background And Objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use.

Design, Setting, Participants, And Measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls.

Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury.

Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia.
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http://dx.doi.org/10.1111/j.1399-0012.2007.00694.xDOI Listing
December 2007

Drug safety evaluation through biomarker analysis--a toxicity study in the cynomolgus monkey using an antibody-cytotoxic conjugate against ovarian cancer.

Toxicol Appl Pharmacol 2007 Oct 29;224(1):12-8. Epub 2007 Jun 29.

Nextcea, Inc., 110 Hartwell Avenue, Lexington, MA 02421, USA.

Antibody-cytotoxin conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify serum biomarkers that correlate with MLN8866 (an Antibody-Cytotoxic Conjugate, mAb8866-CT) pathological events in monkeys and to predict the maximal tolerated dose (MTD) level using biomarkers. Cynomolgus monkeys were administered a single dose MLN8666 (5, 15 or 30 mg/kg) by intravenous infusion and evaluated over a 7-day period. Exposure levels were determined by quantifying MLN8866 levels (Cmax and AUC(0-96 h)) in serum. The increase in MLN8866 Cmax and AUC(0-96 h) was approximately dose proportional. Two biomarkers in serum (m/z 316 and m/z 368) were identified to be correlated with MLN8866 toxicological outcomes. The predicted MTD, 11.4 mg/kg, was within the MTD range set by pathology results (5-15 mg/kg). Administration of MLN8866 at 15 mg/kg and 30 mg/kg dose levels resulted in changes in hematology parameters associated with impaired hematopoiesis and bone marrow toxicity. The projected MLN8866 MTD exposure level was integrated with toxicokinetic analysis and showed Cmax=236 microg/mL and AUC(0-96 h)=7246 h mg/mL. The safety of three different MLN8866 dosing regimens with three dosing schedules was explored with pharmacokinetic modeling.
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http://dx.doi.org/10.1016/j.taap.2007.06.009DOI Listing
October 2007