Publications by authors named "Jacob Garcia"

25 Publications

  • Page 1 of 1

Indirect Treatment Comparison of Liso-Cel vs. Salvage Chemotherapy in Diffuse Large B-Cell Lymphoma: TRANSCEND vs. SCHOLAR-1.

Adv Ther 2021 06 10;38(6):3266-3280. Epub 2021 May 10.

Celgene, a Bristol-Myers Squibb Company, Boudry, Switzerland.

Most patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have exhausted their treatment options and are deemed palliative. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has recently been introduced as a new option for these patients. Lisocabtagene maraleucel (liso-cel) is an investigational CAR T-cell therapy that has shown promising activity in this setting. We used an unanchored matching-adjusted indirect comparison (MAIC) methodology to compare liso-cel, using individual patient-level data from the TRANSCEND NHL 001 (TRANSCEND; NCT02631044) trial, to salvage chemotherapy, using summary-level data from the SCHOLAR-1 study, for the treatment of patients with R/R LBCL. Standardized mean differences were used to evaluate imbalances between the TRANSCEND and SCHOLAR-1 studies. MAIC was conducted to determine the relative efficacy of liso-cel vs. salvage chemotherapy with regard to overall survival, complete response rate, and objective response rate. For all efficacy outcomes assessed, comparisons of clinical factors before MAIC showed that five of seven baseline characteristics were similar between the TRANSCEND and SCHOLAR-1 studies; however, age and R/R to last therapy status differed between studies, thus requiring matching and adjusting to ensure the validity of this analysis. The base case analyses demonstrated a significantly lower risk of mortality (hazard ratio, 0.5; 95% confidence interval [CI] 0.4-0.6; p < 0.001) with significantly higher rates of complete response (odds ratio, 12.9; 95% CI 8.0-20.7) and objective response (odds ratio, 7.0; 95% CI 4.6-10.5) for patients treated with liso-cel than patients treated with salvage chemotherapy. MAIC comparisons demonstrated favorable efficacy for liso-cel compared with salvage chemotherapy in the treatment of patients with R/R LBCL.Trial Registration ClinicalTrials.gov identifier: NCT02631044.
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http://dx.doi.org/10.1007/s12325-021-01756-0DOI Listing
June 2021

Effect of lisocabtagene maraleucel on HRQoL and symptom severity in relapsed/refractory large B-cell lymphoma.

Blood Adv 2021 04;5(8):2245-2255

Fred Hutchinson Cancer Research Center, Seattle, WA.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown efficacy as a third-line or later treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire, we evaluated the impact of CAR T-cell treatment with lisocabtagene maraleucel (liso-cel) on health-related quality of life (HRQoL) and symptoms in patients with relapsed/refractory LBCL in the ongoing, open-label, nonrandomized TRANSCEND NHL 001 trial. Clinically meaningful improvement was observed in EORTC QLQ-C30 scores for global health status/QoL, based on a minimally important difference of 10 points at 2 to 18 months after liso-cel infusion. There were no clinically meaningful changes in physical functioning and pain, whereas clinically meaningful improvements were observed in fatigue at 2, 12, and 18 months. The proportion of patients with clinically meaningful improvement in global health status/QoL was generally higher for treatment responders than for nonresponders. A trend toward decreased mean EQ-5D-5L index scores was observed at 1 month after liso-cel infusion, followed by subsequent increases through 18 months. Mean EQ-5D-5L visual analog scale scores increased from 2 through 18 months. In summary, patients with relapsed/refractory LBCL treated with liso-cel had early, sustained, and clinically meaningful improvements in HRQoL and symptoms that correlated with antitumor activity. This study was registered at www.clinicaltrials.gov as #NCT02631044.
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http://dx.doi.org/10.1182/bloodadvances.2020003503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095132PMC
April 2021

Oscillation in Excited State Lifetimes with Size of Sub-nanometer Neutral (TiO) Clusters Observed with Ultrafast Pump-Probe Spectroscopy.

J Phys Chem Lett 2021 Apr 22;12(16):4098-4103. Epub 2021 Apr 22.

School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, United States.

Neutral titanium oxide clusters of up to 1 nm in diameter (TiO), with < 10, are produced in a laser vaporization source and subsequently ionized by a sequence of femtosecond laser pulses. Using a 400 nm pump and 800 nm probe lasers, the excited state lifetimes of neutral (TiO) clusters are measured. All clusters exhibit a rapid relaxation lifetime of ∼35 fs, followed by a sub-picosecond lifetime that we attribute to carrier recombination. The excited state lifetimes oscillate with size, with even-numbered clusters possessing longer lifetimes. Density functional theory calculations show the excited state lifetimes are correlated with charge carrier localization or polaron-like formation in the excited states of neutral clusters. Thus, structural rigidity is suggested as a feature for extending excited state lifetimes in titania materials.
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http://dx.doi.org/10.1021/acs.jpclett.1c00840DOI Listing
April 2021

Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel-treated patients in the TRANSCEND NHL 001 trial.

Blood Adv 2021 03;5(6):1695-1705

Bristol-Myers Squibb, Princeton, NJ.

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell-specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.
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http://dx.doi.org/10.1182/bloodadvances.2020003531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993105PMC
March 2021

Ultrafast pump-probe spectroscopy of neutral FeO clusters (, < 16).

Phys Chem Chem Phys 2020 Nov;22(42):24624-24632

School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA. and Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ 85287, USA.

Neutral iron oxide clusters (FenOm, n, m ≤ 16) are produced in a laser vaporization source using O2 gas seeded in He. The neutral clusters are ionized with a sequence of femtosecond laser pulses and detected using time-of-flight mass spectrometry. Small clusters are confirmed to be most prominent in the stoichiometric (n = m) distribution, with m = n + 1 clusters observed above n = 4. Pump-probe spectroscopy is employed to study the dynamics of an electron transfer from an oxygen orbital to an iron nonbonding orbital of iron oxide clusters that is driven by absorption of a 400 nm photon. A bifurcation of the initial wavepacket occurs, where a femtosecond component is attributed to electron relaxation assisted through internuclear vibrational relaxation and high density of states, and a slow relaxation shows the formation of a bound excited state. The lifetime and relative ratio of the two pathways depend on both the cluster size and iron oxidation state. The femtosecond lifetime decreases with increased cluster size until a saturation timescale is achieved at n > 5. The relative population of the long-lived excited state decreases with cluster size and suggests that the excited electron remains on the Fe atom for >20 ps.
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http://dx.doi.org/10.1039/d0cp03889jDOI Listing
November 2020

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.

Lancet 2020 09 1;396(10254):839-852. Epub 2020 Sep 1.

City of Hope National Medical Center, Duarte, CA, USA.

Background: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.

Methods: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 10 CAR T cells [one or two doses], 100 × 10 CAR T cells, and 150 × 10 CAR T cells), which were administered as a sequential infusion of two components (CD8 and CD4 CAR T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044.

Findings: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 10 CAR T cells (50 × 10 CD8 and 50 × 10 CD4 CAR T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 10 CAR T cells.

Interpretation: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.

Funding: Juno Therapeutics, a Bristol-Myers Squibb Company.
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http://dx.doi.org/10.1016/S0140-6736(20)31366-0DOI Listing
September 2020

Sternoclavicular Joint Instability: Symptoms, Diagnosis And Management.

Orthop Res Rev 2020 28;12:75-87. Epub 2020 Jul 28.

University Of Alabama At Birmingham, Department Of Orthopedic Surgery, Birmingham, AL 35294, USA.

Sternoclavicular joint (SCJ) instability is a rare condition and results from either a traumatic high energy impact, such as a motor vehicle crash or contact sports injury, or non-traumatically as a result of structural pathology. The infrequency of this injury has contributed to its diagnosis being missed as well as the paucity of literature on treatment and outcomes. Patients with SCJ instability often report diminished range of motion as well as shoulder girdle pain. The presentation of instability in the sternoclavicular joint can vary in severity and anterior or posterior directionality. Variation in severity of the instability changes the course of treatment regarding either operative or non-operative interventions to stabilize the SCJ. In general, anterior instability of the SCJ (the medial clavicle is displaced anterior to the sternum) is less urgent and generally manageable by symptom alleviation and rehabilitation, although some anterior instability cases require surgical intervention. In the case of posterior SCJ instability (the medial clavicle is displaced posterior to the sternum), patients require prompt joint reduction as they are at the greater risk of life-threatening injury due to the location of critical structures of the mediastinum posterior to the SCJ. Computed tomography visualization is useful to confirm dislocation or subluxation direction to better formulate a proper treatment plan. The purpose of this review is to report the clinical presentation and management of SCJ instability including pertinent symptoms, the diagnostic approaches to evaluating SCJ instability, as well as operative and non-operative management of the joint instability.
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http://dx.doi.org/10.2147/ORR.S170964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395708PMC
July 2020

The economic burden to payers of patients with diffuse large B-cell lymphoma during the treatment period by line of therapy.

Leuk Lymphoma 2020 07 9;61(7):1601-1609. Epub 2020 Apr 9.

Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

We retrospectively analyzed treatment patterns and healthcare costs among patients diagnosed with diffuse large B-cell lymphoma (DLBCL) during each line of therapy (LOT) using data from the IBM MarketScan Commercial and Medicare Supplemental Databases from January 2011 to May 2017. Patients were included if they had a diagnosis of DLBCL, ≥12 months of disease-free continuous enrollment prediagnosis, and ≥1 month of postdiagnosis follow-up. Of 2066 eligible patients receiving first-line treatment, 17% ( = 340) received second-line treatment; of these, 23% ( = 77) received third-line treatment. Mean healthcare expenditures (treatment duration) for first, second, and third LOTs were $111,314 (124.5 days), $88,472 (80.8 days), and $103,365 (70.9 days), respectively. When adjusted to 30-day period costs, first, second, and third LOT healthcare expenditures increased to $26,825, $32,857, and $43,854, respectively. Patients with newly diagnosed and relapsed/refractory DLBCL incur a significant cost burden (for payers), and such costs increase as patients proceed through subsequent LOTs.
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http://dx.doi.org/10.1080/10428194.2020.1734592DOI Listing
July 2020

Global alteration of T-lymphocyte metabolism by PD-L1 checkpoint involves a block of de novo nucleoside phosphate synthesis.

Cell Discov 2019 26;5:62. Epub 2019 Nov 26.

2Department of Molecular, Cellular, and Integrative Physiology, University of California Los Angeles, Los Angeles, CA 90095 USA.

Metabolic obstacles of the tumor microenvironment remain a challenge to T-cell-mediated cancer immunotherapies. To better understand the interplay of immune checkpoint signaling and immune metabolism, this study developed and used an optimized metabolite extraction protocol for non-adherent primary human T-cells, to broadly profile in vitro metabolic changes effected by PD-1 signaling by mass spectrometry-based metabolomics and isotopomer analysis. Inhibitory signaling reduced aerobic glycolysis and glutaminolysis. A general scarcity across the panel of metabolites measured supported widespread metabolic regulation by PD-1. Glucose carbon fate analysis supported tricarboxylic acid cycle reliance on pyruvate carboxylation, catabolic-state fluxes into acetyl-CoA and succinyl-CoA, and a block in de novo nucleoside phosphate synthesis that was accompanied by reduced mTORC1 signaling. Nonetheless, exogenous administration of nucleosides was not sufficient to ameliorate proliferation of T-cells in the context of multiple metabolic insufficiencies due to PD-L1 treatment. Carbon fate analysis did not support the use of primarily glucose-derived carbons to fuel fatty acid beta oxidation, in contrast to reports on T-memory cells. These findings add to our understanding of metabolic dysregulation by PD-1 signaling and inform the effort to rationally develop metabolic interventions coupled with immune-checkpoint blockade for increased treatment efficacy.
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http://dx.doi.org/10.1038/s41421-019-0130-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877514PMC
November 2019

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer.

Support Care Cancer 2020 Feb 7;28(2):925-932. Epub 2019 Jun 7.

Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA, USA.

Purpose: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC.

Methods: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models.

Results: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality.

Conclusions: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.
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http://dx.doi.org/10.1007/s00520-019-04875-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954126PMC
February 2020

Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer.

Clin Breast Cancer 2018 10 16;18(5):380-386. Epub 2018 Feb 16.

Duke University Medical Center, Durham, NC.

Background: The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer.

Patients And Methods: This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models.

Results: Among 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality.

Conclusion: Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.
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http://dx.doi.org/10.1016/j.clbc.2018.02.003DOI Listing
October 2018

NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim.

Support Care Cancer 2018 Apr 16;26(4):1323-1334. Epub 2017 Nov 16.

Amgen Inc., Thousand Oaks, CA, USA.

Purpose: Mild-to-moderate bone pain is a commonly reported adverse event (AE) associated with pegfilgrastim. We evaluated the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on pegfilgrastim-associated bone pain.

Methods: In this open-label study (NCT01712009), women ≥ 18 years of age with newly diagnosed stage I-III breast cancer and an ECOG performance status ≤ 2 who were planning ≥ 4 cycles of adjuvant or neoadjuvant chemotherapy with pegfilgrastim support starting in cycle 1 were randomized 1:1:1 to receive naproxen, loratadine, or no treatment to prevent pegfilgrastim-associated bone pain. The primary endpoint was all-grade bone pain in cycle 1 from AE reporting. Secondary endpoints included bone pain in cycles 2-4 and across all cycles from AE reporting and patient-reported bone pain by cycle and across all cycles.

Results: Six hundred patients were enrolled. Most patients (83.0%) were white, and mean (SD) age was 54.2 (11.1) years. The percentage of patients with all-grade bone pain in cycle 1 from AE reporting in the naproxen, loratadine, and no prophylaxis groups was 40.3, 42.5, and 46.6%, respectively; differences between the treatment groups were not statistically significant. Maximum, mean, and area under the curve for patient-reported bone pain were consistently lower in the naproxen and loratadine groups than in the no prophylaxis group; some of these differences were significant. Loratadine was associated with fewer treatment-related AEs and discontinuations than naproxen.

Conclusions: Given its tolerability, its ease of administration, and its potential benefit, treatment with loratadine should be considered to help prevent bone pain in patients receiving chemotherapy and pegfilgrastim.

Clinical Trial Registration: ClinicalTrials.gov ; NCT01712009.
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http://dx.doi.org/10.1007/s00520-017-3959-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847062PMC
April 2018

Encapsulation of Human Islets Using a Biomimetic Self-Assembled Nanomatrix Gel for Protection against Cellular Inflammatory Responses.

ACS Biomater Sci Eng 2017 Sep 11;3(9):2110-2119. Epub 2017 Jul 11.

Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.

The major concern of pancreatic islet transplantation is that the implanted islets are exposed to the immune system of the recipient. To overcome this challenge, the peptide amphiphile (PA) nanomatrix gel was used for immunoisolation of islets through microencapsulation. The PA can self-assemble to form a nanomatrix gel with an extracellular matrix-mimicking, islet nurturing microenvironment and a semipermeable immune barrier. In this study, the islet protective effect of the PA nanomatrix gel was evaluated by coculture of PA-encapsulated human islets with differentiated U937 cells (human monocyte cell-line) for 3 and 7 days. The coculture of the bare islets with the differentiated U937 cells stimulated proinflammatory cytokine (IL-1 and TNF-) secretion and caused islet death after 7 days, which simulated an early inflammatory response environment after islet transplantation. The PA-encapsulated islets, however, did not stimulate proinflammatory cytokine secretion and maintained islet viability up to 7 days. More insulin-producing cells were observed when islets were PA-encapsulated than control islets with the differentiated U937 cells for 7 days compared to the bare islets. This result was also confirmed by dithizone staining analysis. Further evaluation of islet functionality was assessed by a glucose-stimulated insulin secretion test. The PA-encapsulated islets showed greater insulin secretion response to glucose stimulation than the bare islets with the differentiated U937 cells after 3 and 7 days. These results demonstrated that islet encapsulation with the PA nanomatrix gel was able to improve islet survival and function in the presence of inflammatory responses, which will increase the success rate of islet engraftment and the efficacy of islet transplantation.
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http://dx.doi.org/10.1021/acsbiomaterials.7b00261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615894PMC
September 2017

The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.

Support Care Cancer 2017 08 8;25(8):2619-2629. Epub 2017 May 8.

Policy Analysis Inc. (PAI), Brookline, MA, USA.

Purpose: Granulocyte colony-stimulating factors (G-CSF) are commonly used in clinical practice to prevent febrile neutropenia (FN). US and EU prescribing information and treatment guidelines from the NCCN, ASCO, and EORTC specify that pegfilgrastim, a long-acting (LA) G-CSF, should be administered at least 24 h after myelosuppressive chemotherapy. Nevertheless, many patients receive LA G-CSFs on the same day as chemotherapy. This systematic literature review evaluated the relative merits of same-day versus next-day dosing of LA G-CSFs.

Methods: A broad Ovid MEDLINE® and Embase® literature search was conducted that examined all publications indexed before May 9, 2016 that compared same-day versus next-day LA G-CSF administration. A congress abstract literature search included congresses from January 1, 2011 to April 6, 2016. The parameters for this review were prospectively delineated in a research protocol and adhered to the PRISMA Guidelines.

Results: The first part of the systematic literature search identified 1736 publications. After elimination of duplicates, title/abstract screening was conducted on 1440 records, and full text review was conducted on 449 publications. Eleven publications met all criteria and are included in this systematic review; of these, four included data from randomized or single arm prospective studies, and seven were retrospective studies. In most studies included in this review and across a variety of tumor types, administration of pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in improved patient outcomes.

Conclusions: Data from multiple publications support administration of pegfilgrastim at least 1 day after chemotherapy.
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http://dx.doi.org/10.1007/s00520-017-3703-yDOI Listing
August 2017

Progress and challenges of the bioartificial pancreas.

Nano Converg 2016 1;3(1):28. Epub 2016 Nov 1.

Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294 USA ; 806 Shelby, 1825 University Boulevard, Birmingham, AL USA.

Pancreatic islet transplantation has been validated as a treatment for type 1 diabetes since it maintains consistent and sustained type 1 diabetes reversal. However, one of the major challenges in pancreatic islet transplantation is the body's natural immune response to the implanted islets. Immunosuppressive drug treatment is the most popular immunomodulatory approach for islet graft survival. However, administration of immunosuppressive drugs gives rise to negative side effects, and long-term effects are not clearly understood. A bioartificial pancreas is a therapeutic approach to enable pancreatic islet transplantation without or with minimal immune suppression. The bioartificial pancreas encapsulates the pancreatic islets in a semi-permeable environment which protects islets from the body's immune responses, while allowing the permeation of insulin, oxygen, nutrients, and waste. Many groups have developed various types of the bioartificial pancreas and tested their efficacy in animal models. However, the clinical application of the bioartificial pancreas still requires further investigation. In this review, we discuss several types of bioartificial pancreases and address their advantages and limitations. We also discuss recent advances in bioartificial pancreas applications with microfluidic or micropatterning technology.
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http://dx.doi.org/10.1186/s40580-016-0088-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271153PMC
November 2016

Reply to Barroso-Sousa R et al.

Breast 2017 08 10;34:131. Epub 2016 Dec 10.

Amgen, Inc, Thousand Oaks, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.breast.2016.12.003DOI Listing
August 2017

Burden of Chemotherapy-Induced Febrile Neutropenia Hospitalizations in US Clinical Practice, by Use and Patterns of Prophylaxis with Colony-Stimulating Factor.

Support Care Cancer 2017 02 12;25(2):439-447. Epub 2016 Oct 12.

Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.

Introduction: Evidence suggests that many cancer chemotherapy patients who are candidates for colony-stimulating factor (CSF) prophylaxis do not receive it or receive it inconsistent with guidelines, and that such patients have a higher risk of febrile neutropenia hospitalization (FNH). Little is known about the number and consequences of FNH by use/patterns of CSF prophylaxis in US clinical practice.

Methods: A retrospective cohort design and private healthcare claims data were employed. Study population comprised adults who received a chemotherapy course with a high-risk regimen, or an intermediate-risk regimen (if ≥1 FN risk factor present), for non-metastatic breast cancer or non-Hodgkin's lymphoma (NHL); each chemotherapy cycle within the course and each FNH episode within the cycles were identified. Consequences included mortality, inpatient days, and costs (US$2013) during FNH. Use (yes/no) and patterns (agent, administration day/duration) of CSF prophylaxis were evaluated within cycles in which FNH episodes occurred.

Results: Among all FNH episodes (n=6,355; 109 episodes per 1,000 patients), 41.3% (95% CI: 40.1-42.5) occurred among patients who did not receive CSF prophylaxis in that cycle, and 8.8% (8.1-9.5) occurred among those who received CSF prophylaxis on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CSF agents (2% of CSF use), 56.1% (44.1-68.0) received prophylaxis <7 days during the cycle. Results for FNH consequences were comparable.

Conclusions: In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CSF prophylaxis occurred in those who either did not receive it or received it inconsistent with guidelines.
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http://dx.doi.org/10.1007/s00520-016-3421-xDOI Listing
February 2017

"Same-Day" administration of pegfilgrastim following myelosuppressive chemotherapy: clinical practice and provider rationale.

Support Care Cancer 2016 09 23;24(9):3889-96. Epub 2016 Apr 23.

Amgen Inc, Thousand Oaks, CA, USA.

Purpose: To describe patient- and practice-related factors that physicians report affect their clinical decision to administer prophylactic pegfilgrastim to patients <24 h after completion of a myelosuppressive chemotherapy cycle (i.e., "same-day" pegfilgrastim).

Methods: Oncologists, hematologists, and hematologist-oncologists enrolled in a US national physician panel were invited to participate in a cross-sectional, web-based survey to assess physicians' reasons for prescribing "same-day" pegfilgrastim. Physicians were screened as eligible if they reported prescribing "same-day" pegfilgrastim within the previous 6 months. The survey assessed physician perspectives and physician-perceived patient/caregiver preferences.

Results: Of 17,478 invited physicians, 386 answered the screening questions; 151 (39.1 %) were eligible, agreed to participate, and completed the survey. Physicians estimated that overall 41.3 % of their patients treated with myelosuppressive chemotherapy received pegfilgrastim and that 31.6 % treated with pegfilgrastim received it on a "same-day" schedule. Approximately 36 % of physicians relied primarily on their clinical judgment when deciding to administer "same-day" pegfilgrastim. The clinical consideration reported most commonly by physicians as moderately or very important when deciding to administer "same-day" pegfilgrastim was previous febrile neutropenia (77.6 %). The most important patient-related consideration in the decision to administer "same-day" pegfilgrastim was patient/caregiver travel distance, and the most important practice-related consideration was the burden to the physician's practice of "next-day" administration (vs. same-day), reported by 84.7 % and 65.1 % of physicians as moderately or very important, respectively.

Conclusions: While clinical judgment, patients' risk factors, and practice burden were principal influences favoring "same-day" pegfilgrastim administration, physician-perceived patient preferences and logistical barriers also have important roles in this decision.
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http://dx.doi.org/10.1007/s00520-016-3193-3DOI Listing
September 2016

Comparative effectiveness of granulocyte colony-stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: A systematic review.

J Oncol Pharm Pract 2016 Oct 13;22(5):702-16. Epub 2016 Jan 13.

RTI Health Solutions, Manchester UK NUS Yong Loo Lin School of Medicine, Singapore.

Introduction: Febrile neutropenia (FN) is a serious side-effect of myelosuppressive chemotherapy. Several clinical trials and observational studies have evaluated the effects of prophylactic granulocyte colony-stimulating factors (G-CSFs) on risk of FN and related complications; however, no systematic reviews have focused on effectiveness in routine clinical practice. Here, we perform a systematic review assessing the comparative effectiveness of prophylaxis with a long-acting G-CSF (pegfilgrastim) versus short-acting G-CSFs (filgrastim, lenograstim, and filgrastim biosimilars) in cancer patients in real-world clinical settings.

Methods: A systematic review was performed based on a pre-specified protocol and was consistent with the Cochrane Collaboration Handbook (2009) and the Centre for Reviews and Dissemination's Guidance for Undertaking Reviews in Health Care (2011). MEDLINE, Embase, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library databases were searched for articles published from January 2002 to June 2014. Congress databases (MASCC/ASCO/ESMO) and Google Scholar were searched for abstracts published from January 2012 to August 2014. Filgrastim (NEUPOGEN®), lenograstim and nivestim (a filgrastim biosimilar) were the only short-acting G-CSFs and pegfilgrastim (Neulasta®) was the only long-acting G-CSF described in eligible studies. Outcomes of interest were FN, FN-related hospitalisation and other FN-related complications (death, chemotherapy dose delays and reductions, antimicrobial treatment, severe neutropenia and costs and resource use).

Results: Of 1259 unique records identified, 18 real-world observational studies met predefined inclusion criteria; 15 were retrospective studies, and 3 were prospective studies. Multiple tumour types, chemotherapy regimens and geographical regions were included. Seven studies provided statistical comparisons of the risk of FN; risk of FN among patients receiving prophylaxis with pegfilgrastim versus short-acting G-CSF was significantly lower in three studies, numerically lower in three studies, and numerically higher in one study. Six studies provided statistical comparisons of the risk of FN-related hospitalisation; risk of FN-related hospitalisation among patients receiving prophylaxis with pegfilgrastim versus short-acting G-CSF was significantly lower in all six studies, though some variation was seen in subanalyses. Data for other outcomes were sparse with available results being generally consistent with the results seen for risk of FN and FN-related hospitalisation.

Conclusions: Based on the findings from this review of real-world comparative effectiveness studies, risks of FN and FN-related complications were generally lower for prophylaxis with pegfilgrastim versus prophylaxis with short-acting G-CSFs.
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http://dx.doi.org/10.1177/1078155215625459DOI Listing
October 2016

Risk of chemotherapy-induced febrile neutropenia with early discontinuation of pegfilgrastim prophylaxis in US clinical practice.

Support Care Cancer 2016 06 15;24(6):2481-90. Epub 2015 Dec 15.

Amgen Inc., Thousand Oaks, CA, USA.

Purpose: Accumulating evidence suggests that not all cancer chemotherapy patients who receive first-cycle pegfilgrastim prophylaxis continue to receive it in subsequent cycles and that these patients may be subsequently at higher risk of febrile neutropenia (FN). Additional evidence from US clinical practice is warranted.

Methods: Data from two US private healthcare claims repositories were employed. The source population comprised adults who received "intermediate-risk" or "high-risk" chemotherapy regimens for solid cancers or non-Hodgkin's lymphoma and first-cycle pegfilgrastim prophylaxis. From the source population, all patients who did not receive second-cycle pegfilgrastim prophylaxis ("comparison patients") were matched (1:1) to those who received it ("pegfilgrastim patients") based on cancer, regimen, and propensity score. Odds ratios (OR) for FN-broad and narrow definitions-during the second chemotherapy cycle were estimated for comparison patients versus pegfilgrastim patients using generalized estimating equations.

Results: A total of 2245 comparison patients (5.3 % of source population) were matched to pegfilgrastim patients; cohorts were well-balanced on baseline characteristics. Second-cycle FN incidence proportions for comparison and pegfilgrastim patients were 3.8 versus 2.2 % based on broad definition and 2.6 versus 0.8 % based on narrow definition; corresponding OR were 1.7 (95 % CI 1.2-2.5, p = 0.002) and 3.5 (95 % CI 2.0-6.0, p < 0.001). Results were similar within cancer/regimen-subgroups and were robust when using alternative methods for confounding adjustment.

Conclusions: In this retrospective evaluation of cancer chemotherapy patients who received first-cycle pegfilgrastim prophylaxis in US clinical practice, a clinically relevant minority did not receive second-cycle prophylaxis. Second-cycle FN odds among this subset were significantly higher than they were among those who continued prophylaxis.
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http://dx.doi.org/10.1007/s00520-015-3039-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846701PMC
June 2016

Dose Delays, Dose Reductions, and Relative Dose Intensity in Patients With Cancer Who Received Adjuvant or Neoadjuvant Chemotherapy in Community Oncology Practices.

J Natl Compr Canc Netw 2015 Nov;13(11):1383-93

From Virginia Cancer Specialists PC and The US Oncology Network, Arlington, Virginia; McKesson Specialty Health and The US Oncology Network, The Woodlands, Texas; Amgen Inc., Thousand Oaks, California; Virginia Cancer Specialists PC and The US Oncology Network, Fairfax, Virginia; Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: A wide variety of myelosuppressive chemotherapy regimens are used for the treatment of cancer in clinical practice. Neutropenic complications, such as febrile neutropenia, are among the most common side effects of chemotherapy, and they often necessitate delays or reductions in doses of myelosuppressive agents. Reduced relative dose intensity (RDI) may lead to poorer disease-free and overall survival.

Methods: Using the McKesson Specialty Health/US Oncology iKnowMed electronic health record database, we retrospectively identified the first course of adjuvant or neoadjuvant chemotherapy received by patients without metastases who initiated treatment between January 1, 2007, and March 31, 2011. For each regimen, we estimated the incidences of dose delays (≥7 days in any cycle of the course), dose reductions (≥ 15% in any cycle of the course), and reduced RDI (<85% over the course) relative to the corresponding standard tumor regimens described in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).

Results: This study included 16,233 patients with 6 different tumor types who received 1 of 20 chemotherapy regimens. Chemotherapy dose delays, dose reductions, and reduced RDI were common among patients treated in community oncology practices in the United States, but RDI was highly variable across patients, regimens, and tumor types (0.486-0.935 for standard tumor regimen cohorts). Reduced RDI was more common in older patients, obese patients, and patients whose daily activities were restricted.

Conclusions: In this large evaluation of RDI in US clinical practice, physicians frequently administered myelosuppressive agents at dose intensities lower than those of standard regimens.
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http://dx.doi.org/10.6004/jnccn.2015.0166DOI Listing
November 2015

Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use.

J Natl Compr Canc Netw 2015 Aug;13(8):979-86

From Policy Analysis Inc. (PAI), Brookline, Massachusetts; Amgen Inc., Thousand Oaks, California; Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, Texas Medical Center, University of Houston, Houston, Texas; and Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.

Background: Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors.

Methods: A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as "low" or "intermediate," or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities.

Results: Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8-1.3) to 2.2 (95% CI, 1.5-3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities.

Conclusions: In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.
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http://dx.doi.org/10.6004/jnccn.2015.0118DOI Listing
August 2015

Comprehensive profiling of the cell surface proteome of Sy5Y neuroblastoma cells yields a subset of proteins associated with tumor differentiation.

J Proteome Res 2009 Aug;8(8):3791-6

Children's Hospital and Research Center at Oakland, California 94609, USA.

Neuroblastoma tumors are derived from the neural crest and exhibit substantial phenotypic heterogeneity and various degrees of differentiation and maturation. The identification of new cell surface markers in neuroblastoma has relevance to disease classification and therapy. As a means to categorize neuroblastomas based on cell surface protein expression, we have obtained a comprehensive profile of the cell surface proteome of the MYCN nonamplified SH-SY5Y neuroblastoma cell line. Biotinylated cell surface proteins were captured using an avidin affinity column, fractionated by reversed-phase chromatography and subjected to in-depth analysis by LC-MS/MS. An extensive list of proteins was established and a subset of surface membrane proteins was assessed by immunohistochemistry in a set of neuroblastoma tissue microarrays. Among identified proteins tested, NCAM and CD147 exhibited increased expression in poorly differentiated tumors (p < 0.01 and <0.03, respectively). CD147 expression was previously associated with aggressive carcinomas but has not been described in neuroblastoma. This comprehensive neuroblastoma cell surface profile has identified novel potential markers for neuroblastoma classification and novel potential targets for therapy.
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http://dx.doi.org/10.1021/pr800964vDOI Listing
August 2009

Epidural metastases from endodermal sinus tumor arising from benign sacral teratoma. Case report and review of the literature.

J Neurosurg 2007 Oct;107(4 Suppl):303-6

Department of Neurological Surgery, University of Washington, Seattle, 98104-2499, USA.

The recurrence of benign sacral teratomas is a small but significant possibility. Recurrence as an endodermal sinus tumor (EST) with epidural metastases, however, has not been previously reported. The authors describe a case of a mature sacrococcygeal teratoma in a 4-day-old female patient that recurred after 22 months as an EST with epidural metastases. The child presented with abdominal pain, urinary retention, and difficulty walking. On imaging, a large pelvic mass and an epidural spinal mass were revealed. The patient's alpha-fetal protein (AFP) level was 68,000 ng/ml. Her neurological examination was significant for 3/5 plantar and dorsiflexion strength bilaterally. The patient underwent L-3, L-4, and L-5 bilateral laminectomies followed by subtotal resection of the recurrent pelvic tumor. Pathological testing of samples of both the recurrent pelvic and the extradural spinal tumors led to a diagnosis of EST. The patient underwent four cycles of chemotherapy with normalization of her AFP level to 13 ng/ml. In the weeks that followed, her AFP level steadily rose again to 167 ng/ml. Follow-up imaging revealed no tumor recurrence. The patient underwent a second course of chemotherapy followed by two tandem courses of high-dose chemotherapy with autologous stem-cell rescue. Since completing this therapy the patient has been clinically stable with an AFP level of 1.3 ng/ml for 14 months. At the 1-year follow-up examination, her plantar and dorsiflexion strength had markedly improved to 4+/5 bilaterally. To the authors' knowledge, this is the first case of a mature sacrococcygeal tumor that recurred as an EST and caused spinal canal compromise.
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http://dx.doi.org/10.3171/PED-07/10/303DOI Listing
October 2007

Epidural metastases from endodermal sinus tumor arising from benign sacral teratoma. Case report and review of the literature.

J Neurosurg 2007 Oct;107(4 Suppl):303-6

Department of Neurological Surgery, University of Washington, Seattle, 98104-2499, USA.

The recurrence of benign sacral teratomas is a small but significant possibility. Recurrence as an endodermal sinus tumor (EST) with epidural metastases, however, has not been previously reported. The authors describe a case of a mature sacrococcygeal teratoma in a 4-day-old female patient that recurred after 22 months as an EST with epidural metastases. The child presented with abdominal pain, urinary retention, and difficulty walking. On imaging, a large pelvic mass and an epidural spinal mass were revealed. The patient's alpha-fetal protein (AFP) level was 68,000 ng/ml. Her neurological examination was significant for 3/5 plantar and dorsiflexion strength bilaterally. The patient underwent L-3, L-4, and L-5 bilateral laminectomies followed by subtotal resection of the recurrent pelvic tumor. Pathological testing of samples of both the recurrent pelvic and the extradural spinal tumors led to a diagnosis of EST. The patient underwent four cycles of chemotherapy with normalization of her AFP level to 13 ng/ml. In the weeks that followed, her AFP level steadily rose again to 167 ng/ml. Follow-up imaging revealed no tumor recurrence. The patient underwent a second course of chemotherapy followed by two tandem courses of high-dose chemotherapy with autologous stem-cell rescue. Since completing this therapy the patient has been clinically stable with an AFP level of 1.3 ng/ml for 14 months. At the 1-year follow-up examination, her plantar and dorsiflexion strength had markedly improved to 4+/5 bilaterally. To the authors' knowledge, this is the first case of a mature sacrococcygeal tumor that recurred as an EST and caused spinal canal compromise.
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http://dx.doi.org/10.3171/PED-07/10/303DOI Listing
October 2007