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Web Resources: Abraxane
Recent Research Publications

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Recent Research Publications

Murakami T, Murata T, Kawaguchi K, et al.
Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel.
Anticancer Res. 2017; 37(1):61-65 [PubMed] Related Publications
BACKGROUND: Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective.
MATERIALS AND METHODS: Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX.
RESULTS: H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42±0.36) than the control group (tumor volume ratio: 3.47±1.66) (p<0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85±1.45) (p=0.47). CDDP-treated tumor weight (50±50 mg) was significantly less than control (238±114 mg) (p<0.01). NAB-PTX-treated tumors were not reduced in weight (246±136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX-treated tumors.
CONCLUSION: The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease.

Fukuchi M, Mochiki E, Ishiguro T, et al.
Efficacy of Nab-Paclitaxel as Second-line Chemotherapy for Unresectable or Recurrent Gastric Cancer.
Anticancer Res. 2016; 36(12):6699-6703 [PubMed] Related Publications
AIM: To evaluate the efficacy and safety of nanoparticle albumin-bound-paclitaxel (nab-PTX) as second-line chemotherapy (CT) for patients with unresectable or recurrent gastric cancer (GC).
PATIENTS AND METHODS: The clinicopathological and survival data of 37 patients with unresectable or recurrent GC who underwent nab-PTX monotherapy as second-line CT, were retrospectively analyzed.
RESULTS: The median number of cycles and relative dose intensity administered per patient were 5 and 90%, respectively. Their overall response rate was 24.3% and the disease control rate was 59.5%. Median progression-free survival (PFS) and overall survival were 4.8 months and 10.4 months, respectively. Thirteen patients had grade 3 or 4 toxicities and were managed. In multivariate Cox regression analysis, cycles of chemotherapy ≥5 (odds ratio, 0.20; 95% confidence interval, 0.08-0.50; p<0.01) was the only significant independent predictor of longer PFS.
CONCLUSION: Nab-PTX may effectively prevent disease progression as second-line CT by increasing treatment cycles and managing adverse effects.

Sakaguchi K, Nakatsukasa K, Taguchi T
Phase I Study of Triweekly Nab-Paclitaxel Combined with S-1 in Patients with HER2-negative Metastatic Breast Cancer.
Anticancer Res. 2016; 36(12):6515-6519 [PubMed] Related Publications
AIM: We conducted a phase I study to determine the maximum tolerated dose (MTD) and recommended dose (RD) of triweekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and S-1 combination therapy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC).
PATIENTS AND METHODS: This study was carried out with a 3+3 dose escalation design; patients with HER2-negative MBC received nab-paclitaxel at 180-260 mg/m(2) on day 1 and S-1 at 65-80 mg/m(2) daily on days 1-14, repeated every 3 weeks.
RESULTS: The MTD was level 3 (260 mg/m(2) nab-paclitaxel with 80 mg/m(2) S-1) and the RD was level 2 (260 mg/m(2) nab-paclitaxel with 65 mg/m(2) S-1). Dose-limiting toxicity was observed in two patients at level 3, who had grade 4 neutropenia and grade 3 myalgia, respectively.
CONCLUSION: The response rate was 66.7%. The clinical benefit rate was 77.8%. Our study shows the efficacy and the feasibility of this combination therapy.

Chun SG, Hughes R, Sumer BD, et al.
A Phase I/II Study of Nab-Paclitaxel, Cisplatin, and Cetuximab With Concurrent Radiation Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck.
Cancer Invest. 2017; 35(1):23-31 [PubMed] Related Publications
Nab-paclitaxel might impact efficacy of radiation for head and neck (H&N) cancer. Nab-paclitaxel, cisplatin, cetuximab, and radiation were evaluated in patients with locally advanced head and neck cancer in this phase I/II trial. Median follow-up was 24 months for 34 patients. The maximum tolerated dose of nab-paclitaxel was 20 mg/m(2) with 20 mg/m(2) cisplatin and 250 mg/m(2) cetuximab. The 2-year progression-free survival (PFS) was 60% (95% confidence interval (CI) 0.42, 0.78), local control 71% (95% CI 0.55, 0.87), and overall survival 68% (95% CI 0.50, 0.86). This is the first study evaluating these agents with radiation in humans, with similar 2-year PFS as historic control.

Kataoka K, Matsubara H, Urano F, et al.
Nab-paclitaxel+gemcitabine therapy for adenosquamous carcinoma of the pancreas: an autopsy case.
Nihon Shokakibyo Gakkai Zasshi. 2016; 113(10):1777-1784 [PubMed] Related Publications
A male patient aged over 60 years presented with abdominal pain. A solid lesion measuring 7cm was detected in the pancreatic body and tail, along with periaortic lymphadenopathy. Endoscopic ultrasound-guided fine-needle aspiration suggested squamous cell carcinoma. Nab-paclitaxel+gemcitabine therapy was effective;however, tumor progression was noted after the completion of the fourth course, and the patient died from the primary cancer 7 months after the initial consultation. Autopsy led to a definitive diagnosis of adenosquamous carcinoma of the pancreas. Non-resected adenosquamous carcinoma of the pancreas treated by chemotherapy is rare. Here, we report such an example in the present case study.

Schettini F, Giuliano M, De Placido S, Arpino G
Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives.
Cancer Treat Rev. 2016; 50:129-141 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Despite an increasing understanding of the molecular heterogeneity of TNBC, clinical trials of targeted agents have thus far been disappointing; chemotherapy, in particular with anthracycline and taxanes, remains the backbone medical management for both early and metastatic TNBC. Nab-paclitaxel is a solvent-free, albumin-bound, nanoparticle formulation of paclitaxel and represents a novel formulation of an established, effective chemotherapeutic agent. Nab-paclitaxel has been specifically designed to overcome the limitations of conventional taxane formulations, including the barriers to effective drug delivery of highly lipophilic agents. It has shown significant efficacy and better tolerability than conventional taxanes in metastatic breast cancer and is approved for use in this setting. Increasing evidence suggests that nab-paclitaxel is effective in patients with more aggressive tumours, as seen in TNBC. Indeed, results of Phase II/III studies indicate that nab-paclitaxel may be effective as neoadjuvant treatment of TNBC. This article reviews the rationale and evidence supporting a role for nab-paclitaxel in the treatment of TNBC, including ongoing studies such as ADAPT-TN and tnAcity. In addition, the article reviews ongoing research into targeted therapies and immuno-oncology for the treatment of TNBC, and explores the potential role, current evidence and ongoing studies of nab-paclitaxel as the chemotherapy partner in combination with immunotherapy, where the unique properties of this taxane, including the lack of requirement for steroid pre-medication, may present an advantage.

Bernabeu E, Gonzalez L, Legaspi MJ, et al.
Paclitaxel-Loaded TPGS-b-PCL Nanoparticles: In Vitro Cytotoxicity and Cellular Uptake in MCF-7 and MDA-MB-231 Cells versus mPEG-b-PCL Nanoparticles and Abraxane®.
J Nanosci Nanotechnol. 2016; 16(1):160-70 [PubMed] Related Publications
Nanomedicines have become an attractive platform for the development of novel drug delivery systems in cancer chemotherapy. Polymeric nanoparticles (NPs) represent one of the best well-investigated nanosized carriers for delivery of antineoplastic compounds. The "Pegylation strategy" of drug delivery systems has been used in order to improve carrier biodistribution, however, some nanosized systems with PEG on their surface have exhibited poorly-cellular drug internalization. In this context, the purpose of the present study was to compare in vitro performance of two paclitaxel (PTX)-loaded NPs systems based on two biocompatible copolymers of alpha tocopheryl polyethylene glycol 1000 succinate-block-poly(ε-caprolactone) (TPGS-b-PCL) and methoxyPEG- block-poly(ε-caprolactone) (mPEG-b-PCL) in terms of citotoxicity and PTX cellular uptake. Fur- thermore, TPGS-b-PCL NPs were also copared with the commercially available PTX nano-sized formulation Abraxane®. Both TPGS-b-PCL and mPEG-b-PCL derivates were synthesized by ring opening polymerization of ε-caprolactone employing microwaved radiation. NPs were obtained by a solvent evaporation technique where the PTX content was determined by reverse-phase HPLC. The resulting NPs had an average size between 200 and 300 nm with a narrow size distribution. Also both NPs systems showed a spherical shape. The in vitro PTX release profile from the NPs was characterized employing the dialysis membrane method where all drug-loaded formulations showed a sustained and slow release of PTX. Finally, in vitro assays demonstrated that PTX-loaded TPGS- b-PCL exhibited a significant higher antitumor activity than PTX-loaded mPEG-b-PCL NPs and Abraxane® against an estrogen-dependent (MCF-7) and an estrogen independent (MDA-MB-231) breast cancer cells lines. Furthermore TPGS-b-PCL NPs showed a significant increase on PTX cellular uptake, for both breast cell lines, in comparison with mPEG-b-PCL NPs and Abraxane®. Overall findings confirmed that NPs based on TPGS-b-PCL as biomaterial demonstrated a better in vitro performance than NPs with PEG, representing an attractive alternative for the development of novel nanosized carriers for anticancer therapy.

Neuzillet C, Babai S, Kempf E, et al.
Severe hyponatremia caused by nab-paclitaxel-induced syndrome of inappropriate antidiuretic hormone secretion: A case report in a patient with metastatic pancreatic adenocarcinoma.
Medicine (Baltimore). 2016; 95(26):e4006 [PubMed] Free Access to Full Article Related Publications
Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. Most patients have advanced disease at diagnosis and therapeutic options in this setting are limited. Gemcitabine plus nab-paclitaxel regimen was demonstrated to increase survival compared with gemcitabine monotherapy and is therefore indicated as first-line therapy in patients with metastatic PDAC and performance status Eastern Cooperative Oncology Group (ECOG) 0-2. The safety profile of gemcitabine and nab-paclitaxel combination includes neutropenia, fatigue, and neuropathy as most common adverse events of grade 3 or higher. No case of severe hyponatremia associated with the use of nab-paclitaxel for the treatment of PDAC has been reported to date.We report the case of a 72-year-old Caucasian man with a metastatic PDAC treated with gemcitabine and nab-paclitaxel regimen, who presented with a severe hyponatremia (grade 4) caused by a documented syndrome of inappropriate antidiuretic hormone secretion (SIADH). This SIADH was attributed to nab-paclitaxel after a rigorous imputability analysis, including a rechallenge procedure with dose reduction. After dose and schedule adjustment, nab-paclitaxel was pursued without recurrence of severe hyponatremia and with maintained efficacy.Hyponatremia is a rare but potentially severe complication of nab-paclitaxel therapy that medical oncologists and gastroenterologists should be aware of. Nab-paclitaxel-induced hyponatremia is manageable upon dose and schedule adaptation, and should not contraindicate careful nab-paclitaxel reintroduction. This is of particular interest for a disease in which the therapeutic options are limited.

Suenaga M, Yamada S, Fujii T, et al.
S-1 plus nab-paclitaxel is a promising regimen for pancreatic cancer in a preclinical model.
J Surg Oncol. 2016; 113(4):413-9 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to investigate the efficacy and mechanism of action of combined S-1 and nab-paclitaxel in pancreatic cancer.
METHODS: Three human pancreatic cancer cell lines were treated with S-1, nab-paclitaxel, alone or in combination. Mice bearing subcutaneous xenograft of the cell line, PANC-1, were treated with the same drugs.
RESULTS: The growth-inhibitory effect of combined S-1 and nab-paclitaxel was greater than that of the individual drugs, and the combination index value indicated that S-1 and nab-paclitaxel had a synergistic effect in vitro. The combination of S-1 and nab-paclitaxel showed greater efficacy in vivo than monotherapy, and the growth-inhibitory effect was significantly greater when compared with the controls (P = 0.009), although no significant reduction in body weight was observed. Fractional tumor volume analysis indicated that the combination had a synergistic effect. Tumor stroma staining with α-smooth muscle actin was significantly decreased by nab-paclitaxel (P < 0.001) while the number of CD31-stained microvessel lumina was significantly increased by the combination therapy when compared with the control (P = 0.046).
CONCLUSIONS: S-1 and nab-paclitaxel had a synergetic effect in preclinical studies with good tolerability, and may play a role in stromal depletion and tumor angiogenesis. J. Surg. Oncol. 2016;113:413-419. © 2016 Wiley Periodicals, Inc.

Ueno NT, Mamounas EP
Neoadjuvant nab-paclitaxel in the treatment of breast cancer.
Breast Cancer Res Treat. 2016; 156(3):427-40 [PubMed] Free Access to Full Article Related Publications
Neoadjuvant chemotherapy has the advantage of converting unresectable breast tumors to resectable tumors and allowing more conservative surgery in some mastectomy candidates. Chemotherapy agents, including taxanes, which are recommended in the adjuvant setting, are also considered in the neoadjuvant setting. Here, we review studies of nab-paclitaxel as a neoadjuvant treatment for patients with breast cancer. PubMed and conference or congress proceedings were searched for clinical studies of nab-paclitaxel in the neoadjuvant treatment of breast cancer. We also searched ClinicalTrials.gov for ongoing trials of nab-paclitaxel as a neoadjuvant agent in breast cancer. Twenty studies of nab-paclitaxel in the neoadjuvant setting were identified. In addition to reviewing key efficacy and safety data, we discuss how each trial assessed response, focusing on pathologic complete response and residual cancer burden scoring. Safety profiles are also reviewed. nab-Paclitaxel demonstrated antitumor activity and an acceptable safety profile in the neoadjuvant treatment of breast cancer. Ongoing and future trials will further evaluate preoperative nab-paclitaxel in breast cancer, including in combination with many novel immunological targeted therapies.

Goldstein DA, Krishna K, Flowers CR, et al.
Cost description of chemotherapy regimens for the treatment of metastatic pancreas cancer.
Med Oncol. 2016; 33(5):48 [PubMed] Related Publications
Multiple chemotherapy regimens are available for the treatment of metastatic pancreas cancer (mPCA). Choice of regimen is based on the patient's performance status and toxicity profile of the regimen. The objective of this study was to analyze the costs of first-line regimens to further aid in decision-making and develop a platform upon which to assess value. We calculated the monthly cost for individual standard regimens (gemcitabine, gemcitabine/nab-paclitaxel, gemcitabine/erlotinib and FOLFIRINOX) and the overall treatment cost for a course of therapy based on the median progression-free survival achieved in published studies. In addition to cost of drugs, we included administration costs and costs of toxicities (including growth factor support, blood product transfusion and hospitalization for toxicities). Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services. Drug costs were based on Medicare average sale prices (all 2014 US$). The monthly costs for gemcitabine, FOLFIRINOX, gemcitabine/erlotinib and gemcitabine/nab-paclitaxel were $1363, $7234, $8007 and $12,221, respectively. The overall treatment costs for a course of the same regimens based on median PFS were $5043, $46,298, $51,004 and $67,216, respectively. The choice of chemotherapy regimen for mPCA should be based on tolerability and efficacy of the regimen individualized to patient's performance status. Healthcare systems have finite resources; thus, there is increasing emphasis on metrics to define value in health care when outcomes of therapy are similar or produce marked differences in value. These data provide useful financial information to incorporate into the decision-making process.

Moser M, Wiedemann D, Kitzwögerer M, Frank H
Adenocarcinoma of the ampulla of Vater metastasising into the right ventricle.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A 43-year-old woman, after resected adenocarcinoma of the ampulla of Vater, presented dyspnoea and beginning signs of right heart failure. Echocardiography revealed a mass within the right ventricle (RV) suspicious for a metastasis of the known adenocarcinoma. The decision for surgical resection was made by cardiovascular MR, which was able to delineate the infiltrative growth of a metastasis. An extensive resection had to be performed. Parts of the intraventricular septum as well as the tricuspid valve had to be resected. After six cycles of adjuvant systemic chemotherapy with gemcitabine and nab-paclitaxel, the patient had no macroscopic tumour recurrence. To our knowledge, this is the first report of a pancreatobiliary tumour metastasising exclusively to the RV of the heart. We conclude that in this special case aggressive surgical management following chemotherapy was very effective in controlling the disseminated adenocarcinoma of the ampulla of Vater.

Zhou J, Zhao R, Wen F, et al.
Cost-effectiveness analysis of treatments for metastatic pancreatic cancer based on PRODIGE and MPACT trials.
Tumori. 2016; 2016(3):294-300 [PubMed] Related Publications
PURPOSE: Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GEM-N) have shown a significant survival benefit for the treatment of metastatic pancreatic cancer. The objective of this study was to assess the cost-effectiveness of FOLFIRINOX versus GEM-N for treating metastatic pancreatic cancer based on the PRODIGE and MPACT trials.
METHODS: A decision model was performed to compare FOLFIRINOX with GEM-N. Primary base case data were identified from PRODIGE and MPACT trials. Costs were estimated and incremental cost-effectiveness ratio (ICER) was calculated at West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALY). Finally, sensitive analysis was performed by varying potentially modifiable parameters in the model.
RESULTS: The base-case analysis showed that FOLFIRINOX cost $37,203.75 and yielded a survival of 0.67 QALY, and GEM-N cost $32,080.59 and yielded a survival of 0.51 QALY in the entire treatment. Thus, the ICER of FOLFIRINOX versus GEM-N was $32,019.75 per QALY gained.
CONCLUSIONS: The GEM-N regimen was more cost-effective compared with the FOLFIRINOX regimen for the treatment of metastatic pancreatic cancer from a Chinese perspective.

Weiss J, Grilley Olson J, Deal AM, et al.
Using the galactose-α-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab.
Cancer. 2016; 122(11):1697-701 [PubMed] Related Publications
BACKGROUND: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab.
METHODS: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol.
RESULTS: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects.
CONCLUSIONS: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. © 2016 American Cancer Society.

Lakshmanan VK
Therapeutic efficacy of nanomedicines for prostate cancer: An update.
Investig Clin Urol. 2016; 57(1):21-9 [PubMed] Free Access to Full Article Related Publications
Recent advances in cancer nanomedicine have attracted remarkable attention in medical sectors. Pharmacologic research on nanomedicines, including targeted cancer therapy, has increased dramatically in the past 5 years. The success stories of nanomedicines in the clinical field include the fabrication of nanomedicines that show maximum loading efficiency into carriers, maximal release kinetics, and minimum toxicity to healthy cells. Nanoparticle-mediated medicines have been developed to specifically target prostate cancer tissue by use of aptamers, antibody targeting, and sustained release of nanomedicines in a dose- and time-dependent manner. Nanomedicines have been developed for therapeutic application in combination with image-guided therapy in real time. The scope of one of these nanomedicines, Abraxane (paclitaxel), may be extended to prostate cancer therapeutic applications for better quality of patient life and longer survival. This review provides an update on the latest directions and developments in nanomedicines for prostate cancer.

Jain MM, Gupte SU, Patil SG, et al.
Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.
Breast Cancer Res Treat. 2016; 156(1):125-34 [PubMed] Free Access to Full Article Related Publications
Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

Mantripragada KC, Safran H
Optimizing initial chemotherapy for metastatic pancreatic cancer.
Future Oncol. 2016; 12(9):1125-33 [PubMed] Related Publications
The two combination chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel represent major breakthroughs in the management of metastatic pancreatic cancer. Both regimens showed unprecedented survival advantage in the setting of front-line therapy. However, their application for treatment of patients in the community is challenging because of significant toxicities, thus limiting potential benefits to a narrow population of patients. Modifications to the dose intensity or schedule of those regimens improve their tolerability, while likely retaining survival advantage over single-agent chemotherapy. Newer strategies to optimize these two active regimens in advanced pancreatic cancer are being explored that can help personalize treatment to individual patients.

Jin F, Zhu H, Shi F, et al.
A retrospective analysis of safety and efficacy of weekly nab-paclitaxel as second-line chemotherapy in elderly patients with advanced squamous non-small-cell lung carcinoma.
Clin Interv Aging. 2016; 11:167-73 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The aim of this retrospective study was to investigate the anticancer effect and toxicity of weekly administered nab-paclitaxel as a second-line chemotherapy in elderly patients with relapsed squamous non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: We retrospectively reviewed the treatment of 42 elderly patients with relapsed squamous NSCLC, who received nab-paclitaxel monotherapy as a second-line treatment from January 2010 to March 2014. A dose of 100 mg/m(2) nab-paclitaxel was administered weekly on days 1, 8, and 15, followed by 1 week of rest. The protocol was maintained for at least two cycles.
RESULTS: The overall response rate (ORR) and the disease control rate (DCR) were 21.43% (9/42) and 47.62% (20/42), respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.6 and 10.9 months, respectively. In the subgroup analysis, there was no significant difference in ORR, DCR, PFS, and OS, accounting for the first-line therapy factors (taxane agent, radiotherapy, or surgery). There was a statistically significant difference in DCR for stages III and IV (62.96% vs 20%, P=0.008), but there was no such difference in either PFS or OS. The ORR of 29 patients receiving more than three cycles of treatment was higher than that of those receiving less than three cycles of treatment (31.03% vs 0%, P=0.038), and there was a significant difference in PFS (7.6 vs 4.9 months, P=0.004) and OS (11.7 vs 8.9 months, P=0.002). No hypersensitivity reactions or treatment-related grade 4 adverse events were reported.
CONCLUSION: Nab-paclitaxel monotherapy administered weekly at a dose of 100 mg/m(2) is shown to be an effective and safe regimen for elderly patients with relapsed squamous NSCLC, especially for patients with stage III disease or good performance status.

Cohen SJ, O'Neil BH, Berlin J, et al.
A phase 1b study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: an Academic Oncology GI Cancer Consortium study.
Cancer Chemother Pharmacol. 2016; 77(4):693-701 [PubMed] Related Publications
PURPOSE: Addition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy.
METHODS: In this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard "3 + 3" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals.
RESULTS: Nineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3.
CONCLUSION: The addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing.

Russo S, Ammori J, Eads J, Dorth J
The role of neoadjuvant therapy in pancreatic cancer: a review.
Future Oncol. 2016; 12(5):669-85 [PubMed] Related Publications
Controversy remains regarding neoadjuvant approaches in the treatment of pancreatic cancer. Neoadjuvant therapy has several potential advantages over adjuvant therapy including earlier delivery of systemic treatment, in vivo assessment of response, increased resectability rate in borderline resectable patients and increased margin-negative resection rate. At present, there are no randomized data favoring neoadjuvant over adjuvant therapy and multiple neoadjuvant approaches are under investigation. Combination chemotherapy regimens including 5-fluorouracil, irinotecan and oxaliplatin, gemcitabine with or without abraxane, or docetaxel and capecitabine have been used in the neoadjuvant setting. Radiation and chemoradiation have also been incorporated into neoadjuvant strategies, and delivery of alternative fractionation regimens is being explored. This review provides an overview of neoadjuvant therapies for pancreatic cancer.

Hara N, Fujimoto N, Miyamoto Y, et al.
Angiosarcoma of the thoracic wall responded well to nanoparticle albumin-bound paclitaxel: A case report.
Drug Discov Ther. 2016; 10(2):114-6 [PubMed] Related Publications
An 81-year-old woman visited a local clinic due to chest pain and a skin induration on the right precordia. She had a history of right breast cancer, and she had undergone a mastectomy and radiation therapy 10 years prior. Computed tomography (CT) imaging of the chest demonstrated a lobular mass that involved the right anterior thoracic wall and partially extruded from the thoracic cavity into the subcutaneous tissue. The tumor was surgically excised, and pathological analyses yielded a diagnosis of angiosarcoma. Five months after the operation, CT imaging showed multiple masses on the right pleura, indicating a local relapse and pleural dissemination of the angiosarcoma. Systemic chemotherapy composed of nanoparticle albumin-bound paclitaxel (nab-PTX) (80 mg/m(2)) was delivered weekly. After 4 courses of chemotherapy, the tumors regressed remarkably. Nab-PTX may be an effective treatment option for recurrent or metastatic angiosarcoma.

Villaruz LC, Socinski MA
Is there a role of nab-paclitaxel in the treatment of advanced non-small cell lung cancer? The data suggest yes.
Eur J Cancer. 2016; 56:162-71 [PubMed] Free Access to Full Article Related Publications
Nab-paclitaxel is a novel therapeutic agent, which was approved in combination with carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) regardless of histologic subtype in the United States of America by the Food and Drug Administration in 2012 and by the European Commission in 2015. This approval was based on the results of a phase III clinical trial showing superior response rates compared with solvent-based paclitaxel in combination with carboplatin. This review will focus on the early development and clinical data to date supporting the use of nab-paclitaxel in advanced NSCLC. The clinical question central to this review is whether nab-paclitaxel has a place in the current therapeutic landscape of advanced NSCLC.

Untch M, Jackisch C, Schneeweiss A, et al.
Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial.
Lancet Oncol. 2016; 17(3):345-56 [PubMed] Related Publications
BACKGROUND: In metastatic breast cancer, nab-paclitaxel has been shown to significantly increase progression-free survival compared with solvent-based paclitaxel. The GeparSepto (GBG 69) trial assessed whether weekly nab-paclitaxel could increase the proportion of patients achieving pathological complete response compared with weekly solvent-based paclitaxel, both followed by epirubicin plus cyclophosphamide as neoadjuvant treatment.
METHOD: In a phase 3 randomised trial, we enrolled patients with previously untreated unilateral or bilateral primary invasive breast cancer and randomly assigned them in a 1:1 ratio using dynamic allocation and Pocock minimisation by breast cancer subtype, Ki67 and SPARC expression. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m(2) (after study amendment, 125 mg/m(2)) on days 1, 8, and 15 for four 3-week cycles, or solvent-based intravenous paclitaxel 80 mg/m(2) on days 1, 8, and 15 for four 3-week cycles. Taxane treatment was followed in both groups by intravenous epirubicin 90 mg/m(2) plus intravenous cyclophosphamide 600 mg/m(2) on day 1 for four 3-week cycles. Patients with HER2-positive tumours received concurrent trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) on day 1 of every 3-week cycle. Trastuzumab and pertuzumab were given every 3 weeks concomitantly with chemotherapy for all cycles. This report is the final analysis of the primary endpoint, pathological complete response (ypT0 ypN0), analysed for all patients who started treatment (modified intention to treat). We used a closed test procedure to test for non-inferiority, with the nab-paclitaxel group calculated as non-inferior to the solvent-based paclitaxel group if the lower 95% CI for the OR was above 0·858 (OR equivalent to pathological complete response [33%] minus a 10% non-inferiority margin [3·3%]; 29·7%). We planned to test for superiority only in case of a positive non-inferiority test, using an α of 0·05. Safety was assessed in all patients who received study drug. The trial is registered with ClinicalTrials.gov, number NCT01583426.
FINDINGS: Between July 30, 2012, and Dec 23, 2013, we randomly assigned 1229 women, of whom 1206 started treatment (606 with nab-paclitaxel and 600 with solvent-based paclitaxel). The nab-paclitaxel dose was reduced after enrolment of 464 participants to 125 mg/m(2) due to increased treatment discontinuation and sensory neuropathy in this group. Pathological complete response occurred more frequently in the nab-paclitaxel group (233 [38%, 95% CI 35-42] patients) than in the solvent-based paclitaxel group (174 [29%, 25-33] patients; OR 1·53, 95% CI 1·20-1·95; unadjusted p=0·00065). The incidence of grade 3-4 anaemia (13 [2%] of 605 patients in the nab-paclitaxel group vs four [1%] of patients in the solvent-based paclitaxel group; p=0·048) and peripheral sensory neuropathy grade 3-4 (63 [10%] patients receiving any nab-paclitaxel dose; 31 [8%] of patients starting with 125 mg/m(2) and 32 [15%] of patients starting with 150 mg/m(2); vs 16 [3%] in the solvent-based paclitaxel group, p<0·001) was significantly higher for nab-paclitaxel than for solvent-based paclitaxel. Overall, 283 (23%) patients were noted to have at least one serious adverse event (based on study drug received), 156 (26%) in the nab-paclitaxel group and 127 (21%) in the solvent-based paclitaxel group (p=0·057). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group (due to sepsis, diarrhoea, and accident unrelated to the trial) versus one in the solvent-based paclitaxel group (during paclitaxel treatment; cardiac failure).
INTERPRETATION: Substituting solvent-based paclitaxel with nab-paclitaxel significantly increases the proportion of patients achieving a pathological complete response rate after anthracycline-based chemotherapy. These results might lead to an exchange of the preferred taxane, solvent-based paclitaxel, for nab-paclitaxel in therapy for primary breast cancer.
FUNDING: Celgene, Roche.

Ueno H, Ikeda M, Ueno M, et al.
Phase I/II study of nab-paclitaxel plus gemcitabine for chemotherapy-naive Japanese patients with metastatic pancreatic cancer.
Cancer Chemother Pharmacol. 2016; 77(3):595-603 [PubMed] Related Publications
PURPOSE: Efficacy and safety of nab-paclitaxel plus gemcitabine have not been clarified in Japanese patients with metastatic pancreatic cancer. No pharmacokinetic profile of co-administration of nab-paclitaxel and gemcitabine has been reported. We conducted a phase I/II study of the efficacy, safety, and pharmacokinetics in Japanese patients with metastatic pancreatic cancer.
METHODS: The patients were administered 125 mg/m(2) nab-paclitaxel followed by 1000 mg/m(2) gemcitabine on day 1, 8, and 15 every 4 weeks. Treatment was continued until disease progression, unacceptable adverse events, or withdrawal of consent, whichever occurred first. The primary endpoints were tolerability in phase I and overall response rate according to RECIST in phase II.
RESULTS: A total of 34 patients were enrolled. At the time of 1-year follow-up analysis since the last patient enrollment, the objective response rate by independent review committee was 58.8% (20 of 34 patients; 95% confidence interval [CI], 40.7-75.4%). The median progression-free survival and median overall survival were 6.5 months (95% CI, 5.1-8.3) and 13.5 months (95% CI, 10.6--not reached), respectively. Main adverse drug reactions of grade 3 or higher were neutropenia (70.6%), leukopenia (55.9%), anemia (14.7%), lymphocytopenia (14.7%), thrombocytopenia (14.7%), and peripheral sensory neuropathy (11.8%). There were no treatment-related deaths and no marked differences in pharmacokinetics of combined paclitaxel and gemcitabine in historical comparison between co-administration and monotherapies.
CONCLUSIONS: Nab-paclitaxel plus gemcitabine regimen showed highly promising efficacy with manageable safety profile under careful observation and with appropriate supportive care in Japanese patients with metastatic pancreatic cancer.
CLINICAL TRIAL NUMBER: JapicCTI-121987.

Kamisawa T, Wood LD, Itoi T, Takaori K
Pancreatic cancer.
Lancet. 2016; 388(10039):73-85 [PubMed] Related Publications
Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.

Chiorean EG, Von Hoff DD, Reni M, et al.
CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer.
Ann Oncol. 2016; 27(4):654-60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial.
PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks.
RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively.
CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.

Ramanathan RK, Goldstein D, Korn RL, et al.
Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas.
Ann Oncol. 2016; 27(4):648-53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial.
PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity.
RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001).
CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response.
CLINICALTRIALSGOV: NCT00844649.


Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Pancreatic Adenocarcinoma.
Ann Acad Med Singapore. 2015; 44(10):388-96 [PubMed] Related Publications
INTRODUCTION: The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.
MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.
RESULTS: Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed.
CONCLUSION: These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.

Saxena A, Schneider BJ, Christos PJ, et al.
Treatment of recurrent and platinum-refractory stage IV non-small cell lung cancer with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a single agent.
Med Oncol. 2016; 33(2):13 [PubMed] Free Access to Full Article Related Publications
The role of single-agent nab-paclitaxel in relapsed or platinum-refractory advanced non-small cell lung cancer (NSCLC) has not been well reported in Western populations. We reviewed our own institution's experience using nab-paclitaxel in these settings. We analyzed the records of stage IV NSCLC patients with relapsed or platinum-refractory disease treated with single-agent nab-paclitaxel at Weill Cornell Medical College between October 2008 and December 2013. The primary endpoint of the study was treatment failure-free survival (TFFS), defined as the time from the start of nab-paclitaxel therapy to discontinuation of the drug for any reason. The best overall response was recorded for each patient, and overall response and disease control rates were calculated. Thirty-one stage IV NSCLC patients received a median of 4 cycles (range 1-40) of nab-paclitaxel. Dose reduction or drug discontinuation due to toxicity occurred in 10 patients, mainly because of grade 2/3 fatigue or peripheral neuropathy. The overall response rate was 16.1 %, and the disease control rate was 64.5 %. Median TFFS was 3.5 months (95 % CI 1.3-5.3 months). No statistically significant difference in TFFS based on line of therapy or prior taxane exposure was identified. There was a statistically significant decrease in TFFS for patients with non-adenocarcinoma histology, although there were only five patients in this group. There was a trend toward reduction in the risk of treatment failure with increasing age. One patient remained on nab-paclitaxel therapy for over 3 years. Single-agent nab-paclitaxel was well tolerated and demonstrated efficacy in advanced NSCLC patients with relapsed or platinum-refractory disease. Further prospective clinical trials with nab-paclitaxel in these settings are warranted.

Tanei T, Leonard F, Liu X, et al.
Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases.
Cancer Res. 2016; 76(2):429-39 [PubMed] Free Access to Full Article Related Publications
Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects.

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