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had improvement, which was not different from Sally P. Stabler, M.D. the rates in the respective parenteral-treatment University of Colorado School of Medicine CO groups. The route of vitamin B12 delivery may be Aurora, sally.stabler@ucdenver.edu less important than the expected quantity delivSince publication of her article, the author reports no further ered to tissues. Oral vitamin B12 at a daily dose potential conflict of interest. of 2000 μg (20 μg absorbed on average) is equiv- 1. Environmental Protection Agency. Integrated Risk Informaalent to weekly injections of cyanocobalamin at tion System (IRIS) home page (http://www.epa.gov.iris). 2. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindena dose of 1000 μg (150 μg retained). Oral treat- baum J. Effective treatment of cobalamin deficiency with oral ment has been successfully used in Sweden for cobalamin. Blood 1998;92:1191-8. almost 50 years.4 However, patients with life- 3. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Baructa S, Senturk T. Oral versus intramuscular cobalamin treatment in threatening megaloblastic anemia or severe mye- megaloblastic anemia: a single-center, prospective, randomized, lopathy may benefit from rapid replacement with open-label study. Clin Ther 2003;25:3124-34. daily injections, although in the past cure has 4. Nilsson M, Norberg B, Hultdin J, et al. Medical intelligence in Sweden; vitamin B12: oral compared with parenteral? Postbeen accomplished with much lower and less- grad Med J 2005;81:191-3. frequent doses. DOI: 10.1056/NEJMc1304350

Transient Sunitinib Resistance in Gastrointestinal Stromal Tumors To the Editor: Sunitinib — an oral tyrosine kinase inhibitor targeting KIT, platelet-derived growth factor receptors α and β, vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and other receptors — is an effective secondline therapy for metastatic gastrointestinal stromal-cell tumors after the use of first-line imatinib.1,2 If disease progresses during treatment with sunitinib, current therapeutic options are limited. We describe two patients who were successfully rechallenged with sunitinib after disease progression and had an objective response and a persistent clinical benefit. Both patients, a 62-year-old man and a 58-yearold woman, underwent a gastric resection for a high-risk gastrointestinal stromal-cell tumor harboring KIT exon 11 mutations. When progression occurred to the peritoneum and liver, each patient began to receive imatinib at a dose of 400 mg per day and continued treatment for almost 3 years, with a prolonged partial response. When disease progression was detected on computed tomography (CT), the dose of imatinib was increased to 800 mg per day. A few months later, for progressing disease, both patients began to receive sunitinib at a dose of 37.5 mg per day. They had a partial response that lasted more than 2 years. After further disease progression, both patients received nilotinib with-

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out a response and reexposure to imatinib without any benefit. Each patient had a rapid decline in performance status, and sunitinib treatment was tried again. Within a few days, both patients’ symptoms started to improve. CT scans showed a partial response. The male patient had stable disease after 12 months of retreatment with sunitinib, whereas the female patient had progression after 9 months and began to receive regorafenib. Mechanisms of resistance to sunitinib and other tyrosine kinase inhibitors that target VEGFRs are largely unknown, but studies involving patients with renal-cell carcinoma suggest that resistance may be transient.3 The clinical histories of these two patients have similar features: the gastrointestinal site of the tumor, a prolonged response to imatinib and sunitinib, and a months-long interval before reexposure. In contrast to imatinib, in which secondary resistance is mostly due to emergence of new KIT mutations, mechanisms of sunitinib resistance are unclear.4 Is resistance routinely reversible after a sunitinib-free interval, similar to the responses to platinum-based chemotherapy in patients with ovarian cancer after a platinum-free interval? The positive trial with regorafenib as third-line therapy versus supportive care is en-

n engl j med 368;21  nejm.org  may 23, 2013

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couraging, but given that regorafenib also targets angiogenesis, could it be just reexposure to an antiangiogenic drug that is effective? 5 Raffaella Bracci, M.D. Ospedali Riuniti di Ancona Ancona, Italy raffaellabracci@libero.it

Elena Maccaroni, M.D. Stefano Cascinu, M.D. Università Politecnica delle Marche Ancona, Italy Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

1. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy

and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-38. 2. Blay JY. Pharmacological management of gastrointestinal stromal tumours: an update on the role of sunitinib. Ann Oncol 2010;21:208-15. 3. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010;116:5400-6. 4. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592-603. 5. Demetri GD, Reichardt P, Kang YK, et al. Randomized phase II trial of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib and sunitinib: GRID trial. J Clin Oncol 2012;30:Suppl:LBA 10008. abstract. DOI: 10.1056/NEJMc1301237

Bioresorbable Airway Splint Created with a Three-Dimensional Printer To the Editor: Tracheobronchomalacia in newborns, which manifests with dynamic airway collapse and respiratory insufficiency, is difficult to treat.1,2 In an infant with tracheobronchomalacia, we implanted a customized, bioresorbable tracheal splint, created with a computer-aided design based on a computed tomographic image of the patient’s airway and fabricated with the use of laser-based three-dimensional printing, to treat this life-threatening condition. At birth at 35 weeks’ gestation, the patient did not have respiratory distress and otherwise appeared to be in normal health. At 6 weeks of age, he had chest-wall retractions and difficulty feeding. By 2 months of age, his symptoms progressed and he required endotracheal intubation to sustain ventilation. The workup revealed the following: an anomalous origin and malposition of the pulmonary arteries, with crisscross anatomy; right pulmonary-artery hypoplasia; compression of the left mainstem bronchus between an abnormally leftward-coursing ascending aorta and an anteriorly displaced descending aorta; air trapping; and postobstructive pneumonia. Despite placement of a tracheostomy tube, mechanical ventilation, and sedation, ventilation that was sufficient to prevent recurring cardiopulmonary arrests could not be maintained. We reasoned that the localized tracheobronchomalacia was the cause of this physiological abnormality and made a custom-designed and

custom-fabricated resorbable airway splint. Our bellowed topology design, similar to the hose of a vacuum cleaner, provides resistance against collapse while simultaneously allowing flexion, extension, and expansion with growth. The splint was manufactured from polycaprolactone with the use of a three-dimensional printer (Fig. 1A through 1D). The institutional review board of the University of Michigan consulted with the Food and Drug Administration and approved the use of the device under the emergency-use exemption, and written informed consent was provided by the patient’s parents. After transposition of the right pulmonary artery and failed aortopexy, sutures were placed around the circumference of the malacic left bronchus and tied through interstices of the splint, and the bronchus was expanded (Fig. 1E). Subsequent bronchoscopy revealed normal patency of the bronchus without dynamic collapse (Fig. 1F) and normal ventilatory variation in the size of the left lung. The partial pressure of carbon dioxide in venous blood decreased from 88 to 48 mm Hg. Seven days after placement of the airway splint, weaning from mechanical ventilation was initiated, and 21 days after the procedure, ventilator support was discontinued entirely and the child was discharged home with the tracheostomy in place. One year after surgery, imaging and endoscopy showed a patent left mainstem bronchus (Fig.

n engl j med 368;21  nejm.org  may 23, 2013

The New England Journal of Medicine Downloaded from nejm.org on July 6, 2013. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.

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