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1 Department of Radiology, Istituto Nazionale Tumori, Via Venezian, 1, Milano
20133, Italy.
2 Department of Radiotherapy, Istituto Nazionale Tumori, Milano 20133,
Italy.
3 Department of Nuclear Medicine, Istituto Nazionale Tumori, Milano 20133,
Italy.
4 Department of Head and Neck Surgery, Ospedale di Lodi, Lodi 26900, Italy
5 Department of Head and Neck Surgery, Istituto Nazionale Tumori, Milano 20133,
Italy.
6 Department of Statistics and Biometry, Istituto Nazionale Tumori, Milano
20133, Italy.
Received October 22, 2002;
accepted after revision December 17, 2002.
Partially supported by research grants from Associazione Italiana per la
Ricerca sul Cancro and from Lega Italiana per la Lotta contro i Tumori, and
partially supported by licensee for ABI-007, ACS Dobfar, Milano 20067,
Italy.
Abstract
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SUBJECTS AND METHODS. Twenty-three previously untreated patients (age range, 27–75 years) who had carcinoma of the tongue (stage T3—T4, any N) received intraarterial therapy with paclitaxel incorporated into albumin nanoparticles delivered by transfemoral catheterization into the external carotid artery (10 patients), selectively into the lingual artery (12 patients), or into a faciolingual trunk (1 patient). Each patient received two to four infusions, with a 3-week interval between infusions. The dose administered was 230 mg/m2 in eight patients, 180 mg/m2 in six patients, and 150 mg/m2 in nine patients. Sixteen patients underwent surgery. Of these 16 patients, eight subsequently received radiotherapy, and three received a combination of chemotherapy and radiotherapy. Of the remaining seven patients, one received chemotherapy alone, four received radiotherapy alone, one received chemotherapy plus radiotherapy, and one refused any further treatment.
RESULTS. Sixty-seven infusions were performed successfully. Eighteen patients (78%) had a clinical and radiologic objective response (complete, 26%; partial, 52%). Three patients (13%) showed stable disease, and two (9%) showed disease progression. The four patients with complete clinical response who underwent surgery showed microscopic residual carcinoma measuring less than 1 mm in two patients, less than 5 mm in one patient, and less than 1 cm in one patient. The toxicities encountered were hematologic (grade 3) in two patients (8.6%) and neurologic (grade 4) in two patients (reversible paralysis of the facial nerve, 8.6%). Two catheter-related complications occurred: one reversible brachiofacial paralysis and one asymptomatic occlusion of the external carotid artery.
CONCLUSION. Intraarterial infusion of paclitaxel in albumin nanoparticles proved reproducible and effective and deserves further investigation as induction chemotherapy before definitive treatment of advanced tumors of the tongue, with a view to organ preservation.
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Treating tumors of the tongue can cause a significant functional deficit. Therefore, various therapeutic modalities must be considered, alone or in combination. Combined therapy is virtually the rule for patients with advanced disease [4]. At present, stage T3—T4 tumors of the tongue are generally treated by radical surgery followed by radiotherapy. This strategy is practicable for tumors of the mobile tongue, but for tumors of the base of the tongue, organ preservation via a combination of chemotherapy and radiotherapy should be considered. Radical surgery should ensure tumor-free margins of 5–10 mm. However, the strong tendency of these tumors to infiltrate, together with the inflammatory reaction of the surrounding tissues, makes determining the true extent of the tumor difficult at physical examination or with the imaging methods currently available. Those making therapeutic decisions are dogged by a tendency to overtreat or undertreat a tumor of the tongue, leading to functional deficits in the former case and tumor recurrences in the latter. Thus, in patients with a stage T3—T4 tumor of the tongue, every effort to improve outcomes in terms of disease-free survival and quality of life is justified [5, 6].
In recent years, chemotherapy has taken on an increasingly important role with the introduction of a new class of drugs, the taxanes, that have taken their place alongside cisplatin and 5-fluorouracil [7, 8]. However, systemic chemotherapy has not had a significant impact on survival, despite the fact that squamous cell carcinomas are known to be particularly responsive to tumoricidal agents. This characteristic had already led us to consider intraarterial chemotherapy in the past and has prompted us to reconsider it recently, on the assumption that greater exposure of the tumor to the drug might provide better local control with reduced systemic toxicity [9, 10].
Advances in interventional radiology techniques for superselective arterial infusions, improvements in materials for percutaneous transfemoral catherization of the neck vessels, and development of advanced medical supporting techniques have recently led to more encouraging results than had ever been achieved in the past, at least in terms of objective response [11, 12].
Taxanes had not previously been used intraarterially, probably because of the difficulties involved in the intraarterial administration of this class of drugs. Even with IV use, severe allergic reactions are often encountered, making premedication necessary [13]. Taxanes are lipophilic substances; therefore, surface active agents must be added to taxanes if they are to be dissolved in organic fluids. The best known commercial product, Taxol (paclitaxel, Bristol-Myers Squibb Caribbean, Mayaguez, PR), contains polyoxyethylated castor oil (Cremophor EL; BASF, Brussels, Belgium) and alcohol, which cause discomfort when injected intraarterially unless considerably diluted. The difficulty in handling these important antitumoral agents has prompted the pharmaceutical industry to study different formulations and, among these, paclitaxel incorporated into human albumin nanoparticles has been selected for clinical trials [14] (Fig. 1). The purpose of our study was to assess the effectiveness of intraarterial infusion of this new formulation of paclitaxel given before definitive treatment of squamous cell carcinomas of the tongue.
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Patients
The study population comprised 23 consecutive patients, 19 men and four
women, with a median age of 57 years (range, 27–75 years). Six of the
men had a tumor of the base of the tongue, and 13 a tumor of the mobile
tongue. All four women had tumors of the mobile tongue. The tumors of the base
of the tongue were confined to the base in five patients (stage T3 N1—N3
in four patients; stage T4 N0 in one patient) and had extended into the
oropharynx in one (stage T4 N1). The tumors of the mobile tongue were confined
to the mobile part in 10 patients (stage T3 N0—N2, six patients; stage
T4 N0—N2, four patients) and had extended to the base in five patients
(stage T3 N0—N2, three patients; stage T4 N1, two patients), to the
floor of the mouth in one (stage T3 N2), and to the tonsil in one (stage T4
N0).
All patients had an ECOG (Eastern Cooperative Oncology Group) [15] performance status not greater than 2 and signed an informed consent form before enrollment in our study. The inclusion and exclusion criteria were identical for all patients. The study protocols were approved by the institutional ethical and scientific committee.
Protocol
At the time of enrollment and at each infusion, the patients were evaluated
with a physical examination, chest radiography, and multidetector CT (MDCT) of
the head and neck; in addition, the tumor was photographed. In the absence of
a gold standard for tumor staging and assessment of treatment response, MDCT
was preferred to MR imaging both for organizational reasons and because MR
imaging has a high incidence of artifacts caused by dental prostheses.
Laboratory tests were performed at the time of enrollment and before each
infusion. Positron emission tomography (PET) with FDG was not initially
included in the study protocol but was tentatively introduced as an optional
test to obtain additional information on the objective tumor response. FDG PET
was performed during staging and at the end of treatment in 15 patients. The
only criterion for selection of patients for FDG PET was the availability of
the equipment.
ABI-007 (paclitaxel-charged human albumin nanoparticles, American BioScience, Los Angeles, CA) was supplied as a lyophil in 30- or 100-mg vials. The 100- to 200-nm particles do not clump or precipitate and do not have an embolizing effect, even in the smallest capillaries. Binding of ABI-007 to albumin is satisfactory because only 2% of the active ingredient in the preparation is free (i.e., dispersed in the solution outside the albumin particles). The product was diluted at administration with 15 mL of 0.9% saline solution per 30 mg.
According to the protocol, each patient received a minimum of two to a maximum of four infusions at 3-week intervals. Discontinuation of the infusions was considered if a complete clinical or radiologic response was achieved or if tumor progression or grade 4 toxicity was observed. If a patient showed signs of grade 3 toxicity, treatment was suspended and resumed only after regression of the toxicity level to grade 1 or 2.
Three dose levels were used: 230 mg/m2 in eight patients, 180 mg/m2 in six patients, and 150 mg/m2 in nine patients. The initial dose level of 230 mg/m2 had been established in a preliminary dose-finding study [16]. After treating eight patients at this dose level, we had one unexpected instance of a particular grade 4 neurologic toxicity (facial nerve paralysis) that had not been encountered during the dose-finding study. Therefore, we reduced the dose to 180 mg/m2 for the six patients subsequently treated; we reduced the dose further to 150 mg/m2 when another patient developed facial nerve paralysis.
We assessed toxicity in patients weekly by performing a complete blood
count. We also assessed toxicity before each infusion through physical
examination, ECG, and measurement of cutaneous toxicity. Patients were
evaluated for signs of alopecia and flulike syndrome and for symptoms of
neurologic, gastrointestinal, and ocular toxicity. Hematologic parameters
(complete blood count, hematocrit levels, prothrombin time, and total
prothrombin time), hepatic function (protein electrophoresis and levels of
bilirubin, aspartate aminotransferase—alanine aminotransferase, alkaline
phosphatase, 
-glutathione-S-transferase, and cholineresterase), and
renal function (blood urea nitrogen, creatinine, and electrolytes levels in
addition to urinalysis) were measured. Toxicity was graded according to
criteria set by the World Health Organization
[17].
Tumor response to therapy was determined by physical examination and CT before each infusion and 3 weeks after the last infusion. PET was also performed whenever possible to obtain additional information on tumor response. The response was classified as complete response (complete disappearance of all clinical and radiologic evidence of disease), partial response (≥ 50% decrease in tumor size), stable disease (< 50% decrease or < 25% increase in tumor size), or tumor progression (25% increase in tumor size). Each patient was assessed by at least two radiologists and two clinicians who determined the response by consensus.
Angiography Procedure and Intraarterial Chemotherapy
Either the external carotid artery or the lingual artery
(Fig. 2) was reached by
transfemoral catheterization. After insertion of a vascular introducer, a
5-French guide catheter (Envoy-H1, Cordis—Johnson & Johnson, Miami,
FL) was positioned in the common carotid artery. We avoided using manifolds by
designing a Y-connector attached to a special line with clamps (produced by
SIDAM, Mirandola, Italy). The connector was mounted on the guide catheter for
perfusion with heparinized saline solution (5 U/mL) under pressure. This
expedient, essential for preventing clotting between the guide catheter and
the microcatheter (Transit-Prowler Plus infusion catheter,
Cordis—Johnson & Johnson), was also applied to the microcatheter to
allow manipulation of the guidewire inside the microcatheter during selective
and superselective catheterization procedures and to prevent clotting in the
microcatheter during the time before drug infusion.
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The final position of the microcatheter for infusion of the drug was determined by digital angiography. For tumors of the base of the tongue, the drug was infused into the external carotid artery, just above the emergence of the upper thyroid artery in four patients, into a faciolingual trunk in one patient, and selectively into the lingual artery in one patient. The choice of selective or superselective catheterization was based on which arteries were identified on angiography as tumor-feeding and on the extent of the tumor. For tumors of the mobile tongue, infusion was performed selectively into the lingual artery in 11 patients and selectively into the external carotid artery in six patients in whom tumor spread made semiselective infusion preferable. The ABI-007 colloidal suspension was injected for 30 min via an angiography injector.
The side used for femoral access was alternated at each infusion. After receiving an infusion, the patient was observed and then discharged the next day. Each treatment required a 3-day hospital stay, during which imaging was performed for tumor staging or for evaluation of tumor response. Weekly outpatient blood chemistry evaluations were prescribed to monitor toxicity.
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The angiography and chemotherapy procedure was successful in all patients and was reproducible for all cycles in all patients, except in the one patient who was unable to complete the treatment after two cycles because of the asymptomatic occlusion of the external carotid artery.
All 23 patients met the World Health Organization criteria for evaluation of tumor response applicable to the objective examination most suitable for evaluation of the tumor (physical examination or imaging). For organizational reasons, the imaging examination most frequently used was MDCT both without and with a contrast agent. Although judged adequate for tumor staging, MDCT failed to provide accurate information in patients in whom a significant objective response was observed (i.e, when a reduction in tumor volume was observed, particularly in tumors at the base of the tongue). Physical examinations and serial photographs compensated for this deficiency in evaluating the response of tumors of the mobile tongue. FDG PET was performed preliminarily and at the end of treatment in 15 patients (Figs. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J and 4A, 4B, 4C, 4D). We soon found FDG PET improved our evaluation of the objective response because the metabolic activity of that tumor could be detected on PET, even in patients in whom MDCT and physical examination showed no evidence of residual tumor.
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Of the six patients with tumors of the base of the tongue, four had partial responses, one had a complete clinical response (overall response rate, 83.3%), and one showed disease progression. Of the 17 patients with tumors of the mobile tongue, eight had partial responses, five had complete clinical responses (overall response rate, 76.5%), three had stable disease, and one showed disease progression. To date, 22 patients have received definitive local treatment: 14 patients underwent surgery, one received chemotherapy, and seven patients received radiotherapy. The remaining patient refused any further treatment.
Of the 16 patients who subsequently underwent surgery, the four who had been classified as having a complete clinical and radiologic response were found to have microscopic residual disease. In two patients, the residual disease measured less than 1 mm; in one, it measured less than 5 mm; and in one, it measured less than 1 cm. In the remaining 12 patients who underwent surgery (eight with partial response, three with stable disease, and one with disease progression), the residual disease was consistent in size with the physical and imaging evaluations. Surgical healing was not affected by the arterial infusions. After surgery, eight of the 16 patients received radiotherapy, and three received chemotherapy and radiotherapy.
Every three months, the patients have undergone follow-up examinations that included physical examinations, cervicofacial MDCT, and chest radiography. Follow-up findings for the 23 patients are as follows: Seventeen have had no recurrence during a follow-up period ranging from 3 to 23 months. One patient had a local recurrence 6 months after treatment ended. Another patient who showed disease progression after two cycles of intraarterial chemotherapy and who subsequently underwent surgery shows no sign of disease after 11 months. One patient with partial response refused further treatment and is alive 6 months later. Three patients died of disease progression in the lymph nodes 25, 8, and 5 months, respectively, after treatment.
Toxicities
Hematologic and nonhematologic toxicities of all types and grades were
evaluated according to World Health Organization criteria. The toxicities that
we recorded were typical of chemotherapy with taxanes and are well known in
systemic treatment [18]. The
most important expected toxicities are bone marrow depression and neuropathy,
most notably paresthesias, motor sensory deficits, and neuromuscular pain. The
minor toxicities observed with taxanes are alopecia, flulike syndrome,
keratitis, and generic gastrointestinal disturbances. Among the most serious
toxicities in our study were two cases of grade 3 hematologic toxicity (one at
the dose of 230 mg/m2 and the other at 180 mg/m2) and
two cases of neurologic toxicity (one at the dose of 230 mg/m2 and
one at 180 mg/m2). Both toxicities had an incidence of 8.6%.
The occurrences of hematologic toxicity did not require treatment changes. However, cases of neurologic toxicity required adjustment of the dose level. After the third infusion, one of the eight patients treated with a 230 mg/m2 dose developed peripheral paralysis of the facial nerve on the side that had received the infusion of ABI-007; therefore, we decreased the dose to 180 mg/m2 for all subsequent patients. Among the six patients treated at the lower dose, one more case of facial nerve paralysis occurred after the second infusion. In the first patient, the paralysis regressed over a 6-month period, whereas in the other patient, a partial regression has occurred over a period of 16 months. The two patients with facial nerve paralysis belonged to the group of 10 patients in whom the drug was infused into the external carotid artery without superselective catheterization. Nine patients subsequently received 150 mg/m2 without any further occurrence of neurologic toxicity.
Catheter-Related Complications
Two catheter-related complications occurred—one reversible
brachiofacial cerebral ischemic syndrome and one asymptomatic occlusion of the
external carotid artery. The brachiofacial cerebral ischemic syndrome was of
brief duration and regressed spontaneously without any interruption of
treatment. In our opinion, this incident was due to catheter manipulation near
a carotid bifurcation lined with soft atheromatous plaque. In the case of the
occluded external carotid artery, the patient was unable to receive the third
infusion.
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One of the major criticisms of neoadjuvant chemotherapy is that in reality the objective response in tumor size does not correlate with a true increase in tumor-free margins, and therefore, the impact on the prevention of recurrence is small. This disappointing outcome may be due to the development of drug resistance, which results in the persistence of viable tumor cell colonies [23].
Drug resistance can be overcome in part through increasing the dose or using more than one drug simultaneously. Both strategies lead to increased toxicity, and systemic administration of drugs has a narrower therapeutic window than does local or regional treatment with intraarterial injection of the same drugs. Therefore, some practices have returned to intraarterial treatment of tumors of the head and neck as the only modality that allows consistent differential exposure of the tumor to the chemotherapeutic agent while simultaneously reducing systemic exposure [24].
The objective clinical—radiologic responses of 91% [25] and 86% [11] reported in two recent studies with intraarterial administration of high-dose cisplatin in patients with squamous cell carcinoma of the head and neck were quite interesting, but histologic controls on the primary tumor are neither numerous nor complete. In one series, 10 of 58 patients who were treated underwent surgery, and complete pathologic response was found in three [25], whereas in another series, only multiple biopsies were performed in 11 of 13 patients with complete response, revealing viable tumor in six patients [11].
Today, along with the fluoropyrimidines, cisplatin, and its derivatives, a new class of drugs is available, the taxanes. This class of drugs, essentially paclitaxel and docetaxel (Aventis Pharma, Antony, France), has a particular mechanism of action that interferes selectively with the epidermal growth factor receptors expressed to a varying degree by squamous cell tumors [26]. Systemic use of taxanes has yielded encouraging results but no appreciable improvement in overall outcomes. A new formulation of the taxane paclitaxel incorporated into human albumin nanoparticles (ABI-007) [14] that are smaller than an RBC can be used for intraarterial administration without the premedication necessary for the commercially available formulations [27] and can be infused even into small arteries without causing discomfort. Tolerance of ABI-007 by the oral mucosa is excellent, and the general toxicity is acceptable.
The percentage (78%) of objective responses we achieved with intraarterial infusion of the new formulation of paclitaxel in patients with squamous cell carcinomas of the tongue was striking. In our study, the histologic findings in four patients with complete response who underwent surgery were particularly encouraging: microscopic tumor residue measured less than 1 mm in two patients, less than 5 mm in another patient, and less than 1 cm in another. In addition, one patient had superficial residual disease that measured less than 1 cm, was visible only at physical examination, and was removed completely during biopsy. This patient subsequently received radiotherapy. Reduction in the tumor mass was concentric, with no peripheral islands of residual tumor cells and with an excellent correlation among the clinical, radiologic, and histologic findings in surgical patients. Despite the small number of patients, we find it interesting that the five patients who underwent intraarterial chemotherapy followed by surgery alone have shown no evidence of disease during a follow-up period that ranges from 3 to 20 months (mean, 12.8 months).
The response to treatment appears to be dependent on the individual patient, possibly because of differences in expression of epidermal growth factor by the tumor that ultimately affects drug uptake. In fact, human albumin is the principal source of energy for the tumor cell and is actively transported across the cell membrane by a mechanism that is not saturable and is probably modulated by growth factor receptors [28, 29]. The small number of patients in our study did not allow us to perform a statistical analysis, but we found no correlation between the dose or number of treatments received and tumor response, with a good response rate being maintained even at the lowest dose level.
Although tumors of the head and neck can be staged with considerable confidence using volumetric CT, in our experience, evaluation of the therapeutic response of tumors of the oral cavity, particularly those of the tongue, can be challenging with this technique. Malignancies deep in the tissues are difficult to evaluate on CT. In view of these limitations, we decided to use FDG PET [30, 31] in our study whenever possible. This noninvasive functional tomographic procedure not only integrates well with the other methods but also contributes additional diagnostic information that is not based on an anatomic or morphologic evaluation of the disease but rather on its metabolic changes.
FDG is a fluorine-18—labeled analog of endogenous glucose, a substance that has been widely used in clinical settings. This marker is taken up extensively by most malignant tumors and provides useful information not only on the site and extension of the disease but also on its biologic aggressiveness. Studies in experimental and clinical tumor models have shown a correlation between FDG accumulation and tumor cell viability. Therefore, evaluation of FDG up-take before and after treatment can provide important information, accurately documenting the extent of the therapeutic response.
FDG PET was performed in 15 patients who had been examined with MDCT. In seven of these patients, FDG PET was judged by consensus of all the authors to show greater diagnostic accuracy than MDCT. Seven of the 15 patients who had an FDG PET scan subsequently underwent surgery. In five patients, FDG PET findings were found to coincide with histologic evaluation of the surgical specimen and to depict residual disease more precisely than did MDCT. In the other two patients, FDG PET findings were negative, as were MDCT findings; histologic examination revealed microscopic tumor residue in one patient and residual disease measuring less than 1 cm in the other. FDG PET also showed an objective response in regional lymph node metastases, documenting a systemic effect of intraarterial chemotherapy. These encouraging results warrant further investigation of this technique for assessment of response in tumors of the head and neck, which pose particular problems because of the complexity of the anatomy in that region.
Paclitaxel in albumin nanoparticles is well tolerated, requires no premedication, and can be administered in 30 min by selective arterial catheterization in a dose equivalent to that of IV administration regimens that are based mainly on a 5-hr infusion.
Among the expected toxicities, the most significant was not hematologic toxicity, as is the case with systemic administration but rather neurologic toxicity, with two peripheral paralyses of the facial nerve (8.6%) on the side of drug administration. In one patient, nerve function recovered completely over a 6-month period, whereas in the other patient, the paralysis of the facial nerve has not completely regressed at the time of writing, 16 months from onset of the paralysis.
Both cases of paralysis of the facial nerve occurred in patients in whom arterial chemotherapy was performed by injecting the drug into the external carotid artery. In its extracranial course, the facial nerve is fed by the stylomastoid branches of the occipital artery and by the posterior auricular arteries that originate from the external carotid artery. However, in some patients, the facial nerve may be vascularized by the middle meningeal artery that originates from the internal carotid artery. In this case, the facial nerve would be protected because the drug is injected into the external carotid artery [32]. None of the patients with tumors of the tongue in whom it was possible and desirable to administer paclitaxel into the lingual artery experienced facial paralysis, probably because the facial nerve either was not exposed to the drug or was exposed to a lesser extent than in the two patients who developed paralysis.
Neurotoxicity after systemic administration of drugs has been reported for other cranial nerves such as the optic nerve [33, 34], but the facial nerve is undoubtedly particularly sensitive [35]. In one reported case of bilateral facial paralysis during systemic administration of Taxol [36], the paralysis regressed over a long period (23 months). The mechanism of the neurologic toxicity has not yet been elucidated, but the cause is thought to be the damage by the drug to the microtubular apparatus of the cell, leading to compromised cell mitosis not only in tumor tissues but also in various tissues including the dorsal ganglia, axons, and Schwann cells. Experience with systemic use of Taxol has led to the conclusion that the neurotoxicity is generally cumulative, moderate, and rare when the systemic doses are between 135 and 175 mg/m2 [34].
A dose of 150 mg/m2, which we propose for intraarterial administration in further studies, represents a compromise between maintenance of therapeutic efficacy and acceptable toxicity, without the allergic reactions reported with the currently available commercial formulations of paclitaxel [18]. Performing transfemoral percutaneous catheterization of the neck vessels undoubtedly requires experience, organization, and availability of materials, but the procedure has proven highly reproducible with a low complication rate. The significant objective response achieved in our series makes intraarterial infusion of paclitaxel in albumin nanoparticles by percutaneous catheterization a promising new alternative to existing modalities as a preliminary induction therapy for squamous cell tumors of the tongue. Our patient population was small and the follow-up period was too short to allow evaluation of the impact of this treatment on tumor recurrence and life expectancy. However, because this treatment does not interfere with and can potentially be integrated into other therapeutic options, it deserves further investigation in combination with radiotherapy or other drugs or both in patients with advanced tumors of the tongue before they undergo surgery, with a view to preservation of organ function.
Acknowledgments
We thank Patrick Soon-Shiong and Neil Desai, the inventors of ABI-007;
Angelo Nicolin for encouragement and suggestions; Marco Falciani, Giuseppe
Grossi, Gianni Brega, Carlo Gerosa, and Raffaele Attianese without whose
support this study would not have been possible; Maura Francolini for the
electron microscopy studies; Sauro Ceccarini and Pier Luigi Gatto for the
photography and illustration; and Flora Stivan and Mary Trotter for assistance
in preparation of the manuscript.
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