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Microvascular Transplantation and Replantation of the Rabbit Submandibular Gland
Jeffrey H. Spiegel, MD;
Daniel G. Deschler, MD;
Mack L. Cheney, MD
Arch Otolaryngol Head Neck Surg. 2001;127:991-996.
ABSTRACT
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Background Xerostomia is a devastating complication of radiation therapy. Previous
research has demonstrated that submandibular glands may be removed from the
neck and transplanted using microvascular techniques, with good gland survival.
However, microvascular transplantation and replantation has never been attempted
on a composite tissue such as a salivary gland.
Objective To evaluate the ability of a rabbit submandibular gland to undergo 2
successive microvascular transplantations.
Subjects and Design Study rabbits underwent a midline neck incision with dissection of a
submandibular gland to its arterial and venous pedicle. Microvascular techniques
were then used to transplant the gland to the femoral system of the right
groin. The incisions were reopened later under surgical conditions. The transferred
gland was examined for survival and patency of its artery and vein. Healthy
glands were dissected and transferred to a suitable artery and vein within
the neck, where they were again reanastamosed using microvascular surgical
techniques. After additional time, the gland was again examined for survival
and pedicle patency, then removed and evaluated for histopathological evidence
of survival.
Results Surgical technique evolved during the course of this work to avoid encountered
pitfalls. After refining the technique, we have determined that the rabbit
submandibular gland is able to withstand successive microvascular transplantation
and replantation with good likelihood of long-term survival, according to
histopathological criteria.
Conclusions The rabbit submandibular gland is able to undergo microvascular transplantation
and replantation with evidence of long-term survivability and preserved function.
The body's natural response to surgery and tissue transplantation makes replantation
a technical challenge; however, methods delineated herein alleviate many of
the potential pitfalls. Extending these results to humans, patients who are
to undergo radiation therapy could have a disease-free gland removed from
the neck, transferred outside of the field of radiation, and then returned
to the neck at the completion of radiation therapy. This may enable them to
maintain salivary gland function and maintain oral cavity function and comfort.
INTRODUCTION
XEROSTOMIA IS a devastating complication of radiation therapy to the
upper aerodigestive tract. Patients receiving as little as 1000 to 2000 rad
(10-20 Gy) suffer substantial discomfort and functional loss, whereas those
receiving 3500 rad (35 Gy) must endure a permanent loss of saliva, as less
than 7% of normal salivary flow will remain.1-3
Typically, these patients can be expected to experience dry mouth, thick mucus,
dysphagia, odynophagia, difficulty with speech, and a painful burning sensation.4-5 As the protective barrier of saliva
is lost, dental caries result, as well as candidiasis, esophagitis, and increased
gastroesophageal reflux.6-8
Treatment of xerostomia represents a significant challenge, and many
treatment modalities have been tried. These include the use of artificial
saliva substitutes, saliva storage, electrostimulation of salivary flow, and
acupuncture.8-10
Medical treatments have focused on stimulation of remnant glandular tissue.
Pilocarpine hydrochloride is the most widely available medical treatment for
xerostomia, but unfortunately only seems to increase saliva for a limited
time after administration, and most patients need to continue pilocarpine
therapy simultaneously with other symptomatic treatments.1, 11
As stimulation of residual glandular tissue has provided only moderate
improvement, prevention of xerostomia has become a focus for some investigators.
When possible, salivary glands are excluded from radiation fields, or lead
shields are used to minimize exposure. Unfortunately, altering treatment fields
and diminishing radiation doses can compromise the oncologic treatment of
the radiation therapy. A new agent being examined for prevention of radiation-induced
mucositis and protection of salivary glands is the free thiol amifostine.
Amifostine has been approved by the US Food and Drug Administration for study
of its possible protection against cisplatin-induced nephrotoxicity. In addition,
some work, predominantly done in Germany, has evaluated the ability of amifostine
to reduce xerostomia resulting from radiochemotherapy for head and neck tumors
and high-dose radioiodine therapy for thyroid tumors.12-13
Initial studies have found decreased subjective complaints of xerostomia and
improved salivary gland function by sialoscintigraphy findings in patients
receiving the drug during radiochemotherapy.12
Similarly, rabbits receiving high-dose radioiodine therapy had a 46% to 63%
decrease in salivary gland function. This decrease was not noted in rabbits
receiving amifostine.13
To preserve salivary gland function, Jha et al14
have reported transferring a submandibular gland into the anterior submental
space to move the gland outside the radiation field. Sixteen patients with
carcinoma of the larynx, oropharynx, or hypopharynx without previous irradiation
underwent selective neck dissection of 1 submandibular gland, which was left
pedicled on the distal aspects of the facial artery and vein. The gland, remaining
attached to the submandibular ganglion, was then rotated anteriorly beneath
the anterior belly of the digastric muscle, where it received nutrients via
retrograde flow. Clips were placed to mark the gland during radiation treatment
planning. These researchers found that xerostomia did not develop in their
patients and that they had a more mild overall radiotherapy course, with decreased
weight loss and mucositis that was less than usual.14
Other approaches to the treatment of xerostomia have focused on the
restoration of salivary gland function to the oral cavity. Krause et al15 injected a suspension of immortalized parotid acinar
cells beneath the oral mucosa of rats and noted cell survival after 30 days.
Unfortunately, duct formation did not occur and these cells proved to be of
little functional benefit. Similar work performed by Greer et al16
found that hamster salivary gland tissue placed as a free autogenous graft
into the cheek pouch can demonstrate histological evidence of viability. Again,
these authors note that subsequent practical function of such glands is unclear.
Similarly, sublingual glands have been transferred as a free graft (no
microvascular reanastamosis) to the fornix of the eye of rabbits as treatment
for xerophthalmia.17 These glands atrophied,
and only minimal acinar regeneration was shown. In a human trial of a similar
technique, in 5 patients only 3 glands survived, and of these, only 1 maintained
any function.17 The authors then used microvascular
techniques to transfer revascularized submandibular glands to the lacrimal
basin. Of 3 patients, 1 patient experienced duct stenosis as a technical surgical
failure, and 2 patients had success receiving enhanced corneal humidity.
This success prompted Kumar et al18 to
perform a rabbit study to evaluate submandibular gland transplantation for
the treatment of xerophthalmia. Their treatment group experienced decreased
corneal ulceration, and 75% of transplanted gland remained at least 50% functional
after transplantation. MacLeod and Robbins19
followed this with a similar procedure in 8 human patients, 7 of whom reported
significant improvement in their xerophthalmia, several with complete cessation
of other treatments. Viability of transplanted salivary glands has also been
demonstrated in a rat model.20
Lauer et al21 and Geerling et al22 have each described the same 20 to 22 patients who
underwent microvascular submandibular gland transplantation for the treatment
of xerophthalmia. They reported 88% gland survival at 3 months and 75% survival
after 1 year. Of those patients with viable transplants, 75% were able to
stop using eye drops, and epiphora even developed in some, requiring surgical
reduction of gland size.
Follow-up reports by Sieg and Geerling23
and Geerling and Sieg24 contain details of
30 transplants with 25 viable glands. Epiphora developed in 10 patients, which
resulted in microcystic epithelial edema. This was thought to be due to the
relative hypotonicity of saliva vs normal tears; nonetheless, the authors
conclude that salivary gland transfer is suitable treatment for severe keratoconjunctivitis
sicca.
As inferred by the work of Jha et al,14
a single preserved submandibular gland provides adequate protection against
xerostomia. This is consistent with studies of gland physiology, which show
that the paired submandibular glands produce more than 70% of total salivary
volume.25-29
The submandibular gland receives its blood supply through branches of the
facial artery and vein and parasympathetic innervation via the submandibular
ganglion off the lingual nerve. Sympathetic innervation is along a plexus
following the facial artery. The gland drains into the oral cavity through
a duct, and salivary flow is maintained with advancing age (when flow volume
is controlled for medication use).30-31
On the basis of work initiated in a rat model, Spiegel et al20 hypothesized that xerostomia could be prevented by
protecting a submandibular gland outside of head and neck radiation fields
during the course of radiotherapy, and then by replacing that gland at the
conclusion of treatment. Microvascular transplantation of the gland to the
groin, followed by replantation to the neck, would ensure survival of the
gland during the period of cancer treatment.
Although microneurovascular tissue transplantation is used for reconstruction
of many surgical, traumatic, and congenital defects, microsurgical techniques
to permit the heterotopic protective storage of tissue have not been explored.
This study was designed to evaluate the viability of the rabbit submandibular
gland after 2 successive microvascular transplantations. Technical challenges
have encouraged the evolution of a more precise surgical method that permits
successful transfer and replantation.
MATERIALS AND METHODS
Six female white rabbits (Oryctolagus cuniculus;
weight approximately 4 kg each) were used in this study. All work was approved
by our institutional research board and animal care committee.
Each rabbit was anesthetized by pretreatment with acepromazine maleate,
1 mg/kg, followed by ketamine hydrochloride, 30 mg/kg, and xylazine hydrochloride,
7 mg/kg, given intramuscularly. Animals were then shaved in the neck and groin
bilaterally and prepared for surgery using povidone-iodine (Betadine) solution.
Each animal received 300 000 U of intramuscular penicillin G benzathine
before incision.
A paramedian incision was made along the right groin and the inferior
epigastric vessels were identified. These were used to locate the femoral
artery and vein, which were then dissected free of surrounding tissues using
magnification from an operating microscope. Injury to the femoral nerve was
avoided. The distal artery and vein were ligated, and the proximal ends were
then clamped with size 2V microvascular clamps and divided.
A midline incision was then made along the ventral surface of the neck,
and self-retaining retractors were placed. A microscope was used for subsequent
dissection. The right salivary gland was dissected to identify its duct, artery,
and vein. The vessels were followed to their origins at the external carotid
artery and internal jugular vein. A battery-powered, handheld cautery was
used to assist with hemostasis. These larger vessels were selected, as the
rabbit facial artery and vein have diameters of less than 1 mm. At this point,
the distal external carotid artery and internal jugular vein and then the
proximal aspects of these vessels were ligated and divided. The duct was divided
without ligation. This provided a free gland that could be removed from the
neck. The neck was irrigated with isotonic sodium chloride solution and closed
using running polypropylene (Prolene; Ethicon, Inc, Somerville, NJ) suture.
With the use of microvascular techniques, 10-0 nylon suture was used
to reanastamose the femoral artery to the external carotid artery and the
femoral vein to the internal jugular vein. Care was taken to avoid twisting
the pedicle. When anastamoses were complete, the vascular clamps were released
and the anastomoses were inspected. Good flow was ensured and small leaks
were repaired using 10-0 nylon suture. When a successful transfer was obtained,
the gland was sutured to the muscles of the leg to maintain good vessel position,
and the wound was irrigated, then closed using running polypropylene suture.
Animals were then returned to the animal care facility for recovery.
After a period ranging from 3 to 14 days, the animals were anesthetized
in the same manner and the transplant site was reopened. The transferred gland
was evaluated grossly as to overall viability, function (presence of a sialocele),
and patency of the pedicle vessels. The midline neck incision was then reopened,
and the gland on the contralateral side was dissected to the external carotid
artery and internal jugular vein. The distal ends of these vessels were ligated
and divided after placing 2V vascular clamps on the proximal ends. With the
recipient bed thus prepared, the femoral artery and vein at the groin transfer
site were ligated proximally and then cut for transfer of the gland back to
the neck.
Once the gland was transferred to the neck, a microvascular anastamosis
was performed using 10-0 nylon suture of the femoral artery to the external
carotid artery, and of the femoral vein to the internal jugular vein. Clamps
were then removed and blood flow through the gland was assessed. When blood
flow was deemed adequate, the wound was irrigated and the gland was sutured
to the deep neck musculature to ensure proper vessel orientation. The neck
and groin incisions were then closed using 3-0 polypropylene suture.
After an additional 4 days, the rabbit was anesthetized and the neck
wound was opened. The gland was evaluated grossly for viability and pedicle
patency. The gland was then removed and placed in formalin for histopathological
evaluation.
RESULTS
Six rabbits were used in this experiment, and they underwent operation
successively, rather than simultaneously. This serial approach proved very
important, as the surgical technique required frequent modification to achieve
eventual success. Table 1 describes
the surgical course and outcome of each rabbit.
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Rabbit Surgical Course and Outcome
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Rabbit 1 underwent an aborted first transplantation, as the small arterial
branches of the submandibular artery (diameter, <0.5 mm between the facial
artery and gland) were damaged during dissection. This occurred as the arterial
and venous branches were separated to follow them back to the external carotid
artery and internal jugular vein. Surgical procedure was thus modified at
this point to eliminate dissection of the feeder vessels and to begin dissection
with the external carotid artery and internal jugular vein, and then to keep
the smaller branches off these as an undissected bundle. Only the duct was
dissected as a separate structure.
Rabbit 2 underwent a successful transplantation of the right gland to
the right groin. After 10 days, the groin was reopened and a large sialocele
was identified originating from the free end of the submandibular gland duct.
The gland appeared grossly viable. However, during dissection of the pedicle
for transplantation back to the neck, the submandibular artery was injured.
This occurred during dissection through inflamed and scarred tissue to identify
the site of initial anastamosis. As a result of this development, surgical
technique was modified to anastamose the gland to a very distal point along
the femoral vessels. This was done in anticipation of being able to work with
the previously undissected proximal portions of the femoral vessels for the
replantation, and thus to obviate the need to dissect around the submandibular
branches.
Rabbit 3 underwent successful transplantation of the right gland to
the right groin, as evidenced by a grossly viable gland and a moderate sialocele
on inspection at 14 days. The left salivary gland was damaged at the time
of removal of the right gland, and was thus removed at the time of the initial
procedure. On 14-day inspection, again, significant scarring was present around
the femoral vessels, but the proximal vessels were isolated. Dissection of
the gland from the muscle bed proved very difficult in the inflamed scar tissue,
but the gland was nonetheless removed. Reanastamosis to the left groin femoral
vessels was performed, as we believed that damage to the remaining left submandibular
gland would make finding vessels in the neck difficult. After 4 days, the
gland was reevaluated, appeared viable, and was removed for pathological evaluation.
Rabbit 4 underwent successful transplantation of the right gland to
the right groin, and after 14 days, it had a viable gland with moderate sialocele
and significant scarring. Despite planning to use the proximal femoral vessels,
the scarring was too significant and the femoral vessels were damaged during
gland harvest.
At this point, it was determined that scarring and inflammation needed
to be curtailed to allow for a successful return transfer. These problems
were magnified by the need to dissect through thigh muscle to isolate the
femoral vessels, and by the lack of duct drainage outside the wound. Previous
rat experimentation demonstrated that a successful transplant was feasible
without duct repair; however, in the rabbit model, this proved to cause too
much inflammation to permit successful repeated dissection.20
Thus, the surgical technique was modified to place a segment of sterile latex
glove beneath the gland and between the femoral vessels and the thigh muscle
bed. This prevented adherence of the gland and its vasculature to the underlying
tissues. In addition, the time between transplant and return was decreased.
Three days has proved to be adequate time to determine the success of a microvascular
transplant.20
Rabbit 5 underwent successful transplantation of the right gland to
the right groin. After 3 days, the wound was inspected and the distal end
of the wound had been opened. Apparently, the rabbit chewed out the distal-most
sutures and opened approximately one third of the wound. In addition, the
rabbit had chewed through the distal sutures that held the gland to the thigh
musculature. On inspection, the gland appeared to be nonviable. No sialocele
was present. The glove segment was present and permitted dissection and inspection
of the anastamoses. These were intact with good flow. However, with inadequate
suturing to the thigh bed, the gland had twisted and kinked the submandibular
vessels off the external carotid artery. Surgical technique was again modified
to suture the gland more securely to the surrounding tissues (over the glove
segment), to prevent twisting and vascular compromise.
Rabbit 6 underwent successful transplantation of the right gland to
the right groin. After 3 days, this rabbit underwent evaluation, and again
the distal segment of the wound (approximately one third) was devoid of sutures
and open. Nonetheless, the gland was grossly viable and a moderate sialocele
was present. The latex glove segment that had been placed beneath the gland
was removed and a clear plane was visible. This greatly facilitated dissection
of the gland and more proximal femoral vessels. The neck was then reopened,
and the left salivary gland was dissected to its external carotid artery and
internal jugular vein pedicle. The left gland was removed, and then the former
right gland was anastamosed to the left-side vasculature on transplantation
from the right groin. After 4 days, the neck was reopened and a large sialocele
was visible. The gland appeared grossly viable and the vessels demonstrated
good flow. This gland was then removed and sent for pathological evaluation.
Thus, 5 rabbits had at least 1 transferred gland. Of these, all were
initially successful, but only 4 were viable on reinspection (1 gland twisted
and had kinked vessels). Presence of a sialocele is interpreted as gross evidence
of preserved gland function. Three rabbits had significant scarring at the
groin donor site, and only 1 of these underwent a successful replantation.
Two rabbits had placement of a glove segment to decrease scarring between
the gland and recipient bed. Of these, both had easily dissected glands and
good flow through the anastamoses. However, 1 segment twisted, so only 1 of
the 2 underwent successful replantation to the neck.
Histopathological evaluation of hemotoxylin-eosin stains was performed
on all removed glands. Rabbit 1 showed normal architecture consistent with
gland excision. Rabbits 2 and 4 demonstrated mild inflammation and minimal
ischemic injury, as manifested by some acinar loss and vacuolization. Rabbit
5 showed marked ischemic injury with inflammatory infiltrate; acini seen were
atrophic and necrotic. Evaluation demonstrated that the 2 glands with 2 successful
transplantations (rabbits 3 and 6) showed good preservation of gland architecture
with some inflammation (Figure 1). Acinar structure was maintained with minimal damage. Ducts remained patent,
and no evidence of endothelial injury was seen within the microvasculature.
This is thought to be consistent with, at most, mild ischemic damage and predictive
of good long-term survival of the transplanted organ.
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Replanted gland in rabbit 6. Tissue architecture includes patent
ducts and microvasculature and normal acinar lobules (hematoxylin-eosin, magnification
unknown).
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COMMENT
Transplantation of the submandibular gland by using microvascular techniques
is feasible and can be shown in rat and rabbit models to maintain a cellular
structure predictive of long-term gland survival.20
The surgical techniques are straightforward and consistent with those used
throughout microsurgical procedures. However, to our knowledge, replantation
of a transplanted organ has not been reported and requires several variations
in surgical technique.
Several problems encountered are particular to the animal model. The
very small vessel size for the submandibular vasculature in the rabbit necessitates
dissection of the larger vessels from which they originate. However, the small
vessels remain susceptible to injury during initial dissection and all subsequent
manipulation. In humans, the submandibular gland vasculature (facial artery
and vein) is larger and more easily handled. Nonetheless, minimizing dissection
of gland vessels close to the parenchyma of the organ would seem prudent.
In addition, animals are often able to chew through sutures and open
surgical incisions. The presence of thick fur makes placement of an occlusive
dressing over the wound difficult. In future studies, the use of surgical
skin staples may better protect closure of the groin incision. An increased
number of sutures between the gland and the groin wound bed can better protect
the gland from changing position should the skin incision open.
The most significant difficulty encountered was the robust scar tissue
formation at the groin transplant site. This was eventually circumvented by
placement of a segment of latex glove beneath the gland. Several factors contribute
to this scar tissue formation, but perhaps the 2 most significant reasons
are no drainage port for saliva and dissection through muscle.
The small size of the rabbit submandibular gland duct prevented us from
restoring drainage by suturing the duct to the external groin skin. In addition,
previous experience with rat submandibular gland transfer demonstrated that
the gland could withstand the presence of a local sialocele.20
Although this may be the case when evaluating a single transfer, replantation
requires a more pristine recipient bed. Second, a vigorous scar reaction developed
along the raw muscle edges formed during preparation of the femoral vessels
for involvement in the anastamoses. Vessels surrounded by fat or fascia (eg,
the rabbit external carotid system) were less likely to exhibit dense scar
formation.
In humans, the inferior epigastric vessels could be selected for an
initial transplantation site for a submandibular gland to be banked during
head and neck radiation therapy. These vessels are typically surrounded by
fat and thus should be more easily dissected on subsequent evaluation. In
addition, the human submandibular gland duct should be spatulated and sutured
to the groin skin to permit drainage of saliva outside the wound. This would
also provide a monitor of gland function. On subsequent replantation to the
oral cavity, a small segment of abdominal wall skin could be taken around
the duct drainage site to preserve the length of the duct and to make reanastamosis
of the duct drainage port to the oral cavity easier. Still, placement of a
sterile segment of Silastic sheeting around the gland and vessels may greatly
facilitate dissection for replantation to the neck.
The paired submandibular glands produce 70% of the total saliva.25-29
Previous work has demonstrated that a transferred and deinnervated gland produces
adequate salivary flow to protect the cornea. Furthermore, if additional saliva
was necessary, light pressure on the transferred gland resulted in expression
of the necessary moisture. It is certainly technically possible to tag the
submandibular ganglion at the time of gland resection and to plan on reanastamosis
during replantation, but the success and necessity of this maneuver is unknown.
Xerostomia is a very distressing problem for affected patients and is
commonly the most frequent complaint of patients who have undergone head and
neck radiation therapy. As described, current therapeutic options provide
limited relief. The proposed procedure of microvascular transplantation and
replantation of a salivary gland to protect it from the radiation field is
technically challenging. However, identifying the vascular pedicle of the
human submandibular gland is a common procedure for otolaryngologists (a standard
part of submandibular gland excision), and the vessels are of relatively large
diameter.
Microvascular tissue transfer is often considered to be a very time-consuming
and thus expensive undertaking. Much of the time involved in microvascular
free-tissue transfer is spent properly insetting the flap or contouring the
tissue to provide the best possible anatomic and functional reconstruction.
In addition, closing the donor site can be slow and often requires obtaining
a split-thickness skin graft. In comparison, the proposed procedure can be
predicted to be relatively quick. Resection of the submandibular gland is
not particularly time-consuming, and the recipient vessels in the groin are
readily identified. In addition, no complicated inset is required and the
skin incisions are short. Replantation will require more time, as dissection
will occur in sites undergoing previous operation and full-course radiation.
Clearly, the cost associated with 2 procedures is higher than the cost
of a lifetime of water bottles. Similarly, the cost of a fibula free flap
for reconstruction of a hemimandibulectomy is greater than that incurred in
providing no mandible reconstruction. In each case, the patient's anatomic
and functional rehabilitation is maximized, thus increasing their quality
of life.
CONCLUSIONS
Histological findings consistent with a prediction for long-term survival
in multiple transplanted glands are encouraging. To our knowledge, no previous
work on multiple transplantations of composite organs via microvascular techniques
have been published. This rabbit pilot study has provided many insights into
problems that may develop during multiple transplantations of a single organ.
Many of these problems are unique to an animal model.
Xerostomia remains a difficult sequela of head and neck radiation therapy.
Removal of a gland to a site distant from the head and neck will effectively
protect the organ from radiation damage. Return of the gland at the completion
of treatment can be predicted to provide adequate saliva to eliminate the
devastating effects of xerostomia.
AUTHOR INFORMATION
Accepted for publication March 17, 2001.
Corresponding author: Jeffrey H. Spiegel, MD, Department of Otolaryngology–Head
and Neck Surgery, Boston University School of Medicine, D-616, 88 E Newton
St, Boston, MA 02118 (e-mail: jeffrey.spiegel{at}bmc.org).
From the Richard C. Webster Division of Facial Plastic and Reconstructive
Surgery, Department of Otolaryngology–Head and Neck Surgery, Boston
University School of Medicine (Dr Spiegel), and the Division of Facial Plastic
and Reconstructive Surgery (Dr Cheney), Department of Otolaryngology–Head
and Neck Surgery (Dr Deschler), Massachusetts Eye and Ear Infirmary, Harvard
Medical School, Boston, Mass.
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