Long-term quality of life after surgery of head and neck cancer with microvascular reconstruction: a prospective study with 4.9-years follow-up.

PURPOSE: The aim of this study was to evaluate the long-term health-related quality of life (HRQoL) of head and neck cancer patients with microvascular surgery. Surgical treatment causes great changes in patient HRQoL. Studies focusing on long-term HRQoL after microvascular reconstruction for head and neck cancer patients are scarce. METHODS: We conducted a prospective study of 93 patients with head and neck cancer and microvascular reconstruction in Helsinki University Hospital Finland. HRQoL was measured using the 15D instrument at baseline and after a mean 4.9-years follow up. Results were compared with those of an age-standardized general population. RESULTS: Of the 93 patients, 61 (66%) were alive after follow-up; of these, 42 (69%) answered the follow-up questionnaire. The median time between surgery and HRQoL assessment was 4.9 years (range 3.7-7.8 years). The mean 15D score of all patients (n = 42) at the 4.9-years follow up was statistically significantly (p = 0.010) and clinically importantly lower than at baseline. The dimensions of "speech" and "usual activities" were significantly impaired at the end of follow up. There was a significant difference at the 4.9-years follow-up in the mean 15D score between patients and the general population (p = 0.014). After follow up, patients were significantly (p < 0.05) worse off on the dimensions of "speech," "eating," and "usual activities." CONCLUSIONS: Long-term HRQoL was significantly reduced in the whole patient cohort. Speech and usual activities were the most affected dimensions in head and neck cancer patients with microvascular reconstruction at the end of the 4.9-years follow up.

Complications and loss of free flaps after reconstructions for oral cancer.

The aim of this retrospective study was to analyse the incidence of complications and loss of flaps after primary reconstructions for oral cancer in 191 patients at our hospital over the five years 2005-2010. The patients' clinical and personal details, characteristics of the tumours, types of microvascular flap, complications, and outcomes were recorded. The soft tissue flaps used most often were the fasciocutaneous radial forearm free flap (RFFF) (n=86, 45%) and the anterolateral thigh free flap (ALTFF) (n=48, 25%) while the most commonly used osseous flap was the deep circumflex iliac artery flap (DCIA) (n=25, 13%). There were postoperative complications that required intervention in a quarter of the patients, most often in the age group 41-50 years (p=0.018). Older age was not associated with the development of complications. The overall survival of all free flaps was 181/191 (95%), and the only significant individual predictor of loss of a flap was reconstruction with a DCIA (p=0.016), five of the 25 of which were lost. We conclude therefore that DCIA free flaps are associated with an increased risk of failure; the method of osseous reconstruction for maxillofacial reconstruction should be selected carefully; and carefully chosen older patients do not seem to be at increased risk of morbidity.

Postoperative nausea and vomiting in facial fracture patients: A Randomized and controlled trial on the effect of dexamethasone.

This study aimed to establish the incidence of postoperative nausea and vomiting (PONV) in facial fracture patients. The specific aim was to investigate the effect of perioperative dexamethasone on PONV. A total of 119 adult patients with facial fractures were analysed in this prospective study. Patients were randomized to receive perioperatively either a total dose of 30mg of dexamethasone i.v. and i.m., or no glucocorticoid (control). PONV was evaluated every 6hours during the first postoperative 24hours and when pain medications were given. PONV occurred in 20 out of 119 patients (16.8%). The only significant (P=0.016) association with PONV was postoperative administration of opioids. Slightly more cases of PONV occurred for patients who had not received dexamethasone (20%) compared to those who had (13.6%). PONV was also non-significantly more common in patients ≥40 years (21.3%) than in patients < 40 years (12.1%), after orbital floor reconstruction (28.0%) compared with mandibular (11.6%) and zygomatic (15.6%) fractures surgeries, and also after anaesthesia lasting >97minutes (21.7%) compared with a shorter duration (11.3%). Alternative medications should be used for prevention of post-surgery nausea and vomiting in facial fracture patients.

Dexamethasone in head and neck cancer patients with microvascular reconstruction: No benefit, more complications.

OBJECTIVES: Glucocorticoids are widely used in association with major surgery of the head and neck to improve postoperative rehabilitation, shorten intensive care unit and hospital stay, and reduce neck swelling. This study aimed to clarify whether peri- and postoperative use of dexamethasone in reconstructive head and neck cancer surgery is associated with any advantages or disadvantages. MATERIALS AND METHODS: This prospective double-blind randomized controlled trial comprised 93 patients. A total dose of 60mg of dexamethasone was administered to 51 patients over three days peri- and postoperatively. The remaining 42 patients served as controls. The main primary outcome variables were neck swelling, length of intensive care unit and hospital stay, duration of intubation or tracheostomy, and delay to start of possible radiotherapy. Complications were also recorded. RESULTS: No statistical differences emerged between the two groups in any of the main primary outcome variables. However, there were more major complications, especially infections, needing secondary surgery within three weeks of the operation in patients receiving dexamethasone than in control patients (27% vs. 7%, p=0.012). CONCLUSIONS: The use of dexamethasone in oral cancer patients with microvascular reconstruction did not provide a benefit. More major complications, especially infections, occurred in patients receiving dexamethasone. Our data thus do not support the use of peri- and postoperative dexamethasone in oropharyngeal cancer patients undergoing microvascular reconstruction.

CT findings of necrotizing sialometaplasia.

An otherwise healthy 56-year-old Caucasian female was referred to the radiology department because of an ulceration of her palatal mucosa. Clinically the lesion was suspected to be malignant and a multislice CT examination of the head and neck region was performed. This revealed an ulcer-like cavity with no tumour-like contrast enhancement. No relevant bone changes or suspicious lymph nodes of the neck were detected. Based on the multislice CT findings, necrotizing sialometaplasia was suspected and the diagnosis was verified histopathologically. This report describes the CT findings of necrotizing sialometaplasia at the ulceration stage.

Occurrence and types of dental injuries among patients with maxillofacial fractures.

The aim of this retrospective study was to clarify the occurrence and types of dental injuries in 389 patients who had been diagnosed with facial fractures, and to analyze whether the occurrence of dental injury correlates to gender, age, trauma mechanism and type of facial fracture. Dental injuries were observed in 62 patients (16%). The most common type of injury was a crown fracture (48%). Dental injuries were multiple in most patients (63%). Almost half (48%) of all injured teeth were severely injured. Most injured teeth (61%) were in the maxilla. The incisor region was the most prevalent site in both the mandible (45%) and the maxilla (56%). The occurrence of dental injury correlated significantly with trauma mechanism and fracture type: motor vehicle accidents and mandibular fracture were significant predictors for dental trauma. The notable rate of dental injury observed in the present study emphasizes the importance of a thorough examination of the oral cavity in all patients who have sustained facial fracture. Referral to a dental practice for further treatment and follow up as soon as possible after discharge from hospital is fundamental.

Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells.

Microvascular reconstruction is the state-of-the-art in many fields of defect surgery today. Currently, reconstruction of large bony defects involves harvesting of autologous bone causing donor site morbidity and risk of infection. Specifically, utilizing autologous adipose stem cells (autoASCs), large quantities of cells can be retrieved for cell therapy applications and the risk of tissue rejection is diminished. The authors describe the first case report of a microvascular custom-made ectopic bone flap employing good manufacturing practice (GMP) level ASCs. The patient underwent a hemimaxillectomy due to a large keratocyst. After 36 months of follow-up, the defect was reconstructed with a microvascular flap using autoASCs, beta-tricalcium phosphate and bone morphogenetic protein-2. ASCs were isolated and expanded in clean room facilities according to GMP standards and were characterized in vitro. After 8 months of follow-up, the flap had developed mature bone structures and vasculature and was transplanted into the defect area. Postoperative healing has been uneventful, and further rehabilitation with dental implants has been started. The in vitro characterization demonstrated multipotentiality and mesenchymal stem cell characteristics in ASCs. This is the first clinical case where ectopic bone was produced using autoASCs in microvascular reconstruction surgery and it will pave way for new clinical trials in the field.

Protein kinase C expression in salivary gland acinar epithelial cells in non-obese diabetic mice, an experimental model for Sjögren's syndrome.

We planned to investigate the expression of protein kinase C (PKC) isoforms in acinar epithelial cells of salivary glands in the non-obese diabetic (NOD) mouse to find out if they develop changes of the PKC system like those seen in the human counterpart, i.e. in Sjögren's syndrome. Parotid, submandibular, and sublingual glands from NOD and control BALB/c mice were stained with a panel of monoclonal antibodies directed against conventional (alpha, beta, and gamma), novel (delta, epsilon, and theta), and atypical (lambda and iota) PKC isoforms using the streptavidin/HRP method. Similarly to human labial salivary glands, acinar epithelial cells of the healthy control BALB/c mice contained two of the conventional PKC isoforms, alpha and beta. Acinar and ductal epithelial cells also contained the atypical PKC isoforms lambda and iota. PKC isoforms gamma, delta, epsilon, and theta were not found. NOD mice which displayed focal sialadenitis contained the same conventional and atypical PKC isoforms. The acinar cells in NOD mice, in contrast to the Sjögren's syndrome patients, did not lack PKC alpha or beta. On the contrary, PKC alpha and beta staining was stronger than in the control BALB/c mice. The present results demonstrate that both conventional and atypical PKC isoforms participate in the salivary epithelial cell biology and that there are mouse strain-associated and/or disease state-associated changes in their expression. The lack of PKC alpha and beta isoforms found in Sjögren's syndrome was not reproduced in NOD mice, which discloses one more difference between the human disease and its NOD mouse model.

The protein kinase C system in focal adenitis of the lacrimal gland in the non-obese diabetic mouse model for Sjögren's syndrome.

PURPOSE: Non-obese diabetic (NOD) mice develop an autoimmune exocrinopathy characterized by hyposecretion of saliva and acinar cell atrophy. As the protein kinase C (PKC) system is involved in the signal transduction pathways associated with primary secretion and acinar cell differentiation and growth, the PKC profile was analysed in NOD mice. METHODS: Lacrimal glands from BALB/c, NOD, NOD scid and transgenic NOD x interferon-gamma (IFN-gamma) mice were analysed for their PKC profiles using antibodies against several conventional (alpha, beta, gamma), novel (delta, epsilon, theta) and atypical (iota, lambda) PKC isoforms using the Streptavidin/HRP (horseradish peroxidase) method. RESULTS: Acinar cells in BALB/c control mice expressed two conventional (alpha, beta) and two atypical (iota, lambda) PKC isoforms. In NOD and transgenic NOD x IFN-gamma mice the same isoforms were more strongly expressed. NOD scid mice lacked all other PKC isoforms except PKC lambda. CONCLUSIONS: Co-expression of several PKC isoforms in single cell type may be necessary for transcriptional activation and agonist-induced secretory responses. Hyposecretion in NOD mice was paradoxically associated with up-regulation of the PKC system. This may be associated with a deranged signal transduction per se rather than with the immune-inflammation, as the transgenic NOD x IFN-gamma mice showed similar PKC profiles. The NOD model does not reproduce lack/consumption of PKC II and PKC as in Sjögren's syndrome. This may be because the receptor autoantibodies in mice are directed against the adrenergic, not muscarinic, receptors. Lack and/or low level PKC expression in NOD scid mouse may explain the excessive acinar cell apoptosis in this model.

Neuropeptides in experimental and degenerative arthritis.

Classical symptoms of both inflammatory and degenerative arthritides may contribute to neurogenic responses like wheal, flare, edema, and pain. Rheumatoid arthritis (RA) is an autoimmune disease with an immunogenetic background. Neurogenic inflammation has been considered to play an essential role in RA, in part because of the symmetrical involvement (cross-spinal reflexes) and the predominant involvement of the most heavily innervated small joints of the hands and the feet (highly represented in the hominiculus). In contrast, osteoarthritis (OA) is considered to arise as a result of degeneration of the hyaline articular cartilage, which secondarily results in local inflammation and pain. However, it is possible that the age-related and predominant (compared to nociceptive nerves) degeneration of the proprioceptive, kinesthetic and vasoregulatory nerves can represent the primary pathogenic events. This leads to progressive damage of tissue with extremely poor capacity for self-regeneration. Inflammation, be it primary/autoimmune or secondary/degenerative, leads to peripheral sensitization and stimulation, which may further lead to central sensitization, neurogenic amplification of the inflammatory responses and activation of the neuro-endocrine axis. Neuropeptides serve as messengers, which modulate and mediate the actions in these cascades. Accordingly, many neuropeptides have been used successfully as experimental treatments, most recently VIP, which effectively controlled collagen-induced arthritis in mice. Therefore, it can safely be concluded that better treatment/control of disease activity and pain can be achieved by blocking the cascade leading to initiation and/or amplification of inflammatory process combined with effects on central nociceptive and neuroendocrine responses.

The in vivo expression of the collagenolytic matrix metalloproteinases (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in adult and localized juvenile periodontitis.

Periodontal inflammation is characterized by irreversible degradation of periodontal ligament collagen fibers leading to loss of tooth attachment. Cultured gingival keratinocytes and fibroblasts express, in vitro, various matrix metalloproteinases (MMPs) which can degrade fibrillar collagens. We hypothesized that several MMPs are also synthesized in vivo by sulcular epithelium, and analyzed the collagenolytic MMPs (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in gingival tissue specimens and gingival crevicular fluid from adult and localized juvenile periodontitis patients by in situ hybridization, immunohistochemistry, and Western immunoblotting. MMP-2, -7, -8, and -13 were expressed in gingival sulcular epithelium. MMP-7 and -13 were also located in fibroblasts and macrophages, and MMP-8 in neutrophils. MMP-8- and -13-positive cells/mm2 were higher in periodontitis gingiva when compared with healthy control tissue (p < 0.01). In periodontal diseases, gingival sulcular epithelium expresses several, rather than a single, collagenolytic MMPs, and this proteolytic cascade is evidently responsible for the tissue destruction characteristic of adult and juvenile periodontitis.

Current issues in the diagnosis and treatment of Sjögren's syndrome.

Modification of the European Cooperative Group (EEC) criteria for Sjögren's Syndrome (SS) should lead to less confusion in diagnosis and therapeutic trials. The proposed EEC modification will require either a positive minor salivary gland biopsy or a positive autoantibody against Sjögren's-associated A (Ro) or B (La) antigen. This modification will decrease the proportion of women fulfilling EEC criteria from 3-5% to about 0.5%, which is similar to San Diego and San Francisco criteria. Genetic studies have shown increased frequency of alleles for peptide transporter genes TAP1 (0101) and TAP2 (0101) genes as well as tumor necrosis factor microsatellite a2 alleles. Although these markers confer markedly increased risk, they are found in only a small proportion of patients. An increased frequency of drug (antibiotic) allergy and other allergic manifestations appears present in patients with SS and may be linked to HLA-DR3. Hepatitis C as a cause of sicca symptoms, positive anti-nuclear autoantibodies, and mixed cryoglobulinemia is increasingly reported in different parts of the world. Antibodies against muscarinic M3 receptor and expression of costimulatory molecules (CD80 and CD86) by ductal epithelial cells may play a role in pathogenesis. Treatment with pilocarpine is effective in double-blind trials and low dose oral alpha interferon looks promising in initial open studies. In pregnant patients who exhibit evidence of neonatal heart block, treatment with dexamethasone is preferred over prednisone, since the placenta is unable to metabolically activate the latter compound.

T cell attractant chemokine expression initiates lacrimal gland destruction in nonobese diabetic mice.

By inducing both adhesion and migration of lymphocytes, chemokines play an important role in immune and inflammatory responses. To learn how these processes promote disease, we have examined the activities of chemokines in the lacrimal glands (LG) of nonobese diabetic (NOD) mice, an animal model of Sjogren's syndrome (SS). The expression of three molecules in the chemokine superfamily, RANTES, IP-10 and lymphotactin, correlated with the local recruitment of lymphocytes into the LG of NOD mice. Both RANTES and IP-10 gene transcripts were first detected in these LG when the mice were 8 weeks of age and amounts increased markedly during the course of active disease; lymphotactin mRNA was also expressed but at lower levels. In situ hybridization of LG indicated that lymphocytic cells in the inflammatory infiltrates were responsible for the production of RANTES and IP-10. Concomitant with the induction of chemokine expression was the appearance of cellular receptors for RANTES (CCR1, CCR5) and IP-10 (CXCR3). Furthermore, anti-RANTES treatment significantly reduced inflammation in the LG from NOD mice. In the SS-like disease of NOD mice, this distinct pattern of activity provides evidence for the contribution of these components to site- and time-specific recruitment of lymphocytes in the characteristic destruction of glandular structures.

Estrogen in autoimmunity: expression of estrogen receptors in thymic and autoimmune T cells.

OBJECTIVE: To identify the targets of estrogen in immune system lymphocytes and to examine gender differences in autoimmunity. DESIGN: RNA samples from purified lymphocyte subsets were analyzed for the presence of mRNA for estrogen receptor alpha and beta (ER alpha and ER beta). Groups of male, female, and testicular-feminized mice were compared for autoantibody production. SUBJECTS: Autoimmune-prone lpr (Fas-deficient), testicular-feminized (Tfm, androgen receptor-deficient) and wild-type mice were studied. METHOD: Lymphocyte subsets were purified by fluorescence-activated cell sorting (FACS) and RNA was assessed for the presence of estrogen receptor sequences using specific oligonucleotide primers and the reverse transcription-polymerase chain reaction (RT-PCR). Spontaneous and induced antibody production in mice was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ER alpha was expressed in all lymphocyte subsets examined. ER beta was expressed at low levels in thymic CD4/CD8- T cells in wild-type mice and at high levels in the peripheral CD4-/CD8- T cells in lpr mice. Both spontaneous and induced autoantibody production was higher in female lpr mice than in male lpr mice. CONCLUSIONS: The presence of ERs in lymphocytes indicates that estrogen may affect immune cells during their development and mature function. The selective expression of ER beta may help explain some of the physiological effects of estrogen and its pharmacologic analogues and may lead to means to direct estrogen analogues to such cells. Such effects may be explored in lpr mice, given the enhanced capacity of female lpr mice for autoantibody production.

Evolving concepts of diagnosis, pathogenesis, and therapy of Sjögren's syndrome.

Differences in diagnostic criteria for Sjögren's Syndrome (SS) have led to confusion in the research literature and in clinical practice. A particular challenge is the clinical diagnosis of the patients with sicca symptoms, fibromyalgia, chronic fatigue, vague cognitive defects, and a low titer antinuclear antibody. Until recently, many of these patients would have been classified as primary SS using the European criteria. A suggested revision of the European criteria will require inclusion of anti SS-A antibody or characteristic minor salivary gland biopsy, leading to greater agreement between European and San Diego criteria. Recent studies have emphasized that lacrimal and salivary gland flow involves an entire "functional" unit that includes the mucosal surface (the site of inflammation), efferent nerve signals sent to the midbrain (lacrimatory and salvatory nucleus), efferent neural signals from the brain, and acinal/ductal structures in the gland. Thus, symptoms of dryness or pain can result from interferences with any part of this functional unit. The initiating antigens in SS remain unknown, but immune reactivity against SS-A, SS-B, fodrin, alpha- amylase, and carbonic anhydrase have been demonstrated in patients with established disease. The inflammatory process in the gland releases metalloproteinases that alter the relationship of epithelial cells to their matrix, an interaction that is necessary for glandular function and survival. Therapies for SS remain inadequate. In SS patients with immune-mediated extraglandular manifestation (ie, lung, kidney, skin, nerve), the therapeutic approach is similar to systemic lupus erythematosus, although these therapies have relatively little effect on tear or saliva flow.

The early experiences of a national system for the identification and assessment of emerging health care technologies in Sweden.

This article presents the experiences from a pilot study and the establishment of a permanent system called SBU Alert. The question of establishing a system for the identification and assessment of emerging technologies in health care in Sweden has been on the agenda since the late 1980s. The demand came primarily from policy makers. The pilot study showed that the awareness of the project in the target group (politicians, leading managers, hospital directors, and senior medical advisors) was high. Almost all of those who replied to an assessment questionnaire were in favor of a continuation of the work. In 1997, the Swedish Council on Technology Assessment in Health Care (SBU) was selected to establish a permanent organization. This work has resulted in the identification of a number of methodological problems and tentative solutions concerning all components in the SBU Alert system. We have found that a system for systematic identification and early assessment of emerging technologies is a new and promising tool in the health technology assessment arsenal. Still, experiences are limited. Methodology and the impact of early judgments on decision making need further evaluation.

Role of nitric oxide in Sjögren's syndrome.

OBJECTIVE: To measure levels of salivary nitrite (NO2-) and to localize nitric oxide synthases (NOS) in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS). METHODS: NO2- was measured by the Griess reaction. LSGs were analyzed using NADPH-diaphorase histochemical and immunohistochemical studies to determine the constitutive NOS (neuronal [ncNOS] and endothelial [ecNOS]) and inducible NOS (iNOS) isoforms. RESULTS: The NO2- concentration (mean +/- SEM 307 +/- 51 microM versus 97 +/- 16 microM; P < 0.05) and output (166 +/- 46 nmoles/minute versus 37 +/- 7 nmoles/minute) were increased in SS patients compared with healthy control subjects. NADPH-diaphorase was found in some nerve fibers and endothelial cells, and, in SS, was found in myoepithelial, acinar, and ductal epithelial cells, but in only a few inflammatory cells. In SS, ncNOS-immunoreactive nerve fibers were sparse and ecNOS was found in a minority of the CD31-positive vascular endothelial cells and acinar cells, whereas iNOS was localized in myoepithelial, acinar, and ductal epithelial cells, often together with tumor necrosis factor alpha. CONCLUSION: Nitrite was found in normal human saliva. NO produced by ncNOS probably acts as a nonadrenergic, noncholinergic neurotransmitter, whereas that produced by ecNOS exerts a vasodilatory effect. SS patients had increased NO2- concentrations, with most of the superfluous salivary NO being produced not by the immigrant inflammatory cells, but rather, by the resident salivary gland cells. NO may contribute to inflammatory damage and acinar cell atrophy in SS.