The impact of harvest length and detachment of the interosseous membrane on donor-site morbidity following free fibula flap surgery-a biomechanical experimental study.

PURPOSE: The fibula flap has been established for orofacial reconstruction following ablative surgery. Donor-site morbidity of the lower leg may be explained by the harvest technique and particularly by detachment of the M. extensor halluces longus (EHL) and M. extensor digitorum longus (EDL). MATERIAL AND METHODS: On cadaveric lower leg specimens, the tendons of the EHL and EDL were dissected at the proximal phalanges and loaded with corresponding weights. The average displacement of the muscle was evaluated during the harvesting procedure. RESULTS: Cumulative detachment of the interosseous membrane caused considerable displacement of the EHL but less impairment of the EDL. Segmental and cumulative osteotomy of the fibula implicated significant displacement of both EHL and EDL. CONCLUSION: A recommendation can be given for cautious selection of osteotomy site of the fibula and for limited sacrifice of the fibula and adjacent attachments of the extensors to keep local-site morbidity at a minimum.

Oral rehabilitation with dental implants and quality of life following mandibular reconstruction with free fibular flap.

OBJECTIVES: Bony reconstruction of jaw defects using the free fibular flap and dental rehabilitation mostly requires insertion of dental implants within the transferred fibula bone. The aim of this paper was to discuss results of the implant stability with data on the possible benefit for the patient's quality of life after such treatment. MATERIAL AND METHODS: For clinical outcome of implants, we evaluated 26 patients with a total number of 94 dental implants after a follow-up period of 12 to 132 months. A group of 38 patients who underwent mandibular reconstruction with free fibular flap could be included in the life-quality study. Evaluation included 23 patients with and 15 patients without implant-borne restoration. The quality of life was assessed using the standard QLQ C-30 questionnaire and the H&N35 module of the European Organisation for Research and Treatment of Cancer (EORTC). RESULTS: Of implants, 94.7 % were stable at the time of investigation and could be used for prosthesis. Patients with dental implants reported improvement of life quality along with better scores in most function and symptom scales; however, only values for global health status (QL2), absence of dyspnea (DY) and absence of feeding tube (HNFE) were significantly better than in the control group. CONCLUSION: Dental implant insertion in fibula grafts along with implant-borne restoration is a proven concept and might lead to improved quality of life following ablative surgery of the jaw. The effect on the quality of life is not as predictable as on the implant stability. CLINICAL RELEVANCE: Patients with bony defects of the jaw require bony reconstruction. This allows further masticatory rehabilitation using dental implants and might lead to improved quality of life.

Impact of body mass index, gender, and smoking on thickness of free soft tissue flaps used for orofacial reconstruction.

Donor-site selection may play an important role in the reconstruction of large orofacial defects. The thickness and structure of transplanted tissue has to fit those of the recipient site to achieve a satisfactory outcome. To evaluate the thickness of free flaps that are frequently used for orofacial reconstruction and its association with body mass index (BMI), gender, and smoking, a prospective study was conducted. A total of 122 volunteers were included in the study, and their data regarding BMI, gender, and tobacco use were documented. Ultrasonography was used to evaluate the thickness of the radial and ulnar forearm flaps (RFFF and UFFF, respectively), the scapular and parascapular flaps (SF and PSF, respectively), the anterolateral thigh flap (ALT), and the free fibular flap (FF). Correlation and regression analysis were performed to assess any relationship among parameters and to investigate their effect on flap thickness. The UFFF showed the lowest thickness (0.65 ± 0.16 cm), followed by the RFFF (0.83 ± 0.20 cm). The FF showed a comparable thickness (0.82 ± 0.26 cm), followed by the SF (0.99 ± 0.13 cm) and the PSF (1 ± 0.14 cm). The ALT flap displayed the greatest thickness (1.42 ± 0.42 cm) and correlated especially with BMI and gender, whereas the UFFF was the thinnest with relatively constant values, regardless of potential influential factors.

Differential Gene Expression of the Proto-oncogene VAV3 and the Transcript Variant VAV3.1 in Oral Squamous Cell Carcinoma.

The VAV proteins VAV1, VAV2 and VAV3 have been identified as important molecules in tumorigenesis, tumor growth and cell migration. In addition to the full-length isoforms, a much shorter family member, VAV3.1, also known as VAV3 isoform 2, is known to be differentially expressed in a broad variety of tissues. Furthermore, VAV3.1 was shown to be down-regulated in cultured keratinocytes by the growth factors epidermal growth factor (EGF) EGF and transforming growth factor beta (TGFß) TGFß which in turn play important roles in the pathogenesis of oral squamous cell carcinoma (OSCC). Herein we showed that VAV3.1 is underexpressed in OSCC tissue samples compared to corresponding normal mucosa. We further demonstrated a trend of distinctive down-regulation of mRNA for VAV3.1 in tissues of locally advanced OSCC that have already metastasized to regional lymph nodes, indicating an increased malignant potential of tumors with low VAV3.1 mRNA expression. Moreover, in other studies a correlation between increased VAV3 expression and cancer progression was shown. In the present study, the analyzed OSCC tissue samples showed no significant change of VAV3 mRNA expression. Taken together, our data support the hypothesis that molecular interactions and signaling cascades of VAV3 can be regulated or directed by the competing molecule VAV3.1. Additionally, discrete and different functions of VAV3.1 in metastasis and tumorigenesis are conceivable.

Masticatory rehabilitation following upper and lower jaw reconstruction using vascularised free fibula flap and enossal implants-19 years of experience with a comprehensive concept.

OBJECTIVES: Conventional prosthesis is generally inapplicable following reconstruction with free fibula flaps (FFF) due to impaired bone and soft tissue conditions, and rehabilitation via enossal implants in FFF is relatively novel. This retrospective study aimed to document the surgical aspects of this option and to describe related supplementary procedures that can help optimise the definitive outcome. MATERIAL AND METHODS: One hundred nineteen implants were inserted within FFFs in 37 patients (mean age 51.8 ± 10.6 years), who underwent ablative surgery of the maxilla (3) and mandible (34). In a cross-sectional study design with a follow-up period of 3-172 months, we analysed types and configurations of graft design, patterns of implant insertion and methods for prosthetic rehabilitation as well as primary stability and survival rate. RESULTS: Most patients underwent jaw reconstruction using a mono-barrel FFF (14 osseous and 18 osteocutaneous/osteomyocutaneous); three patients received double-barrel reconstruction of the mandible. Three patients with maxillary defects were reconstructed using mono-barrel grafts (one osteocutaneous and two prefabricated grafts). Pre-prosthetic procedures were required in 23 patients to optimise conditions in the peri-implant soft tissue. Iliac bone onlay graft was used in six patients to achieve appropriate vertical height in mono-barrel grafts. A total of 10 implants in eight patients (five irradiated) could not be loaded. All other implants showed stable osseous integration and satisfactory peri-implant soft tissue conditions. CONCLUSION: Masticatory rehabilitation can be achieved using enossal implants inserted in FFF. Special requirements can be met through selection of an appropriate graft configuration and optimal implant positioning. Supplementary pre-prosthetic procedures are usually required as they improve long-term survival. CLINICAL RELEVANCE: This overview provides a reliable and comprehensive algorithm for standard implant-borne rehabilitation of patients with fibula grafts.

Ulnar artery-based free forearm flap: review of specific anatomic features in 322 cases and related literature.

BACKGROUND: The ulnar free forearm flap (UFFF) represents a variant of soft tissue transplants for orofacial reconstruction with specific topographic anatomy of the donor-site, which has to be considered during flap raising. METHODS: Analysis of intraoperative findings during harvest of 322 UFFFs for head and neck reconstruction was performed. Harvest technique in view of variations of skin flap, vascular, and neuronal anatomy is described herein and related literature is reviewed. RESULTS: Aberrant superficial ulnar artery was observed in 1.5% of cases. The Martin-Gruber anastomosis was seen in 11.5%. The dorsal branch of the ulnar nerve was always visible and had to be dissected and separated under the flexor carpi ulnaris muscle and donor-site morbidity was low. CONCLUSION: Considering local anatomic features and variations, the harvest of the UFFF is safe and survival rates are comparable with those of the radial forearm flap.

Imaging of mandible invasion by oral squamous cell carcinoma using computed tomography, cone-beam computed tomography and bone scintigraphy with SPECT.

OBJECTIVES: The objective of this paper is to evaluate the predictability of preoperative tumour bone invasion of the mandible by squamous cell carcinoma of the oral cavity using CT, cone-beam CT and bone scintigraphy with SPECT. MATERIAL AND METHODS: Eighty-four patients who had received CT, SPECT or cone-beam computed tomography (CBCT), as well as a further 48 patients who undergone all these investigations for preoperative evaluation of bone invasion were included in the study. A case-control analysis and the receiver operating characteristics were performed. Histological results of bone specimens served as the gold standard for assessment of bone invasion. RESULTS: CBCT and SPECT showed a comparable sensitivity for bone invasion (93 % [CI 0.816-0.972] and 96 % [CI 0.867-0.990], respectively) which was significantly higher than that of CT (63 % [CI 0.488-0.752]). Further, CBCT obtained higher specificity than SPECT (62 % [CI 0.478-0.743] and 48 % [CI 0.342-0.614], respectively), whereas CT showed the best specificity among the investigation methods (81 % [CI 0.677-0.896]). CONCLUSIONS: CT scan provides by its high specificity and positive predictive value a precise imaging technique for clinical routine. However, CBCT shows a much higher sensitivity for cortical bone invasion and a better negative predictive value. With a significantly lower exposure dose it can rule out this invasion effectively and prevent overtreatment. CLINICAL RELEVANCE: Considering the high-resolution images delivered by CBCT along with minimized artefacts in the mandible it provides an alternative imaging technique, which could be combined and accomplished with another soft-tissue imaging modality like MRI to obtain optimal hard and soft-tissue visualisation in patients with squamous cell carcinoma of the oral cavity.

Allogenic submandibular gland transplantation following hematopoietic stem cell transplantation.

BACKGROUND: Autologous submandibular gland transfer for treatment of progressive dry eye symptoms requires a functionally intact submandibular gland. In cases of total function loss of both lacrimal and submandibular glands this procedure has to be modified. Here we report on the first two cases of the allogenic transplantation of a submandibular gland to treat patients suffering from complete functional loss of both glands due to graft-versus-host disease (GvHD) following stem cell transplantation. METHODS: We carried out allogenic transplantation of the submandibular gland of the matched former stem cell donor to the temporal fossa of the stem cell recipient suffering from GvHD-induced dry eye. The treatment was carried out in two male patients who showed complete donor chimerism to the stem cell donors, so that no immunosuppressive therapy was applied. RESULTS: Postoperative clinical assessment of the patients revealed primary success of the procedure. The ocular surface showed improvement of lubrication and reduction of inflammatory signs. In the long-term follow-up sialoscintigraphy revealed lower tracer activity than expected and secretion of saliva-tears decreased. CONCLUSION: Even though the so-called total donor chimerism was assessed allogenic transplantation of the submandibular gland following GvHD-induced dry eye showed signs of organ rejection and therefore initial immunosuppressive therapy after allogenic transplantation has to be considered.

Long-term functional donor site morbidity after ulnar forearm flap harvest.

BACKGROUND: The purpose of this study was to evaluate long-term functional donor site morbidity following ulnar forearm flap harvest taking both subjective and objective criteria into consideration. METHODS: In this retrospective analysis, 61 patients were evaluated for subjective and objective donor site morbidity 3 to 164 months after flap harvest, and the Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire was used for evaluation of subjective hand function. RESULTS: There was no significant grip strength decrease in the donor limbs. Two patients developed severe functional impairment of the donor forearm. DASH scores displayed only minor functional impairment, with marginally improving scores with increasing time lag to surgery. CONCLUSIONS: Low donor site morbidity was found after ulnar flap harvest. However, minor rates of patients suffered from severe impairment of the hand function. Therefore, we recommend using the nondominant limb and informing the patients in detail about the specific functional limitations.

Expression of Wnt-1, TGF-ß and related cell-cell adhesion components following radiotherapy in salivary glands of patients with manifested radiogenic xerostomia.

BACKGROUND: Radiation-induced xerostomia still represents a common symptom following radiotherapy of head and neck malignancies, which significantly impairs the patient's quality of life. In this cross-sectional study, human salivary glands were investigated to assess the role of Wnt/ß-catenin and TGF-ß pathways in the pathogenic process of radiogenic impairment of salivary function. METHODS: Irradiated human salivary glands were investigated in patients with manifested xerostomia. Alteration of Wnt-1 and cell-cell adhesion was evaluated immunohistologically as well as changes in the expression of TGF-ß were assessed in salivary gland tissue. RESULTS: We assessed two alteration patterns in which Wnt-1 expression represents one change along with up-regulation of ß-catenin and E-cadherin in irradiated but viable acinar cells. Increased expression of tenascin-C was observed in sites of epithelial-mesenchymal interaction and loss of cell-cell adhesion was assessed in translocated epithelial cells in the stroma. CONCLUSION: Increased transdifferentiation and remodeling of acinar structures was associated with decrease of viable acinar structures. The role of Wnt and TGF signaling may provide a potential therapeutic approach to prevent radiation-induced damage to salivary glands during radiotherapy for head and neck cancer.

Altered expression of cell-cell adhesion molecules ß-catenin/E-cadherin and related Wnt-signaling pathway in sporadic and syndromal keratocystic odontogenic tumors.

Differential diagnosis of the keratocystic odontogenic tumor (KCOT) still represents a challenging problem especially if compared with the dentigerous cyst, which is similar in clinical and radiological course. Histological assessment of this entity may therefore draw crucial attention since various radical procedures are recommended for such lesions in contrast to dentigerous cysts. Since recent reports could prove the involvement of wingless(Wnt)-signaling pathway and ß-catenin in the pathogenesis of many odontogenic and neoplastic lesions indicating impairment of cell-cell adhesion, we investigated the expression of two Wnt-signaling pathways, Wnt-1 and Wnt-10A as well as ß-catenin and E-cadherin along with other related proteins in both lesions. We found a significant down-regulation in the expression of cell adhesion proteins ß-catenin and E-cadherin along with alteration of Wnt-1 and Wnt-10A expression in the epithelium of KCOT. We assessed a specific focal distribution pattern of p63 in the suprabasal cell layer and a significant up-regulation of cyclin D1. Furthermore, laminin α-2 was a characteristic marker labelling only the basement membrane of dentigerous cysts. These results provide a new hypothesis explaining a molecular mechanism to understand initiating and development of KCOTs and an alternative therapeutic approach, especially for syndromal patients, where these multilocal lesions may involve and destroy wide orofacial bony structures.

Effect of head and neck cancer supernatant and CpG-oligonucleotides on migration and IFN-alpha production of plasmacytoid dendritic cells.

BACKGROUND: Plasmacytoid dendritic cells (PDCs) infiltrating solid tumor tissues and draining lymph nodes of head and neck squamous cell carcinoma (HNSCC) show an impaired immune response. Immunosuppressive cytokines secreted by HNSCC have been recognized to account for reduced interferon-alpha (IFN-alpha) production, whereas the influence on PDC migration has not yet been investigated. MATERIALS AND METHODS: PDCs were isolated from human peripheral blood by magnetic bead separation. Cellular functions and characteristics were analyzed using flow cytometry, migration assays and ELISA techniques. RESULTS: We show that HNSCC and CpG oligonucleotides controversially influence the migration and IFN-alpha production of PDCs. Furthermore we demonstrate that HNSCC induced migration towards stromal cell-derived factor-1 (SDF-1) and macrophage inflammatory protein 1 beta (MIP-1beta) is not dependent upon the surface density of chemokine (CXC motif) receptor 4 (CXCR4) and chemokine (C-C motif) receptor 5 (CCR5). CONCLUSION: We propose that HNSCC triggered PDC migration is most likely linked to a multilevel process strongly modulated by tumor microenvironmental influences.

Decreased levels of circulating regulatory NK cells in patients with head and neck cancer throughout all tumor stages.

BACKGROUND: Natural killer (NK) cells play a crucial role in innate immunity as effectors against tumor cells and pathogen-infected cells. Human NK cells can be subdivided into two functional subsets, the immunoregulatory CD56(bright) NK cells and the cytotoxic CD56(dim) NK cells. NK-mediated host defence against tumor cells is strongly impaired in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: NK cells were isolated from peripheral blood of 70 HNSCC patients and 22 healthy donors by magnetic bead separation and subsequently analyzed using flow cytometric as well as immunohistochemical methods. RESULTS: In this work we demonstrate that the population of circulating immunoregulatory CD56(bright) NK cells is lower in the peripheral blood of patients with HNSCC as compared with that in healthy donors, regardless of the individual tumor stage or tumor type. CONCLUSION: These data underline the complex network of HNSCC-mediated immunomodulation as part of the immune escape mechanisms of malignant head and neck tumors.

Potential stem cell marker CD44 is constitutively expressed in permanent cell lines of head and neck cancer.

BACKGROUND: Despite significant advances in the use of diagnosis and therapy to treat head and neck squamous cell carcinoma (HNSCC), the prognosis has improved only marginally in the last decades. Thus, there is an enormous need for better understanding of tumor biology and reversely novel immunotherapeutic approaches. It is becoming increasingly obvious that stem cells play an important role in tumor development and progression. The identity of these cells and the underlying cellular and molecular mechanisms are mostly unknown in HNSCC to date. MATERIALS AND METHODS: Solid HNSCC tumors, as well as permanent HNSCC cell lines, were analyzed by flow cytometry concerning the expression of different putative stem cell marker proteins. RESULTS: Distinct populations of CD44 expressing potential stem cells could be identified in solid tumors of HNSCC patients with strong individual deviations. Surprisingly, the potential stem cell marker CD44 was found to be constitutively expressed on the surface of all the permanent HNSCC cell lines analyzed. CONCLUSION: CD44+ 'tumor stem cells' may play a key role in the establishment of permanent HNSCC cell lines, selecting especially robust cell entities that might drive the progression and metastasis of HNSCC. Individual analysis of 'tumor stem cell' markers will be an important tool for innovative therapies and for determining the prognosis of patients with HNSCC.

Early and late immunohistochemical and ultrastructural changes associated with functional impairment of the lachrymal gland following external beam radiation.

The aim of this study was to investigate scintigraphic, immunohistological and ultrastructural changes associated with radiation-induced dysfunction of the lachrymal gland in an established experimental animal model. Ten rabbits were randomized into two groups and used for the study; in the control as well as experimental group, the Schirmer-test, lachrymal gland scintigraphy, and immunohistological and ultrastructural investigations were carried out prior to irradiation and 72 h as well as 1 month after single-dose irradiation with 15 Gy. Seventy-two hours after irradiation, secretion reduction evaluated by the Schirmer-test was evident. At this phase, we could observe a decrease in the expression of alpha-SMA and a re-distribution of tenascin-C matrix. Ultrastructural changes of acinar and myoepithelial cells were noticed; simultaneously, disturbance in the primary (99m)TcO(4)- uptake as well as significant reduction of the lachrymal ejection fraction was assessed scintigraphically. These changes were still evident 1 month following irradiation but became less intensive. Single-dose irradiation with 15 Gy implicates a functional impairment of the lachrymal gland, which is associated with early immunohistological and ultrastructural alterations. These changes may represent objective surrogate parameters for radiogenic dysfunction and prerequisites for further investigations on radioprotection of lachrymal glands during radiotherapy of the periorbital region.