Neal D. Futran

Osteoradionecrosis of the mandible.

Purpose of reviewOsteoradionecrosis of the mandible is a serious complication of radiation therapy to the head and neck. Given the increased use of radiation therapy and combined chemotherapy-radiation therapy regimens in treatment of head and neck malignancies, it is anticipated that osteoradionecrosis will continue to be an important clinical problem. Recently, new concepts have been introduced regarding the pathogenesis of osteoradionecrosis, and these ideas help outline new guidelines for treatment. Recent findingsCurrent literature focuses on the probability of a fibroatrophic mechanism for the development of osteoradionecrosis, rather than the traditional vascular insufficiency mechanism. Because of the evolution of this new idea, as well as a double-blinded, placebo-controlled study finding no benefit from the use of hyperbaric oxygen for advanced osteoradionecrosis of the mandible, new treatment considerations have emerged. Ongoing research is also being conducted to clarify the role of osteoclasts in the pathogenesis of osteoradionecrosis. Restoration of blood supply or vascularized tissue to the affected area continues to be of primary importance in the resolution of osteoradionecrosis. SummaryIt is clear that the cause and pathogenesis of osteoradionecrosis are far more complex than originally believed. Current and future research on this multifaceted topic will focus on the cellular basis of this condition, because as it is elucidated, more effective medical treatment regimens will become evident.

Gene Expression Profiling Identifies Genes Predictive of Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is associated with substantial mortality and morbidity. To identify potential biomarkers for the early detection of invasive OSCC, we compared the gene expressions of incident primary OSCC, oral dysplasia, and clinically normal oral tissue from surgical patients without head and neck cancer or preneoplastic oral lesions (controls), using Affymetrix U133 2.0 Plus arrays. We identified 131 differentially expressed probe sets using a training set of 119 OSCC patients and 35 controls. Forward and stepwise logistic regression analyses identified 10 successive combinations of genes which expression differentiated OSCC from controls. The best model included LAMC2, encoding laminin-γ2 chain, and COL4A1, encoding collagen, type IV α1 chain. Subsequent modeling without these two markers showed that COL1A1, encoding collagen, type I α1 chain, and PADI1, encoding peptidyl arginine deiminase, type 1, could also distinguish OSCC from controls. We validated these two models using an internal independent testing set of 48 invasive OSCC and 10 controls and an external testing set of 42 head and neck squamous cell carcinoma cases and 14 controls (GEO GSE6791), with sensitivity and specificity above 95%. These two models were also able to distinguish dysplasia (n = 17) from control (n = 35) tissue. Differential expression of these four genes was confirmed by quantitative reverse transcription-PCR. If confirmed in larger studies, the proposed models may hold promise for monitoring local recurrence at surgical margins and the development of second primary oral cancer in patients with OSCC. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2152–62)

Developments in reconstruction of midface and maxilla

Loss of the maxilla and midfacial structures after tumour removal has substantial functional and aesthetic consequences. The variable loss of soft tissue, bone, or both, leading to collapse of the lip, cheek, periorbital soft tissues, and palatal competence present a challenging dilemma for reconstructive surgeons. Efforts have been made to classify these midfacial defects and provide appropriate algorithms for optimum reconstruction. Not only does the cavity need to be obliterated and midfacial contours recreated, but swallowing function, phonation, and mastication need to be restored for an ideal result. Traditionally, these defects would have been repaired by a maxillofacial prosthesis but advances in tissue transfers, particularly of microvascular free flaps, have greatly increased reconstructive options. The wide variety of free flaps that contain both soft tissue and bone offer unique properties that could be applicable depending on the defect. Combinations of free tissue transfer, local flaps, and maxillofacial prostheses might achieve a more ideal result than one technique alone. Advances in osseointegration have also enhanced the ability to achieve the best function and form. No one flap or technique is sufficient to reconstruct midface defects in all patients. The choices should be tailored to the bony and soft-tissue needs of each specific defect, denture-bearing potential of the original tissues, and available prosthodontic support. Use of a multidisciplinary approach to reconstruct these defects can yield excellent results. The complexity of the techniques should match the desired goals and needs of each individual patient.

Pentoxifylline in the Treatment of Radiation-Related Soft Tissue Injury: Preliminary Observations

Soft tissue or mucosal injuries following radiotherapy of head and neck cancer include ulceration (necrosis), fibrosis, pain, and atrophy. Current management includes analgesics, wound debridement, antibiotics, and physical therapy depending on the type of injury. Pentoxifylline is a methylxanthine derivative that produces dose‐related hemorrheologic effects, lower blood viscosity, improved erythrocyte flexibility, and increased tissue oxygen levels. Twenty‐six patients with late radiation complications (occurring more than two months after x‐ray therapy) were given treatment with oral pentoxifylline: 15 for soft tissue necrosis (STN), six for fibrosis, and five for mucosal pain. Nine of 12 patients with STN completely healed. In all three failures osteoradionecrosis developed. Mucosal pain resolved in all five patients. Fibrosis improved in 67% of those patients. Pentoxifylline appears to accelerate healing of STN and reverse some late radiation injuries. This is the first series to our knowledge that documents activity of this agent in moderate radiotherapy complications such as fibrosis, pain, or mucosal fragility.

Single versus dual venous drainage of the radial forearm free flap

PURPOSE To compare single versus dual venous drainage of radial forearm free flaps (RFFF) and its impact on flap survival. DESIGN A retrospective case series of 43 consecutive patients undergoing radial forearm free flap reconstruction for head and neck cancer defects, combined with a meta-analysis of 218 reported cases. SETTING Two academic, tertiary referral medical centers. INTERVENTION All 43 RFFFs were harvested and inset in a similar fashion. In 16 patients (group 1), two venous anastomoses were performed. In 27 patients (group 2) one anastomosis was created. The arterial anastomosis was similar in both groups. OUTCOME MEASURES Clinically noted viability of the radial forearm free flap over the first 6 postoperative weeks. RESULTS All 43 RFFFs maintained complete viability. No flap loss, complete or partial, was identified. Two patients in group 1 and one patient in group 2 developed postoperative pharyngocutaneous fistulae, but complete healing occurred with local wound care. One patient in group 2 developed a postoperative neck hematoma, which was evacuated with no insult to the free flap. Single venous anastomosis shortened operative time by 21 to 36 minutes. CONCLUSION Though two venous anastomoses may provide a more fail-safe mechanism for adequate venous drainage, a single venous anastomosis employing a subcutaneous vein provides adequate drainage with reduced operative time and no additional morbidity. Meta-analysis statistically confirmed the equivalency of single and dual venous anastimoses (correction of amastimoses) with respect to flap survival.

Influences and predictors of long-term quality of life in head and neck cancer survivors

OBJECTIVE To examine the impact of clinical predictors (pretreatment variables) and other influences (treatment and posttreatment variables) on long-term quality of life (QOL) in patients treated for squamous cell carcinoma of the upper aerodigestive tract. We hypothesized that baseline QOL and comorbidity would be predictors of QOL 1 year after treatment. DESIGN Retrospective cohort study. SETTING Academic Medical Center in Seattle, Washington. PATIENTS Patients (N = 173) with baseline (pretreatment) and 1-year posttreatment QOL data. MAIN OUTCOME MEASURE Head and neck-specific QOL scores at 1 year after treatment (as measured by the University of Washington Quality of Life [UW-QOL] scale). RESULTS We identified strong relationships between 1-year UW-QOL scores and baseline UW-QOL scores (correlation coefficient [Pearson r] = 0.58; P < .001) and pretreatment comorbidity (as measured by the Adult Comorbidity Evaluation scale) (Spearman rho = 0.23; P < .001). T stage and N stage were also predictive. Although not a predictive variable, the presence of a gastrostomy tube at 1 year also strongly influenced 1-year UW-QOL scores. Patients with gastrostomy tubes had UW-QOL scores 11.5 points worse than those without (P < .001), when a 7-point difference is considered clinically significant. In predictive multivariate regression models, pretreatment QOL scores, comorbidity, and T stage had the strongest prognostic impact on 1-year UW-QOL scores. CONCLUSIONS In bivariate analyses, the presence of a gastrostomy tube worsens UW-QOL scores at 1 year and requires further investigation. When considering predictive variables only, baseline QOL and comorbidity appear to have strong influences on posttreatment QOL and have greater impact than treatment modality. Greater attention to these baseline predictors should be given when counseling patients about long-term function after treatment.

Human papillomavirus-positive oral cavity and oropharyngeal cancer patients do not have better quality-of-life trajectories

Objective. To determine the role of human papillomavirus (HPV) status on quality of life (QOL) in patients with oral cavity and oropharyngeal squamous cell carcinoma (OSCC). Since OSCC that are associated with high-risk HPV have an improved response to treatment and survival, we hypothesized that patients with these tumors would have better QOL trajectories. Study Design. Prospective cohort study. Setting. Tertiary care academic medical center and 2 affiliated hospitals. Subjects and Methods. Head and neck–specific QOL was determined using the University of Washington Quality of Life scale version 4 in patients with newly diagnosed invasive OSSC (N = 228). Results. Pretreatment QOL was higher in patients with high-risk HPV-associated tumors compared with patients with HPV-negative or low-risk HPV-associated tumors (P = .015). Patients with high-risk HPV-associated tumors had larger decreases in QOL from pretreatment to immediate posttreatment compared with patients with HPV-negative or low-risk HPV-associated tumors (P = .041). There was no association between HPV status and 1-year posttreatment QOL. Conclusion. Among OSCC patients, high-risk HPV-associated tumors were associated with higher pretreatment QOL and a larger decrease in QOL from pretreatment to immediate posttreatment, suggesting that treatment intensity in this unique population may adversely affect QOL.

Reconstruction After Temporal Bone Resection

Reconstruction of soft tissue defects after temporal bone resection can vary from simple closure of the external auditory canal to complex flap coverage of extensive defects. Between 1987 and 1996, 34 patients underwent lateral skull base resections and reconstruction for invasive carcinoma of the temporal bone. Seven underwent sleeve resection and/or radical mastoidectomy. Sleeve resection was managed with tympanoplasty, canalplasty, or obliteration of the external auditory canal (10). There were 24 lateral temporal bone resections and four subtotal temporal bone resections. Larger defects created by lateral and subtotal temporal bone resections required closure with a combination of temporalis flaps and local rotational cutaneous flaps (13). Lower island trapezius flaps (five), free flaps (four), and pectoralis major flaps (two) were also used. Indications and efficacy of each method are discussed, and treatment outcomes are presented.

Simultaneous Isolation of DNA and RNA from the Same Cell Population Obtained by Laser Capture Microdissection for Genome and Transcriptome Profiling

Laser capture microdissection (LCM) is used extensively for genome and transcriptome profiling. Traditionally, however, DNA and RNA are purified from separate populations of LCM-harvested cells, limiting the strength of inferences about the relationship between gene expression and gene sequence variation. There have been no published protocols for the simultaneous isolation of DNA and RNA from the same cells that are obtained by LCM of patient tissue specimens. Here we report an adaptation of the Qiagen AllPrep method that allows the purification of DNA and RNA from the same LCM-harvested cells. We compared DNA and RNA purified by the QIAamp DNA Micro kit and the PicoPure RNA Isolation kit, respectively, from LCM-collected cells from adjacent tissue sections of the same specimen. The adapted method yields 90% of DNA and 38% of RNA compared with the individual methods. When tested with the GeneChip 250K Nsp Array, the concordance rate of the single nucleotide polymorphism heterozygosity calls was 98%. When tested with the GeneChip U133 Plus 2.0 Array, the correlation coefficient of the raw gene expression was 97%. Thus, we developed a method to obtain both DNA and RNA material from a single population of LCM-harvested cells and herein discuss the strengths and limitations of this methodology.

Crosslinking of an oesophagus acellular matrix tissue scaffold.

The oesophagus acellular matrix (EAM) tissue‐scaffold has the potential to serve as the foundation for a tissue‐engineered oesophagus for repair of ablative defects. Similar to all collagen‐based biomaterials, the EAM is subject to enzymatic degradation in vivo. The introduction of exogenous crosslinks to collagen molecules via glutaraldehyde (Glu) is the most accepted method of stabilizing collagen biomaterials, but fixation with Glu incurs adverse effects. Genipin (Gp), a naturally occurring crosslinking agent, has shown to be effective at improving the stability of collagen‐based biomaterials with less cytotoxicity and reduced in vivo inflammatory responses than Glu. The aim of this study was to show that crosslinking with Gp improves the stability of the EAM while maintaining minimal biological reactivity and preserving EAM regeneration potential in a rat model. EAMs were crosslinked with Gp and Glu. Uncrosslinked EAMs served as controls. Denaturation temperature measurement and burst‐pressure measurement after enzymatic degradation assays were used to determine the effectiveness of crosslinking on in vitro stability. Subcutaneous allograft implantation and oesophageal epithelial cell‐seeding studies assessed the crosslinking effects on biological reactivity and regeneration potential, respectively. Both Gp and Glu improved EAM stability. After 30 days of implantation, the EAM elicited a minimal inflammatory response and crosslinking did not increase inflammation. Gp‐crosslinked EAMs supported epithelial adhesion and proliferation while Glu‐crosslinked EAMs did not. Gp improves the stability of the EAM while maintaining minimal biological reactivity and preserving EAM epithelial proliferation capacity, yielding a tissue scaffold that may form the basis of a durable and biocompatible tissue‐engineered oesophagus. Copyright