A cadaveric study of auricular lymphatics and implications for sentinel lymph node biopsy.

Malignant cutaneous tumors of the auricle are known to have a high rate of spread to the regional lymph nodes, and, for this reason, removal of the lymph nodes, for diagnostic or therapeutic purposes, is often required. Recent experience with sentinel node biopsy in cutaneous tumors of the head and neck has questioned the traditional lymphatic pathways and prompted a new study. Lymphatic pathways from the auricle were demonstrated by India ink injection of five auricles in three cadavers followed by block dissection and Spalteholz clearing of en bloc specimens. Lymphatics descend adjacent to the mastoid bone periosteum and lie deep to the insertion of the sternocleidomastoid muscle. There are five different locations for sentinel nodes: superficial parotid, anterior mastoid, infra-auricular parotid, deep to sternocleidomastoid, and lateral mastoid. Two of these nodal locations (anterior and lateral mastoid) may be bypassed by anastomotic pathways. We conclude that, first, echelon lymph nodes lie in five different sites, some bypassed by anastomotic lymphatics. Lymphatics from the ear lie close to the mastoid bone and pass deep to the insertion of sternocleidomastoid where they may be difficult to follow. Sentinel lymph node biopsy for cutaneous tumors of the auricle is possible, but the presence of skip metastases should be considered.

Role of sentinel lymph node biopsy in oral cancer.

Squamous cell carcinoma of the oral cavity represents about 2% of all malignant neoplasms and 47% of those developing in the head and neck area. The tongue is the most common site involved, and this incidence is increasing mainly in young people, possibly related to human papilloma virus infections. Prognosis depends on the stage: the 5-year survival rate of tongue squamous cell carcinoma, whatever the T stage, is 73% in pN0 cases, 40% in patients with positive nodes without extracapsular spread (pNl ECS-), and 29% when nodes are metastatic with extracapsular spread (pNl ECS+: p > or = 0.0001). Nodal micrometastases (cN0 pN1) are found in up to 50% of cN0 tongue squamous cell carcinoma patients operated on the neck. At present, no clinical, imaging staging modalities or biological markers are available to diagnose nodal micrometastases. The sentinel node biopsy has been tested since 1996 in order to find a solution to this problem. The sentinel node is the first node reached by the lymphatic stream, assuming an orderly and sequential drainage from the tumour site, and should be predictive of the nodal stage. According to the literature, sentinel node biopsy is a reliable technique in selected cN0 cases, but the procedure is still experimental and should not be performed outside validation trials. Successful application of sentinel node biopsy in the head and neck region requires surgical experience and specific technical devices, including pre-operative lymphoscintigraphy and intra-operative gamma-probe. Moreover, dynamic lymphoscintigraphy seems to be able to show the lymphatic stream from the primary tumour and could allow a selective neck dissection to be tailored thus reducing the related morbidity.

Inappropriate retinoic acid receptor-beta expression in oral dysplasias: correlation with acquisition of the immortal phenotype.

Retinoids are useful in the treatment of premalignant oral lesions and in preventing the occurrence of second primary cancers after resection of the initial primary oral cancer, but long-term prognosis is still poor, presumably due to malignant cells escaping retinoid control. Previous work has shown that loss of expression of retinoic acid receptor beta is one of the most consistent molecular changes during oral cancer progression in vivo. In this report we demonstrate, using a novel panel of primary cultures of oral lesions, that loss of retinoic acid receptor beta expression at the dysplasia stage occurs during the transition from senescent to immortal phenotype but may occur independently to the loss of CDKN2A/p16 expression.

An allelotype of squamous carcinoma of the head and neck using microsatellite markers.

The detection in tumors of genomic regions with a high frequency of loss of heterozygosity has led to the localization and subsequent cloning of a number of tumour suppressor genes. To identify such regions involved in the development of squamous carcinoma of the head and neck we have analyzed 28 paired normal and tumor DNA samples. Using the polymerase chain reaction to amplify 50 simple sequence repeats or microsatellite markers we have studied all 22 q limbs and 17 of the p limbs in 21 patients. In informative cases we observed a high incidence of loss of heterozygosity at five specific chromosomal regions: 3p (44%); 5q (43%); 9q (35%); 11q (45%); and 17p (31%). In addition, further analysis of tumors showing loss of heterozygosity at 5q suggests that a gene at or near the APC locus is involved in squamous carcinoma of the head and neck.

A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer.

An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.

Steroid hormone receptors in human salivary gland tumours.

Major salivary gland tumours were studied for the presence of hormone receptors for oestrogen and progesterone. Of the eight salivary gland tumours exhibiting varied histology, none showed high affinity receptors for oestrogen or progesterone. Salivary tissue from four patients with non-neoplastic salivary gland disease was also studied and found not to contain high affinity receptor sites. The absence of hormone receptors in these glands suggests that such tumours are not dependent on endocrine function.

Immediate reconstruction of the mandible using a vascularized segment of radius.

Resection of a segment of mandible, particularly when associated with malignant disease, carries a high morbidity and mortality. Traditional methods of autogenous bone grafting have proved unreliable in immediate reconstruction of such mandibular defects because of the variability of the recipient bed. These unfavorable conditions for bone graft survival can be largely overcome using vascularized bone and vascularized soft tissue reconstruction. The radial forearm free flap has proved a versatile and useful method in intraoral reconstruction and can be used together with a segment of radius as a composite flap. The technique of raising a segment of vascularized radius is described and its use in immediate reconstruction of the mandible at the time of resection illustrated in a series of 14 consecutive cases. There was one microvascular failure in this series and one postoperative death. The remaining 12 cases have had a successful outcome and show clinical union in the follow-up period varying from 11-36 months. There is evidence indicating that the bone maintains its viability even in the presence of preoperative or early postoperative radiotherapy.

Current role of gene therapy in head and neck cancer.

Our increasing knowledge of cancer molecular biology has led to the development of new genetic therapies for the treatment of cancer. Such therapies are advantageous in that they can selectively target tumour tissue leaving normal tissue relatively unaffected. In squamous cell cancer of the head and neck, such therapies may be beneficial in the treatment of loco-regional recurrence, minimal residual disease and in the treatment of distant metastatic disease. This article describes the principles of cancer gene therapy reviews some early clinical trials of gene therapy in head and neck cancer.

Psychological distress at follow-up after major surgery for intra-oral cancer.

A cohort of patients who had received major intra-oral surgery, up to 10 yr (mean 3.5 yr) prior to this study were reviewed and assessed for evidence of current psychological disturbance. Forty-one per cent of patients were found to have significant levels of psychological distress comprising mood disorder, social dysfunction or both types of difficulty. Prevalence of clinical anxiety and depression per se was within the range 22-32%, but few patients were receiving any form of active therapy for these problems. Investigation of predictors revealed that females and younger people were more at risk to psychological distress. Tentative evidence for variability in psychological outcome in relation to tumour site is also reported. Results are discussed with reference to service provision needs and further research priorities.

The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically N0 neck for patients with head and neck squamous cell carcinoma.

This study aimed to evaluate the ability of lymphoscintigraphy (LSG) to direct sentinel node biopsy (SNB) in the identification of occult metastases in the clinically N0 neck for patients with head and neck squamous cell carcinoma (HNSCC). 57 clinically N0 neck sides in 48 patients were assessed using the triple diagnostic approach of pre-operative LSG, intra-operative use of a gamma probe and blue dye. SNB was performed after radiocolloid and blue dye injection. Pre-operative LSG and the intra-operative use of a gamma probe identified radioactive sentinel nodes, and visualization of blue stained lymphatics identified blue sentinel nodes. 104 sentinel nodes were harvested from 43 patients. The identification rate was 90% (43 of 48). Of the 104 nodes harvested, 17 of 62 (27%) nodes identified as both radioactive and blue were positive for occult metastases compared with 5 of 42 (12%) nodes identified as hot or blue only (p<0.05). Sentinel nodes were identified in 39 of 48 (81%) patients using LSG. Of 39 patients in whom sentinel nodes were identified using LSG, 37 of 39 (95%) had radioactive sentinel nodes harvested intra-operatively. In patients who had no sentinel nodes identified on LSG, 4 of 9 (44%) had radioactive sentinel nodes harvested intra-operatively. This difference was statistically significant using the t-test (p<0.05). LSG directs SNB and is essential in the identification of occult metastases within the clinically N0 neck for patients with HNSCC.

Treatment of oral cancer: the need for defined protocols and specialist centres. variations in the treatment of oral cancer.

The authors of this study aimed to identify treatment philosophies for oral cancer within the west of Scotland and to investigate any survival differences associated with the various treatment options by means of a retrospective review of case notes and cancer registry data. All patients with squamous cancer of the tongue or floor of the mouth were identified from the West of Scotland Cancer Registry for the period 1984-1990. A total of 206 patients were available for study. Five different treatment protocols were identified: 5% of patients underwent biopsy only, 16% biopsy plus radiotherapy, 11% excisional biopsy, 25% radical surgery, and 42% radical surgery plus radiotherapy. Tumour staging by the TNM classification was an important factor that determined outcome. When adjusting for T stage and nodal involvement, there was a significant effect of treatment protocol on both the disease-free period (P < 0.001) and on survival (P < 0.001). The treatment options were used differently by individual clinicians and were related to stage of the disease. One hundred and forty-four (70%) of the patients were treated by a single combined head and neck unit based within the plastic surgery unit at Canniesburn Hospital. The remaining 62 were treated in 13 different units throughout the west of Scotland. For those not treated in the combined head and neck unit, the increased hazard for recurrence was 1.43 (95% confidence interval (CI) 1.01-2.02), and the increased hazard ratio for death was 1.48 (95% CI 1.06-2.06) when adjusting for tumour stage, and nodal involvement. Treatment philosophies for oral cancer have a significant effect on outcome. There is a need to develop clearly defined protocols based on staging and site of disease. We believe that treatment should be carried out within a multidisciplinary setting in a combined head and neck cancer unit.

The management of tumours arising in the maxillary antrum.

Eighty-eight cases of tumours arising in the maxillary antrum undergoing treatment between 1967 and 1989 are reported. The series comprised 34 females and 54 males. Sixty-two patients had squamous cell carcinoma (SCC). Forty of those with SCC were treated by XRT only, four cases by surgery only, while the remaining 18 patients had surgery and post-operative XRT as a combined modality treatment. Early SCC (T2N0) was adequately controlled by radical radiotherapy alone with a 5-year survival of 69.1%. In more advanced SCC (T3N0 and (T4N0) radical radiotherapy alone was less successful with the 5-year survival falling to 19%. Combined modality treatment comprising radical surgery followed by radical postoperative radiotherapy improved 5-year survival in advanced SCC to 61%. It is therefore recommended that if patients are treated for cure, major surgery followed by radical postoperative radiotherapy is preferable in advanced squamous tumours ((T3/T4) of the maxillary antrum.

Interstitial iridium-192 implantation for recurrent and/or locally advanced head and neck cancer.

We report our experience with the use of interstitial iridium-192 implantation in the management of patients with recurrent and locally advanced squamous cell carcinoma of the head and neck. Between June 1992 and July 1998 this technique was employed in the management of two groups of patients: (1) a primary group, comprising 42 patients who had presented for the first time with advanced head and neck disease, and had therefore not undergone any previous treatment; and (2) a salvage group of 16 patients with recurrent disease previously treated with external beam radiotherapy (four received therapy to the neck, one to the cheek, eight to the tongue and three to the floor of the mouth). The follow-up in each group was short, ranging from 3 to 56 months. The overall response in the primary group was 38/42 (90%). A complete response was achieved in 35/42 (83%). In the salvage group, the overall response was 13/16 (81%); 4/16 (25%) showed a complete response and 9/16 (56%) a partial response. The estimated percentage surviving at 1 year for patients with primary disease is 70% (95% confidence interval (CI) 54-86). For those receiving salvage therapy the estimated percentage surviving at 1 year is 45% (95% CI 19-71).

Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours.

Tumours of the oral cavity/oropharynx occur relatively infrequently in the UK. The management of such lesions, especially the squamous cell carcinomas, is still a little controversial. Some centres advocate radiotherapy while others adopt surgery and radiotherapy. In an attempt to resolve the question of which approach gives the better results, a multicentre randomized trial was established to compare surgery plus postoperative radiotherapy with radical radiotherapy alone. It was anticipated that 350 patients would be required to give a statistically significant result, but, after 35 patients had been entered, the trial was closed prematurely with a marked difference in overall survival in favour of the combination arm (P = 0.0006). At this analysis, carried out 23 months after trial closure, the survival difference between the two arms remains statistically significant for all causes of mortality (P = 0.001; relative death rate = 0.24; 95% CI 0.10-0.59).

Lessons in integration--operations research in an Indian leprosy NGO.

Since the Alma Ata Declaration in 1978, health systems supporting the treatment and control of infectious diseases like leprosy and tuberculosis have been encouraged to 'integrate' into the primary health care structure within countries. Now, more than 20 years later, countries are still grappling with the concept of integration and looking for ways to achieve it. This study reports findings from a leprosy/Tuberculosis/AIDS awareness pilot project conducted by LEPRA India, a leprosy non-governmental organization (NGO), between 1996 and 2000 in Koraput district, Orissa. The project addressed the issue of integration on two levels. On the one hand LEPRA used the context of the project to explore ways in which to integrate TB services into their existing leprosy control structure. On the other hand, lessons from the pilot study were intended to help the organization find ways of linking with the government health care structure. Following a 'qualitative approach', this operations research project assessed the perceptions of communities and providers about leprosy and tuberculosis services. Providers across the spectrum of this plural healthcare system were asked to provide comment on developing stronger networks with each other, with NGOs and with government, while patients and communities were asked to describe the resources available to them and the constraints they face in accessing health care in general, and for leprosy and TB in particular. LEPRA staff from top management to the outreach workers were also approached for their views. Patients and communities noted that physical access to treatment was a major constraint, while the existence of local providers and family support structures facilitated health and health care. Providers expressed a willingness to collaborate (with LEPRA and the government), but lacked training, adequate staff support and the appropriate equipment/technical resources. Also lacking were adequate information campaigns to inform the public about these diseases and their treatment. This information has provided LEPRA with an understanding of how they might best fill gaps in the existing system and therefore assist in the process of integrating services in their own organization and through the primary health care structure. To achieve this aim, LEPRA will increasingly become involved in developing relationships and partnerships with government in the delivery of training and services and in infrastructure development.

The sandwich Abbe flap in sceondary cleft lip deformity.

The history and use of the Abbe flap in the correction of secondary cleft lip deformity is outlined. A modification, the sandwich Abbe flap, is presented and its advantages are described from a cosmetic and functional standpoint. An extension of this method is also used in the revision of unsatisfactory conventional Abbe flap results.

The radial forearm flap in intraoral reconstruction: the experience of 60 consecutive cases.

Sixty consecutive patients in whom a free radial forearm flap was used to reconstruct an intraoral defect have been reviewed. The ages ranged from 54 to 85 years, the majority of patients presenting with intraoral carcinoma. There were 6 microvascular failures, and the remaining 54 patients (90 percent) healed uneventfully, with no incidence of fistula. Intraoral healing time was reduced to 11 days on average, and hospitalization was similarly reduced to 17.8 days. A slower postoperative recovery did not appear to be related to age or to the site of the defect within the oral cavity but closely paralleled the extent of excisional surgery. The postoperative mortality was less than 2 percent, but the overall prognosis remained poor, with a 21.6 percent mortality at follow-up (minimum 15 months). Thirty-nine patients (72 percent) underwent early postoperative radical radiotherapy without any evidence of intraoral wound breakdown or problems with flap viability. The results demonstrate the effectiveness of this method of intraoral reconstruction and indicate that such complicated and prolonged surgical techniques do not increase the risks associated with major head and neck surgery.

Recovery of sensation in the radial forearm free flap in oral reconstruction.

The purpose of this study was to find out to what extent sensory function recovers in a free radial forearm flap used for intraoral reconstruction after surgery for oral cancer. In 40 free radial forearm flaps we investigated the perception of light touch, two-point discrimination, pain, directional sensation, and temperature between 6 months and 11 years after flap transfer to the oral cavity. Four flaps (10 percent) were anesthetic, 21 flaps (52.5 percent) recovered partly, and 15 flaps (37.5 percent) had perception of all sensory modalities tested in at least two-thirds of the flap area. All patients with positive sensation in the surrounding area subsequently had good sensory recovery in the flap. This suggests that recovery of sensation in a nonreinnervated free flap is due to nerve ingrowth from the surrounding mucosa. The present results suggest that sensory function in intraoral free radial forearm flaps returns again. Further study is necessary to define the use of neurofasciocutaneous radial forearm flaps in reconstruction of the oral cavity.

Reducing morbidity in the radial forearm flap donor site.

The radial forearm flap, although widely used, has been criticized for the poor quality of its donor site. To investigate the causes of morbidity, 100 radial artery free-flap donor sites have been reviewed. Sixty-seven patients required skin grafting (group 1), and the remaining 33 patients were closed directly (group 2). Seventeen patients in the series had compound osteocutaneous flaps (group 3). Wound healing proved to be a significant problem in groups 1 and 3, and fracture of the radius occurred in 4 of the 17 patients in group 3 and was the most significant cause of morbidity. The radial artery was reconstructed in 12 patients, but only 6 of the arteries (50 percent) were patent at the time of review. Subjective assessment on a scale of 0 to 10 demonstrated a relatively pain-free donor site with low pain scores (2.5 of 10). The cosmetic result was acceptable in men (1.5 of 10) but was less so in women (4 of 10). Angulated fracture of the radius produced an unacceptable cosmetic result (7 of 10). In light of this experience, we no longer reconstruct the radial artery as a matter of routine. The donor defect is closed directly wherever possible using an ulnar artery-based transposition flap when required. A "boat shaped" osteotomy is used in preference to right-angled bone cuts when harvesting a segment of radius to avoid the complications and sequelae of fracture. These changes in surgical technique have improved the acceptability and minimized the problems associated with this donor site.

Free flaps in reconstructive surgery.

Advances in technique, training and instrumentation have improved the patency rates for small vessel anastomosis. This, together with the introduction of more reliable donor sites for free tissue transfer, have resulted in success rates in excess of 90%. The technique is not associated with an increase in mortality or morbidity; on the contrary there is the advantage of primary reconstruction with a wide choice of donor sites offering the correct amount and type of tissue required. Single-stage, effective reconstruction, aimed at primary wound healing remains the aim of the reconstructive surgeon and free tissue transfer offers the most versatile and reliable method currently available.