Konstantinos Vahtsevanos

Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients.

The incidence, characteristics and risk factors for the development of osteonecrosis of the jaw (ONJ) were evaluated among 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Zoledronic acid produced 9·5‐fold greater risk for developing ONJ than pamidronate alone (P = 0·042) and 4·5‐fold greater risk than subsequent use of pamidronate + zoledronic acid (P = 0·018). Use of thalidomide and number of bisphosphonate infusions also increased the risk for ONJ by 2·4‐fold (P = 0·043), and 4·9‐fold respectively (P = 0·012). ONJ developed earlier among patients receiving zoledronic acid. Our data indicates that administration of zoledronic acid for more than 2 years or in combination with thalidomide requires caution in myeloma.

Longitudinal Cohort Study of Risk Factors in Cancer Patients of Bisphosphonate-Related Osteonecrosis of the Jaw

PURPOSE The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate. PATIENTS AND METHODS Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated. RESULTS We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP. CONCLUSION The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study of Risk Factors in Breast Cancer Patients

PURPOSE Osteonecrosis of the jaws (ONJ) was initially described in 2001 in patients receiving intravenous bisphosphonate (BP) treatment. The objective of the present study was to determine whether routine dental procedures can be considered as possible risk factors for the development of ONJ in breast cancer patients receiving BP. PATIENTS AND METHODS Twenty breast cancer patients who developed ONJ receiving BP treatment were included in group A, whereas group B consisted of 40 matched controls (breast cancer patients who did not progress to ONJ receiving BP treatment). Routine dental care, smoking habits, history of tooth extraction, use of dentures, and root canal therapy were recorded. RESULTS Our results indicate that history of tooth extraction during zoledronic acid treatment (adjusted odds ratio [OR] = 16.4; 95% CI, 3.4 to 79.6) and the use of dentures (adjusted OR = 4.9; 95% CI, 1.2 to 20.1) increase the risk of developing ONJ. CONCLUSION The outcome of the present study suggests early referral by oncologists for dental evaluation for every patient to be treated with BP. These results raise the current American Society of Clinical Oncology Level of Evidence linking certain dental procedures with ONJ from V to III. Further studies are needed to assess other possible risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.

BACKGROUND Head and neck cutaneous squamous cell carcinoma (HNCSCC) although rarely fatal has significant adverse public health effects due to high medical costs, compromised quality of life, functional impairment and other serious consequences. The present longitudinal cohort study of HNCSCC was designed to determine whether certain clinical-pathologic features of HNCSCC are associated with reduced overall and recurrence-free survival, as suggested by previous data. PATIENTS The cohort sample consisted of 315 consecutive patients presenting with primary HNCSCC of the head and neck. Life-table analysis and Kaplan-Meier survival analysis were performed. Multivariate Coxs proportional hazards regression models were used to assess the effects of covariates on the length of the interval. RESULTS There were 145 male and 170 female Caucasian patients. At the time of analysis, 222 patients were alive. The mean follow-up time of a patient after enrolment has been 46.7 months (range, 12-124 months). Broders differentiation grade, perineural involvement, the presence of inflammation and T-stage were independent adjusted predictors for overall survival. pT and N-stage, inflammation and perineural involvement were significant predictors for recurrence-free survival while adjuvant irradiation was associated with a 92% reduced risk for recurrence. Life-table analysis showed that 87% and 69% study patients were free from recurrence at years 3 and 5, respectively. CONCLUSIONS Certain clinico-pathological predictors can be used to discriminate subsets of high-risk patients that could benefit from long-term follow-up. After excision in negative margins, patients with HNCSCC should be referred to specialised multidisciplinary oncology clinics for counselling on adjuvant radiotherapy and follow-up.

Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes

Abstract:  Extrinsic skin ageing or ‘photoageing’, as opposed to intrinsic skin ageing, is the result of exposure to external factors, mainly ultraviolet irradiation. Glycosaminoglycans (GAG) and particularly hyaluronic acid (HA) are major components of the cutaneous extracellular matrix involved in tissue repair. However, their involvement in extrinsic skin ageing remains elusive. In this study, we investigated the expression of HA and its metabolizing enzymes in photoexposed and photoprotected human skin tissue specimens, obtained from the same patient. Total GAG were isolated, characterized using specific GAG‐degrading enzymes and separated by electrophoresis on cellulose acetate membranes and polyacrylamide gels. Quantitation of HA in total GAG was performed using ELISA. Gene expression of hyaluronan synthases (HAS), hyaluronidases (HYAL) and HA receptors CD44 and receptor for HA‐mediated motility (RHAMM) was assessed by RT‐PCR. We detected a significant increase in the expression of HA, of lower molecular mass, in photoexposed skin as compared with photoprotected skin. This increase was associated with a significant decrease in the expression of HAS1 and an increase in the expression of HYAL1‐3. Furthermore, the expression of HA receptors CD44 and RHAMM was significantly downregulated in photoexposed as compared with photoprotected skin. These findings indicate that extrinsic skin ageing is characterized by distinct homoeostasis of HA. The elucidation of the role of HA homoeostasis in extrinsic skin ageing may offer an additional approach in handling cutaneous ageing.

5-Fluorouracil and cisplatin in the treatment of advanced oral cancer

The benefit of the effect of chemotherapy in patients with advanced head and neck squamous cell tumors have been demonstrated by recent meta-analyses of randomized studies. However, the role of chemotherapy-especially in advanced oral cancer-is not fully clear, because of the very small amount of phase II literature available. From January 1994 to December 2000, a total of 44 pts aged 33-75 years (mean age 60 years) with advanced and histologically proved squamous cell carcinomas of the oral cavity received at least one chemotherapy course. Seven patients had stage III and 37 stage IV disease. The chemotherapy was the initial therapy in a group of 21 patients. In a second group of 23 patients the chemotherapy was delivered after relapse of their disease. The pre-chemotherapy treatment of the second group was radiotherapy in 11, surgery in 4, combination of radiotherapy and surgery in 8 patients. The chemotherapy regimen consisted of cisplatin 100 mg/m(2) in 3-h infusion, day 1 and 5-FU 1000 mg/m(2) in 24-h infusion, days 1-5. Treatment was repeated every 21 days. A total of 154 treatment courses (3.5 per patient, ranged 1-10) were administered. Myelotoxicity, nausea and vomiting were the major treatment complications. The overall response rate to the induction chemotherapy was 52.3%, with 19% complete (CR), and 33.3% partial responses (PR) and to the chemotherapy for recurrent/metastatic disease 30.4% with 8.7% CR, and 21.7% PR. No difference was found in the median survival of the two subgroups (12 months). The median survival of the responders was 15 months (95% CI 11.3-18.7 months), and of the non-responders 9 months (95% CI 5.6-12.4 months) (P = 0.0067). Chemotherapy with cisplatin and 5-FU combination is effective in pts with advanced squamous cell oral cancer and appears to improve the survival of patients who have a good response.

Clinical, histological and demographic predictors for recurrence and second primary tumours of head and neck basal cell carcinoma. A 1062 patient-cohort study from a tertiary cancer referral hospital

Basal cell carcinoma (BCC) accounts for nearly 25% of all cancers in the human body and for almost 75% of skin malignancies; approximately 85% of basal cell carcinomas develop in the head and neck region. Limited demographic, clinical and histological predictors for second primary and/or recurrent BCC have been identified to date. Our objective was to identify predictors of recurrence and second primary tumour development of BCC in the head and neck region. We included 1062 patients with a histologically confirmed diagnosis of BCC. Multivariate and Cox regression analysis were used to access demographic, clinical and histological predictors. Study follow up included 4,302 patient-years, each patient was followed-up for an average 4.0 +/- 1.8 years (range 1-12). Overall recurrence rate was 4%. High-risk histology type was associated with an increased risk for recurrence (odds ratio (OR) = 3.47, 95%CI: 1.07-11.25). We calculated a 4-fold increased risk for recurrence with positive excision margins (OR = 4.31, 95%CI: 1.82-10.22), a 21% increased risk for recurrence (OR = 1.21, 95%CI: 1.06-1.37) and a 25% increased risk for second primary BCC development (OR = 1.25, 95%CI: 1.17-1.34) per year of follow-up. The median time free of second primary tumour was 7 years, while the median time free of recurrence was 12 years. The strongest predictors for recurrence are positive excision margins and high-risk histology type, indicating the need for additional patient care in such cases.

New concepts for basal cell carcinoma. Demographic, clinical, histological risk factors, and biomarkers. A systematic review of evidence regarding risk for tumor development, susceptibility for second primary and recurrence.

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians and its incidence is increasing. Whilst ultraviolet radiation (UVR) is recognized as the main etiological factor, the relationship between exposure and host phenotype is still unclear. We systematically searched Medline, Embase, and the Cochrane databases for studies assessing the genetic basis of host response to UVR DNA damage, the effect of UVR on generation of reactive oxygen species (ROS), and their detoxification, UVR induced skin immunity modifications, and the role of genomic instability with a focus on the potential use of these biomarkers to the surgical treatment planning and prognosis of BCC patients. Data suggest that risk for BCC development is likely to result from the combined effect of many genes, each with a relatively weak individual contribution. Certain genomic alterations have been associated with increased or reduced risk for BCC development, with a second primary BCC or with recurrence of BCC. However, use of these biomarkers in everyday practice should be supported by further studies, mainly for its cost-effectiveness. In addition, not enough information exists on the prognostic value of existing demographic and clinical risk predictors for BCC regarding development of second primary or recurrent tumors. Information reviewed suggests that these predictors are of higher predictive value compared with biomarkers whilst they are indisputably cheaper and easier to monitor even in developing countries. Conclusively, we suggest that further studies aimed in investigating second primary or recurrent BCC are needed to provide better information on the predictive value of certain demographic, clinical and histological factors.

Treatment protocols of bisphosphonate-related osteonecrosis of the jaws.

To theEditor: We read with great interest the article by Wutzl et al, reporting awell-designed prospective study for the treatment of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in a cohort of multiple myeloma, breast cancer, and other diseases in patients. The authors duly report patients’ underlying diseases and also dose schemas administered. However, they do not report any data from the previous dental history of these patients, ie, history of tooth extraction. Recently, we carried out a matched case–control study in patients with breast cancer. In this study, we reported that tooth extraction could pose up to 44 times higher risk for BRONJ development. We also found an almost 5-fold increased risk for BRONJ development among patients with breast cancer under zoledronic acid medication using dentures. The evidence provided from the latter study associated BRONJ with tooth extraction and use of dentures and updated the American Society of Clinical Oncology (ASCO) level of evidence from V to III. Wutzl et al report that 72.7% of their patients received zoledronic acid for the disease. We believe that dental history of the 58 patients is available to Wutzl et al and we look forward to reading these data in a forthcoming publication. Despite being well designed and original, the study by Wutzl et al also has an important limitation not addressed by the authors. Their followup period may be uniform for almost all patients included; however, we feel that 6 months may not be enough for a precise evaluation of the proposed treatment modalities. We also carry a prospective cohort of patients under treatment with biphosphonates, some of whom had progressed to BRONJ. Logically, we designed a separate prospective study to evaluate different treatment modalities for these patients. Preliminary results were published but the study is still ongoing, and the results will be published when it will be concluded. Nonetheless, we have witnessed relapse of BRONJ in surgically treated patients up to 14 months after surgery. We have also witnessed healing at the surgically treated site up to 8 months from surgery. Therefore, based on our partially unpublished data, we suggest that the therapeutic effect of the proposed modality may be exacerbated or enhanced if the follow-up period is extended to 18 months. The authors report having performed surgery in patients with stage 1 BRONJ as well. We concur with this modality, which we also employ. Another issue noted by Wutzl et al is discontinuing intravenous administration of biphosphonates or changing it to oral for those patients who were selected for surgery. The authors state that it is not clear whether the discontinuation had a positive effect on the outcome data. The protocol of the study we are conducting controls this effect, and we expect to have some results on this issue. Nevertheless, we feel that discontinuation of biphosphonates is unlikely to have a positive impact on the outcome of the treatment. Recent studies provide Head & Neck 31: 1112–1114, 2009 Published online 1 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21148

Agenesis of Sphenoid Sinus

Although the sphenoid sinuses can be identified in sections of the fetus at 4 months, at birth the sinus remains small and is little more than an evagination of the sphenoethmoid recess. After the 3rd