B.F.A.M. van der Laan

Radiation-induced tumours of the head and neck

In order to study the induction of malignancy in normal tissues due to ionizing radiation, we reviewed the files of 2500 patients with a tumour of the head and neck treated at the Netherlands Cancer Institute (Antoni van Leeuwenhoek Ziekenhuis), Amsterdam, from 1977 to 1993. We then checked whether or not these patients had been previously irradiated. Patients with a thyroid carcinoma or skin cancer were excluded from the study, since it is generally known that previous irradiation is a risk factor in these tumours. Eighteen patients were found to have a malignancy within a previously irradiated area (0.70 per cent). The mean interval between radiation and diagnosis of the head and neck tumour was 36.5 years. There were five soft tissue sarcomas, nine squamous cell carcinomas and four salivary gland tumours. Fourteen patients were operated upon whereas four received palliative treatment only. The median survival of the total group was 3.5 years. Particularly, in young patients because of the better cancer therapy and prolonged survival one must be aware of the increased risk of radiation-induced tumours.

Overexpression of Intrinsic Hypoxia Markers HIF1{alpha} and CA-IX Predict for Local Recurrence in Stage T1-T2 Glottic Laryngeal Carcinoma Treated With Radiotherapy

PURPOSE To examine the prognostic value of three endogenous hypoxia markers (hypoxia inducible factor 1 alpha subunit [HIF1 alpha], carbonic anhydrase IX [CA-IX], and glucose transporter type 1 [GLUT-1]) on the clinical outcome in patients with early-stage glottic carcinoma primarily treated with radiotherapy (RT) and to determine the predictive hypoxic profile to choose the optimal treatment of early-stage laryngeal carcinoma. METHODS AND MATERIALS Immunohistochemistry for HIF1 alpha, CA-IX, and GLUT-1 was performed on formalin-fixed, paraffin-embedded, pretreatment tissue samples of 91 glottic squamous cell carcinoma specimens. The patient group consisted only of those with early-stage (T1-T2) glottic carcinoma, and all patients were treated with RT only. Relative tumor staining was scored on the tissue samples. Receiver operating curve analysis was performed to determine the optimal cutoff value for each tumor marker. Cox regression analyses for the variables HIF1 alpha, CA-IX, GLUT-1, gender, age, hemoglobin level, T category, N category, tobacco use, and alcohol use were performed with local control and overall survival as endpoints. RESULTS HIF1 alpha overexpression in early-stage glottic carcinoma correlated significantly with worse local control (hazard ratio [HR], 3.05; p = 0.021) and overall survival (HR, 2.92; p = 0.016). CA-IX overexpression correlated significantly with worse local control (HR, 2.93; p = 0.020). GLUT-1 overexpression did not show any correlation with the clinical outcome parameters. Tumors with a nonhypoxic profile (defined as low HIF1 alpha and low CA-IX expression) had significantly better local control (HR, 6.32; p = 0.013). CONCLUSION The results of our study have shown that early-stage glottic laryngeal carcinomas with low HIF1 alpha and CA-IX expression are highly curable with RT. For this group, RT is a good treatment option. For tumors with HIF1 alpha or CA-IX overexpression, hypoxic modification before RT or primary surgical treatment should be considered.

Shoulder and neck morbidity in quality of life after surgery for head and neck cancer

Quality of life has become a major issue in determining the outcome of treatment in head and neck surgery with curative intent. The aim of our study was to determine which factors in the postoperative care, especially shoulder and neck morbidity, are related to quality of life and how these outcomes compared between patients who had undergone surgery and a control group.

Shoulder complaints after neck dissection; is the spinal accessory nerve involved?

UNLABELLED The purpose of the current study was to investigate the relation between shoulder morbidity (pain and range of motion), and the function of the spinal accessory nerve after neck dissection. Identifying dysfunction of the nerve gives insight in the mechanisms of post-operative shoulder complaints. In total 112 patients after neck dissection (73 males/39 females), mean (SD) age 61 (13) years, participated in the study. The mean duration of follow up was 3 (2) years. Five patients had radical, 43 modified radical, 48 supraomohyoid, and 16 posterolateral neck dissection. Thirty-nine complained of shoulder pain of whom 20 (51%) had dysfunction of the spinal accessory nerve, and 19 (49%) did not. In total 29 patients (26%) had dysfunction of the spinal accessory nerve of whom 20 (69%) had shoulder pain. Shoulder pain was significantly related to dysfunction of the nerve (P < 0.001). Twenty-three patients had a difference in active range of motion in shoulder abduction of > or =40 degrees, of whom 22 (96%) had dysfunction of the nerve. A difference in active shoulder abduction of > or =40 degrees was significantly related to loss of function of the spinal accessory nerve (P < 0.001). CONCLUSION Shoulder pain after neck dissection can only be attributed to dysfunction of the spinal accessory nerve in about 50%. If patients experience shoulder pain after neck dissection examination of the trapezius muscle and active bilateral abduction of the shoulder should be made to find out if the spinal accessory nerve is involved.

DT-DIAPHORASE ACTIVITY IN NORMAL AND NEOPLASTIC HUMAN TISSUES - AN INDICATOR FOR SENSITIVITY TO BIOREDUCTIVE AGENTS

DT-diaphorase (DTD) is an important enzyme for the bioreductive activation of the new alkylating indoloquinone EO9. In preclinical studies, EO9 has shown selective anti-tumour activity against solid tumours and under hypoxic conditions. The levels of three reductive enzymes have been determined in three types of human solid tumours, together with corresponding normal tissues and normal liver. DTD enzyme activities were measured in tumour extracts using 2,6-dichlorophenolindophenol (DCPIP) and NADH as substrates; cytochrome P450 reductase or cytochrome b5 reductase activities were assessed with cytochrome c and NADPH or NADH respectively. DTD activity was highest in non-small-cell lung (NSCLC)-tumours (mean 123 nmol DCPIP min-1 mg-1), followed by colon carcinoma (mean 75 nmol min-1 mg-1) and squamous cell carcinoma of the head and neck (6-fold lower than NSCLC). DTD activity was very low in normal liver and normal lung (4-6 nmol min-1 mg-1), while the levels in normal colon mucosa or normal mucosa of the head and neck region were in the same range as the corresponding tumours. The levels of the two other reductive enzymes, cytochrome P450 reductase (CP450R) and cytochrome b5 reductase (Cb5R), were 5 to 25-fold lower than those of DTD in all the tissues, except for normal liver, in which DTD was 2 to 4-fold lower. The degree of variation found for DTD (range 4-250 nmol min-1 mg-1), was not observed for these enzymes (CP450R, 0.8-7.8 nmol cytochrome c min-1 mg-1; Cb5R, 3.5-27.6 nmol min-1 mg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Difficulties in the fixation of prostheses for voice rehabilitation after laryngectomy

In most patients with advanced or recurrent laryngeal or hypopharyngeal cancer, total laryngectomy is indicated. This means the loss of three main functions: phonation; respiration; and the prevention of aspiration during deglutition. Laryngectomy patients have various options to restore phonation: an oesophageal voice; an electrolaryngeal voice; or a tracheo-oesophageal voice. In the last case a silicone rubber shunt valve is placed in the tracheo-oesophageal wall and phonation is generated when exhaled air is forced through the oesophagus and neopharynx. This method is widely applied in Western Europe. In this paper we review the literature on fixation problems with shunt valves, tracheostoma valves and heat and moisture exchange (HME) filters. Tracheo-oesophageal speech without a valve is not considered. Despite 22 years of experience with the implantation of tracheo-esophageal shunt valves and many improvements in the design, problems still remain, such as biofilm formation with subsequent leakage through the valve, the need for frequent and inconvenient replacements, fistula enlargement leading to leakage around the device and reduced fixation, and infections. The high cost of shunt valves is a drawback to their use worldwide. To enable hands-free speech, different types of tracheostoma valve have been developed. These valves are fixed to the skin or to the tracheostoma by means of an intra-tracheal device. An HME filter is used to protect the airway and maintain physiological balance. Such devices are only suitable for a selected group of patients as fixation to the skin or trachea can be a major problem. Speaking and coughing cause pressure increases, which often result in mucous leakage and disconnection of the valve and/or HME filter. Recommendations are made for future improvements in fixation techniques.

The role of N-methyl-d-aspartate receptors and nitric oxide in cochlear dopamine release

Dopamine (DA) released from lateral olivocochlear (LOC) terminals may have a neuroprotective effect in the cochlea. To explore the role of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) in the modulation of a cochlear DA release, we measured the release of [3H]DA from isolated mouse cochlea in response to the application of NMDA. NMDA at 100 muM significantly increased the electrical-field stimulation-evoked and resting release of DA from the cochlea. The NO donor sodium nitroprusside enhanced the basal outflow of DA but failed to influence the evoked release. The administration of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) alone was ineffective, but it significantly inhibited the initial phase of the NMDA-induced elevation of DA outflow, which suggested the role of NO in the NMDA-induced DA release. The DA uptake inhibitor nomifensine increased the electrically evoked release of DA. Nomifensine failed to change the effect of NMDA on the resting or electrically-evoked DA release, which suggested that the uptake mechanism does not play a role in NMDA-evoked and NO-mediated DA release. In summary, we provide evidence that NO can modulate the release of DA from the cochlea following NMDA receptor activation, but does not affect the uptake of DA.

Predictive value of the Groningen Frailty Indicator for treatment outcomes in elderly patients after head and neck, or skin cancer surgery in a retrospective cohort

Careful selection of patients eligible for extensive head and neck cancer surgery is extremely important. A reliable predictor for postoperative outcomes in the vulnerable elderly population is not yet available. The concept of frailty describes a clinical state of increased vulnerability and can be assessed using frailty tests, such as the Groningen Frailty Indicator. In the current study, the influence of Groningen Frailty Indicator‐measured frailty on clinical outcome was investigated in elderly patients surgically treated for head and neck cancer.

Does the patch fit the stoma? A study on peristoma geometry and patch use in laryngectomized patients

Clin. Otolaryngol. 2011, 36, 235–241

Functional buckling behavior of silicone rubber shells for biomedical use

BACKGROUND The use of soft elastic biomaterials in medical devices enables substantial function integration. The consequent increased simplification in design can improve reliability at a lower cost in comparison to traditional (hard) biomaterials. Functional bi-stable buckling is one of the many new mechanisms made possible by soft materials. The buckling behavior of shells, however, is typically described from a structural failure point of view: the collapse of arches or rupture of steam vessels, for example. There is little or no literature about the functional elastic buckling of small-sized silicone rubber shells, and it is unknown whether or not theory can predict their behavior. Is functional buckling possible within the scale, material and pressure normally associated with physiological applications? An automatic speech valve is used as an example application. METHOD OF APPROACH Silicone rubber spherical shells (diameter 30mm) with hinged and double-hinged boundaries were subjected to air pressure loading. Twelve different geometrical configurations were tested for buckling and reverse buckling pressures. Data were compared with the theory. RESULTS Buckling pressure increases linearly with shell thickness and shell height. Reverse buckling shows these same relations, with pressures always below normal buckling pressure. Secondary hinges change normal/reverse buckling pressure ratios and promote symmetrical buckling. All tested configurations buckled within or closely around physiological pressures. CONCLUSIONS Functional bi-stable buckling of silicone rubber shells is possible with adjustable properties in the physiological pressure range. Results can be predicted using the proposed relations and equations.