Electrophysiological and behavioral properties of 4-aminopyridine-induced epileptic activity in mice.

4-aminopyridine (4-AP) is a widely used drug that induces seizure activity in rodents, especially in rats, although there is no consensus in the literature on the dose to be used in mice. The aim of the present study was to investigate the effect of the intraperitoneal administration of 4-AP in two doses (4 and 10 mg/kg) in vivo. EEG, movement, and video recordings were made simultaneously in male B6 mice to specify the details of the seizures and to determine whether there is a suitable non-lethal dose for seizure induction and for further molecular studies. Seizure behavior in mice differs from that seen in rats, with no characteristic stages of epileptic seizures, but with spiking and seizure activity. Seizure activity, although produced at both doses without being lethal, induced different changes of the EEG pattern. Smaller dose induced a lower amplitude seizure activity, decreased spiking activity and later onset of seizures, while higher dose induced a much more intense brain seizure activity and severe trembling. It is concluded that the intraperitoneal administration of 4-AP at a dose of 10 mg/kg induces explicit seizure activity in mice which is repeatable and can be suitable for further molecular research.

Degree of tumour differentiation as a prognostic factor in advanced laryngeal cancer.

Degree of tumour differentiation as a prognostic factor in advanced laryngeal cancer. As part of a retrospective analysis on treatment results in 139 patients with advanced laryngeal squamous cell carcinoma (T3-4) differentiation grade of the tumour was analyzed as a prognostic factor. Univariate analysis differentiation grade was related to tumour size, presence of neck node metastasis and conversion of N-stage during follow-up. For statistical analysis, patients with G1-G2 and G3-G4 were grouped. Prognosis for G3-G4 carcinomas is significantly worse for disease specific survival (p < 0.025), due to significantly more regional recurrence (p = 0.05). At multivariate analysis it turned out that regional control and disease specific survival in patients with no palpable neck nodes were adversely affected by the histological degree of differentiation of the diagnostic biopsy. For this group of patients extensive treatment of neck nodes is recommended.

T3 squamous cell carcinoma of the larynx treated by a split-course radiation protocol. A multiinstitutional study.

A retrospective multiinstitutional study was initiated analyzing patients with T3 squamous cell carcinoma of the larynx, treated between 1975 and 1984 in eight Dutch head and neck cancer centers. In two institutions the treatment modalities used depended on the assessment of the response of the primary tumor to a first series of radiation. According to this split-course regime protocol, poor responders were offered surgery, that is, subsequent to a first series of radiation, a laryngectomy was performed (RT + S). For good responders (RT-I) or poor responders but medically unfit for and/or refusing surgery (RT-II), the radiation was continued after variable rest periods had elapsed (split-course radiation therapy). This paper analyzes 131 patients treated in the two institutions by this split-course regime protocol. Mean follow-up was 84 months; 89% were male, 11% female. At 10 years a corrected survival of 55% and an overall survival of 20% was observed. For the RT-I the actuarial local relapse rate was 56% versus a relapse rate of only 13% for the RT + S group. The corrected survival rates of the RT-I and RT + S were 54% and 70%, respectively. In contrast: 10 of 12 RT-II patients relapsed locally, and a corrected survival of only 21% was observed. The influence of overall treatment time (OTT) was studied by using the equation of the biological effective dose (BED), being defined as D(1 + d/alpha/beta) - (ln 2/alpha*Tp)*OTT). However, no clear relationship between BED and the risk for local and/or regional relapse could be established.

Uni- and multivariate analysis of eight indications for post-operative radiotherapy and their significance for local-regional cure in advanced head and neck cancer.

Eighty consecutive patients with advanced head and neck cancer were treated with combined therapy of radical surgery and post-operative radiotherapy. Indications for post-operative radiotherapy were pathological staging of the primary tumour (pT3 or pT4), poorly differentiated or undifferentiated carcinoma (G3, G4), tumour thickness, tumour invasion in the surrounding tissues with slender tumour strands and solitary tumour cells, perineural spread, lymphangio-invasive tumour growth, multiple positive neck nodes or extranodal spread, and microscopical irradicality of the surgical margins. The contribution for prognosis of these indications for post-operative radiotherapy were retrospectively calculated in an univariate and multivariate analysis. Of all investigated parameters, the mode of tumour invasion and lymphangio-invasive growth were independent prognostic factors. If these unfavourable prognostic signs are present, post-operative radiotherapy has to be intensified to at least curative doses of 66 Gy or more to the areas at risk.

Treatment of advanced laryngeal cancer (T3-4).

Various treatment options for advanced laryngeal cancer are discussed. Although no results of prospective studies are available, combined treatment of total laryngectomy and radiotherapy seems to offer the best locoregional control rates and maybe survival rates. This, however, results in the loss of natural voice. Radiotherapy alone (RA) will result, in unselected cases, in a local failure rate of approximately 50%. However, when the radiation schedule will be tailored to radiobiological parameters like potential doubling time of clonogenic cells local control may be enhanced. The choice of treatment may be related to known prognostic factors like severe airway obstruction, sex, tumorextension and involvement of neck nodes. Since in females and in patients with tumors confined to the glottic region only local control with RA is high, primary radiotherapy is advocated. For patients with severe airway obstruction or N2-3 neck nodes, locoregional control rates with RA are poor, so surgery combined with postoperative radiotherapy is advisable. For the remaining group of patients RA may be tested against combined treatment in a prospective trial.

Radiotherapy in T1 laryngeal cancer: prognostic factors for locoregional control and survival, uni- and multivariate analysis.

From 1975 through 1985, 194 patients with T1 glottic, 37 patients with T1 supraglottic, and 3 patients with T1 subglottic cancer were treated with radiotherapy. Local control and ultimate locoregional control (after salvage surgery) was 91% and 97% for T1 glottic, 84% and 81% for T1 supraglottic, and 2/3 and 3/3, respectively for subglottic tumors. In uni- and multivariate analysis local control for glottic tumors was associated with extension of the tumor on the vocal cord (entire length of vocal cord vs others, p = 0.01) and continuation of smoking after therapy (yes/no, p = 0.03). No prognostic factor for local control was found in supraglottic tumors. However, regional control and survival were impaired by N stage (N0 vs N+, p less than 0.0005), local recurrence (yes/no, p less than 0.0005), and extension of the tumor (one supraglottic subsite vs more than one, p less than 0.05). Mild late complications were seen in 13% of patients without salvage therapy. Following univariate analysis, field size, fraction size (greater than 2 Gy), maximum tumor dose (greater than 70 Gy), age, post-treatment biopsy, and tumor site were associated with complication rate. Following multivariate analysis, site, fraction size, maximum tumor dose, and continuation of smoking after therapy were independent prognostic factors for mild late complications (mostly arytenoid edema).

The status of the resection margin as a prognostic factor in the treatment of head and neck carcinoma.

The value of the status of the resection margin as a prognostic factor after surgical treatment was investigated in 80 patients with squamous cell carcinoma of the oral cavity, oropharynx and laryngohypopharynx. The relation of locoregional recurrence with the presence or absence of tumour at the surgical margin was analysed together with other indications for postoperative radiotherapy. Locoregional recurrence was observed in 20% and was correlated with tumour thickness over 5 mm, spidery growth and tumour-positive margins. Tumour-positive margin as a single indication for postoperative irradiation was not related to an increased recurrence rate. When however occurring together with other indications for postoperative irradiation, the recurrence rate was higher than in the patient group with the same number of indications for postoperative radiotherapy but without tumour at the surgical margins.

The importance of vocal cord mobility in T2 laryngeal cancer.

In a retrospective study 75 patients with T2 laryngeal cancer treated from 1981 through 1985 were analysed. Of this group 71 patients had a full course of radiotherapy as primary therapy. All 71 patients were given 70 Gy/7 weeks on the primary and 50 Gy/5 weeks on the neck, 2 Gy per fraction. Various prognostic factors for local control and survival were studied. In our patient group we found vocal cord mobility to be an important prognostic factor for ultimate local control and survival. Patients with impaired cord mobility had a significantly worse ultimate local control (76%) than patients with normal cord mobility (98%) and a significantly worse corrected actuarial survival. It is concluded that impaired cord mobility means more advanced disease. Future studies will have to answer the question how to improve the local control rate in patients with impaired cord mobility, for example, by incorporating laryngectomy earlier in the treatment program of those patients who can not be cured by radiotherapy alone or by using innovative radiotherapy protocols.

Radiotherapy in epithelial tumors of the parotid gland: case presentation and literature review.

A group of 113 patients irradiated for parotid tumor was studied retrospectively. Sixty-two patients were irradiated after superficial parotidectomy or enucleation of a pleomorphic adenoma. None of them had a recurrence after 5-15 years. Sixteen patients were irradiated postoperatively after surgery for a recurrence of pleomorphic adenoma. Only one of them had developed a recurrent tumor. Thirty-five patients with a malignant parotid tumor were treated by irradiation, 22 after surgery and 13 after biopsy only. Patients with a low malignancy tumor (10/11) and adenoid cystic carcinoma (6/12) responded better than patients with a high malignancy carcinoma (2/12). A tumor larger than 4 cm, facial nerve palsy, lymph node metastasis, and inoperability indicate a poor prognosis. With high dose radiotherapy it is possible to treat inoperable tumors successfully. Adenoid cystic carcinomas can respond well to irradiation alone.

Panendoscopy: a valuable procedure?

The significance of panendoscopy, performed as part of the routine diagnostic procedure, must be questioned when the incidence of synchronous primary tumors found by this procedure is only 1% to 2%, as in patients with head and neck cancer in the Dutch population. In order to detect a group of patients with a higher probability of secondary tumors, patients were selected for panendoscopy on the following criteria: localization and histology of the index tumors, as well as on smoking and drinking habits. In spite of this selection, the yield of panendoscopy was still below 2%. Until other criteria for the selection of a subset of patients with a high incidence of synchronous tumours are found, the indication for panendoscopy as part of a routine diagnostic procedure has to be constantly questioned, and panendoscopy should therefore be performed only when this procedure is part of a prospective study.

[Is there a role for radiotherapy in the treatment of patients with pleomorphic adenoma of the parotid gland?]. / Heeft radiotherapie een plaats in de behandeling van patiënten met pleomorf adenoom in de glandula parotis?

A group of 79 patients primarily operated (n = 63) or operated for local recurrence after previous surgery (n = 16) and irradiated post-operatively was studied retrospectively. Indications for radiation treatment were: enucleation and spill after pseudo-penetration of the capsule or remnants of tumour after partial or total parotidectomy respectively. During follow-up (4-16 years) only one of the patients, irradiated because of recurrence, had a second recurrence. No major complications or malignant degenerations took place. Partial or total parotidectomy with saving of the facial nerve is the treatment of choice rather than a combination of enucleation with radiotherapy. However, in case of remnants after radical surgery or re-excision for recurrent tumour postoperative irradiation appears to be indicated and effective.

Induction chemotherapy with cisplatin and continuous infusion 5-fluorouracil in locally far-advanced head and neck cancer.

Induction combination chemotherapy with cisplatin, 100 mg/m2 i.v. day 1, and 5-fluorouracil, 1,000 mg/m2/24-h infusion days 1-4, was applied in 76 patients with locally far advanced squamous-cell cancer of the head and neck. The treatment program consisted of 3 cycles of chemotherapy, followed by local radiotherapy and/or surgery. Hematologic side effects were leukocytopenia (50%) and thrombocytopenia (35%). Other side effects included renal toxicity (23%), nausea and/or vomiting (86%), alopecia (18%), and phlebitis (45%). Thirteen patients (17%) achieved a complete remission and 37 patients (49%) a partial remission. Median progression-free and overall survival were 8 and 11 months, respectively. Only patients achieving a complete remission had a better prognosis. Although induction chemotherapy may facilitate further local treatment in about half of the patients, on the basis of presently available data, this procedure should not be routinely applied with the aim of better survival.

Regression after 50 Gy as a selection for therapy in advanced laryngeal cancer.

Radiation alone for advanced laryngeal cancer will result in an initial local control rate of 50%. When a local recurrence is diagnosed, only 50% will be successfully salvaged by surgery. To identify patients with a high chance of local control with radiation alone in advanced laryngeal cancer, the clinical response following radiotherapy was assessed a few days after 50 Gy/5 weeks. In patients with T-stage reduction or greater than 50% tumor regression radiotherapy was continued, if not, laryngectomy was performed after 4-6 weeks. According to this protocol 30 patients (out of 50) with T3/T4 laryngeal cancer were treated. Initial local control was assessed 6 weeks after radiotherapy, the ultimate local control included successful salvage surgery. Initial local control in patients, treated with a full course of radiotherapy after T-stage reduction or greater than 50% tumor regression, was 69% for T3 and 43% for T4 while the ultimate local control rate was 85% and 71% respectively. Although the percentage of voice preservation in our study was slightly lower (40%) than data from literature with radiation alone, the ultimate local control was high and comparable with those of combined therapy (in which laryngectomy is a part). The corrected actuarial 5-year survival in all T3 and T4 patients treated with radiation alone and salvage surgery was 73% and 31% respectively and was not different compared to surgery with pre- or post-operative radiotherapy, 74% and 53% respectively. We believe that this protocol may select a favorable group of patients for high dose radiation alone in T3 and probably in T4 laryngeal cancer.

Adjuvant postoperative radiotherapy in carcinoma of the rectum and recto-sigmoid.

The adjuvant postoperative irradiation is an efficient treatment method to diminish the chance on pelvic recurrences in high risk group patients having rectosigmoid or rectumcarcinomas Dukes B or C and/or in case of positive surgical margins. We reviewed the literature and our own patient material treated at the University Hospital Utrecht in the years 1980-1983. Our results are comparable with the results published in Boston. Because of the high percentage local recurrence in the perineum following APR, we changed our technique and dose. Our results from 1980-1983 and the technique and dose used since 1985 is described. We also recommend some preventive measures to lower the complication rate.