Value of patient-reported symptoms in the follow up of patients potentially cured of laryngeal carcinoma.

OBJECTIVE: To evaluate the significance of patients' ability to recognise symptoms that signify recurrence. METHODS: A retrospective analysis was conducted in Norway of demographic, clinical and follow-up data for patients with laryngeal carcinoma considered free of disease following treatment. The study included clinical data from 732 patients with glottic tumours and 249 patients with supraglottic tumours who were considered cured of disease. Data on the site, time and type of recurrence (symptomatic or asymptomatic) were retrieved. RESULTS: Recurrence was observed in 127 patients with glottic tumours and 71 with supraglottic tumours. A total of 103 glottic recurrences and 53 supraglottic recurrences were symptomatic. For patients with glottic carcinoma, recurrence detection through symptoms was associated with a favourable post-salvage survival rate compared with asymptomatic recurrences (p = 0.003). CONCLUSION: A patient's ability to self-detect 'red flag' symptoms and self-initiate visits represents a previously ignored prognostic factor, and may rationalise follow up and improve survival.

Quality of life in head and neck cancer patients: validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35.

PURPOSE: The aim of this study was to define the scales and test the validity, reliability, and sensitivity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-H&N35, a questionnaire designed to assess the quality of life of head and neck (H&N) cancer patients in conjunction with the general cancer-specific EORTC QLQ-C30. PATIENTS AND METHODS: Questionnaires were given to 500 H&N cancer patients from Norway, Sweden, and the Netherlands as part of two prospective studies. The patients completed the questionnaires before, during (Norway and Sweden only), and after treatment, yielding a total of 2070 completed questionnaires. RESULTS: The compliance rate was high, and the questionnaires were well accepted by the patients. Seven scales were constructed (pain, swallowing, senses, speech, social eating, social contact, sexuality). Scales and single items were sensitive to differences between patient subgroups with relation to site, stage, or performance status. Most scales and single items were sensitive to changes, with differences of various magnitudes according to the site in question. The internal consistency, as assessed by Cronbach's alpha coefficient, varied according to assessment point and within subsamples of patients. A low overall alpha value was found for the speech and the senses scales, but values were higher in assessments of patients with laryngeal cancer and in patients with nose, sinus, and salivary gland tumors. Scales and single items in the QLQ-H&N35 seem to be more sensitive to differences between groups and changes over time than do the scales and single items in the core questionnaire. CONCLUSION: The QLQ-H&N35, in conjunction with the QLQ-C30, provides a valuable tool for the assessment of health-related quality of life in clinical studies of H&N cancer patients before, during, and after treatment with radiotherapy, surgery, or chemotherapy.

The value of follow-up in patients treated for squamous cell carcinoma of the head and neck.

Clinical findings, treatment and results have been recorded prospectively in 661 patients with carcinoma of the head and neck. With an average follow-up of 3 years 7813 follow-up consultations revealed 220 recurrences. The overall "recurrence pick-up rate" and subsequent "cure rate" was 1:36 and 1:113 consultations, respectively. Laryngeal carcinomas treated with radiotherapy and oral carcinomas receiving radiotherapy and limited resections showed recurrence "cure-rates" of 1:89 and 1:110, respectively. For other tumour sites the average "cure-rate" was 1:238. Only 39% of the recurrences were detected through physical examination. Follow-up consultations revealed 9.1% of second primaries. More time should be spent on training patients to recognise symptoms and signs of recurrence. Routine follow-up is rarely indicated beyond the third year after completion of treatment, or in patients for whom we have little to offer in terms of curative treatment.

Histological grading in the deep invasive front of T1 and T2 glottic squamous cell carcinomas has high prognostic value.

The characteristics of the deep invasive front area of squamous cell carcinomas may reflect tumour prognosis better than other parts of the tumour. Consequently, the authors have recently developed a simple malignancy grading system based solely on the characteristics of the deep invasive front area of oral squamous cell carcinomas, which has great prognostic value. Our previous materials were somewhat heterogeneous, and the prognostic value of our system needed to be confirmed in homogeneous patient material. In the present study of 95 T1-2/N0 glottic carcinomas all treated by radiation, the high prognostic value for invasive front grading of biopsy specimens is confirmed. The grading significantly predicted local recurrence, i.e. treatment failure (P = 0.001). Histological characteristics of the deep invasive front proved to be a better indicator of prognosis than the T-category (size of tumour), and our findings may be of value in the selection of treatment. Of the individual variables in the grading system (pattern of invasion, degree of keratinization, nuclear polymorphism and host response), pattern of invasion and degree of keratinization were the strongest prognosticators in the multivariate analyses. Invasive front characteristics may also prove to be of prognostic value in other cancers.

Transcranial Doppler ultrasonography-guided management of internal carotid artery closure.

OBJECTIVE: To emphasize the integrated use of transcranial Doppler ultrasonography (TCD) in the management of internal carotid artery (ICA) closure. METHODS: Thirty-three patients being considered for ICA closure underwent TCD assessment, vasomotor reserve testing/estimation, and carotid artery test occlusion with concomitant middle cerebral artery (MCA) blood velocity (V(MCA)) monitoring, including calculation of the MCA pulsatility index. Twelve of these patients proceeded to undergo ICA sacrifice. Sequential TCD sonograms guided their postoperative treatment. RESULTS: ICA aneurysms and neck neoplasms affected the TCD results and vasomotor reserve insignificantly, whereas carotid-cavernous fistulae induced characteristic circulatory alterations. The 10 subjects who tolerated ICA sacrifice hemodynamically all showed an initial decrease in the ipsilateral V(MCA) to > or =60% of the preocclusion value and a progressively decreasing MCA pulsatility index during carotid artery test occlusion. The two patients who developed hemodynamic cerebral infarctions exhibited a decrease in V(MCA) to <60% and a MCA pulsatility index that remained stable after a vast initial reduction. Postoperative hypervolemic and hypertensive support was safely titrated in all patients who received postoperative TCD surveillance, providing an ipsilateral V(MCA) of > or =80% of the preocclusion value. ICA closure permanently altered the cerebral circulatory pattern. CONCLUSION: The hemodynamic outcome of ICA sacrifice can be correctly predicted by using the TCD occlusion test. TCD provides the means to titrate the extent of postoperative hypervolemic/hypertensive support.

p53 protein expression in adenoid cystic carcinoma of the head and neck.

Forty-one adenoid cystic carcinomas were investigated retrospectively with the polyclonal antibody CM-1 against the p53 protein and the results compared with clinicopathological parameters and the proliferative activity estimated by Ki-67 expression. p53 acted as a significant explanation variable in simple linear regression with Ki-67 as the dependent variable (r=0.39, p<0.02). High p53 expression was observed in tumors with violated margins during primary surgery. No significant correlations were demonstrated with other clinicopathological parameters or treatment outcome. Alterations in the p53 gene may be responsible for increased proliferative activity in the tumors, but elevated antigen expression has little prognostic value.

Stereologic estimation of nuclear volume in glottic squamous-cell carcinoma.

By means of a newly developed stereologic model, the point sample intercept technique, we estimated the mean nuclear volume (nuclear (V) over bar v) in 106 T1-4 glottic carcinomas. The original formalin fixed, routinely processed H&E stained diagnostic sections were used. The overall average nuclear (V) over bar v was 782 mu m(3). Neither T- nor N-stage revealed significant differences in nuclear (V) over bar v. Patients dying from glottic carcinoma had a higher nuclear (V) over bar v compared to survivors/patients dying from intercurrent diseases, 917 and 713 mu m(3) respectively (p=0.0042). The distribution of nuclear (V) over bar v suggested that a cut-off level of 900 mu m(3) would give a better separation between clinically favourable and poor prognostic cases (p=0.0004). Both T- and N-stage were highly significant in relation to survival by univariate analysis. Multivariate analysis retained only N-stage (p=0.0001) and nuclear (V) over bar v (p=0.0022). Our results suggest that nuclear (V) over bar v is a strong independent prognostic marker in glottic carcinomas.

Proliferating cell nuclear antigen in adenoid cystic carcinomas of the head and neck.

This retrospective study was performed on formalin fixed, paraffin-embedded specimens from 50 patients with adenoid cystic carcinomas to investigate if proliferating cell nuclear antigen (PCNA) correlated with DNA ploidy and S-phase value. Moreover, we have analysed whether PCNA could be used in the prediction of treatment failures, i.e. inability to eradicate the disease or recurrences. The PCNA expression showed values ranging from 0-78%. The mean PCNA value for DNA aneuploid and DNA diploid tumours were 9.5% and 4.8% respectively. No correlation was found between PCNA expression and S-phase value. Nor did we find any relation between the PCNA expression and treatment failure. Our results indicate that PCNA expression of archival material from adenoid cystic carcinomas is not a reliable prognostic factor.

Prognostic value of nuclear volume in adenoid cystic carcinoma of the head and neck.

Modem stereologic techniques enable unbiased, objective and reproducible assessment of histologic parameters. The purpose of this study was to investigate the prognostic impact of the volume-weighted mean volume of tumor nuclei (nuclear (V) over bar v) in 62 patients with adenoid cystic carcinoma (ACC) and to correlate nuclear (V) over bar v and some traditional prognostic parameters with treatment failures. The observation time of the patients ranged from 2 to 11 years. Disregarding the well known histopathological subtypes of ACC and using random sampling it was found that treatment failures, i.e. inability to eradicate the disease and recurrences, were more often seen in specimens with small nuclear (V) over bar v when-compared to non-failures. Using a cut-off point of 250 mu m(3) the prognostic significance of nuclear (V) over bar v was 0.0177 by log rank analysis. For tumor stage vs. treatment failures/nonfailures log rank analysis revealed p=0.0147. Cox regression analysis left only the nuclear (V) over bar v (p=0.0234) as a prognostic factor. Estimations of nuclear (V) over bar v appears to be a reliable indicator of short term treatment failures in ACC.

Lack of prognostic significance for p53-overexpression and Ki-67-immunoreactivity in oral T1-2 squamous cell carcinomas.

Previous investigations on squamous cell carcinomas (SCC) of the head and neck region have failed to reveal a significant correlation between p53-overexpression or Ki-67-immunoreactivity and survival. Contrary to these studies we restricted the evaluation to T1-2 SCC from the oral cavity. Immunohistochemically identified p53-overexpression was observed in 69% of the tumours, and Ki-67-positive cancer cells ranged from 12 to 83% in individual rumours (median 37%). No significant correlation was found between p53-overexpression or Ki-67-positivity and survival. Although the degree of tumour differentiation and the pattern of invasion correlated with prognosis (p=0.0387 and 0.0319 respectively), these associations were too weak to be used as prognostic markers.

Prognostic significance of proliferative and apoptotic markers in oral tongue squamous cell carcinomas.

The prognostic impact of proliferative and apoptotic markers was studied in 85 T1-4 oral tongue squamous cell carcinomas (SCCs). Ki67 immunoreactivity and AgNOR counts, including mean AgNOR counts (mAgNOR) and the percentage of nuclei with more than one AgNOR (pAgNOR > 1), were used as proliferative parameters. The apoptotic index (AI) was assessed using the TUNEL method. Bax expression was detected immunohistochemically and scored. Bax expression correlated positively with AI (p = 0.0122). Ki67 correlated with both pAgNOR > 1 (p = 0.0042) and mAgNOR (p = 0.0189). Low Bax expression and low AI correlated significantly with the disease-free period (p = 0.0001 and p = 0.0024, respectively). High values for Ki67, pAgNOR > 1 and mAgNOR correlated with poor prognosis (p = 0.0021, p = 0.0001 and p = 0.0244, respectively). Combinations of proliferative and apoptotic parameters were stronger predictors than individual parameters (p < 0.0001). pAgNOR > 1-Bax expression appeared to be the best combination (p < 0.0001). We conclude that proliferative and apoptotic markers, especially their combinations, have prognostic value in tongue SCC.

The invasive front of carcinomas. The most important area for tumour prognosis?

Various molecular events of importance in tumour spread, like the gain and loss of adhesion molecules, secretion of proteolytic enzymes, increased cell proliferation, and the initiation of angiogenesis occur at the tumour-host interface (invasive front). We have hypothesised that molecular or morphological characteristics at the invasive front area of various carcinomas may reflect tumour prognosis better than other parts of the tumour. Consequently, we recently developed a simple malignancy grading system restricted to the deep invasive front area of head and neck squamous cell carcinomas. This grading system proved to have additional prognostic value over the established prognostic factors. All similar studies performed so far have confirmed the high prognostic significance of the invasive front grading in squamous cell carcinomas at different locations. In this review paper we describe the system and the hypothesis on which it has been developed. The reproducibility of the grading is acceptable for further extended studies. Interestingly, observations of similar invasive front alterations in different adenocarcinomas suggest that the invasive tumour front may underlie the biological aggressiveness of carcinomas of glandular origin, as well.

Detection of Penicillium species in complex food samples using the polymerase chain reaction.

Rapid identification of filamentous fungi is becoming increasingly important in food mycology both for monitoring the production process and for the identification of food spoilers. This paper describes the development and trial of two specific PCR primer sets. A 336 bp fragment from species belonging to Penicillium subgenus Penicillium was amplified by the primers ITS 212d and ITS 549. The other primer set, ITS 183 and ITS 401 specifically identified two species, Penicillium roqueforti and P. carneum, both known as spoilers in the bread industry, by amplification of a 300 bp fragment. The future perspectives of PCR based identification of filamentous fungi in food are discussed.

Ki-67 as a prognostic marker in adenoid cystic carcinoma assessed with the monoclonal antibody MIB1 in paraffin sections.

The monoclonal antibody MIB1 recognizing the Ki-67 antigen in formalin-fixed, paraffin-embedded tissue was used to study the proliferative activity in 44 adenoid cystic carcinomas of the salivary glands. The antigen expression was compared with clinical factors, histopathological grading, and prognosis. The Ki-67 value was significantly higher in tumors from patients suffering from treatment failure than in nonfailures (P<0.001). The Ki-67 expression was also higher in tumors exhibiting areas more than 30% of the solid growth pattern and higher in sinonasal tumors than in other locations. By Cox regression analysis, Ki-67 more than 4% was the strongest prognostic indicator (P<0.005). Clinical stage and violation of surgical margins were also found to be independent significant prognostic indicators. We conclude that Ki-67 expression estimated by the use of MIB1 is a powerful tool for predicting the short-term prognosis for patients with adenoid cystic carcinoma.

Prognostic value of Le(y) and H antigens in oral tongue carcinomas.

OBJECTIVE: To investigate the prognostic significance of the carbohydrate epitopes H and Le(y) and their relationship with proliferation and apoptosis. STUDY DESIGN: Eighty randomly selected patients with T1-T4 oral tongue squamous cell carcinoma (SCC) were studied. Serial sections were cut from diagnostic, formalin-fixed, paraffin-embedded specimens. METHODS: Sections were stained immunohistochemically for H antigen and Le(y). RESULTS: Expression of H antigen was associated positively with Le(y) expression (P = .0001). Expressions of H antigen or Le(y) correlated with the proliferative markers Ki67 (P = .0442 and P = .0003, respectively) and pAgNOR > 1 (P = .0674 and P = .0047, respectively), but not with apoptotic markers such as Bax expression or the apoptotic index (AI). Tumors that expressed H antigen and high levels of Le(y) (> 50%) had a poor prognosis (P = .0006 and P = .0056, respectively). Combinations of expression of H antigen and Le(y), and either proliferative or apoptotic markers revealed an enhanced prognostic potential (P < .0001). The combination of pAgNOR score greater than 1 and H-antigen expression appeared to be the best combination to predict good prognosis. CONCLUSION: The expression of H antigen and Le(y), especially their combination with proliferative or apoptotic markers, has prognostic value in tongue SCC.

A prospective study of quality of life in head and neck cancer patients. Part II: Longitudinal data.

OBJECTIVES: To evaluate the health-related quality of life (HRQL) of patients with head and neck cancer during and after treatment with radiotherapy, surgery, and chemotherapy. STUDY DESIGN: Prospective, descriptive study. METHODS: All new patients in four institutions in Norway and Sweden were asked to participate. Health-related quality of life was assessed at baseline and at 1, 2, 3, 6, and 12 months after start of treatment by means of the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire and the EORTC head and neck cancer-specific questionnaire. Baseline results are described elsewhere; longitudinal results are presented in the current article. Three hundred fifty-seven patients with cancer in the oral cavity, pharynx, larynx, nose, sinuses, and salivary glands and neck node metastases from unknown primaries filled in the questionnaires at baseline. RESULTS: Seventy-eight percent of the patients who were alive after 12 months filled in all questionnaires (218/280). The general trend was that HRQL deteriorated significantly during treatment, followed by a slow recovery until the 12-month follow-up with few exceptions (senses, dry mouth, and sexuality). Patients who later died reported worse HRQL at each assessment point compared with patients who filled in all six questionnaires, whereas those who dropped out of the study for other reasons were quite similar to patients who filled in all questionnaires. The patients with pharyngeal cancer in general reported worse HRQL compared with the other groups and did not reach pretreatment values in several domains. Stage was also an important factor for HRQL in patients with head and neck cancer. CONCLUSION: Detailed knowledge about the differences between groups and changes over time may aid us in the communication with patients and in the design of intervention studies focusing on improvement of the support and rehabilitation of patients with head and neck cancer.

A prospective study of quality of life in head and neck cancer patients. Part I: at diagnosis.

PURPOSE: A Swedish and Norwegian study was designed to examine health-related quality of life (HQL) in patients with head and neck cancer (head and neck) at diagnosis and during treatment and rehabilitation. The overall aim was to examine the impact on HQL at diagnosis depending on tumor location, stage, sex, and age (part I) and to describe HQL longitudinally and determine for which patients and during which period HQL deteriorated most (part II). This article presents the results at diagnosis. METHOD: Patients with head and neck cancer at five hospitals in Sweden and Norway were consecutively requested to participate. They were asked to answer the EORTC QLQ-C30 and QLQ-H&N35 (the European Organization for Research and Treatment of Cancer, Core 30 questionnaire and head and neck cancer module) repeatedly during 1 year. A total of 357 patients (mean age, 63 y; 72% males) were included. RESULTS: Patients with different tumor locations all had their special problems at diagnosis, for example, those with tumors in the larynx with communication, those with oral tumors with pain, and those with pharyngeal tumors with nutrition and pain. The patients with hypopharyngeal cancer reported the worst HQL. Stage appeared to have the strongest impact on HQL. Patients with a more advanced tumor stage reported significantly worse HQL scores for 24 of 32 variables reflecting functioning or problems. The females scored worse than the males for some areas, in particular, emotional functioning. The older patients scored significantly better for emotional and social functioning than patients <65 years but worse for physical functioning and various symptoms. The traditional way of grouping the tumor locations into oral, pharyngeal, laryngeal, and "other" tumors (salivary gland, sinus and nose, and unknown primary) was tested from a HQL point of view and found to be consistent. CONCLUSIONS: The chosen questionnaires differentiated between different sites of head and neck cancer at diagnosis. Tumor stage had the most powerful impact on HQL score.

Prognostic significance of nucleolar organizer regions in adenoid cystic carcinomas of the head and neck.

OBJECTIVE: To determine the prognostic use of nucleolar organizing region (AgNOR) counts and clinical and histopathological features in adenoid cystic carcinoma. DESIGN: Argyrophilic staining was applied to ordinary formalin-fixed, paraffin-embedded specimens and evaluated to obtain the mean number of AgNORs and the percentage of nuclei with more than 1 (pAgNOR > 1), more than 2, more than 3, and more than 4 AgNORs. RESULTS: Using the log rank test, the mean AgNOR count showed no correlation with the disease-free period. All pAgNOR parameters exceeding the respective overall mean had poorer prognosis when compared with those below the mean (P = .02). The pAgNOR > 1 appeared as the best discriminator, singling out all treatment failures (P < or = .001). This parameter also showed a high degree of intraobserver and interobserver reproducibility. Stage of the disease, violated resection margins, and presence of the histopathological solid subtype were markers of an unfavorable prognosis. Multivariate analysis by the Cox model showed that pAgNOR > 1 (P < or = .001) and tumor stage (P = .03) were the only statistically significant parameters. CONCLUSIONS: Estimation of pAgNOR > 1 is easy, quick, and highly reproducible. It may become a useful prognostic parameter in adenoid cystic carcinoma, but larger studies should be performed to confirm the reliability of this method.

A general model for the light and electron microscopic morphometry/stereology (M & S) of precancerous epithelial transformation using clinical biopsies.

A morphometric model is presented which has proved valuable in the analysis of precancerous lesions at the light and electron microscopic level. The material consisted of biopsies of nasal mucosa embedded in plastic and sectioned perpendicular to the luminal surface. Sampling was restricted to the basal layer in order to compare in the different metaplastic and dysplastic stages a common cell type which is easy to identify in all stages and to reduce the workload. The application of digitizers, classical point counting procedures and linear parameters all allow a good separation between the different types of epithelium. The latter method is especially advisable in diagnostic pathology since the workload becomes drastically reduced as a consequence of linear instead of area parameters (e.g. cell width, i.e. contract zone with basement membrane, instead of cell size) and classifying instead of counting points. A 3-class ruler served for the estimation of the transverse diameters of nuclei, cell width and the sum of the longitudinal and transverse nucleolar axes. The use of a weighted index is more sensitive than simple measurements. The reliability of the method was also tested in a prospective study in which the biopsies were first analyzed by morphometry. The agreement between the prior morphometric classification and the subsequent histologic classification was 91%. The results demonstrate that basal cells alone carry the information for grading metaplastic and dysplastic changes in epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)