Chromosome abnormalities in eighty-three head and neck squamous cell carcinomas: influence of culture conditions on karyotypic pattern.

Short-term cultures from 115 squamous cell carcinomas (SCC) of the head and neck were cytogenetically investigated. Thirty-six of the tumors have been reported previously, whereas 79 are new cases. The material was divided into two series based on the medium used. The 80 tumors of series I were cultured in RPMI 1640 supplemented with fetal calf serum, glutamine, antibiotics, insulin, cholera toxin, and epidermal growth factor. The 35 tumors of series II were cultured in a chemically defined, serum-free medium with a low calcium concentration, MCDB 153, which stimulates epithelial growth while inhibiting fibroblasts. A total of 83 tumors with clonal karyotypic abnormalities were detected in the two series. Series II had a higher proportion of tumors with complex karyotypic changes than series I (43% versus 15%), a lower proportion of tumors with pseudo- or neardiploid clones characterized by simple rearrangements (3% versus 34%), and a lower frequency of unrelated clones (3% versus 24%), indicating that the different culture conditions favored growth of different cell populations. Except for rearrangements of 1p22, which were mainly found in series I, the distribution of breakpoints in structural aberrations was similar in the two series and clustered to several chromosomal bands or regions, in particular 11q13, 1p22, 1p11-12, 3p11-q11, 5q13, 1q25, 15q10, and 8q10. Unbalanced structural aberrations were more common in series II, frequently leading to loss of segments from chromosome arms 3p, 7q, 8p, 11q, 13p, 14p, and 15p, whereas gain of genetic material often involved chromosome arms 1q, 3q, 8q, and 15q.

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.

Intra-arterial mitomycin C and intravenous bleomycin as induction chemotherapy in advanced head and neck cancer--a phase II study.

Fifty-six patients with previously untreated, unresectable squamous cell carcinomas of the head and neck region were treated with repeated intra-arterial chemotherapy with mitomycin C using a selective or super-selective angiographic technique, and bleomycin given i.v., followed by radical radiotherapy. In addition, restricted tumour-reductive surgery was done in 18 of these patients. The response rate (CR + PR) after completion of the integrated treatment was 89%, with 63% of the patients showing CR. The toxicity of this regimen was, however, far from negligible. The median survival for this series of patients with advanced head and neck cancers is 19 months, and 17 are still alive after 16 + -66 + months.

Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study.

BACKGROUND AND PURPOSE: In 1986 a prospective, randomized, multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated. As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only. METHODS: Four-hundred sixty-one patients from Denmark, Norway and Sweden with tumors in oral cavity, oropharynx, hypopharynx and larynx were randomized to receive either standard treatment (radiotherapy or radiotherapy followed by surgery) or neoadjuvant chemotherapy followed by standard treatment. Chemotherapy included three courses of cisplatin 100 mg/m2 i.v. infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v. infusion for 120 hours. Radiotherapy 64-70 Gy in 2 Gy per fraction, 5 times/week, was given to patients in both treatment arms. RESULTS: Response rate was 71% for patients randomized to chemotherapy-radiotherapy and 66% for patients randomized to standard treatment (not statistically significant). Residual tumors were excised if possible. After surgery 62% of the patients randomized to chemotherapy-radiotherapy and 60% of the patients in the standard treatment group were clinically tumor free. CONCLUSIONS: No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy. Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment.

Binding affinities of four tricyclic antidepressive drugs to muscarinic cholinergic receptors in human parotid gland.

The binding kinetics of tritiated quinuclidinyl benzilate (QNB) were studied in membrane preparations from human parotid and rabbit submandibular glands. Inhibition of 3H-QNB was then used to compare the anticholinergic activity of lofepramine, desipramine, imipramine and amitriptyline for muscarinic receptor in the salivary glands. The apparent dissociation constant (KD) for 3H-QNB binding in human parotid and rabbit submandibular gland was 33 and 61 pM and the Bmax value 507 and 169 f mol/mg protein, respectively. The mean values for the inhibition constant (Ki) for lofepramine, desipramine, imipramine and amitriptyline in human parotid gland were 285, 135, 102 and 13 nM, respectively. Very similar values were obtained for the rabbit submandibular gland. The binding affinity of tricyclic antidepressants for muscarinic cholinergic receptor sites in human parotid gland closely paralleled clinical data on the inhibition of salivary flow by these drugs.

Multiple unrelated clonal chromosome abnormalities in an in situ squamous cell carcinoma of the skin.

We have cytogenetically analyzed short-term cultures from an in situ squamous cell carcinoma of the skin (Bowen's disease). The following mosaic tumor karyotype was found: 46,XX, -1, +der(1)(pter----p22::q11----cen----p22:), -9, +der(9)t(1;9)(q11; p24)/46,XX,t(3;6) (q21;p21)/46,XX,t(5;14)(q13;q24),t(7;18)(q32;q11)/46,XX,t(8;11)(p22;q13) /46, XX,t(8;11) (p22;q13),t(15;17) (q13;q24)/46,XX,t(12;15)(q12;p11). None of the rearrangements correspond to previously known cancer-associated abnormalities. Two of the clones are obviously related, and it is reasonable to assume that the t(15;17) developed as an evolutionary change in a cell that already contained t(8;11)(p22;q13). Since five clones without cytogenetic similarities were found in this in situ skin carcinoma, we suggest that the tumor was of polyclonal origin. It is impossible to decide whether all, or indeed any, of the visible abnormalities constitute pathogenetically essential primary changes, or merely represent chromosomal markers of secondary importance in tumorigenesis.

Multiple apparently unrelated clonal chromosome abnormalities in a squamous cell carcinoma of the tongue.

We have cytogenetically examined short-term cultures from a squamous cell carcinoma of the tongue, a tumor type in which chromosome aberrations hitherto have not been reported. No less than 12 pseudodiploid clones were detected, giving the tumor karyotype 46,X,der(X)t(X;1)(q26;p32),der(1)(Xqter----Xq26::1p32 ----cen----1q42:), del(13)(q11q21),t(15;?) (q26;?)/46,XX,t(1;?)(p34;?),inv(2)(p21q11)/46,XX,t(1;10)(p32;q24)/ 46,XX, + der(1)(12pter----12p11::1p11----cen----1q32:: 11q13----11q22::1q32----1q42:), del(11)(q13q22), -12, der(17)t(1;17) (q42;p13)/46,XX,inv(1)(p22q44)/47,XX,del(1)(q32),der(17)t(1; 17)(p22;q25), der(1)inv(1) (q25q44)t(1;17)(p22;q25),ins(14;7)(q11;q22q36), + 14/46,XX,t(1;4)(q23;q35)/46, XX,t(1;21) (q25;q22),t(2;10)(q31;q26),t(22;?)(q12;?)/46,XX,del(1)(q32)/46,XX, t(1;8)(q44;q21)/46,XX, t(2;21)(q11;p11)/46,XX,t(9;11)(q34;q13). The large number of apparently unrelated abnormalities leads us to suggest that the carcinoma may have been of multiclonal origin.

Unique karyotypic abnormalities in a squamous cell carcinoma of the larynx.

We have cytogenetically examined short-term cultures from a squamous cell carcinoma of the larynx, a type of carcinoma in which chromosome aberrations have hitherto not been reported. The tumor karyotype was 46,XY,inv(2)(p22q24),t(9;13)(q34;q12),t(11;18)(q23;q21). None of these abnormalities have been described in carcinomas before.

Two unrelated clonal chromosome rearrangements in a nasal papilloma.

We have cytogenetically examined short-term cultures from a nasal papilloma, a tumor type in which chromosome aberrations have hitherto not been reported. Two pseudodiploid clones were detected, giving the tumor karyotype 46,XY,t(1;3)(p31;p12)/46,XY,t(11;?)(q25;?).

Multiple clonal chromosome aberrations in squamous cell carcinomas of the larynx.

Short-term cultures from five squamous cell carcinomas of the larynx were subjected to cytogenetic analysis. In the first three cases, two, three, and 10 chromosomally abnormal clones were detected. Single clonal abnormalities were found in cases 4 and 5. In addition to the clonal aberrations, a number of nonclonal changes were also present in all five tumors. None of the aberrations, clonal or nonclonal, was found in more than one tumor, nor did the rearrangements correspond to any of the consistently cancer-associated aberrations known from other tumors. The remarkably diverse karyotypic picture of the five squamous cell larynx carcinomas, in particular the finding of cytogenetically unrelated clones in three of them, suggests that some of these neoplasms are polyclonal rather than monoclonal.

Diverse chromosome abnormalities in squamous cell carcinomas of the skin.

Short-term cultures from three invasive squamous cell carcinomas of the skin were cytogenetically analyzed. Clonal chromosome aberrations were found in all tumors. In the first case, two of three abnormal clones were related, and in the second case, two of five clones demonstrated cytogenetic similarities. Both clones detected in case 3 had a structural rearrangement in common. Several nonclonal changes were seen in all three cases in addition to the clonal aberrations. None of the rearrangements detected, clonal or nonclonal, corresponds to any of the consistently cancer-associated aberrations known from other neoplasms. The remarkably diverse karyotypic picture of the three squamous cell carcinomas, in particular the finding of unrelated clones in two of them, hints that these neoplasms may be poly-rather than monoclonal. The lack of a common cytogenetic denominator argues that if chromosomal changes are of pathogenetic importance in this tumor type, a wide variety of apparently dissimilar changes exist that are roughly equal in their capacity to malignantly transform skin epithelium.

Clonal chromosome aberrations in a keratoacanthoma and a basal cell papilloma.

Clonal chromosome abnormalities were found in short-term cultures from two epithelial skin tumors, a basal cell papilloma and a keratoacanthoma. The three-way translocation t(2;6;11)(q21;q27;p13) was the sole clonal rearrangement in the basal cell papilloma. The karyotype of the keratoacanthoma was more complex: 46,XX,der(2)(2pter----2p13::2p11----cen----2q37: :5q33----5qter),der(2) (:2p13----cen----2q37::6q23----6qter),der(5)t(2; 7;5)(q37;q11;q33),der(6) (6pter----cen----6q23::2p13----2pter),der(7)t(2; 7;5)(q37;q11;q33), del(13)(q11q14). In addition, several nonclonal structural changes were seen in both tumors.

Basosquamous papilloma. A benign epithelial skin tumor with multiple cytogenetic clones.

Cytogenetic analysis of short-term cultures from a basosquamous papilloma revealed the following mosaic karyotype: 46,XX,t(2;5)(q31;q31),t(8;15)(p21;q21)/46,XX,t(7;17)(p13;p13)/47,XX, t(3;20)(q12;p13),+7/46,XX,t(1:12)(p12;q13). The finding of four abnormal, cytogenetically unrelated clones suggests a multicellular origin of this benign skin tumor. None of the structural rearrangements encountered have previously been associated with neoplasia.

Merkel cell carcinoma: management of primary, recurrent and metastatic disease. A clinicopathological study of 17 patients.

The clinicopathology of Merkel cell carcinoma (MC) has been evaluated in 17 patients, and its outcome and clinical management in 14 of these. The histopathologic diagnosis was confirmed by electronmicroscopy and/or immunohistopathology. The location of the primary lesions demonstrated a predilection for the skin of the face and the extremities. The primary treatment usually consisted of a wide excision only. Four out of five patients with MC of the face suffered from local and/or nodal relapses, in contrast to only one out of seven patients with primary lesion on the extremities. The three patients treated for local recurrences and/or regional node metastases were alive and disease-free 22-72 months after recurrences. Three patients developed distant metastases. Two of these died within 4 months after initial diagnosis. One patient completely responded to chemotherapy. The high frequency of local recurrences would justify an excision with generous margins, except when the tumour is close to a vital structure. Radiotherapy could in these cases obviate the necessity for extensive operations. If the primary lesion is located on an extremity, regional lymphadenectomy seems only to be necessary whenever nodal involvement is suspected. Node dissection is also recommended for suspected nodes in the face or on the neck, but the guidelines for elective node dissections in these sites are not obvious since the results of salvage therapy were excellent and the location of relapses unpredictable.

Malignant melanoma of the nasal cavity and nasopharynx treated with cisplatin and accelerated hyperfractionated radiation.

Primary malignant melanoma of the nasal cavity and paranasal sinuses is an uncommon disease, accounting for only 0.5-2% of all malignant melanomas. The primary treatment has been surgery. The frequency of local recurrence is high and recurrence is also the major determinant of treatment failure. Here we report on six patients with locally advanced disease, four of whom were too advanced for surgery, who were treated with accelerated hyperfractionated radiation in combination with cis-platinum. Three of four patients treated for local recurrent disease achieved a local cure and died of disseminated disease after 9-21 months. One patient given preoperative cisplatin and radiation is still alive with no evidence of disease 34 months after the completion of treatment. The present protocol may be a useful approach to obtain local control with the possibility of long-term cure.

Carcinoma of the parotid and submandibular glands--a study of survival in 2465 patients.

Salivary gland carcinomas demonstrate a wide diversity of histopathological types and biological behavior. The aim of this study was to analyze relative survival of patients with major salivary gland carcinomas with special reference to histopathology, gender and age. All new carcinomas of the major salivary glands reported to the National Swedish Cancer Registry 1960-1995 were searched for and the vital status of the cases was updated by record linkage to the Swedish Population Registry through December 31 1996. The study comprised 2465 patients with carcinoma of the parotid or submandibular glands. Relative survival differed markedly according to histopathological typing (P<0.001). For parotid tumors, acinic cell carcinomas had the best prognosis with a 10-year relative survival of 88%. The corresponding figures for mucoepidermoid carcinomas, adenoidcystic carcinomas and carcinoma ex pleomorphic adenoma were 80, 74 and 73%. Adenocarcinoma NOS and undifferentiated carcinoma had worse prognosis, with 10-year relative survival of 55 and 44%. Patients with submandibular gland cancer had similar relative survival to those with parotid cancers, besides those with mucoepidermoid cancer and adenocarcinoma NOS, who carried worse prognosis. Age and gender had an impact on relative survival for patients with mucoepidermoid carcinoma, adenocarcinoma and undifferentiated cancer of the parotid.

Histopathological characteristics predictive for growth of squamous cell carcinomas of the head and neck heterotransplanted to nude mice.

Human tumours heterotransplanted to nude mice vary both with respect to take rate and the rate of tumour line establishment, according to their histological type and between primary and recurrent tumours. The acceptance rate of squamous cell carcinomas of the head and neck is also thought to vary, according to their degree of differentiation and their site of origin. This provided the basis of the present analysis of different tumour characteristics predicting growth of squamous cell carcinomas of the head and neck. Eighty-five attempted heterotransplantations were analysed with respect to T-stage, site of origin, degree of differentiation, and a histopathological malignancy grading score based upon four tumour variables and four tumour-host variables. Of the 85 attempted transplantations, first passage was successful in 24 cases (28%), of which sixteen (19% of 85) resulted in established tumour lines. The frequency of established tumour lines was higher among T4 and poorly differentiated tumours (33% and 22%, respectively), than among less advanced or more differentiated tumours. Tumour size was a more crucial factor than degree of differentiation, and tumours of the oral cavity grew less readily than those from other sites. The take rate was strongly correlated to malignancy grading scores, increasing as they increased. The most predictive information was provided by tumour-host variables, of which vascular invasion and lack of lymphocytic response were the most important in this respect.

The effect of continuous bleomycin infusion on the growth and cell kinetics of heterotransplanted squamous cell carcinoma of the head and neck.

The schedule-dependent effect of bleomycin (BLM) on human squamous cell carcinoma (SCC) was investigated using a xenografted SCC line originating from the head and neck region. A total dose of 200 mg BLM/kg was administered according to one of three different schedules: one single i.p. injection; i.p. injection every four hours for seven days; and continuous s.c. administration for seven days via osmotic mini-pump. Both single dose treatment and iterated injections caused significant retardation of tumour growth, and continuous infusion had a more pronounced effect, almost completely retarding increase in tumour volume; these differences in effect in between the treatment schedules were not, however, statistically significant. The effect of continuous BLM infusion on cell cycle phase distribution and histopathological picture was also recorded. During the first three days of infusion, there was an accumulation of cells in Go/G1-phase paralleled by a depletion of cells in S-phase. This was followed by a normalisation during the rest of the infusion period, concomitant with a transient increase of the cells in G2-phase. Histopathologically, there were no changes during the first four days. A swelling of the cytoplasm cold then be seen; and after seven days, scattered groups of necrotic cells were observed which later formed necrotic foci. It is noteworthy that the major perturbances in cell cycle phase distribution preceded both retardation of tumour volume growth and histopathological changes.

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.