Characterization of matrix metalloproteinase-2 and matrix metalloproteinase-9 and their inhibitors in equine granulosa cells in vivo and in vitro.

Matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) regulate tissue remodeling events necessary for ovulation. Thus, changes in MMP and TIMP expression and protein enzyme activity were examined in vivo and in vitro during follicular development and atresia in the horse. Equine granulosa cells and follicular fluid from medium (15 to 29 mm) healthy and atretic follicles and from large (>30 mm) healthy and preovulatory follicles were collected by transvaginal aspiration. The cells were either snap-frozen (in vivo study) or cultured for 48 h (in vitro study) to determine gene expression and protein enzyme activity of MMP-2 and MMP-9 and TIMP-1 and TIMP-2. Concentrations of progesterone and estradiol were determined by RIA in follicular fluid and conditioned media and were used along with follicle dynamics to classify follicles. In vivo, expression of MMP-2 and TIMP-2 was increased (P < 0.05) in large-preovulatory follicles, whereas TIMP-1 was decreased. The ratio of MMP-2:TIMP-2 expression was decreased (P < 0.05) in medium-healthy and large-preovulatory follicles, whereas the MMP-9:TIMP-1 ratio was increased only in large-preovulatory follicles compared with large-healthy follicles. Estradiol was greatest (P < 0.05) in the fluid of large-healthy and large-preovulatory follicles. However, medium-atretic follicles were associated with the least estradiol concentrations, both in vivo and in vitro. Progesterone concentrations were greatest (P < 0.05) in large-preovulatory follicles both in vivo and in vitro. In healthy follicles in vivo, the diameter was correlated with estradiol concentration, the estradiol:progesterone ratio, MMP-9 and TIMP-1 expression, and MMP-2 and MMP-9 protein activity. In contrast to in vivo studies, the ratio of MMP-9:TIMP-1 expression was increased (P < 0.05) in medium-healthy follicles; TIMP-2 expression decreased in large-preovulatory follicles in vitro. In addition, MMP-9 protein activity was decreased (P < 0.05) in the media samples of cells from large-healthy follicles compared with those from medium-healthy follicles. These results indicate that changes in MMP-2 and MMP-9 activities may be essential to the tissue reorganization necessary for ovulation in the equine ovary.

Relationships among inflammatory cytokines, obesity, and insulin sensitivity in the horse.

Recent studies associate obesity and insulin resistance in horses with development of abnormal reproductive function and debilitating laminitis. The factors contributing to insulin resistance in obese horses are unknown. However, human studies provide evidence that elevated inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), IL1, and IL6 play direct roles in development of obesity-associated insulin resistance. Thus, inflammation may be a key link between obesity and insulin resistance in horses. The aim of the current investigation was to examine possible relationships between obesity, inflammatory cytokines, and insulin sensitivity (IS) in the horse. Age was recorded and BCS and percent body fat (% FAT) were determined as measures of obesity in 60 mares. In addition, blood mRNA expression of IL1, IL6, and TNFalpha and circulating concentrations of TNFalpha protein (TNFp) were determined in each mare. Finally, fasted concentrations of insulin were determined, and IS was determined using the hyperinsulinemic, euglycemic clamp. Significant correlations between several variables provided evidence for the design of 4 population regression models to estimate relationships between measures of obesity, inflammatory factors, and IS in the sample population. The results of these analyses revealed that IS decreased as BCS and % FAT increased (P < 0.001) in the sample population. Additionally, increased IL1 (P < 0.05) and TNFp (P < 0.01) were associated with decreased IS. However, increased TNFalpha (P < 0.001) was associated with decreased IS only in mares 20 yr of age and older. Increased BCS and % FAT were associated with increased expression of TNFalpha (P = 0.053) and IL1 (P < 0.05), and increased TNFp (P < 0.05). Surprisingly, increased BCS and % FAT were associated with decreased IL6 expression (P = 0.05) in mares <20 yr of age. Finally, evaluation of the influence of obesity and inflammatory cytokines on IS within the same model suggested that BCS and % FAT (P < 0.001) with TNFalpha [mRNA (P = 0.07) and protein (P < 0.05)] are inversely associated with IS independently of one another. Combined, these results provide the first evidence associating obesity with increased inflammatory factors in the horse. Furthermore, the results suggest that an interrelationship exists among obesity, inflammatory cytokines, and IS in the horse and emphasize the need for further studies to elucidate the nature of these relationships.

Obesity is associated with altered metabolic and reproductive activity in the mare: effects of metformin on insulin sensitivity and reproductive cyclicity.

In mares, obesity is associated with continuous reproductive activity during the non-breeding season. To investigate the effect of obesity and associated alterations in metabolic parameters on the oestrous cycle, two related studies were conducted. In Experiment 1, obese (body condition score > 7) mares were fed ad libitum or were moderately feed restricted during the late summer and autumn months. Feed restriction did not alter the proportion of mares entering seasonal anoestrus. However, obese mares exhibited a significantly longer duration of the oestrous cycle, significant increases in circulating concentrations of leptin and insulin, and decreased insulin sensitivity and concentrations of thyroxine compared with feed-restricted mares throughout the experiment. Experiment 2 was designed to investigate the effects of administration of the insulin-sensitising drug metformin hydrochloride on insulin sensitivity and the characteristics of the oestrous cycle in obese mares. In a dose-response trial, metformin increased insulin sensitivity after 30 days following administration of 3 g day(-1), but not 6 or 9 g day(-1), compared with controls receiving vehicle only. However, there were no differences in insulin sensitivity or oestrous cycle characteristics between control and metformin-treated groups when the 3 g day(-1) dose was tested for a longer period of 2 months. These results demonstrate that obesity is associated with aberrations in the oestrous cycle and perturbations in several markers of metabolic status. The results also indicate that metformin is not an effective long-term monotherapy for increasing insulin sensitivity in horses at the doses tested. Additional studies are needed to examine possible effects of increasing insulin sensitivity on reproductive activity in obese mares.

Development of a model for inducing transient insulin resistance in the mare: preliminary implications regarding the estrous cycle.

Peripheral insulin resistance is the failure of proper cellular glucose uptake in response to insulin. Insulin resistance and hyperinsulinemia are associated with several disease states in the horse and reproductive function disturbances in humans, including polycystic ovarian syndrome. To test the hypothesis that insulin resistance (IR) and hyperinsulinemia disrupt the estrous cycle in mares, two experiments were conducted to first develop a model to induce IR and to then examine the effect of this model on the duration of the estrous cycle. In Exp. 1, a hyperinsulinemic-euglycemic clamp (HEC) procedure was performed on seven mares to determine insulin sensitivity before and immediately following infusion of a heparinized lipid solution. The HEC procedure was repeated 1 wk after lipid infusion. Mares developed IR following the lipid infusion (P < 0.05), and some individuals maintained IR for up to 1 wk. Mares also exhibited increased blood insulin both immediately following treatment and 1 wk later (P < 0.05). In Exp. 2, induction of insulin resistance by lipid solution was not accompanied by changes in circulating concentrations of luteinizing hormone, and duration of the luteal phase, compared with the duration of untreated luteal phases. Nonetheless, lipid infusion and the resultant insulin resistance were associated with an increased interovulatory period (P < 0.05), and peak concentrations of progesterone (P < 0.05) were higher during the treated vs. untreated luteal phases of the estrous cycle. The results from the preliminary study suggest that infusion of a lipid solution may induce transient insulin resistance and hyperinsulinemia. The resulting insulin resistance and hyperinsulinemia may modify characteristics of the estrous cycle, perhaps at the level of the ovary.

Effect of short-term exercise training on insulin sensitivity in obese and lean mares.

Twelve untrained aged mares were used to determine whether 7 days of light exercise improved peripheral tissue insulin sensitivity. Mares were divided into obese-exercised (n = 3), obese-sedentary (n = 3), lean-exercised (n = 3) and lean-sedentary (n = 3) groups. The exercised groups were worked at a trot to a heart rate (HR) of not more than 140 beats/min for 30 min in a round pen. Each group was subjected to 3 euglycaemic hyperinsulinaemic clamps: prior to exercise (P), 24 h following the seventh exercise training session (E) and 9 days postexercise training (PE). Prior to exercise training, the mares in the obese group were confirmed insulin-resistant compared to the mares in the lean group. There was no change in bodyweight or body condition in the obese or lean groups throughout the study. Glucose infusion rate (GIR) was higher (P<0.05) on E compared to P days in the obese-exercised and lean-exercised groups. Insulin sensitivity returned to pre-exercise values by 9 days postexercise in the obese-exercised and lean-exercised groups. The results of this study suggest that improvement in insulin sensitivity occurs in obese mares without a long interval of exercise training and in the absence of a change in bodyweight.

Potential signals mediating the maintenance of reproductive activity during the non-breeding season of the mare.

The seasonal nature of reproductive activity in mares is widely accepted and considerable attention has focused on the mechanisms that lead to the initiation of the breeding season. In contrast, considerably less information is available about the termination of the breeding season. It is interesting to note that each winter a sub-population of mares continues to undergo oestrous cyclicity during the non-breeding season. Continuation of reproductive activity during the winter occurs most frequently in mares that maintain a non-pregnant condition in successive years. The maintenance of a non-pregnant condition in successive years leads to an increase in the percentage of total body fat and it has been proposed that the degree of adiposity may be a determinant of reproductive activity during the winter months. To investigate this hypothesis we have manipulated fat stores by either pharmacological treatments or feed restriction. The studies described in this review demonstrate that manipulation of body fat during the autumn months fails to modify the mechanisms that lead to anoestrus or the proportion of mares that continues to show oestrous cyclicity during the winter months. On the basis of these and related studies two hypotheses are presented that may serve as a template for future work. The first hypothesis proposes that one aspect of the long-term regulation of seasonal reproductive rhythms in mares, specifically anoestrus, may reflect recognition of the availability of metabolic fuels before perception of a change in photoperiod. Alternatively, energy availability may need to reach a critical value before a presumptive inhibitory daylength signal initiates termination of the breeding season. This review describes previous and current studies that have led to development of these proposals.

Esthesioneuroblastoma: the impact of treatment modality.

BACKGROUND: We evaluated the impact of treatment modality on esthesioneuroblastoma. METHODS: Between 1976 and 1996, 25 patients with esthesioneuroblastoma were treated at Mallinckrodt Institute of Radiology. There were 11 male and 14 female patients; their ages ranged from 16 to 73 years (median, 57 years). The tumors were Kadish stage A in 3, Stage B in 13, C in 8, and modified D in 1 (cervical nodal metastasis). Seventeen patients were treated with surgery and radiation therapy, six were treated with irradiation alone, and two were treated with surgery only. Eight patients received neoadjuvant chemotherapy. Median follow-up was 8 years (range, 2-24 years). RESULTS: The 5-year actuarial overall survival, disease-free survival, and local tumor control rates were 66.3%, 56.3%, and 73.0%, respectively. Kadish stage was not a significant prognosticator for local control or disease-free survival. Five-year local control rates were 87.4% for the combination of surgery and radiation therapy and 51.2% for irradiation alone. Two patients with Kadish stage A and B disease underwent surgical resection alone; both failed locally. In contrast, 33.3% of patients (three of nine) with Kadish stage A or B disease who received adjuvant radiation therapy had a local recurrence develop. With adjuvant radiation therapy, the surgical margin status did not influence local tumor control. Among the eight patients who received neoadjuvant chemotherapy, six patients showed no response, one had partial response, and one showed a complete response. CONCLUSIONS: Surgical resection plus adjuvant radiation therapy yielded the best treatment outcome. More effective chemotherapy agents with a reproducible effectiveness are needed for patients with locally advanced esthesioneuroblastoma.

Cancer of retromolar trigone: long-term radiation therapy outcome.

BACKGROUND: Cancer of the retromolar trigone is an uncommon head and neck cancer. In this retrospective study, we identified the prognostic factors and evaluated the therapeutic outcomes of patients treated with preoperative radiation therapy (RT), postoperative RT, and RT alone. METHODS: Between 1971 and 1994, 65 patients with histologically proven epidermoid carcinoma of the retromolar trigone were treated at the Mallinckrodt Institute of Radiology; 10 patients received preoperative RT (30-55.2 Gy), 39 received postoperative RT (46-66.6 Gy), and 15 were treated with RT alone (63-74 Gy). Surgery included 44 composite resections and 7 wide excisions. The minimum follow-up was 5 years. RESULTS: The 5-year disease-free survival rates were 90% with preoperative RT, 63% with postoperative RT, and 31% with RT alone. The 5-year disease-free survival rates were 76% for patients with T1 disease, 50% for T2, 72% for T3, and 54% for T4. The 5-year disease-free survival rates were 69% for patients with NO disease, 56% for N1, and 26% for N2. The locoregional recurrence rates were 10% (1 of 10) for preoperative RT, 23% (9 of 39) for postoperative RT, and 44% (7 of 16) for RT alone. On multivariate analysis, the significant factors for disease-free survival were treatment modality (p =.002) and N stage (p =.012); for locoregional control it was treatment modality (p =.046); and for distant metastasis it was N stage (p =.002). The incidence of bone necrosis, soft tissue necrosis, and severe trismus was 12% with postoperative RT, 11% with RT alone, and none with preoperative RT. CONCLUSIONS: Combination surgery with postoperative or preoperative RT offers better locoregional control and disease-free survival than RT alone for epidermoid carcinoma of the retromolar trigone. Lymph node status significantly influences the disease-free survival and distant metastasis rates.

Free flap reconstruction of the head and neck: analysis of 241 cases.

OBJECTIVE: We undertook this study of free flap reconstruction of the head and neck to stratify patients and procedures, to determine how donor site preference changed over time, to assess medical and surgical outcomes, and to identify variables associated with complications. METHODS: We analyzed computerized medical records from 236 patients who underwent a total of 241 reconstructions at a tertiary academic medical center in St. Louis between 1989 and 1998. We created a more detailed retrospective database of 141 of those patients by using 48 perioperative variables and 7 adverse outcome measures. Multivariate statistical models were used to analyze associations between variables and outcomes. RESULTS: The fibula became the preferred donor site for mandibular reconstruction, and the radial forearm became the preferred donor site for pharyngoesophageal reconstruction. For the 241 procedures, the mortality rate was 2.1%, the median length of stay was 11 days, and the flap survival rate was 95%. Administration of more than 7 L of crystalloid during surgery and age over 55 were associated with major medical complications. Blood transfusion, prognostic comorbidity, and number of surgeons correlated with length of stay. Cigarette smoking and receipt of more than 7 L of crystalloid during surgery were associated with overall flap complications, and weight loss of more than 10% before surgery, more than one operating surgeon, and cigarette smoking were associated with major flap complications. CONCLUSIONS: Risk to patients and transferred tissue is low in free flap head and neck reconstruction. Age, smoking history, and weight loss should be considered during patient selection. Fluid balance should be considered during and after surgery. Division of labor for patient care should be carefully delineated among surgeons in a teaching setting.

Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx.

OBJECTIVE: To determine the impact of delayed regional metastases, distant metastases, and second primary tumors on the therapeutic outcomes in squamous cell carcinomas of the larynx and hypopharynx. STUDY DESIGN: Chart review and statistical analysis. METHODS: A retrospective tumor registry analysis was made of patients with squamous cell carcinomas of the larynx and hypopharynx who were treated with curative intent in the Department of Otolaryngology-Head and Neck Surgery and the Radiation Oncology Center of the Washington University School of Medicine (St. Louis, MO) between January 1971 and December 1991 and developed delayed regional metastases (2 y after treatment), distant metastases, and second primary malignancies. RESULTS: In 2550 patients, the mean age (59.8 y), sex (8.5 male patients and 1 female patient), and tumor differentiation did not affect the incidence of delayed distant, regional, or second primary malignancies. The overall incidence of delayed regional metastases was 12.4% (317/2550 patients); distant metastases, 8.5% (217/2550); and second primary tumors, 8.9% (228/2550), with a 5-year disease-specific survival of 41%, 6.4%, and 35%, respectively. Second primary malignancies were not statistically related to the origin of the primary tumor, tumor staging, or delayed regional and distant metastases (P =.98). Delayed regional metastases and distant metastases were related to advanced primary disease (T4 stage), lymph node metastases (node positive [N+]), tumor location (hypopharynx), and locoregional tumor recurrence (P < or =.028). Advanced regional metastases at initial diagnosis (N2 and N3 disease) increased the incidence of delayed and distant metastases threefold (P =.017). These two metastatic parameters were significantly greater in hypopharyngeal tumors than in laryngeal tumors (P =.037). The incidences of delayed regional metastases by anatomical location of the primary tumor were as follows: glottic, 4.4%; supraglottic, 16%; subglottic, 11.5%; aryepiglottic fold, 21.9%; pyriform sinus, 31.1%; and posterior hypopharyngeal wall, 18.5%. The incidences of distant metastases were as follows: glottic, 4%; supraglottic, 3.7%; subglottic, 14%; aryepiglottic fold, 16%; pyriform fossa, 17.2%; and posterior hypopharyngeal wall, 17.6%. Seventeen hypopharyngeal tumors (2%) presented with M1 disease. Delayed regional metastases to the ipsilateral treated neck had a significantly worse survival prognosis than delayed metastases to the contralateral nontreated neck (P =.001). CONCLUSIONS: Conclusions are as follows: 1) The incidence of second primary tumors is independent from the primary tumor staging and distant and delayed regional metastases. The highest incidence occurred in patient groups with the highest disease-free survival rates (P =.0378). 2) Highest incidence of delayed and distant metastases occurred in hypopharyngeal tumors and was three times greater than in laryngeal cancers (P =.028). 3) Salvage therapeutic rates were poor for delayed metastases to the ipsilateral treated nodes and distant metastases as compared with contralateral neck metastases and second primary tumors (P =.001). 4) Delayed and distant lymph node metastases were significantly higher in advanced primary disease (T4 stage), locoregional recurrences, and regional disease (N2 and N3) (P =.028) in both the larynx and hypopharynx. 5) The higher incidence of delayed and distant metastatic disease was related to more advanced initial tumor presentation in hypopharyngeal cancer as compared with laryngeal cancer (P =.039). 6) Incidence of distant metastases was greatest between 1.5 and 6 years after initial treatment with a mean incidence being less than or equal to 3.2 years.

Analysis of treatment results for floor-of-mouth cancer.

OBJECTIVE: This study reports the results of treating floor-of-mouth cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 280 patients with floor-of-mouth cancer treated in the Department of Otolaryngology-Head and Neck Surgery at Washington University Medical School (St. Louis, MO) from 1960 to 1994. METHODS: Patients with biopsy-proven squamous cell carcinoma of the floor of mouth who were previously untreated were treated with curative intent by one of five modalities and were all eligible for 5-year follow-up. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival (DSS) was 56% with death due to tumor in 44% of patients. The 5-year cumulative disease-specific survival (CDSS) was 0.61 (Kaplan-Meier probability) with a mean of 8.3 years and a median of 9.7 years. The DSS by treatment modality included local resection (76%), composite resection (63%), radiation therapy (43%), local resection with radiation therapy (61%), and composite resection with radiation therapy (55%). Overall, there was no significant difference in DSS by treatment modality. Recurrence at the primary site (41%) was the most common site of treatment failure. Nineteen percent of patients had recurrence in the neck. Eighty-eight percent of initial recurrences occurred within 60 months after the onset of treatment. Metastasis to a distant site occurred in 30% of patients. Twenty percent of these patients had second primary cancers, and 53% of these patients died of their second primary cancers. CONCLUSIONS: Significantly improved 5-year DSS was seen in the patients with clear margins, early clinical tumor stage, and negative nodes. Significantly decreased 5-year survival was seen in the patients with involved margins, advanced clinical tumor stage, positive nodes, and tumor recurrence. Patients with no clinically positive nodes (cNO) can be observed safely for regional nodal disease and subsequent positive nodes can be treated as they occur with no adverse affect on survival. Because of high recurrence rates at the primary site and neck, and an increased rate of both distant metastasis and the development of second primary cancers, patients should be monitored closely for a minimum of at least 5 years.

Stage I (T1 N0 M0) squamous cell carcinoma of the laryngeal glottis: therapeutic results and voice preservation.

BACKGROUND: The therapeutic outcomes for voice preservation in Stage I (T1 N0 M0) glottic carcinoma, treated with conservation surgery, radiation therapy, and endoscopic resection, are controversial. METHODS: A retrospective tumor registry retrieval of data on patients treated with curative intent at Washington University Medical Center-Barnes Hospital between January 1971 and December 1990 for the surgical group, January 1971 to December 1985 for the low-dose radiation group, and January 1986 to January 1995 for the high-dose radiation group, was performed. RESULTS: The 659 patients with Stage I (T1 N0 M0) glottic carcinoma treated with curative intent were subdivided into four groups: (1) 90 patients received low-dose radiation (mean dose 58 Gy, range 55-65 Gy, daily fractionation 1.5-1.8 Gy); (2) 104 patients received high-dose radiation (mean dose 66.5 Gy, range 65-70 Gy, daily fractionation 2-2.25 Gy); (3) 404 patients underwent conservation surgery; and (4) 61 patients had endoscopic resection. T1A (85%) and T1B (15%) disease was equally distributed among the groups. The anterior commissure was involved in 38 patients in the radiation therapy groups and 56 patients in the surgical groups. The overall local control was 89%. The overall local salvage was 84%. The overall unaided laryngeal voice preservation was 90%. The overall 5-year disease specific and actuarial survival rates were 95% and 81%, respectively. Prevalence of 2% regional metastases, 1.2% distant metastases, and 14% second primary malignancies were documented. The cure rate was 69% for regional metastases, 13% for distant metastases, and 44% for second primary malignancies. There were 5 complication deaths (0.1%), and 38 (6%) patients died of intercurrent disease. The use and dose of tobacco products was significantly increased in patients who died of intercurrent disease (p = 0.004) or developed second primary malignancies (p = 0.024). No significant difference was observed among the four therapeutic groups in the 5-year cause-specific survival rate (p, 0.68). Actuarial survival was significantly decreased in the low-dose radiation therapy group as compared with the other three therapeutic groups (p = 0.04). Initial local control was poorer for the endoscopic (77%) and low-dose radiation (78%) groups as compared with the high-dose radiation (89%) and conservation surgery (92%) groups (p = 0.02) but significant differences were not found for ultimate local control following salvage treatment. Unaided laryngeal voice preservation was similar for high-dose radiation (89%), conservation surgery (93%) and endoscopic resection (90%), but significantly poorer for low-dose radiation (80%; p = 0.02). T1B disease (N = 94) had similar local control and voice preservation with conservation surgery (87%) and high-dose radiation (88%) but lower results with low-dose radiation and endoscopic resections (67% unaided laryngeal voice preservation; p = 0.02). CONCLUSION: (1)The four therapeutic groups achieved similar rates of disease specific survival and ultimate local control. (2) Low-dose radiation was associated with significantly lower overall actuarial survival and unaided laryngeal voice preservation. (3) Endoscopic resection was associated with a significantly lower initial local control rate, but following salvage therapy achieved equivalent results to the other treatment methods. (4) Patients with (T1 N0 M0) glottic carcinoma had similar survival, local control, and unaided laryngeal voice preservation rates with high-dose radiation, conservation surgery, and endoscopic resections, but not with low-dose radiation therapy. (c) 1999 John Wiley & Sons, Inc. Head Neck 21: 707-717, 1999.

Management of stage II (T2N0M0) glottic carcinoma by radiotherapy and conservation surgery.

BACKGROUND: The best therapeutic approach for the treatment of stage II (T2N0M0) glottic carcinoma is controversial. METHODS: A retrospective tumor registry data retrieval of patients with stage II glottic carcinoma treated with curative intent at Washington University Medical Center-Barnes Hospital between January 1971 and December 1989 (surgery) and December 1995 (radiotherapy) was performed. RESULTS: Among 134 patients with stage II glottic carcinomas treated with curative intent and function preservation, there were 47 patients treated with low dose radiotherapy (median dose, 58.5 Gy at 1.5-1.8 Gy daily fractions), 16 patients with high dose radiotherapy (67.5-70 Gy) at higher daily fractionation doses (2-2.25 Gy), and 71 patients underwent conservation surgery. The overall local control rate was 85%. The overall salvage rate was 68%. The 5-year actuarial and disease specific survivals were 81.5% and 92%, respectively. Unaided phonation was achieved in 84.4% of the patients. An incidence of 10.4% regional metastases, 2.2% distant metastases, and 6% second primary tumors was documented. There were no statistical differences in local control, voice preservation, and 5-year actuarial and disease specific cure rates between conservation surgery and high dose radiation (p = .89). Low dose radiation had statistically lower local controls, 5-year survival, and voice preservation (p = .014). In advanced T2B disease, treating the ipsilateral neck nodes reduced regional metastases (p = .02). CONCLUSIONS: High dose and daily fractionation (70 Gy at 2 Gy daily fraction doses) radiation achieved results equivalent to those of conservation surgery in 5-year local control, survival, and voice preservation. In advanced T2B disease, treatment of the ipsilateral neck nodes by radiotherapy or functional neck dissection reduced regional metastases.

Carcinoma of the tonsillar fossa: prognostic factors and long-term therapy outcome.

PURPOSE: To identify prognostic parameters and evaluate the therapeutic outcomes for patients with carcinoma of the tonsillar fossa treated with three treatment modalities. METHODS AND MATERIALS: The results of therapy are reported in 384 patients with histologically proven epidermoid carcinoma of the tonsillar fossa; 154 were treated with irradiation alone (55-70 Gy), 144 with preoperative radiation therapy (20-40 Gy), and 86 with postoperative irradiation (50-60 Gy). The operation in all but four patients in the last two groups consisted of an en bloc radical tonsillectomy with ipsilateral lymph node dissection. RESULTS: Treatment modality and total irradiation doses had no impact on survival. Actuarial 10-year disease-free survival rates were 65% for patients with T1 tumors, 60% for T2, 60% for T3, and 30% for T4 disease. Patients with no cervical lymphadenopathy or with a small metastatic lymph node (N1) had better disease-free survival (60% and 70%, respectively) at 5 years than those with large or fixed lymph nodes (30%). Primary tumor recurrence (local, marginal) rates in the T1, T2, and T3 groups were 20-25% in patients treated with irradiation and surgery and 31% for those treated with irradiation alone (difference not statistically significant). In patients with T4 disease treated with surgery and postoperative irradiation, the local failure rate was 32% compared with 86% with low-dose preoperative irradiation and 47% with irradiation alone (p = 0.03). The overall recurrence rates in the neck were 10% for N0 patients, 25% for N1 and N2, and 35-40% for patients with N3 cervical lymph nodes, without significant differences among the various treatment groups. The incidence of contralateral neck recurrences was 8% with the various treatment modalities. On multivariate analysis the only significant factors for local tumor control and disease-free survival were T and N stage (p = 0.04-0.001). Fatal complications were noted in 7 of 144 (5%) patients treated with preoperative irradiation and surgery, 2 of 86 (2%) of those receiving postoperative irradiation, and 2 of 154 (1.3%) patients treated with radiation therapy alone. Other moderate or severe nonfatal sequelae were noted in 30% of the patients treated with preoperative irradiation and surgery, in 53% treated with postoperative irradiation, and in 19% receiving radiation therapy alone. CONCLUSION: Primary tumor and neck node stage are the only significant prognostic factors influencing locoregional tumor control and disease-free survival. Treatment modality had no significant impact on outcome. Radiation therapy remains the treatment of choice for patients with stage T1-T2 carcinoma of the tonsillar fossa. In patients with T3-T4 tumors and good general condition, combination surgery and postoperative irradiation offers better tumor control than single-modality and preoperative irradiation procedures, but with greater morbidity.

Primary subglottic cancer.

This retrospective study reviews 39 patients with primary subglottic cancer seen between 1955 and 1988 by the Department of Otolaryngology at Washington University. This number constitutes 1.8% of laryngeal cancer cases diagnosed during this period. Twenty-eight patients (71.8%) had epidermoid cancer, of which 19 (67.9%) had "early" disease (stages I and II), and nine (32.1%) had "advanced" (stages III and IV). Overall 5-year survival was 57.7%. Disease-free survival was 46.2%. Patients treated with radiotherapy alone, surgery alone, or both had disease-free 5-year survivals of 22.2%, 41.7%, and 100%, respectively. Combination therapy showed a significantly higher (P < .01) disease-free survival than radiotherapy alone.

Primary intrathyroidal paraganglioma with metachronous carotid body tumor: report of a case and review of the literature.

A case of primary intrathyroidal paraganglioma is reported, and the light microscopic and immunohistochemical findings are described. Primary paragangliomas of the thyroid region are extremely uncommon and are therefore often confused clinically and histopathologically with more common intrathyroidal mass lesions. The diagnostic difficulties are underscored by the present case, which was misdiagnosed twice, firstly as a medullary thyroid carcinoma and secondly as a follicular thyroid carcinoma. Immunohistochemistry may be very helpful in arriving at the correct diagnosis. The case was further complicated by a second neck mass contralateral to the original thyroid nodule, which was interpreted as consistent with metastasis. The second lesions was proved angiographically and histologically to be a carotid body paraganglioma.

The impact of surgical margin status and use of an interstitial implant on T1, T2 oral tongue cancers after surgery.

PURPOSE: In patients with T1,T2 oral tongue carcinoma treated with surgical resection, postoperative radiation therapy (RT) is required especially when surgical margins contain tumors. Irradiation techniques include external beam, interstitial implants, or a combination of the two modalities. We investigated whether positive surgical margin remains a poor prognostic factor after radiation therapy, and the contribution of interstitial implants to disease control. METHODS AND MATERIALS: Between 1972 and 1989, 55 patients were treated postoperatively at the Mallinckrodt Institute of Radiology for T1,T2 squamous cell carcinomas of the oral tongue. Surgeries included 26 wide excisions or excisional biopsies and 29 composite resections or hemiglossectomies. Thirty-nine patients received external radiation therapy alone and 16 patients had an interstitial implant (ISI) as part of the treatment. The minimum follow-up is 4 years. RESULTS: At 2 and 5 years, the overall survivals for all patients were 82 and 68%. The disease-free survivals (DFS) were 82 and 70%, respectively. There was no significant difference in the pattern of failure and DFS when stratified by the status of surgical margins and the type of the surgical procedure. Local control was achieved in 15 of 18 patients when surgical margins were involved by tumor and in 29 of 37 patients without tumor involving margins (p > 0.05). Ten of 18 (56%) patients with tumor involving resection margins were treated with ISI, whereas only 3 of 33 (9%) of those with negative margins received ISI. Local control was achieved in 32 of 39 patients treated with external beam RT alone, and 13 of 16 patients who received interstitial implant (p > 0.05). Four patients treated with ISI developed persistent soft tissue ulceration and mandibular bone exposures. CONCLUSIONS: Postoperative radiation therapy converted the ominous outcome of patients with tumor involving surgical margins. Patients with positive surgical margins were often selected to be treated with interstitial implants. We found that the local control was as good as in those with a more favorable pathology (negative margins) and treated with external RT alone. Further investigation is needed to optimize the implant treatment to minimize the complications.

Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx.

Ninety-five patients with laryngeal and hypopharyngeal cancer were examined and staged preoperatively by clinical evaluation (CE) and computed tomography (CT). The CE and CT staging were compared to each other and to the pathologic (PT) staging of the tumors. The CT staging showed high accuracy in staging transglottic (88%), supraglottic (68%), and oropharyngeal tumors invading the larynx (68%) when compared to the PT findings. The CT staging was less effective in evaluating glottic tumors (46%), both overstaging (12%) and understaging (20%) cases. Combined CE-CT evaluation showed higher accuracy in staging all tumors (84%) compared to CE alone (52%) or CT alone (68%). The findings suggest that combined CE-CT should be used to evaluate laryngeal and hypopharyngeal tumors.

Squamous cell carcinomas of the aryepiglottic fold: therapeutic results and long-term follow-up.

Three hundred fifteen patients with squamous cell carcinomas involving the aryepiglottic (A-E) folds were treated between January 1964 and December 1991. The age ranged from 39 to 87 years (mean, 62.4 years; median, 61.3 years) and the male-to-female ratio was 5:1 (54 women and 261 men). Symptom duration prior to diagnosis was 4.8 months. Eighty percent of patients had T3 and T4 lesions and 56.3% had neck metastases at presentation. Six patients (1.8%) had distant metastases and were excluded from this study. Clinically the tumors presented as either exophytic infiltrating lesions which were confined to the A-E fold (n = 57) or mucosally spreading tumors which extended to the lateral supraglottis or pyriform sinus (n = 258). Prior to 1978 preoperative radiation (3000 to 5000 cGy) was used. Higher doses of postoperative radiation (5000 to 6000+ cGy) were used thereafter. After 1982 the use of myocutaneous flaps for closure of partial laryngopharyngectomy defects was routine. Almost all N0 neck disease was treated by radiation or surgery. Combined therapy was used in N1-N3 disease. One quarter of the patients had single-modality therapy (25.7%; 81 patients) with a cumulative 5-year disease-free survival of 53%. The remainder of the patients (n = 234) had combined therapy with a cumulative 5-year survival of 67.2%. The latter group had 163 conservation surgeries and 121 total laryngectomy resections. The 5-year disease-free survival for preoperative radiation with surgery (68%) and postoperative radiation with surgery (64%) was similar. Those treated by radiation alone had a 34% 5-year disease-free survival and those treated with surgery alone had a 61% 5-year disease-free survival. The cumulative locoregional control rate was 77%. The cumulative disease-free survival at 5, 10, 15, and 20 years is 66%, 57%, 55%, and 55%, respectively. Infiltrating tumors had a better disease-free survival (by more than 10%) than spreading tumors. The 5-year survival rates were separated well by clinical stages of tumors. In patients with T1 tumors the 5-year survival was 87%; in those with T2 tumors, 80%; in those with T3 tumors, 78%; and in those with T4 tumors, 41%. The survival rate was greater in those with N0 tumors than in those with N+ tumors by 25% and greater in those with N1 tumors than in those with N2 + N3 tumors by an additional 18%. The overall complication rate was 26% and in 7.7% these were fatal.(ABSTRACT TRUNCATED AT 400 WORDS)