Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck.

BACKGROUND: The objective of this study was to determine prognostic factors for response and survival on three consecutive institutional trials utilizing concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck (SCCHN). METHODS: Since 1985, patients with locally advanced SCCHN at the University of Maryland have been managed with concurrent chemotherapy and radiation therapy (RT). Three consecutive pilot studies have been performed evaluating the utility of weekly chemotherapy with standard fractionated RT. Chemotherapy consisted of carboplatin either alone (28 patients) or in combination with bleomycin (23 patients) or paclitaxel (60 patients). In all three studies, RT was given to 70.2 gray (Gy) at 1.8 Gy/fraction/day to the primary site. All patients had locally advanced SCCHN and were believed to be poor surgical candidates. Sixty-seven percent of patients had T4 disease, and 21% had T3 disease. Seventy-five percent of patients had N2-N3 disease. One hundred eleven patients were examinable for toxicity, response, and survival analysis. Factors including age, race, gender, primary site location, histologic grade, T classification, N classification, and treatment regimen were evaluated to identify predictors of these endpoints. RESULTS: The median follow-up for patients treated on study 1 (carboplatin and RT) and study 2 (carboplatin and bleomycin [C + B]/RT) was 98 months, and it was 30 months for study 3 (carboplatin and paclitaxel [C + P]/RT). The complete response rates were 54%, 52%, and 70% respectively (P = 0.01). Multivariate analysis identified length of treatment break (< 1 week vs. > 1 week) as the only predictor of complete response to therapy. The local control for the entire group was 50%. The local control for C + P/RT was 63%, versus 32% and 36% for C/RT and C + B/RT respectively (P = 0.004). The 2-, 3-, and 5-year disease free and overall survivals for the entire population were 41%, 41%, and 35% and 42%, 36%, and 33%, respectively. The 3-year overall survival rates by treatment regimen were 18% (C/RT), 35% (C + B/RT), and 47% (C + P/RT; P = 0.01). On univariate analysis, age younger than 50 years (P = 0.01), treatment with C + P/RT (P = 0.005), and treatment break of 5 days or fewer (P < 0.05) were also predictive of improved overall survival. On multivariate analysis, only complete response (P < 0.0001) and treatment with C + P/RT (P = 0.02) remained statistically significant. CONCLUSIONS: Chemoradiation provides patients with locally advanced SCCHN the opportunity for long term survival. Among the three chemoradiation regimens studied, C + P/RT was associated with the best complete response and survival rates. Complete response to therapy was the single most important predictor of overall survival. These three consecutive concurrent chemotherapy and radiation trials achieved a 5-year survival of greater than 30% for the entire population. These results support the use of this nonoperative approach for this group of patients with a historically poor prognosis.

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Long-term beta 1-adrenergic blockade restores adrenomedullary activity in primary hypertension.

In this study we examined the effects of long-term treatment of 19 patients with primary hypertension with the beta 1-adrenoceptor antagonist atenolol on norepinephrine and epinephrine kinetics, at rest and during sympathoadrenal stimulation by lower body negative pressure. Norepinephrine and epinephrine kinetics were measured by using the radioisotope-dilution technique by steady-state infusion of tritiated norepinephrine and epinephrine. The patients were studied before and at the end of 3 months of treatment with atenolol (50 or 100 mg daily). A control group of four normotensive subjects was studied before and after 3 months without any drug treatment. In this group, only arterial blood samples were collected without infusion of the tritiated catecholamines. Atenolol decreased blood pressure and heart rate, but forearm vascular resistance was not affected by atenolol. During atenolol, baseline arterial plasma epinephrine decreased from 0.23 +/- 0.02 to 0.17 +/- 0.01 nM (p < 0.05), and this was accompanied by a decrease in total body epinephrine spillover from 0.50 +/- 0.05 to 0.35 +/- 0.04 nmol/min (p < 0.05). In the control group, arterial plasma epinephrine had not decreased after 3 months. In addition, the increment of arterial plasma epinephrine during lower body negative pressure at -40 mm Hg was attenuated during atenolol. Atenolol had no effect on total body and forearm norepinephrine spillover rates, either at rest or during lower body negative pressure. Clearance rates of epinephrine and norepinephrine were not significantly affected by atenolol. These results suggest that treatment of patients with primary hypertension with the beta 1-adrenoceptor blocker atenolol inhibits the adrenomedullary secretion of epinephrine, but it does not affect the biochemical indices of sympathoneural activity. It remains speculative whether this selective effect of atenolol on epinephrine secretion contributes to its hypotensive action and to its cardioprotective effects in the long term.

Adrenomedullary secretion of epinephrine is increased in mild essential hypertension.

To assess whether patients with mild essential hypertension have excessive activities of the sympathoneuronal and adrenomedullary systems, we examined total body and forearm spillovers and norepinephrine and epinephrine clearances in 47 subjects with mild essential hypertension (25 men, 22 women, aged 38.1 +/- 6.7 years) and 43 normotensive subjects (19 men, 24 women, aged 36.5 +/- 5.9 years). The isotope dilution method with infusions of tritiated norepinephrine and epinephrine was used at rest and during sympathetic stimulation by lower body negative pressure at -15 and -40 mm Hg. Hypertensive subjects had a higher arterial plasma epinephrine concentration (0.20 +/- 0.01 nmol.L-1: mean +/- SE) than normotensive subjects (0.15 +/- 0.01) (P < .01). The increased arterial plasma epinephrine levels appeared to be due to a higher total body epinephrine spillover rate in the hypertensive subjects (0.23 +/- 0.02 nmol.min-1.m-2) than the normotensive subjects (0.18 +/- 0.01) (P < .05) and not to a decreased plasma clearance of epinephrine. The arterial plasma norepinephrine level, total body and forearm norepinephrine spillover rates, and plasma norepinephrine clearance were not altered in the hypertensive subjects. The responses of the catecholamine kinetic variables to lower body negative pressure were not consistently different between normotensive and hypertensive individuals. These data indicate that individuals with mild essential hypertension (1) have elevated arterial plasma epinephrine concentrations that are due to an increased total body epinephrine spillover rate, indicating an increased adrenomedullary secretion of epinephrine; (2) have no increased generalized sympathoneuronal activity and no increased forearm norepinephrine spillover; and (3) have similar responses of both the sympathoneuronal and adrenomedullary systems to sympathetic stimulation by lower body negative pressure.

Rodent cell transformation and immediate early gene expression following 60-Hz magnetic field exposure.

Some epidemiological studies suggest that exposure to power frequency magnetic fields (MFs) may be associated with an elevated risk of human cancer, but the experimental database remains limited and controversial. We investigated the hypothesis that 60-Hz MF action at the cellular level produces changes in gene expression that can result in neoplastic transformation. Twenty-four hour 200 microT continuous MF exposure produced negative results in two standard transformation systems (Syrian hamster embryo cells and C3H/10T1/2 murine fibroblasts) with or without postexposure to a chemical promoter. This prompted a reexamination of previously reported MF-induced changes in gene expression in human HL60 cells. Extensive testing using both coded and uncoded analyses was negative for an MF effect. Using the same exposure conditions as in the transformation studies, no MF-induced changes in ornithine decarboxylase expression were observed in C3H/10T1/2 cells, casting doubt on a promotional role of MF for the tested cells and experimental conditions.

Differential effects of low- and high-intensity lower body negative pressure on noradrenaline and adrenaline kinetics in humans.

1. Lower body negative pressure provides a means to examine neurocirculatory reflexive responses to decreases in venous return to the heart. We assessed whether the pattern of catecholaminergic responses to lower body negative pressure depends on the intensity of the stimulus (-15 versus -40 mmHg). 2. In 14 healthy subjects, responses of forearm blood flow and noradrenaline spillover and of total body noradrenaline and adrenaline spillover were assessed during infusion of [3H]noradrenaline and [3H]adrenaline during -15 and -40 mmHg of lower body negative pressure. 3. During lower body negative pressure at -15 mmHg, heart rate and pulse pressure did not change, but forearm vascular resistance increased by 25-50%. Forearm noradrenaline spillover increased by about 50%, from 0.63 +/- 0.16 to 0.94 +/- 0.23 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline spillover did not change, and total body adrenaline spillover increased significantly by about 30%. Clearances of noradrenaline and adrenaline were unchanged. 4. During lower body negative pressure at -40 mmHg, heart rate increased and pulse pressure decreased. Forearm vascular resistance increased by about 100%, and forearm noradrenaline spillover increased by 80%, from 0.73 +/- 0.19 to 1.32 +/- 0.36 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline spillover increased by 30%, and total body adrenaline spillover increased by about 50%. Clearances of both noradrenaline and adrenaline decreased. 5. The results are consistent with the view that selective deactivation of cardiopulmonary baroreceptors during low-intensity lower body negative pressure increases sympathoneural traffic to forearm skeletal muscle and increases adrenomedullary secretion without a concomitant generalized increase in sympathoneural outflows. Concurrent deactivation of cardiopulmonary and arterial baroreceptors during high-intensity lower body negative pressure evokes a more generalized increase in sympathoneural activity, accompanied by further increased adrenomedullary secretion and decreased plasma clearances of noradrenaline and adrenaline. The findings support differential increases in skeletal sympathoneural and adrenomedullary outflows during orthostasis, with more generalized sympathoneural responses to systemic hypotension.

Effects of acute and chronic angiotensin converting enzyme inhibition by spirapril on cardiovascular regulation in essential hypertensive patients. Assessment by spectral analysis and haemodynamic measurements.

1. The effects of a first dose and of chronic treatment with spirapril, a novel angiotensin converting enzyme (ACE) inhibitor, on short-term blood pressure and heart rate fluctuations were assessed by fast Fourier spectral analysis. The effects on systemic haemodynamics in supine and standing position were also studied. We treated 11 patients with 3 mg and 13 patients with 12 mg spirapril for 8 weeks. 2. Overall blood pressure variability was not changed by spirapril. By spectral analysis the changes in blood pressure and heart rate variability in various frequency bands can be assessed, which may be related to changes in activity of the autonomic nervous system. The relative power in the mid-frequency band (0.08-0.12 Hz) of supine systolic pressure was 23 +/- 10% during placebo and decreased during treatment with 12 mg to 11 +/- 4% (P < 0.01 vs placebo, first dose) and to 13 +/- 6% (P < 0.01, chronic treatment). Standing systolic mid-frequency power was 38 +/- 12% during placebo and decreased to 27 +/- 9% (P < 0.01 vs placebo) after the first dose of 12 mg, but it did not decrease after chronic treatment (29 +/- 13%). Treatment with 3 mg induced no changes in mid-frequency blood pressure variability. A decrease in power of the mid-frequency band may point to a decrease in sympathetic vascular drive. The power in the high-frequency band (0.15-0.40 Hz) of heart rate did not change after treatment, suggesting that there is no change in the vagal cardiac drive. 3. Supine blood pressure decreased by a decrease in vascular resistance by 16 +/- 23% (3 mg) and 14 +/- 19% (12 mg) after 8 weeks treatment. Heart rate, stroke volume and cardiac output did not change. No orthostatic hypotension occurred after the first dose. In the 12 mg group the orthostatic induced rise in heart rate (compared with supine) increased from + 9 +/- 5 beats min-1 (placebo) to + 14 +/- 4 beats min-1 (P < 0.05) after the first dose. No changes in the orthostatic heart rate increase occurred in the 3 mg group. The orthostatic changes in stroke volume, cardiac output and vascular resistance were not influenced by spirapril. 4. In conclusion, the decrease in mid-frequency blood pressure variability may suggest an inhibitory effect of acute and chronic ACE inhibition upon sympathetic vasomotor control. Vagal activity was not influenced as high-frequency heart rate variability did not change. Acute and chronic ACE inhibition did not blunt important cardiovascular reflexes, as the haemodynamic response to orthostasis remained intact.

Intravenous instrumentation alters the autonomic state in humans.

Intravascular instrumentation may induce syncope or presyncope. It is not known whether asymptomatic subjects also have autonomic reactions, albeit concealed. We addressed this issue by studying 44 healthy young male subjects of various levels of fitness, ranging from inactivity to athletic [mean maximal oxygen uptake was 49.1 (SD 10.7) ml*kg(-1)*min(-1), range 28.7-71.9 ml*kg(-1)*min(-1)]. The autonomic response to venous cannulation was quantified by measuring heart rate before cannulation (HR(1)), after cannulation (HR(2)), and after complete pharmacological autonomic blockade (HR(0) = the intrinsic heart rate). The sympathovagal balance before and after cannulation was computed as HR(1)/HR(0) and HR(2)/HR(0), respectively. The group means of heart rate and sympathovagal balance decreased significantly (paired Student's t-test P <0.01) from 62.5 to 59.9 beats*min(-1), and from 0.71 to 0.68, respectively. The maximal decrease in heart rate was 8.8 beats*min(-1), and in the sympathovagal balance was 0.11. Our study demonstrated that the asymptomatic subjects responded to intravenous instrumentation with a concealed autonomic reaction. Thus, from our findings it would seem that intravenous instrumentation interferes with measurements relating to autonomic nervous system activity.

Chronic alpha-1-adrenergic blockade increases sympathoneural but not adrenomedullary activity in patients with essential hypertension.

OBJECTIVE: Doxazosin, a selective alpha1-adrenoceptor antagonist, lowers blood pressure by reducing peripheral vascular resistance without causing reflex tachycardia. To discover whether antihypertensive treatment with an alpha1-adrenoceptor blocker is accompanied by an increase in sympathoadrenomedullary activity, we studied plasma catecholamine kinetics before and during treatment with doxazosin. PATIENTS AND METHODS: Eleven patients with essential hypertension were studied before and after 3 months' treatment with doxazosin (4-8 mg a day). 3H-noradrenaline and 3H-adrenaline were infused simultaneously and blood samples were collected to calculate plasma catecholamine kinetics before and during sympatho-adrenomedullary stimulation (lower-body negative pressure). RESULTS: Doxazosin decreased systolic and diastolic blood pressure and forearm vascular resistance, whereas the heart rate did not change significantly. During doxazosin, baseline arterial plasma noradrenaline increased from 0.97 +/- 0.07 to 1.21 +/- 0.07 nmol/l, and this appeared to be due to an increase in total body noradrenaline spillover from 1.54 +/- 0.15 to 1.84 +/- 0.16 nmol/min; noradrenaline clearance did not change significantly. Forearm noradrenaline spillover also increased, from 0.89 +/- 0.18 to 1.48 +/- 0.23 pmol/100 ml per min. In contrast, arterial plasma adrenaline, total body adrenaline spillover and adrenaline clearance were not significantly affected by doxazosin treatment. The response of plasma noradrenaline and total body and forearm spillover of noradrenaline to lower-body negative pressure (-40 mmHg) was significantly increased during doxazosin administration, whereas the response of the adrenaline kinetic parameters were not altered. CONCLUSIONS: The blood pressure reduction induced by a chronic administration of the alpha1-adrenoceptor blocker doxazosin elicits a baroreceptor-mediated reflexive increase in sympathoneural but not in adrenomedullary activity. The latter finding might partly explain why the heart rate is not increased during chronic treatment with this alpha1-adrenoceptor blocking drug.

Highly sensitive and specific HPLC with fluorometric detection for determination of plasma epinephrine and norepinephrine applied to kinetic studies in humans.

An HPLC separation method combined with fluorometric detection was extended to enable simultaneous assessment of plasma 3H-labeled and endogenous epinephrine (E) and norepinephrine (NE). Forearm fractional extraction (FFE) of 3H-labeled E and NE and of endogenous E was measured in 40 healthy volunteers who were receiving a continuous infusion of 3H-labeled E and NE. Concentrations of arterial and venous E were 26.8 +/- 1.95 (mean +/- SE) and 6.8 +/- 0.75 ng/L, respectively. Arterial and venous NE and dopamine (DA) were also measured, with respective values of 140.7 +/- 8.5 and 192.1 +/- 15.1 for NE, and 13.1 +/- 0.78 and 11.3 +/- 0.70 ng/L for DA. The FFE of 3H-labeled E was slightly but significantly higher (0.790 +/- 0.016) than the that of either 3H-labeled NE or endogenous E (0.748 +/- 0.0146 and 0.745 +/- 0.0185, respectively; P < 0.001), the correlations being highly significant (r = 0.80, P < 0.001) in both cases. The small difference between the FFE of E and of 3H-labeled E allows the calculation of the apparent spillover of E. However, this spillover was negligible compared with forearm NE spillover (0.0112 +/- 0.0031 vs 1.369 +/- 0.128 ng/L per minute. The high sensitivity of this measurement of venous E widens the possibilities for studying E kinetics under physiological conditions.

Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines.

Norepinephrine (NE) and epinephrine (E) are metabolized extraneuronally by catechol-O-methyl-transferase to the metanephrines (MNs), normetanephrine (NMN) and metanephrine (MN). Subjects in this study received infusions of tritium-labeled NE and E. Concentrations of MNs and catecholamines were measured in plasma flowing into and out of the heart, forearm, lungs, kidneys, mesenteric organs (gastrointestinal tract, spleen, and pancreas), liver, and adrenals to examine the regional production of MNs from circulating and locally released catecholamines. NE spillover from mesenteric organs and kidneys accounted for 64% of the spillover from all tissues. There was detectable spillover of E from most extraadrenal tissues, but 91% was from the adrenals. The production of MNs from locally released and circulating catecholamines varied widely among tissues. The liver made the largest contribution to removal of circulating NE (57%) and E (32%) and the largest contribution to the production of NMN (54%) and MN (37%) from metabolism of circulating catecholamines. In all other tissues more NMN was produced from locally released than from circulating NE. Thus, the metabolism of circulating NE was responsible for only 19% of the total production of NMN. An even smaller portion (6%) of plasma MN was derived from metabolism of circulating E. Most plasma MN (91%) was produced within the adrenals, which also provided the largest single source (23%) of NMN. The regional variation in extraneuronal production of MNs indicates considerable heterogeneity in how circulating and locally released catecholamines are handled by different tissues. The substantial contribution of the adrenals to the production of MNs explains the extraordinary sensitivity of these metabolites for the diagnosis of pheochromocytoma.

Patch testing with preservatives at St John's from 1982 to 1993.

We have reviewed our patch test results for preservative allergy from 1982 to 1993. 8 preservatives were included: formaldehyde, 2-bromo-2-nitropropane-1,3-diol (Bronopol(TM)), quaternium-15 (Dowicil 200TM), imidazolidinyl urea (Germall 115TM), diazolidinyl urea (Germall IITM), parabens, 5-chloro-2methyl-isothiazolin-3-one (Kathon CG(TM)) and 1,2-dibromo-2,4-dicyanobutane (one of the constituents of Euxyl K 400TM). Whereas the allergy rate to formaldehyde is quite stable, there is a slight increase in the imidazolidinyl urea allergy rate. Quaternium-15's rate is decreasing and 5-chloro-2-methyl-isothiazolin-3-one plus 2-methyl-isothiazolin-3-one's rate, after a rapid rise, seems to have stabilized. Although very important constituents of cosmetics, preservatives not only induce allergies on the face but also on the hands, and, as expected, the allergy rate in men and women generally differs. Among the 5 formaldehyde-releasers, there are some favoured simultaneous reactions: quaternium-15 and formaldehyde, and diazolidinyl urea and imidazolidinyl urea. Concomitant reactions between 1-bromo-2-nitropropane-1,3-diol and formaldehyde are not common, and those between 2-bromo-2-nitropropane-1,3-diol and diazolidinyl urea, and formaldehyde are not very common. This supports the hypothesis that allergic reactions to the Germalls are directed toward the initial molecule rather than to formaldehyde.

Neurohumoral antecedents of vasodepressor reactions.

Vasodepressor (vasovagal) syncope, the most common cause of acute loss of consciousness, can occur in otherwise vigorously healthy people during exposure to stimuli decreasing cardiac filling. Antecedent physiological or neuroendocrine conditions for this dramatic syndrome are poorly understood. This study compared neurocirculatory responses to non-hypotensive lower body negative pressure (LBNP) in subjects who subsequently developed vasodepressor reactions during hypotensive LBNP with responses in subjects who did not. In 26 healthy subjects, LBNP at -15 and -40 mmHg was applied to inhibit cardiopulmonary and arterial baroreceptors. All the subjects tolerated 30 min of LBNP at -15 mmHg, but during subsequent LBNP at -40 mmHg 11 subjects had vasodepressor reactions, with sudden hypotension, nausea, and dizziness. In these subjects, arterial plasma adrenaline responses to LBNP both at -15 and at -40 mmHg exceeded those in subjects who did not experience these reactions. In 16 of the 26 subjects, forearm noradrenaline spillover was measured; in the eight subjects with a vasodepressor reaction, mean forearm noradrenaline spillover failed to increase during LBNP at -15 mmHg (delta = -0.06 +/- (SEM) 0.04 pmol min-1 100mL-1), whereas in the eight subjects without a vasodepressor reaction, mean forearm noradrenaline spillover increased significantly (delta = 0.31 +/- 0.13 pmol min-1 100mL-1). Plasma levels of beta-endorphin during LBNP at -15 mmHg increased in some subjects who subsequently had a vasodepressor reaction during LBNP at -40mmHg. The findings suggest that a neuroendocrine pattern including adrenomedullary stimulation, skeletal sympathoinhibition, and release of endogenous opioids can precede vasodepressor syncope.

Role of radiation therapy in the management of malignant chondroid syringoma.

BACKGROUND: Malignant sweat gland neoplasms are exceedingly rare tumors. Malignant chondroid syringoma (MCS) is one of the rarest subtypes, and as such, still poorly understood. It lacks distinctive clinical features, often delaying initial diagnosis and therapeutic management. OBJECTIVE: A current case and the available literature are reviewed to determine the overall clinical course of the MCS and the potential role of adjuvant therapy. METHODS: A case of MCS was studied by light microscope, immunohistochemistry, and electron microscopy. The clinical data of this case and of other reported cases are summarized and compared. RESULTS: This tumor recurred locally after initial local excision. Subsequent re-excision and radiation therapy rendered the patient without evidence of disease. This case study and the literature review of the 20 reported cases indicate that MCS is highly recurrent with tendency toward metastasis. CONCLUSION: MCS appears to behave in an aggressive manner. An initial treatment modality is aggressive surgery. Adjuvant radiation therapy with or without chemotherapy should be tried in future cases.