Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer.

PURPOSE: A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. PATIENTS AND METHODS: Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. RESULTS: After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. CONCLUSION: Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

Differential oncogenic expression in thyroid follicular and Hürthle cell carcinomas.

Although Hürthle cell tumors are considered to be variants of follicular neoplasms, they have distinct cytologic and behavioral characteristics. To elucidate the basis for these differences, the expression of 5 oncogenes and growth factors (Pan-ras, N-myc, transforming growth factor-alpha [TGF-alpha], transforming growth factor-beta [TGF-beta], and insulin-like growth factor 1 [IGF-1]) was compared between 12 follicular carcinomas and 8 Hürthle cell carcinomas by immunocytochemistry. The percentage of follicular carcinomas and Hürthle cell carcinomas that stained positively for the different oncogenes was as follows and respectively: Pan-ras 8% versus 63%; TGF-alpha 17% versus 63%; TGF-beta 25% versus 88%; IGF-1 17% versus 88%; and N-myc 17% versus 100%. All these differences were highly significant by the chi 2 test. This difference in the expression of oncogenes between Hürthle cell carcinomas and follicular carcinomas suggests that these two tumors could, in fact, represent separate entities.

Stress induced experimental colitis.

Stress induces chemical changes in the central nervous system which alters the biochemistry and physiology of the digestive tract. The present study determines arachidonic acid oxidation and damage in the colon following stress. Ten rats were stressed by the cold-restraint method; ten were controls. Stress induced 0.5 +/- 0.7 (S.D.) mucosal erosions whereas controls had none. Subepithelial hemorrhage and erosions occurred only in the proximal two-thirds of the colon. Prostaglandin E(2) synthesis was increased after stress compared to the control (381 +/- 130 vs. 1610 +/- 372 ng/g/min). Leukotriene C(4) synthesis also increased after stress (4217 +/- 994 vs. 11300 +/- 1662 ng/g/min). Synthesis of prostaglandin E(2) increased (r = 0.9381) with leukotriene C(4). The response of the colon to stress is less severe than that in the stomach and may be related to regional regulation of prostaglandin and leukotriene synthesis.

The effect of cocaine on gastric mucosal PGE(2), LTC(4) and ulcerations.

The association between cocaine use and acute gastroduodenal perforation is known. The effect of cocaine and stress on gastric mucosal ulceration and the levels of prostaglandin E(2) (PGE(2)) and leukotriene C(4) (LTC(4)) was studied in 40 Sprague-Dawley rats. Controls received intraperitoneal (i.p.) saline, ten received i.p. cocaine (35 mg/kg), ten were stressed by the cold restraint method, and ten had i.p. cocaine and stress. Cocaine alone did not induce ulceration, but decreased PGE(2) levels. Stress alone caused ulceration, but was not associated with a change in either PGE(2) or LTC(4) levels. When combined with stress, however, cocaine caused a three-fold increase in ulceration and a significant increase in PGE(2) and LTC(4) levels. Stress may predispose the cocaine addict to loss of gastroduodenal mucosal integrity, which is related to an imbalance of PGE(2) and LTC(4) synthesis.

Oncogene expression in follicular neoplasms of the thyroid.

Oncogene expression has been found to be a potential marker for aggressive biologic behavior in certain tumors. We studied 21 follicular adenomas and 20 follicular carcinomas by immunocytochemistry utilizing specific monoclonal antibodies against HER-2/neu and c-myc oncogenes. Survival data were obtained from our institution's tumor registry. No expression of the HER-2/neu oncogene was found in the specimens studied. Cytoplasmic staining for c-myc was observed in 3 of 21 adenomas (14%) and 9 of 20 (45%) carcinomas (p < 0.05). The incidence of local, regional, and distant metastases was not significantly different in c-myc (+) and c-myc (-) patients. The c-myc oncogene is expressed more often in malignant than in benign follicular neoplasms of the thyroid, but its expression does not appear to be a good prognostic indicator.

Stress-induced gastric lesions and the synthesis of prostaglandins and leukotrienes.

Prostaglandin E2 renders the mucosa of the GI tract more resistant to acute injury by aspirin, acid, bile salts, and stress, whereas leukotrienes promote inflammation and retard healing of ulcers. The relationship of stress ulcer formation to changes in the activities of prostaglandin synthetase and lipoxygenase was evaluated in this study. After a 24 hr fast, 10 rats were stressed by the cold-restraint method for 4 hr and 10 rats were not stressed. Rats were terminated, stomachs were excised, the number of lesions were counted, and the nonulcerated mucosa was assayed for prostaglandin E2 and leukotriene synthesis. The mucosa was minced, washed in buffered saline, and then incubated for 10 min in a 1.3 mM sodium arachidonate solution containing a nonionic detergent (poloxamer 188), NaCl, KCl, KPO4, glutathione, hemin, MgSO4 and Hepes at pH 8.0. An ANOVA was used to compare the groups. Following stress the number of gastric lesions increased from 0.7 +/- 0.6 to 13.5 +/- 2.6, while leukotriene synthesis increased from 173 +/- 20 to 2170 +/- 187 pg/mg/min. A shift in synthesis from prostaglandins to leukotrienes in the mucosa appears to be detrimental to cytoprotection.

Surgical management of BANS malignant melanoma.

Because melanomas of the upper back, posterior arm, neck, and scalp (BANS) have been shown to be at high risk for recurrence and metastases, a tendency is to carry out wide excision (WE) and elective radical node dissection (RND) for patients with such lesions. To investigate whether this regimen improves the survival rate, we reviewed retrospectively 62 patients with clinical stage I BANS melanoma. Forty-five patients were treated by WE alone and 17 patients were treated by WE and RND (WE + RND). The male:female ratio was 1.5:1 for WE and 1.8:1 for WE + RND. The mean age was 52.9 +/- 15.3 years for WE and 48.2 +/- 12.5 years for WE + RND (p = not significant [NS]). The overall survival rate at 1, 3, and 5 years was 98%, 76%, and 71% for WE and 100%, 88%, and 76% for WE + RND (p = NS). The disease-free survival rate at 1, 3, and 5 years was 91%, 76%, and 71% for WE and 100%, 88%, and 76% for WE + RND (p = NS). In conclusion, WE + RND does not improve survival of patients with stage I BANS melanoma.

Measurement of prostaglandin G/H synthase and lipoxygenase activity in the stomach wall by HPLC.

A method for the determination of prostaglandin G/H synthase and lipoxygenase activities in tissues was developed and employed with rat gastric mucosa samples. Tissues and microsomes were incubated in a buffer containing nonionic detergent and 1.32 mM arachidonic acid for 10 min. Following extraction with ethyl acetate, the oxidation products of arachidonic acid were derivatized with panacyl bromide. A reversed-phase column and a quaternary mobile phase were used to separate and quantitate the panacyl bromide esters of prostaglandin E2 and leukotriene C4/D4. Prostaglandin G/H synthase and lipoxygenase activities were determined in gastric mucosa and were 371 +/- 66 and 173 +/- pg/mg/min, respectively.

Multiple parathyroid adenomas: report of thirty-three cases.

An increasing number of patients with primary hyperparathyroidism are found to have two or three enlarged parathyroid glands. Of 865 patients successfully operated on by one surgeon (J.N.A.), multiple enlarged parathyroid glands (adenomas) were found and resected in 33 cases (3.8%), with resulting normocalcemia lasting from 1 to 22 years (mean 5.8). Twenty-nine patients had two adenomas and four had three adenomas. In 28 patients the multiple adenomas were synchronous. Twenty-five patients underwent removal of all of the enlarged parathyroid glands in one operation; in three patients one adenoma was removed, reoperation for persistent hypercalcemia was performed, and a second adenoma was resected with cure. In five patients one adenoma was removed, normocalcemia ensued for 3 to 18 years, and a second (metachronous) adenoma occurred and was resected successfully. Although 10 of 70 enlarged parathyroid glands removed were labeled hyperplasia, cure in all but one of our patients by selective resection of only enlarged parathyroid glands emphasizes the unreliability of histologic criteria in differentiating between parathyroid adenoma and hyperplasia. Based on this study, we support the existence of multiple adenomas and advocate removal of only macroscopically enlarged parathyroid glands in patients with primary hyperparathyroidism.

Prevention of stress-induced erosive gastritis by parenteral administration of arachidonic acid.

Stress-induced mucosal ulcerations are associated with a decreased synthesis of mucosal prostaglandin (PG) E2. This phenomenon is poorly understood. To investigate whether it is due to a decreased availability of the necessary substrates to the mucosa, four groups of 10 Holtzman rats were studied: group 1 received normal saline by intraperitoneal (ip) injection; group 2 also received ip normal saline, then were submitted to stress, by the cold restraint method; group 3 received a solution of arachidonic acid (AA) ip; and group 4 also received ip AA, then were submitted to stress. After sacrifice, the number of gastric ulcerations were counted and specimens of nonulcerated mucosa were assayed for PGE2 by high-performance liquid chromatography; the mean numbers of ulcers were 0, 5.8, 0.8, and 3 and the mean levels of PGE2 were 55, 41, 125, and 62 pg/mg of wet tissue for groups 1, 2, 3, and 4, respectively. It is concluded that parenteral administration of AA reduces but does not completely eliminate stress-induced gastric ulcerations and that the stressed animals synthesized half as much PGE2 as the nonstressed ones after ip administration of equal amounts of AA, suggesting that stress reduces the availability of AA to the gastric mucosa, possibly by vascular spasm.

Initial failure of surgical exploration in patients with primary hyperparathyroidism.

To determine the causes of failures of cervical exploration for primary hyperparathyroidism, we reviewed 892 patients operated on by one surgeon from 1953 to 1990. Twenty-seven patients (3%) remained hypercalcemic or developed hypercalcemia within 6 months of surgery. Of these, five patients had one adenoma removed initially; at reoperation, three patients had a second adenoma that was successfully removed, whereas the other two patients had hyperplasia and required subtotal parathyroidectomies. No enlarged parathyroid glands were identified in 22 patients. Eventually, six patients became normocalcemic spontaneously, seven patients underwent re-exploration with a successful outcome in all but one case, two patients had ectopic hyperparathyroidism associated with carcinoma elsewhere, and seven patients refused reoperation and remain hypercalcemic. The failure rate of surgical exploration for primary hyperparathyroidism can be reduced by systematically exploring all four parathyroid glands. All abnormal parathyroids should be removed with histologic verification. When no abnormal glands are found, localization studies should be performed before re-exploration.

Effect of verapamil on the gastric mucosal level of PGE2 during stress.

Prostaglandin E2 is one of the factors in the maintenance of gastric mucosal integrity and verapamil, a calcium channel blocker, has been shown to reduce gastric mucosal ulcerations during stress. To investigate whether this protective effect of verapamil is mediated via PGE2, four groups of 20 Holtzman rats were given either 1 ml of normal saline (NS) intraperitoneally (ip): 1 mg/kg of indomethacin (I) ip; 2 mg/kg of verapamil (V) ip or I followed by V. Then 10 animals from each group were submitted to stress by the cold-restraint method. After sacrifice, gastric mucosal ulcerations were counted and specimens of nonulcerated mucosa were assayed for PGE2 by HPLC. Stress-induced mucosal ulcerations were associated with a significant decrease in the gastric mucosal levels of PGE2 (from 64.2 to 32.7 pg; P less than 0.05). This effect was magnified by the administration of indomethacin (down to 21.0 pg). Verapamil significantly increased PGE2 levels both in the stressed (48.0 pg) and unstressed (99.9 pg) animals and significantly reduced ulcerogenesis when compared to either NS- or I-treated groups. This effect of verapamil was completely blocked by the administration of indomethacin. In conclusion, verapamil stimulates PGE2 synthesis and its protective effect against stress-induced mucosal damage seems to be mediated by PGE2.

Completion thyroidectomy for initially misdiagnosed thyroid cancer.

Intraoperative frozen sections fails to diagnose thyroid carcinoma accurately in 16% of cases. In such instances, we recommend that completion thyroidectomy be performed in the patient who has invasive carcinoma, is less than 70 years old, and has a reasonable life expectancy. The procedure should be carried out immediately if the error in diagnosis is discovered within a week; otherwise the procedure should be delayed until 3 to 4 months later. At that time, the recurrent laryngeal nerves and at least two parathyroid glands should be dissected and preserved. A paratracheal lymph node dissection should also be performed and the lower jugular lymph nodes should be sampled. If these jugular lymph nodes are found to be positive, a modified radical neck dissection should be added. The morbidity associated with the completion thyroidectomy is minimal. Postoperatively, a 131I scan of the neck should be carried out and ablative doses of radioactive iodine can be given if the uptake in the thyroid bed is greater than 1.5%. Subsequently, all patients are given thyroid suppressive therapy and are monitored closely. This approach will reduce the local recurrence rate and improve the long-term survival.

Nutritional effects of postgastrectomy reconstruction: a clinical evaluation.

To evaluate the nutritional benefits of a jejunal pouch vs. esophagojejunostomy following total gastrectomy, we reviewed 24 consecutive cases of total gastrectomy: 14 males and 10 females, 39 to 85 years of age (mean 66.6 y.) undergoing 9 jejunal pouches (JP) and 15 Roux-en-Y esophagojejunostomy (EJ). Indications for surgery included 15 adenocarcinomas, 3 lymphomas, 1 leiomyoma, and 5 hemorrhagic gastritis. The operative mortality was 12.5%. One JP patient was lost to follow-up. The mean survival for EJ was 13.3 months and for JP 36 months. Total gastrectomy resulted in persistent weight loss and hypoalbuminemia, and the creation of a jejunal pouch did not seem to improve significantly the nutritional status following total gastrectomy.

Starvation and mucosal prostaglandin-E2 in gastric stress ulceration.

To determine whether starvation increases the susceptibility of the gastric mucosa to stress ulceration and whether this effect is linked to a change in the mucosal level of prostaglandin-E2 (PGE2), 100 Holtzman rats were divided into five groups and deprived of food for 0, 12, 24, 48 and 72 h. Then, ten animals within each group were stressed by cold restraint. At the end of the stress period, all these animals as well as their unstressed counterparts were killed, the number of gastric ulcers were counted, and mucosal levels of PGE2 were assayed. Fasting alone caused no ulcerations but a decrease in mucosal PGE2 during the initial 24 h (p less than .05). However, there was a subsequent increase in mucosal PGE2, possibly related to the release of free fatty acids during starvation. Starvation and stress caused a marked and consistent reduction of the mucosal PGE2 and an increase in the number of mucosal ulcerations directly related to the duration of starvation (p less than .05).

Morbidity of completion thyroidectomy for initially misdiagnosed thyroid carcinoma.

We reviewed 757 cases of thyroid carcinoma treated between 1963 and 1986 to investigate the morbidity associated with completion thyroidectomy when a nodule initially reported to be benign by frozen section is subsequently found to be malignant; 66 patients underwent completion thyroidectomy as a second procedure for initially misdiagnosed thyroid carcinoma. Fifty-one patients had papillary carcinoma, 12 follicular carcinoma, and 3 Hürthle cell carcinoma. Final pathology revealed 28 cases of multicentricity of which 19 were bilateral. Complications included transient hypocalcemia (12.1%), recurrent laryngeal nerve palsy (1.5%), and wound hematomas or infections (9.1%). No cases of permanent hypoparathyroidism or vocal cord paralysis were encountered. Reoperation for initially misdiagnosed thyroid carcinoma appears to be warranted in light of the low morbidity and high incidence of bilateral and multicentric disease reported in this series.

Arachidonic acid protection of rat mucosa against stress ulceration.

To evaluate the effect of arachidonic acid (AA), a prostaglandin precursor, on the mucosal level of PGE2 and its possible protective role against stress ulcerations, 40 Holtzman rats were divided into four groups: Group I intragastrically receiving 1 ml of normal saline (NS); Group II, NS pretreatment followed by stress; Group III, intragastric AA pretreatment without stress; and Group IV, intragastric AA followed by stress. AA was administered as a 120 mM solution in a nonionic detergent, adjusted to a pH of 8.0. Stress was provided by the cold-restraint method. After sacrifice, the number of gastric mucosal ulcerations were counted. Specimens of nonulcerated mucosa were assayed for PGE2 by derivatization with panacyl bromide and by using high-performance liquid chromatography. The animals in Groups I, III, and IV developed no gastric ulcerations and their mucosal prostaglandin E2 remained at a normal level, while those in Group II had a significant reduction of mucosal PGE2 (P less than 0.05) and a significantly increased number of gastric ulcerations (P less than 0.002). These data indicate that stress-induced mucosal ulcerations are associated with significant decreases in the gastric mucosal levels of PGE2. Intragastric administration of arachidonic acid prevents the formation of stress mucosal ulcerations and maintains a normal level of mucosal PGE2.

Comparison of intraoperative ultrasonography and cholangiography in detection of small common bile duct stones.

High-resolution intraoperative ultrasonography was compared with conventional radiographic imaging in the detection of small common bile duct (CBD) stones (less than 5 mm in diameter). Sixteen mongrel dogs had laparotomy and ligation of distal CBD; 1 week to 10 days later, 0-3 gallstones of varying sizes (2-5 mm) were introduced into the dilated CBD (6-16 mm). High-resolution intraoperative ultrasonography of the CBD and a conventional intraoperative cholangiogram were performed to detect the presence and number of stones. The results of these two tests were evaluated independently by two ultrasonographers and two surgeons. There were 21 true-positive and five false-negative readings by sonogram compared with 17 and 9, respectively, by cholangiogram. Sensitivity of the sonogram was 81% and 65.4% by cholangiogram. Score of accuracy was 1.06 and 1.62 by cholangiogram and 0.81 and 0.87 by ultrasound (p less than 0.05). Intraoperative ultrasonography was found to be more sensitive in detecting small CBD stones when compared with intraoperative cholangiogram.