Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96.

Immunotherapy with gp96 was highly effective in mice bearing methylcholanthrene-induced fibrosarcomas (Meth A tumors) when treatment began 7 days or less after tumor challenge, but significantly less effective if the treatment began 9 days after challenge. Immunotherapy of pre-existing tumors showed all the hallmarks of specificity of gp96 and dose-restriction observed previously with prophylactic studies. When mice with large primary Meth A tumors were treated with surgery alone, or with surgery followed by therapy with Meth A-derived gp96, the mice that received surgery and immunotherapy did significantly better than those receiving surgery alone. The relationship between the time of initiation of immunotherapy with gp96 and its efficacy was also tested in a metastatic model of the Lewis lung carcinoma. In this model, immunotherapy with gp96 was very effective if treatment began up to 31 days after tumor challenge, but significantly less so if therapy was initiated day 33 post-tumor challenge. These observations suggest that the regulatory phenomena that interfere with immunotherapy gather momentum with surprising speed.

Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride.

Amiloride is an inhibitor of urokinase plasminogen activator (uPA), an essential component of the plasminogen/plasmin enzyme system. Inhibition of uPA prevents the conversion of plasminogen to tumor cell surface bound plasmin which is required for initiation of the metastatic process. MATB rat mammary cancer cells were introduced into the jugular venous system of 80 Fisher 344 female rats. Amiloride at high and low dosages was administered in the drinking water at the time of, prior to or several days following the tumor cell inoculation and continued daily for 10 days post inoculation. Control rats were maintained on water alone. The middle lobe of the right lung was examined microscopically for numbers of metastases. Suppression of metastases was significant at high amiloride dosages in all groups, and at low dosage when administered prior to inoculation. We conclude that amiloride suppresses induced metastases of rat mammary cancer, the effect being dose- and time-dependent.

Carcinoma of the axillary breast.

A review of the world literature regarding carcinoma of ectopic breast tissue along with the addition of one case is reported. A total of 90 cases of carcinoma of ectopic breast tissue were found, 64 of which occurred in the axilla. The combined survival beyond the 4-year post-treatment period was 9.4%. No survival advantage was found for radical or modified radical mastectomy over that of local excision combined with axillary dissection or radiation. The addition of radiation therapy to either type of mastectomy provided no additional benefit. The correct preoperative diagnosis was rarely made. Outcome was reported in 42 cases; 28 survived longer than 1 year, with 12 recurrences at the time of reporting, and 6 were alive with no evidence of disease at 4 years or longer. Improved prognosis requires diagnostic suspicion and early biopsy of unidentified lesions of the axilla or embryonic milk line.

Dose dependency and wound healing aspects of the use of tissue plasminogen activator in the prevention of intra-abdominal adhesions.

Intra-abdominal adhesions have been shown to result from the impairment of peritoneal fibrinolysis by inhibitors present in ischemic tissue. A reproducible model for the formation of intra-abdominal adhesions was utilized for the evaluation of the effectiveness of intraperitoneal applications of recombinant tissue plasminogen activator (rtPA) in adhesion prevention. Concentrations of rtPA required to overcome the inhibition of fibrinolysis in this model were estimated by titration of that amount of rtPA required to lyse blood clot in the presence of a measured amount of ischemic tissue. Adhesions were graded, and the hydroxyproline content of the abdominal wounds was analyzed. The effect of intraperitoneal administration of rtPA on adhesion formation was strongly dose related. Levels of rtPA of 0.01 mg/mL showed no effect (p < 0.75) on adhesion formation, whereas levels of 0.1 mg/mL either prevented or significantly modified the formation of intra-abdominal adhesions (p < 0.05). Concomitantly, wound hydroxyproline content was significantly reduced (p = 0.004). Prior investigations have shown a strong correlation between wound bursting strength and hydroxyproline content. The results of this study indicated that the levels of rtPA required to alter or prevent intra-abdominal adhesion formation also produce a significant impairment of the early phase of wound healing as measured by the wound content of hydroxyproline.

Initial experience with laparoscopic surgery: establishing a new surgical procedure.

Laparoscopic surgery impacted the surgical world in the United States in 1990. This report reviews the initial experience of 34 surgeons in 8 teaching hospitals of the Northeastern Ohio Universities College of Medicine. There were 538 cases reported from May 1, 1990 to January 31, 1991. There was no mortality and the morbidity rate was 4.8%, including three bile duct injuries. The conversion rate to an open procedure was 6.1%. The criteria for credentialing, training, and resident and faculty education are included. The data reported by the Surgery Department of Northeastern Ohio Universities College of Medicine are very similar to reported series from the current literature.

Myocardial infarct size reduction by the synergistic effect of hyperbaric oxygen and recombinant tissue plasminogen activator.

Fasting mongrel dogs underwent hyperbaric oxygen treatment (HBOT), recombinant tissue plasminogen activator (rt-PA) treatment, and simultaneous HBOT and rt-PA treatment following prior experimental left anterior descending coronary artery occlusion for 2 hours. Thrombosis in and around a copper coil was recorded angiographically at regular intervals, and immediately prior to treatment conclusion. Controls (n = 10) were untreated. Group two animals (n = 10) were treated additionally with 90 minutes of HBOT at 2 atm absolute. Group three animals (n = 8) were treated additionally with 50 mg rt-PA over 90 minutes. Group four animals (n = 10) were treated additionally with simultaneous HBOT and rt-PA over 90 minutes. Myocardial injury was determined by a combination of triphenyltetrazolium chloride histochemical staining and by formazan dye extraction. Damage was measured as a percent of left ventricular cross-sectional area studied. HBOT alone restored 35.9% of oxidative enzyme activity (p greater than 0.001). Treatment with rt-PA alone restored 48.9% of enzyme activity (p greater than 0.001). The combination of HBOT and simultaneous rt-PA resulted in 96.9% restoration of oxidative enzyme activity versus the control group (p greater than 0.001).

A reappraisal of appendicitis in the elderly.

Historically, appendicitis in the elderly is associated with higher morbidity and mortality. Ninety-six patients over 60 years of age with appendicitis treated over a 10-year period were reviewed. Only 20% presented classically with anorexia, fever, right lower quadrant pain, and an elevated white blood cell count. One third of the patients had greater than 48 hours delay to admission. Objective diagnostic testing was often confusing and unreliable. At the time of admission, only 51% were diagnosed as having possible appendicitis. Eighty-three percent of our patients underwent surgery within 24 hours, and 72% had frank perforation. Thirty-two percent of those surviving developed complications, and 83% of these patients had perforated appendicitis. Complications were twice as likely in patients with perforation. Despite the relatively high morbidity, there were only four deaths in patients with coexistent carcinoma. Because of the later and atypical presentation of appendicitis in this age group, a high index of suspicion and early operation are important in avoiding perforation and subsequent morbidity.

The utility of intraoperative cholangiography with acute cholecystitis.

An increasingly important subset of patients with biliary tract disease are those with acute cholecystitis. The indications for both routine or selective intraoperative cholangiography (IOC) during elective cholecystectomy may not be appropriate for this group. The utility of IOC in the presence of acute cholecystitis was examined. The medical records of 223 patients with histologically confirmed acute cholecystitis were reviewed. Clinical and laboratory criteria included age, sex, white blood cell count (WBC), serum bilirubin and alkaline phosphatase levels. In 52 (23%) patients, IOC was not attempted and was technically unsuccessful in 15 (7%) patients. IOC was successful in 156 (70%) patients and, of these, six (4%) had a false-positive examination. The remainder are divided into two groups. Group 1 (131 patients) had true-negative IOC, whereas Group 2 (19 patients) had true-positive IOC as evidenced by stone recovery upon surgical exploration. When comparing Group 2 with Group 1, the mean preoperative laboratory values are higher; these differences do not reach statistical significance. Further, within Group 2, five (26%) patients did not demonstrate any clinical or laboratory elevations suggestive of common duct pathology. Thus, in acute cholecystitis, laboratory criteria do not appear to discriminate between the presence or absence of choledocholithiasis. IOC is advocated as an integral component of the operative procedure.

Elevated levels of 6-keto-prostaglandin-F1a from a lower extremity during external pneumatic compression.

The synthesis of either fibrinolytic serine proteases or platelet inhibitory ecosonoids by the intact endothelial cell may limit thrombus development. In a preliminary study from this laboratory, an elevation in the level of 6-Keto-prostaglandin-F1å, the stable metabolite of prostacyclin (PGI2) was demonstrated in femoral vein plasma obtained during surgical treatment from an extremity undergoing external pneumatic compression. Simultaneously, no elevations in thromboxane B2, the stable metabolite of thromboxane A2, were observed. The present study is an inclusive prospective series of 26 patients. A single pneumatic compression stocking was applied to the left limb in patients who underwent an operation under general anesthesia. Base line venous samples (3 milliliters) were obtained from the femoral vein on the experimental side and the control contralateral side, as well as from the upper limb. Additional samples were drawn at 30 and 60 minutes after the onset of compression. Nine samples per patient (234 total) were analyzed for 6-Keto-prostaglandin-F1å by competitive binding radioimmunoassay in duplicate in a single blind manner. Base line values for the upper limb, right leg and left leg were 0.08 + 0.01 nanogram per milliliter; 0.14 + 0.03 nanogram per milliliter, and 0.13 + 0.02 nanogram per milliliter, respectively (no statistical difference). By 60 minutes of compression, control samples increased to 0.40 + 0.07 nanogram per milliliter (right leg) and 0.42 + 0.08 nanogram per milliliter (upper limb) while the experimental leg increased to 0.71 + 0.13 nanogram per milliliter (p less than 0.05 versus right leg, p less than 0.005 versus upper limb). There was no statistical difference at 60 minutes between the men and women.

Mesenteric artery embolization by an unsuspected aortic tumor: diagnostic evaluation and operative management.

Malignant tumor embolus recovered at the time of superior mesenteric artery embolectomy is an uncommon experience. A report of such a case is presented and the literature is reviewed. In this clinical setting, guidelines for further diagnostic evaluation are not well defined. We suggest an algorithm for the evaluation and management of these patients. In the near future, use of intraoperative angioscopy and the intravascular laser to eradicate the tumor may represent the optimal method of treatment.

Endogenous plasminogen activator and venous flow: therapeutic implications.

This study is concerned with the changes in endogenous plasminogen activator (PA), in response to the augmentation of venous blood flow by external pneumatic compression (EPC). EPC was applied to the left leg in ten patients undergoing surgery under general anesthesia. Two-ml samples of venous blood were obtained from the left and right femoral veins and an arm vein at baseline (induction), and then at 30 and 60 min of compression. Ninety samples were analyzed in duplicate in a single blind technique, using an assay specific for PA activity. In the control right arm and leg, PA activity levels increased at 30 min (106% and 110% of baseline, respectively), and then declined to baseline levels by 60 min. These changes did not reach statistical significance. In the leg undergoing compression, however, PA activity decreased progressively, reaching 75% of baseline at 60 min (significant at both 30 [p less than .001] and 60 min [p less than .01] as compared to baseline). In vitro, PA activity varies directly with the concentration of fibrin. The progressive decline in activity in this study may, therefore, represent a decline in substrate (molecular fibrin), as a result of increased venous blood flow. Alterations in the activity of the endothelial cell, as observed, may lead to new approaches in the prophylaxis against thromboembolism.

Stercoral perforation of the colon. Concepts of operative management.

Stercoral perforation of the colon is a direct result of ischemic pressure necrosis by a stercoraceous mass. In over 90 per cent of cases, the perforation will involve either the sigmoid or rectosigmoid colon and is consistently centrally located within a region of mucosal ulceration of varying diameter and magnitude. A review of 33 surgically treated cases from the literature along with four cases presented here, support resection, end colostomy, and either mucous fistula or Hartmann's procedure as the operation of choice with the lowest operative mortality (23%) when compared to those patients treated by either loop colostomy or exteriorization (71%) or proximal colostomy with plication of the perforation (44%). Irrigation of the distal rectal segment as that for penetrating rectal injury is also recommended.

Intestinal polyposis and periampullary carcinoma--changing concepts.

Adenomatous polyps lead directly to carcinoma of the colon in patients with one of the familial syndromes of intestinal polyposis. Elective colectomy is prophylactic and life-saving. A subgroup of patients will develop periampullary carcinoma, again arising from the presence of adenomatous polyps. Such a case is presented. These polyps should be surgically excised to ensure adequate pathologic examination. Yearly upper endoscopic examination is an essential element of management. Either the presence of carcinoma in situ or the recurrence of these polyps following excision is confirmation of behavior with a high propensity for the development of invasive cancer and requires aggressive treatment.