Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors.

PURPOSE: The purpose of our study was to develop an injectable polymeric system for the long-term localized delivery of bioactive interleukin-2 for antitumor immunotherapy. METHODS: IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure the bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were carried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor challenge were rechallenged with tumor in the opposite lobe of the brain to confirm that antitumor immunologic memory had developed. RESULTS: Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL-2 microspheres injected intratumorally were statistically more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Immunologic memory was induced following IL-2 microsphere therapy in the B16-F10 brain tumor model that was capable of protecting 42% of animals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. CONCLUSIONS: Local IL-2 therapy using novel polymeric carriers. aimed at stimulating long-lasting antitumor immunity, may provide an improved method of treating a variety of cancers.

Antigen-specific immunotherapy for human papillomavirus 16 E7-expressing tumors grown in the liver.

BACKGROUND/AIMS: We have previously reported a recombinant vaccinia-based vaccine (vac-Sig/E7/LAMP-1) that demonstrated a significant anti-tumor effect in a subcutaneous tumor challenge model. Since the liver is one of the most common sites for tumor metastasis and organ microenvironments may modulate tumor cell responses to therapies, the aim of the present study was to evaluate the potency of vac-Sig/E7/LAMP-1 in treating E7-expressing tumors grown in the liver. METHODS: For in vivo tumor prevention experiments, mice were vaccinated intraperitoneally with vac-Sig/E7/LAMP-1 followed by intrahepatic tumor challenge. For in vivo tumor regression experiments, mice were first challenged with tumor cells and then vaccinated with vac-Sig/E7/LAMP-1 intraperitoneally. In addition, enzyme-linked immunospot assays were used to determine the frequency of E7-specific T cell precursors. RESULTS: For in vivo tumor protection experiments, tumor growth was observed in all of the mice vaccinated with wild-type vaccinia and 60% of the mice vaccinated with wild-type E7 vaccinia. All of the mice vaccinated with vac-Sig/E7/LAMP-1 remained tumor-free 30 days after tumor challenge. For the tumor regression assays, all of the mice vaccinated with vac-Sig/E7/LAMP-1 remained tumor-free 30 days after vaccination. In contrast, all of those mice receiving culture medium, wild-type vaccinia, or wild-type E7 vaccinia developed tumors in the liver. In addition, mice vaccinated with vac-Sig/E7/LAMP-1 had the highest E7-specific CD8+ T cell precursors. CONCLUSIONS: Our data suggest that vac-Sig/E7/LAMP-1 is an effective vaccine for controlling E7-expressing tumors grown in the liver and our model suggests that antigen-specific immunotherapy may represent a powerful tool for treating liver tumors with characterized tumor-specific antigens. In addition, our data indicate that the number of E7-specific CD8+ T cell precursors directly correlated with the anti-tumor effect generated by Sig/E7/LAMP-1 vaccinia.

Treatment of liver metastases from colon carcinoma with autologous tumor vaccine expressing granulocyte-macrophage colony-stimulating factor.

BACKGROUND AND OBJECTIVES: In preclinical studies, tumor cells genetically altered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate systemic antitumor immunity. Clinically relevant immunotherapeutic approaches for the treatment of colorectal cancer should address efficacy within the liver, a common site of metastatic disease. We investigated the effect of irradiated colon cancer cells engineered to produce GM-CSF on protecting from and treating established liver metastases. METHODS: Using a model of liver metastasis by intrahepatic injection of CT-26 murine colon carcinoma cells in syngeneic BALB/c mice, GM-CSF-producing irradiated cells were given as an intradermal vaccine either 14 days prior to hepatic challenge or in animals with early established tumor (days 5 and 10). The presence of tumor, tumor volume, and survival were endpoint determinants. RESULTS: Animals receiving GM-CSF-producing vaccination demonstrated significant protection from subsequent hepatic challenge of viable tumor cells, even at the highest challenge doses. In animals with early established tumors, a significant response was seen with prolongation in survival. CONCLUSIONS: We conclude that GM-CSF autologous tumor vaccination was effective for the treatment of hepatic colorectal metastases in this murine model. These findings provide support for immunotherapeutic approaches for metastatic liver cancer.

Gene gun-mediated DNA vaccination induces antitumor immunity against human papillomavirus type 16 E7-expressing murine tumor metastases in the liver and lungs.

DNA vaccination has emerged as an attractive approach for tumor immunotherapy. The aim of this study was to evaluate the potency of DNA vaccines in preventing and treating the liver and lung metastases of a human papillomavirus-16 (HPV-16) E7-expressing murine tumor (TC-1). We used the gene gun method to vaccinate C57BL/6 mice intradermally with DNA vaccines containing the HPV-16 E7 gene, the E7 gene linked to the sorting signals of the lysosome-associated membrane protein-1 (Sig/E7/ LAMP-1), or the 'empty' plasmid vector. The in vivo antitumor immunity was analyzed in both tumor prevention and tumor regression experiments. In addition, cytotoxic T lymphocyte (CTL) assays, enzyme-linked immunospot assay and enzyme-linked immunoabsorbent assay were used to assess the E7-specific T cell-mediated and humoral immunity. Mice vaccinated with Sig/E7/LAMP-1 DNA generated the strongest E7-specific CTL activities, the highest numbers of E7-specific CD8+ cell precursors and the highest titers of E7-specific antibodies. While both E7 DNA and Sig/E7/LAMP-1 DNA generated potent antitumor immunity in the liver and lung metastases models, the Sig/E7/LAMP-1 DNA was more potent under stringent conditions. DNA vaccination with E7-expressing plasmids was effective in controlling liver and lung metastases of an E7-expressing murine tumor. Our data suggest that antigen-specific DNA vaccination can potentially be applied to control liver and lung metastases of tumors with defined tumor-specific antigens.

Diagnosis of cervical tuberculous lymphadenitis with fine needle aspiration biopsy and cytologic examination under ultrasonographic guides.

The efficacy of the fine needle aspiration biopsy and cytological examination (FNABC) under ultrasonographic (US) guides for the diagnosis of cervical tuberculous lymphadenitis was assessed. In one hundred and one patients with a neck mass or masses, tuberculous lymphadenitis has been proved by FNABC. US disclosed the physical characteristics of the masses: All the cases that involved two or more lymph nodes were multiple lesions. Eighty lesions (79.1%) were multiregional, and in 19 cases (18.8%), bilateral neck was involved. The posterior triangle of the neck was the most prevalent site (N = 69, 68.3%). Ninety two cases (90.9%) were hypoechoic lesions and 9 (9.1%) showed mixed echo patterns. There was no hyperechoic lesion (p < 0.001). The sensitivity of FNABC was 77.2% and the specificity was 99.0%. The diagnostic accuracy was 85.0%. There was no complication during the procedure. FNABC for the diagnosis of cervical tuberculous lymphadenitis is a safe, convenient procedure and has a relatively high specificity. The limitation of FNABC, the low sensitivity, seemed to be compensated by US examinations.

Roux-en-Y end-to-side esophagojejunostomy with stapler after total gastrectomy.

One hundred gastric cancer patients who underwent total gastrectomy and Roux-en-Y, end-to-side esophagojejunostomy by using stapling devices were analyzed with regard to their operative results. The median time required for the anastomosis was 18 minutes (range of 15 to 45 minutes). A cartridge of 25 mm in diameter was preferred (85% of 25 mm vs. 15% of 28 mm). In 92 patients, procedures were uneventful. Intraoperative problems happened in 8 patients: Two misfirings of stapler due to mechanical problems, in 6 patients, doughnut tissues were incomplete. Mechanical problems were solved by a change of the stapler and for incomplete doughnut tissues, anastomosis was simply reinforced (2 cases) or reanastomosed with restaplings (4 cases). Anastomotic leakage occurred in 2 patients but it was seen only in radiological studies. During the follow up period, two cases of anastomotic stricture were found and they were treated with endoscopic dilatations. There was no operative mortality nor other complication. In addition, routine use of the Levin tube after total gastrectomy was appraised by comparing postoperative courses. Twenty patients were randomly divided into two groups; for 10 patients the Levin tube was removed at the recovery room and for another 10 patients the Levin tube was indwelled until peristalsis returned. Timing of the tube removal did not affect the duration of the hospital stay and starting day of oral intake. We think that the stapler, when properly used, can facilitate the esophagojejunostomy safely and routine use of the Levin tube after total gastrectomy may be unnecessary.

Cartilage-shaving procedure for the control of tracheal cartilage invasion by thyroid carcinoma.

This study was carried out to ascertain whether the cartilage-shaving procedure is appropriate to control thyroid carcinoma with tracheal cartilage invasion. Of 432 thyroid carcinoma patients treated between 1979 and 1988, 16 had tracheal cartilage invasion only. This patient population was made up of 3 men and 13 women, with a mean age of 55.8 years. Fourteen were diagnosed histologically as having papillary carcinoma and the remaining two as having follicular carcinoma. Cartilage shaving was the primary treatment in all the patients, and subsequent radioactive iodine (131I) or external-beam radiotherapy was administered to control any possible residual disease. Lifelong thyroid hormone replacement was instituted in all patients, and the follow-up period averaged 70.7 months. Only four of the 16 patients remained disease free; the disease was not controlled in the other 12, and seven of this latter group eventually died of their disease. We feel that a more extensive resection procedure than cartilage shaving should be considered, even in patients with superficial tracheal invasion, to increase the disease-free survival rate.

Neurilemmomas of the cervical vagus nerve.

Four patients were seen with neurilemmoma which arose in the cervical vagus nerve. Three tumors arose in the upper third of the lateral neck, and the remaining one in the lower third. Lateral neck mass was a prominent symptom in 3 patients, and parapharyngeal mass in the remaining one. The parapharyngeal mass bulged into the oropharynx in the tonsillar and retrotonsillar region and caused mild swallowing difficulty. Complete surgical extirpation by means of intracapsular enucleation was possible in all 4 patients. All patients remained free of disease for periods ranging from 15 to 75 months following surgery. It would appear that an intracapsular enucleation may be advisable for clearance of this kind of tumor.

Surgically correctable causes of sleep apnea syndrome.

This report presents six cases of obstructive sleep apnea associated with discrete anatomic abnormalities of the upper airway tract. All patients were relieved of their sleep apnea by surgical correction of the airway obstruction, and therefore permanent tracheotomy was avoided. The obstructive causative factors were nasal septal deformity, adenoidal hypertrophy, nasopharyngeal stenosis, lingual cyst, lingual tonsillar hypertrophy, and laryngeal cyst. The last-named four conditions have not previously been reported as correctable causes of sleep apnea.

Symptoms, findings, and methods of diagnosis in patients with acoustic neuroma.

The records of 225 patients with surgically documented acoustic neuromas seen at the Mayo Clinic between 1966 and 1976 were studied. Included in this group were 4 patients who had von Recklinghausen's disease with bilateral ear involvement, 7 patients with recurrence of acoustic neuroma, and 8 patients who were referred because of recurrent acoustic neuroma. Symptoms, clinical findings, and results of audiologic, vestibular, and roentgenographic studies were analyzed. Nine patients had a history of sudden onset of hearing loss, and 11 had a history of vertigo. A correlation between the size of the lesion and the symptoms, physical findings, and roentgenographic accuracy was made in an attempt to gain further knowledge of the natural course of the pathologic processes involved.

Inverting papilloma of the nose and paranasal sinuses.

Inverting papilloma of the nose and paranasal sinuses has been classified as a true neoplasm by most authors. It is distinct from the ordinary nasal polyps in that it has a different cause, different histologic features, a higher recurrence rate, and is occasionally associated with carcinoma. This study includes 57 patients seen over a 30-year period who had inverting papilloma and for whom the history, clinical and radiologic findings, treatment methods, pathologic sections, and recurrences were analyzed. Features associated with higher recurrence rate were epithelial atypia and extent of lesions. Females showed higher recurrence rates than males. External approaches (lateral rhinotomy) reduced recurrence remarkably compared with transnasal removal (13 percent versus 45 percent). Four patients had associated carcinoma with inverting papilloma, and more extensive operations were perfomred in these cases; one patient died of the tumor. Radical aggressive treatment and careful follow-up are advocated because of the higher recurrence rate after inadequate removal and because of possible malignant transformation.