Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.

BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Gene therapy for non-small cell lung cancer: a preliminary report of a phase I trial of adenoviral p53 gene replacement.

The identification of genetic lesions that lead a normal cell to become malignant presents us with the opportunity of targeting those lesions as a means of therapy. Given the key role played by the tumor suppressor gene p53 in cell cycle regulation and apoptosis, and the evidence linking p53 mutations with non-small cell lung cancer, attempts at p53 replacement are a logical approach to therapy in this disease. In a phase I study, administration of an adenoviral p53 vector (Adp53) to 21 patients with advanced non-small cell lung cancer produced little toxicity. Up to six intratumoral injections at monthly intervals were well-tolerated. Expression of the p53 transgene was evident, along with potentially useful clinical responses. Time to disease progression in the indicator lesion treated with Adp53 appears to be enhanced by higher doses of vector, concomitant cisplatin therapy, and evidence of apoptosis on tumor biopsy specimens. Phase II trials should now be undertaken to determine the response rate to Adp53.

Glucagonoma syndrome. Rapid response following arterial embolization of glucagonoma metastatic to the liver.

Transcatheter arterial embolization was used to treat a patient with glucagonoma metastatic to the liver after chemotherapy failed. Rapid amelioration of the syndrome's manifestations followed.

The risk of infection associated with intra-arterial catheters for cancer chemotherapy.

OBJECTIVE: To determine the frequency of, and risk factors for, infections associated with intra-arterial catheters used for cancer chemotherapy. METHODS: Between September 1992 and September 1995, we conducted a surveillance study of all 807 intra-arterial catheters placed for chemotherapy at our center. The insertion site was disinfected with povidone iodine and alcohol, and the arterial catheter was placed using maximal sterile barrier precautions. Upon removal, all intravascular segments were submitted for semi-quantitative culture. RESULTS: No episodes of catheter-related bloodstream infection (95% confidence interval [CI95], 0%-1.6%) were observed. However, the risk of colonization (>15 colony-forming units) of arterial catheters was 15% (CI95, 12%-17%). Retrospective risk-factor analysis conducted on 224 intra-arterial catheters placed for chemotherapy in 1993 showed that colonization was associated significantly with duration of catheterization (median of 1 day for culture-negative catheters vs median of 4 days for culture-positive catheters, P<.001). Age, gender, prior radiotherapy, underlying cancer, neutropenia, and hypoalbuminemia were not associated with catheter colonization. CONCLUSION: Intra-arterial catheters for cancer chemotherapy placed under maximal sterile barrier precautions for a short period of time are associated with a very low risk of bloodstream infection.

Reduction of systemic drug exposure after hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration.

BACKGROUND: Hepatic arterial infusion of doxorubicin has produced tumor response in hepatic malignancies; however, the limited success of these treatments is related in part to dose-limiting systemic toxicities. The purpose of this study was to determine whether a novel venous isolation-chemofiltration system could limit systemic exposure to doxorubicin after hepatic arterial infusion. METHODS: Doxorubicin (1 or 3 mg/kg) was infused in the hepatic arteries of domestic pigs after complete hepatic venous isolation was achieved with a dual-balloon vena cava catheter. The hepatic vein effluent was pumped through an extracorporeal carbon chemofiltration circuit. Doxorubicin levels were measured in prefilter (hepatic vein), postfilter, and systemic serum at intervals up to 1 hour after drug infusion. RESULTS: Complete hepatic venous isolation with extracorporeal chemofiltration significantly reduced (> 90%) the postfilter and systemic levels of doxorubicin compared with prefilter levels (p < 0.01). At the time animals were killed 7 days after infusion of doxorubicin (3 mg/kg), tissue levels of doxorubicin in the liver showed a 16-fold increase compared with levels in the heart (p < 0.01). CONCLUSIONS: For chemotherapeutic drugs like doxorubicin with a low first-pass extraction by the liver, the novel system described herein achieved significant reduction in systemic drug exposure. This system will allow dose intensification of doxorubicin administered by hepatic arterial infusion to treat hepatic malignancies.

Palliation of small bowel obstruction by percutaneous gastrostomy in patients with progressive ovarian carcinoma.

Percutaneous gastrostomy is a useful palliative technique for treatment of patients with bowel obstructions in advanced ovarian carcinoma. A description of the technique is presented along with a review of ten cases in which the procedure was used at The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston. In all patients, the procedure was well tolerated and associated with little morbidity. In applicable cases, percutaneous gastrostomy appears to be superior to both nasogastric suction and operative gastrostomy for palliation of small bowel obstruction in terminal ovarian cancer.

Management of tracheal and bronchial stenoses with the Gianturco stent.

Thirty-six cancer patients with symptomatic tracheobronchial stenoses received Gianturco tracheobronchial stents over a 9-year period. Symptoms improved in 28 patients (78%). The overall median survival was 1 month 3 weeks (range, 4 days to 35 months). The median survival for patients who showed improvement after receiving stents was 3 months compared with 1 week for those who did not respond. Complications were minimal. The Gianturco stent may palliate symptoms of tracheobronchial compression in selected cancer patients.

Percutaneous urinary diversion in patients with hormone-refractory prostate cancer.

Twenty-two patients with hormone-refractory prostate cancer underwent percutaneous urinary diversion; at the time, all but one had metastatic disease. Eleven patients received postnephrostomy therapy. The median survival time for all the patients was one hundred nineteen days. Overall, 41 percent of the patients' remaining lifetime was spent in the hospital. Six never left the hospital and 10 required rehospitalization; the remaining 6 patients were never rehospitalized. The median survival time for this group of patients was shorter than the expected survival of similar patients without ureteral obstruction. It appears that percutaneous urinary diversion does not improve the quality of life of these patients.

Angiography of osteosarcoma.

During the last two decades, the excellent sectional imaging provided by computed tomography and magnetic resonance has determined that conventional angiography no longer be routinely performed in the diagnosis of sarcomas. Conventional angiography, however, is a helpful adjunct to the biopsy of parosteal osteosarcoma when chemotherapy is administered intraarterially.

Hepatic arterial infusion of verapamil and doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration: pharmacological evaluation of reduction in systemic drug exposure and assessment of hepatic toxicity.

Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.

Fine needle aspiration biopsy in lymphoma.

Patients with lymphoma undergo excisional biopsy of an affected lymph node for initial classification of their disease because accurate classification depends on the histologic characteristics of the neoplasm. However, fine needle aspiration cytology has a role in the management of lymphoma patients, particularly in those with recurrent or residual masses following treatment. Moreover, immunologic markers, nucleic acid flow cytometry, cytogenetics, and molecular genetics, which do not depend on histologic characteristics and can be performed on fine needle aspirates, are acquiring more importance in the management of patients with these diseases, particularly in those with non-Hodgkin's lymphoma. These latter tests add objectivity to the cytologic diagnosis of the B-cell lymphomas and increase its accuracy. In most series, the accuracy of fine needle aspiration in patients with lymphoma approaches 90%, with minimal complication rates.

Pilot study of intra-arterial cisplatin and intravenous vinblastine and dacarbazine in patients with melanoma in-transit metastases.

For melanoma, in-transit metastases (ITMs) are a harbinger of systemic disease in over 70% of patients and thus warrant a systemic approach to management. In this study, previously untreated patients with ITMs (n=15) received a systemic regimen of 'CVD' in 21 day cycles (median, three cycles) as follows: dacarbazine 800 mg/m2 intravenously (i.v.) on day 1, vinblastine 1.6 mg/m2 i.v. on days 1-5, and cisplatin (CDDP) 100 mg/m2 by 24 h intra-arterial (i.a.) infusion in 1l of heparinized saline via the iliac or subclavian artery on day 3. There were three clinical complete responses (CRs) in patients with a modest burden of ITMs (< 3 cm in size) and seven partial responses (PRs), yielding a 67% response rate (95% confidence interval, 38-88%). One of the clinical CRs had microscopic residual disease at surgery (a pathological PR). The times to progression (TTP) for the CRs were 5, 21 and 38+ months; the median TTP for the PRs was 4.5 months (range, 2-10 months). Overall median survival was 31 months. Systemic toxicities were similar to those induced by i.v. CVD. However, patients noted more pronounced paraesthesia in the infused extremity. Also, two patients experienced severe CDDP-induced burns, one patient developed brachial plexopathy, and one patient had a haemorrhage in an occult brain metastasis. The high clinical activity of this regimen will have to be confirmed in more patients before a first-pass i.a. advantage can be claimed. Furthermore, the dose, schedule and technique of i.a. CDDP delivery must be further refined before it can be routinely incorporated in regimens as an alternative to isolated regional hyperthermic perfusion, which is technically more difficult and is not readily available in community-based hospitals.

Percutaneous techniques for the diagnosis and treatment of localized Langerhans-cell histiocytosis (eosinophilic granuloma of bone).

We retrospectively studied the outcome of percutaneous needle biopsy and intralesional injection of a corticosteroid (methylprednisolone) in thirty-nine patients who had localized Langerhans-cell histiocytosis (eosinophilic granuloma of bone). All thirty-nine patients had a solitary symptomatic lesion at presentation; a second lesion developed in two patients, two and four months after the first lesion was diagnosed. Therefore, there were forty-one lesions in thirty-nine patients. Fine-needle aspiration with or without core-needle biopsy was performed for all forty-one lesions, and the diagnosis of Langerhans-cell histiocytosis was established for thirty-seven (90 per cent). A corticosteroid was injected into thirty-five lesions. Twenty-nine received the injection at the time of the fine-needle aspiration on the basis of the cytological findings in the aspirate. Six patients who had a solitary lesion had a two-stage procedure because the injection was delayed until the diagnosis was confirmed with histological evaluation of specimens obtained by core-needle biopsy. Thirty-four (97 per cent) of the thirty-five lesions healed. The clinical symptoms associated with thirty-one lesions resolved within two weeks after a single injection of the corticosteroid. There were no complications associated with either the biopsy or the injection. At a median of ninety months (range, twenty-four to 199 months), no patient had recurrence of symptoms or of radiographic evidence of the lesion. All patients who had been managed with an intralesional injection of the corticosteroid had full range of motion of the affected extremity and had resumed unlimited activities. Although the mechanism of action of intralesional injection of a corticosteroid has not been defined, use of percutaneous needle biopsy to diagnose localized Langerhans-cell histiocytosis and treatment with intralesional administration of methylprednisolone relieved pain expeditiously, enabled the patient to avoid an operative procedure, and resulted in osseous healing. The specific role of corticosteroid therapy remains to be determined by prospective, randomized studies.

Percutaneous hepatic arterial infusion of cisplatin-vinblastine for refractory breast carcinoma metastatic to the liver.

We treated 34 patients with breast carcinoma metastatic to the liver and refractory to prior chemotherapy with sequential hepatic arterial infusion of cisplatin and vinblastine in an attempt to enhance their antitumor activity. Following the administration of cisplatin at 100 mg/m2 i.v., the patients received a continuous arterial infusion of vinblastine at 1.7 mg/m2 daily for 5 consecutive days. Of 33 patients evaluable for response, eleven (33%) achieved partial responses and eight (24%) had minor responses. Median time to progression for responding patients was 31 weeks (range, 6+ to 74), and median survival was 11 months (range, 5-19). The adverse effects of the regimen were considerable, and seven failures were related to treatment intolerance or major toxicity. One patient who received vinblastine 2.0 mg/m2 daily developed a transient inappropriate secretion of antidiuretic hormone. Percutaneous hepatic arterial infusion of cisplatin and vinblastine has significant activity in the treatment of breast cancer metastatic to the liver, but subjective and objective treatment intolerance hamper the therapeutic value.

Durable clinical and pathologic response of hepatocellular carcinoma to systemic and hepatic arterial administration of platinol, recombinant interferon alpha 2B, doxorubicin, and 5-fluorouracil: a communication.

The case described here illustrates the antitumor activity of a four-drug systemic combination chemobiotherapy with platinol, recombinant interferon alpha 2b, doxorubicin (Adriamycin), and 5-fluorouracil (5-FU) (PIAF) in a patient with diffuse hepatocellular carcinoma involving the liver and lungs.

Osteosarcoma chemotherapy effect: a prognostic factor.

Chemotherapy has become a routine part of the treatment of osteosarcoma. However, the precise role of preoperative chemotherapy remains in question. Between 1979 and 1982, a group of 40 patients were treated by multimodality therapy consisting of preoperative chemotherapy (intra-arterial cis-platinum and systemic adriamycin), surgery, and postoperative chemotherapy. Survival in this group is 64%, while continuous disease-free survival is 58%. Although age, sex, tumor size, site, and classification were found to be prognostic factors, histologic evidence of response to preoperative chemotherapy, measured as percent tumor necrosis, was found to be the most significant prognostic factor. When continuous disease-free survival was calculated as a function of tumor necrosis it was 91% in patients with greater than or equal to 90% tumor necrosis, while it was 14% in patients with less than 90% tumor necrosis. At initial presentation, 7% of patients were judged limb-salvage candidates. But due to the local effects of preoperative chemotherapy, 60% ultimately underwent limb-salvage surgery. Preoperative arteriograms were a reliable means of monitoring response to chemotherapy and served as an indicator of residual viable tumor. Using arteriogram directed planes of section, postchemotherapy, specimens were "mapped" and analyzed for chemotherapy effect. When present, residual viable tumor was preferentially found at the interface of tumor and normal anatomic structures; "sanctuary sites." It is necessary that standard methods for analyzing postchemotherapy specimens be developed; a technique is described.

Giant cell tumors.

This article presents an overview of the giant cell tumor, its treatment and results of treatment. Some topics included are biopsy, pathology, histology, technical considerations, and recurrence.

Giant cell tumor of bone. A cytologic study of 24 cases.

Twenty-three patients with radiologic diagnoses of giant cell tumor of bone underwent fine needle aspiration cytology and needle biopsy for tissue diagnosis before curettage or resection. One patient had two tumors, making a total of 24 cases. The accuracy of the cytologic diagnosis was compared with that of tissue biopsy. Cytologically there were mononucleated and multinucleated cells. The former often occurred in clusters or, less often, were dispersed. They had spindle or plump cell bodies with moderate amounts of cytoplasm and well-defined cytoplasmic membranes. The oval nuclei demonstrated fine, evenly distributed chromatin and small nucleoli. The multinucleated cells were osteoclastlike and were associated with the clusters of mononucleated cells or lying freely. They had a well-demarcated cytoplasm and contained from a few to several dozen monomorphic nuclei. Cytologic diagnosis was made in 20 of 24 cases, and histologic diagnosis was made in 21 of 24. Insufficient diagnostic material for cytology was the reason for failure in 4 cases. This was attributed to faulty technique (2 cases), cystic change (1 case), and massive necrosis (1 case). As other benign and malignant bone tumors may contain benign giant cells, cytologic or histologic findings alone are not diagnostic of giant cell tumor of bone, but should be complemented with the clinicoradiologic findings. Aspiration cytology is as accurate as tissue needle biopsy, may be of high diagnostic value in deeply located lesions not amenable to cutting needle biopsy, and should be done with full knowledge of the clinicoradiographic information.

Diagnosis of eosinophilic granuloma of bone by fine-needle aspiration with concurrent institution of therapy: a cytologic, histologic, clinical, and radiologic study of 27 cases.

Twenty-seven patients with eosinophilic granuloma (EG) of bone seen at our institution between 1979 and 1991 underwent fine-needle aspiration (FNA) with or without concurrent Tru-Cut biopsy. The 16 males and 11 females ranged in age from 2 1/2 to 61 years (median, 10 yr). Twenty-four patients had monostotic lesions. The clinicoradiologic differential diagnosis included osteomyelitis and Ewing's sarcoma (young patients) and primary and metastatic malignancies (older patients). Twenty-four of 28 FNAs (one patient had two FNAs) were diagnostic of EG, and 10 cases were diagnosed by FNA alone. Smears in these cases showed histiocytes, often with grooved or infolded nuclei, and abundant eosinophils. Multinucleated giant cells, foamy histiocytes, neutrophils, lymphocytes, and plasma cells were present in variable numbers. Four FNAs were misdiagnosed: two as osteomyelitis where smears contained abundant neutrophils, sparse eosinophils, and histiocytes misinterpreted as foamy histiocytes, and two as metastatic carcinoma (in adults) where histiocytes in a scant specimen (one case) and skin appendiceal structures without lesional tissue (one case) were misinterpreted. These cases were correctly diagnosed on repeat FNA (one case), Tru-Cut (two cases), or excisional biopsy (one case); however, three cases diagnosed by FNA had nondiagnostic concurrent Tru-Cut biopsies. Treatment consisted of intralesional injection of 125 mg of methylprednisolone (22 cases). Progressive or complete healing of all lesions occurred. FNA is a rapid and useful technique for the immediate diagnosis of EG that allows concurrent institution of therapy.