David D. Lawrence

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 β–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 Sequence With Cisplatin to Tumors of Patients With Non–Small-Cell Lung Cancer

PURPOSE To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Selective Hepatic Arterial Chemoembolization for Liver Metastases in Patients with Carcinoid Tumor or Islet Cell Carcinoma

In many patients with liver metastases from islet cell or carcinoid tumor, vascular occlusion therapy results in prolonged control of symptoms, biochemical response, and also tumor regression. Chemotherapy agents were added to evaluate safety and efficacy. Thirty patients with liver metastases from either carcinoid tumor or islet cell carcinoma underwent sequential vascular occlusion therapy combined with chemotherapeutic agents. In patients with carcinoid tumor, a combination of cisplatin (150 mg) and doxorubicin (50 mg) was used. In patients with islet cell carcinoma, a combination of 5-fluorouracil (350 mg) and streptozotocin (1000-2000 mg) was used. Sixteen patients had carcinoid tumor and 14 had islet cell carcinoma. Biochemical response was observed in 12 of 16 (75%) carcinoid patients and 9 of 10 (90%) islet cell patients. The overall partial response rate was 37% (11/30 patients). Partial response occurred in 4 of 16 (25%) patients with carcinoid tumor and 7 of 14 (50%) with islet cell carcinoma. The median duration of partial responses was 24 months (range, 6-63+ months). The median survival of all patients was 15 months (range, 2-67+ months). No treatment-related deaths occurred. Our data suggest that the addition of these chemotherapeutic agents to vascular occlusion, although safe, has no additional benefit.

Preoperative embolization of bone metastases from renal cell carcinoma.

Abstract. The purpose of this study was to correlate the effectiveness of preoperative embolization with the blood loss and transfusion requirement during surgery for bone metastases from renal cell carcinoma. Twenty-eight preoperative embolizations in 26 patients with renal cell carcinoma metastatic to bone were retrospectively evaluated and divided into two groups: Group A included the embolizations that resulted in complete devascularization of the lesion as defined by the post-embolization arteriograms, and group B included those with an incomplete result. The two groups were compared with regard to blood loss and transfusion requirement during surgery, by unpaired two-tailed Students t-test. Where complete embolization was effected (group A, 10 cases), there was a mean blood loss of 535 ± 390 ml. When a less than complete embolization was achieved (group B, 18 cases), the mean blood loss was 1.247 ± 1.047 ml (p = 0.049). The red blood cell transfusion in group A was 1.3 ± 1 units, whereas in group B it was 2.4 ± 1.2 (p = 0.03). Preoperative embolization of bone metastases from renal cell carcinoma with subsequent complete devascularization leads to significant reduction of blood loss during surgery. Interventional radiologists should pursue and embolize every feeder to the metastasis, because any less than complete devascularization increases the amount of blood loss and the amount of red blood cell transfusion during surgery.

Therapy of Locally Recurrent Renal Cell Carcinoma After Nephrectomy

PURPOSE We evaluated the outcome of patients with locally recurrent renal cell carcinoma treated at our university. MATERIALS AND METHODS We retrospectively analyzed 16 cases of locally recurrent renal cell carcinoma in the renal fossa treated with surgical resection alone or in combination with biological therapy. RESULTS Complete resection was possible in 15 patients of whom 3 had positive surgical margins. Of the 12 patients with negative margins 6 are free of disease while the 3 with positive margins had involvement of a remaining ipsilateral adrenal gland and distant metastasis. Of all 16 patients 12 are alive a median of 23.5 months after the diagnosis of locally recurrent renal cell carcinoma. Of those treated with the combination of biological therapy and surgery 50% have no evidence of disease compared to 25% of those treated with surgery alone. CONCLUSIONS Long-term survival can be achieved with an aggressive surgical approach. Incomplete resection or positive surgical margins are associated with a high risk of local or distant failure, and combined treatment with immunotherapy and surgery may offer a benefit compared to surgery alone.

Cellular and humoral immune responses to adenovirus and p53 protein antigens in patients following intratumoral injection of an adenovirus vector expressing wild-type p53 (Ad-p53)

The immune responses of 10 patients with advanced non-small cell lung cancer receiving monthly intratumoral injections of a recombinant adenovirus containing human wild-type p53 (Ad-p53) to adenovirus and transgene antigens were studied. The predominate cellular and humoral immune responses as measured by lymphocyte proliferation and neutralizing antibody (Ab) formation were to adenovirus serotype 5 vector antigens, with increased responses in posttreatment samples. Consistent alterations in posttreatment cellular and humoral immune responses to p53 epitopes were not observed, and cytotoxic Abs to human lung cancer cells were not generated. Patients in this study had evidence of an antitumoral effect of this treatment with prolonged tumor stability or regression; however, neither Abs to p53 protein nor increased lymphocyte proliferative responses to wild-type or mutant p53 peptides have been consistently detected.

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 lymph node biopsy

Advances in imaging modalities for detecting lymphadenopathy, the ease, safety, and accuracy of the tools and techniques, and the addition of refined ancillary studies for cytologic analysis will continue to increase the acceptance and use of percutaneous lymph node biopsy (PLNB) by fine-needle aspiration (FNA), especially in lymphomas.

Intraperitoneal catheters: percutaneous placement with fluoroscopic guidance.

PURPOSE The authors reviewed their experience with percutaneous placement of catheters into the peritoneal cavity for the administration of intraperitoneal chemotherapy to determine if their approach resulted in a lower complication rate than the reported 12%-16% rate and to demonstrate the technical advantages over surgically placed catheters. PATIENTS AND METHODS Seventy-six patients with gastrointestinal or gynecologic malignancies underwent 152 procedures during a 20-month period. The catheters were used to deliver antineoplastic agents and, in some patients, to drain ascites. Catheter insertion was performed with local anesthesia and a modified Seldinger technique. A 5-F catheter was used in 89% of procedures; in the remainder, the catheter was of a larger caliber. RESULTS The procedure was successful in 145 (95%) instances and failed in seven (5%) attempts because of peritoneal adhesions. The catheters remained in place for less than 2 days in 56%, 2-10 days in 25%, and more than 10 days in 19% of patients. One catheter remained in place for 15 weeks. Complications occurred in seven procedures (5%). Four cases of mild peritonitis responded to a brief course of intravenously administered antibiotics, and severe pain in two patients required premature catheter removal. A single case of inadvertent transcolonic catheter placement occurred without adverse sequelae to the patient. CONCLUSIONS Intraperitoneal catheterization can be performed with local anesthesia by using a simple technique with a very low complication rate. The catheters can remain in place for prolonged periods without significant risks.

A large lumen microcatheter for oncologic intervention

A newly available Tracker-325 catheter (Target Therapeutics, Fremont, CA, USA), modified from the Tracker-18 catheter, has the same outer diameter but a larger lumen. This catheter was used in 15 patients during a 7-month period for superselective arterial catheterization when conventional catheters could not be placed successfully. Arterial embolization (n = 7), chemoembolization (n = 5), and chemoinfusion (n = 3), were performed. The increased luminal diameter of the Tracker-325 allowed an increased flow rate for diagnostic arteriography, accommodated larger embolic particles, and improved the ability to achieve a superselective position.