Mediation of immunity to tumor isografts in mice by heterologous ribonucleic acid.

The growth of tumor isografts in inbred mice is inhibited by intra-peritoneal injections of syngeneic spleen incubated, in vitro, with ribonucleic acid extracted from guinea pigs immunized with the same mouse tumor. This inhibition is partially tumor-specific. Treatment with ribonuclease abolishes the response.

Role of pulmonary vascular resistance measurements in preoperative evaluation of candidates for pulmonary resection.

Pulmonary function tests (PFT), arterial blood gases (ABG), lung scanning, and pulmonary artery balloon occlusion with measurement of pulmonary vascular resistance (PVR) have all been used for preoperative evaluation of pulmonary function. These tests, however, do not always accurately predict tolerance to lung resection. We have evaluated a new technique which promises to increase the accuracy of preoperative evaluation of pulmonary function. Utilizing a balloon flotation catheter, we measured PVR at varying cardiac outputs. Forty-five patients underwent this study without morbidity or mortality. Five of 30 patients who subsequently underwent pulmonary surgery died of respiratory failure. All of these deaths were from the high-risk group as determined by PVR. Only one of the five had been judged to be at high risk by PFT and ABG. This technique has the advantages of low morbidity and simplicity and should be especially helpful in the evaluation of those patients who have borderline pulmonary function as determined by the more standard tests.

Intralesional BCG immunotherapy of pulmonary tumors.

A new method of baccile Calmette Guérin (BCG) immunotherapy has been evaluated in 25 patients with lung cancer. This technique involves the direct intratumor injection of BCG in patients with pulmonary tumors. Four patients underwent transbronchoscopic injections of tumor, with significant resolution of tumor in three. Twenty-one patients underwent percutaneous injection with the aid of fluoroscopic imaging. Twenty of these 21 underwent pulmonary resection. Toxicity was limited to fever and malaise. The severity of this toxicity was closely related to the magnitude of reactivity to PPD. There were no intraoperative or postoperative complications occasioned by BCG injection. The histologic features were characterized by granulomatous inflammatory reactions in the tumors and the regional lymph nodes. These histologic findings are identical to those seen in animal tumor models in which potent systemic antitumor immunity is induced. BCG intratumor injection is technically feasible and safe, and it is appropriate to begin phase 2 and phase 3 clinical trials.

Resection and adjuvant immunotherapy for melanoma metastatic to the lung and thorax.

Although melanoma that metastasizes to distant sites is generally associated with a median survival of only 6 to 8 months, certain metastatic sites including the lung may carry a better prognosis than others. Surgical therapy for pulmonary metastases remains controversial because of the variable survival rates reported for previous small series. To determine the prognosis and optimal management of patients with melanoma with pulmonary metastases, we reviewed our 22-year melanoma database of over 6100 patients. Of 984 patients with metastatic melanoma involving the lung or thorax, 106 underwent resection by posterior lateral thoracotomy or median sternotomy. There were no operative deaths, and the median follow-up period for surgical patients was 55 months. The remaining 878 patients were treated without operation with immunotherapy, chemotherapy, radiation therapy, or a combination. In both treatment groups the male/female ratio was approximately 2:1. The primary lesion's Clark level of invasion and Breslow thickness and the patient's age at diagnosis of metastatic disease were not significantly different between the two groups. The 1-year, 3-year, and 5-year survival rates for surgical patients were 77%, 37%, and 27%, respectively, compared with 32%, 7%, and 3% for nonsurgical patients; these differences were highly significant (p = 0.0001). The highest 5-year survival rate (39%) occurred in those patients with a single metastatic lesion. Sixty-three percent of the surgical patients received some form of immunotherapy, compared with 34% of the nonsurgical patients. Multivariate analysis showed that resection and immunotherapy with a melanoma cell vaccine were both independent predictors of survival (p < 0.0001). These results indicate that the prognosis associated with metastatic melanoma may be less dismal than previously thought when distant metastases involve thoracic sites. We believe that surgical resection is the treatment of choice for patients with melanoma with pulmonary metastases; when combined with immunotherapy, this regimen offers the best chance for long-term survival.

The value of open lung biopsy in the immunosuppressed patient.

To evaluate the impact of the open lung biopsy on diagnosis and therapy in the immunosuppressed patient, 68 such patients managed at UCLA from 1975 to 1980 were reviewed. Most had hematologic malignancies, and all were severely immunosuppressed. The rates of surgical mortality (1 operative death) and morbidity were minimal. There were 10 diagnostic differences apparent when biopsy results were compared with autopsy findings in 28 autopsied patients. Therapy was initiated or modified in 19 patients on the basis of open lung biopsy. Forty-four patients lived 1 year or less, 14 for more than 1 year, and 10 were lost to follow-up. Of 42 patients with an untreatable disease on the basis of lung biopsy, 67% died and 33% lived to leave the hospital. Of 25 patients with a treatable disease, 56% died and 44% left the hospital. Of 28 autopsied patients, only 12 were receiving appropriate medication at time of death despite biopsy. The patient whose disease is generally characterized by brief survival like acute leukemia, and whose situation is most desperate, unfortunately benefits least from open lung biopsy. We conclude that this procedure has only a modest impact in the management of these critically ill patients and should be used conservatively.

Cryosurgical palliation of metastatic neuroendocrine tumors resistant to conventional therapy.

BACKGROUND: Hepatic cryosurgery is a well-recognized modality for hepatic colon metastases. We examined its potential use for refractory neuroendocrine tumors causing progressive symptoms. METHODS: Between July 1992 and February 1997, 19 patients (with islet cell, 7; carcinoid, 8; vasoactive intestinal peptide, 1; gastrinoma, 3) underwent cryosurgery with ultrasonography. The number of lesions frozen ranged from 1 to 16 (median, 8), and their diameters ranged from 2 to 15 cm with an average of 4 cm. Patients underwent resection of the primary tumor either before (37%) or concurrent with (32%) cryosurgery, and half underwent excision of metastases with cryosurgery. Before cryosurgery, patients received chemotherapy (63%), somatostatin (47%), interferon (10%), hepatic artery ligation (5%), radiation (10%), and/or omeprazole (16%). RESULTS: The reduction in tumor markers reached 90% (5-hydroxyindoleacetic acid), 80% (vasoactive intestinal peptide), 90% (gastrin), 90% (pancreatic polypeptide), and 80% (serotonin). At a median follow-up of 17 months, the metastases had progressed in 11 patients (two underwent a second cryosurgical procedure that eliminated symptoms) and five had died. Subsequently an additional five patients received chemotherapy and three somatostatin. Median symptom-free and overall survival were 10 months and more than 49 months, respectively. CONCLUSIONS: Cryosurgery dramatically relieved symptoms with significant reduction in tumor markers. The reduced tumor burden may explain the subsequent response to systemic therapy. Cryosurgery is a useful adjuvant in symptomatic patients with refractory hepatic neuroendocrine metastases.

Hepatic cytoreduction followed by a novel long-acting somatostatin analog: a paradigm for intractable neuroendocrine tumors metastatic to the liver.

BACKGROUND: Optimal management of symptomatic neuroendocrine tumors that metastasize to the liver is controversial. We investigated aggressive hepatic cytoreduction and postoperative administration of octreotide long-acting release (LAR), a long-acting somatostatin analog. METHODS: Between December 1992 and August 2000, 31 patients underwent hepatic surgical cytoreduction (20 carcinoid, 10 islet cell, and 1 medullary). All patients had progressive symptoms refractory to conventional therapy. RESULTS: Hepatic cytoreduction (resection, cryosurgery, and/or radiofrequency ablation) eliminated symptoms in 27 patients (87%) and decreased secretion of hormones by an overall mean of 59%. When minor symptoms returned and/or hormonal levels increased during follow-up, adjuvant therapy was started. Ten patients received adjuvant octreotide LAR once a month, and 21 received other adjuvants. At a median postoperative follow-up of 26 months, 16 patients had progressive/recurrent disease, 13 had died of their disease, and 2 remained free of disease. Median symptom-free interval was 60 months (95% confidence interval, 48-72) with octreotide LAR and 16 months (95% confidence interval, 10-29) with other adjuvants (P = .0007). Two-year symptom-free survival rate was 100% with octreotide LAR and 33% with other adjuvants. CONCLUSIONS: Hepatic surgical cytoreduction can palliate progressive symptoms associated with liver metastases from intractable neuroendocrine tumors. Postoperative adjuvant therapy with octreotide LAR can prolong symptom-free survival.

The use of the implantable chemoinfusion pump in the treatment of hepatic metastases of colorectal cancer.

Fifty-five chemoinfusion devices have been implanted in patients with metastasis of colorectal cancer confined to the liver. There were no episodes of pump malfunction or of catheter clotting. Side effects included gastric ulcers in 13 patients and duodenal ulcers in four patients, including one episode of total gastric obstruction. Chemical hepatitis occurred in 13 patients, sclerosing cholangiolitis in one patient, and duodenal dismotility requiring gastroenterostomy in one patient. The response criterion was taken as reduction by at least 50% of the pretreatment carcinoembryonic antigen level; consequently, the response rate was 88%. Median survival of all patients was 19.2 months from the time of diagnosis of hepatic metastases to death, as determined by the Kaplan-Meier method. Median survival from the time of pump implantation to death was 10.1 months.

Hepatic resection of metastatic colorectal carcinoma: a ten-year experience.

Nineteen patients have undergone partial hepatectomy for metastatic colorectal carcinoma at UCLA during the past ten years, including five trisegmentectomies (TS), eight lobectomies (L), and six segmentectomies (SG), with only one (5.3%) mortality. Twelve lesions were solitary (S) and seven multiple (M). Mean survival is 27.4 months, with three patients surviving over five years and one nearly eight years. Better mean survival exists for S (33.2 months) compared with M (15.8 months) lesions; for lesser resections: SG (44.7 months), compared with L (24.3 months) and TS (11.0 months); and for those with delayed appearance of hepatic metastases: beyond two years (40.5 months), less than one year (24.8 months), and synchronous (23.1 months). Survival figures should improve, as none of the 12 surviving patients have evidence of recurrent disease and many have short follow-up. This experience defends aggressive surgical treatment of resectable colorectal carcinoma metastatic to liver, because systemic therapy is markedly less effective.

Orthotopic liver transplantation for biliary atresia. Evolution of management.

Forty-five patients with biliary atresia were accepted for orthotopic liver transplantation. Nine patients died awaiting transplantation, and 36 underwent transplantation. A portoenterostomy had been performed in 28 of these 36 patients, and its presence did not significantly affect the intraoperative blood loss (5.6 vs 4.1 blood volumes), the need for retransplantation (21% vs 12%), biliary complications (21% vs 12%), postoperative infections (36% vs 25%), or survival (82% vs 63%). These results indicate that early portoenterostomy is appropriate early therapy for biliary atresia; however, prompt referral to a liver transplant center for evaluation at the first sign of cholestasis is needed to attain optimal results for transplantation. Revisions of the portoenterostomy prior to transplantation did not improve the longevity of the procedure but did substantially increase complications and death after orthotopic liver transplantation.

Variables influencing the outcome following orthotopic liver transplantation.

Seventy-two patients who underwent orthotopic liver transplantation (OLT) were studied to identify perioperative variables that would predict survival and intraoperative blood loss. Survival and intraoperative blood loss were not affected by encephalopathy, length of donor liver ischemia, or any of the preoperative laboratory values studied. Survival was significantly decreased in patients requiring postoperative dialysis (41%) and in patients who had severe rejection requiring retransplantation (33%). Intraoperative blood loss was significantly greater in patients over 50 years of age (11.6 blood volumes) and patients with biliary atresia (8.7 blood volumes). These results may aid in choosing future recipients for orthotopic liver transplantation and in anticipating the postoperative support needed.

Is liver transplantation justified for the treatment of hepatic malignancies?

Twenty-eight patients received orthotopic liver transplants for malignant disease between February 1, 1984, and December 31, 1989. Preoperative diagnoses included hepatocellular carcinoma (n = 16), cholangiocarcinoma (n = 3), other primary hepatic tumors (n = 6), and metastatic diseases to the liver (n = 3). Overall actuarial survivals at 6 months, 1 year, and 5 years were 67.3%, 51%, and 31%, respectively. Long-term survival longer than 5 years was achieved in 3 patients. The recurrence rate in patients surviving longer than 3 months is 48% (median, 7 months). Hepatocellular carcinoma and cholangiocarcinoma had the poorest survival and highest recurrence rates. Specific prognostic factors correlating with survival or recurrence could not be elucidated. These results indicate that orthotopic liver transplants can provide long-term cure and palliation for malignant disease; however, patient selection is extremely important in predicting outcome.

Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm.

BACKGROUND: Thermal ablation of unresectable hepatic tumors can be achieved by cryosurgical ablation (CSA) or radiofrequency ablation (RFA). The relative advantages and disadvantages of each technique have not yet been determined. HYPOTHESIS: Radiofrequency ablation of malignant hepatic neoplasms can be performed safely, but is currently limited by size. Cryosurgical ablation, while associated with higher morbidity, is more effective for larger unresectable hepatic malignant neoplasms. DESIGN: Retrospective analysis of prospective patient database. PATIENTS AND METHODS: Between July 1992 and September 1999, 308 patients with liver tumors not amenable to curative surgical resection were treated with CSA and/or RFA (percutaneous, laparoscopic, celiotomy). No patient had preoperative evidence of extrahepatic disease. All patients underwent laparoscopy with intraoperative ultrasound if technically possible. Both RFA and CSA were performed under ultrasound guidance. Resection, as an adjunctive procedure, was combined with ablation in certain patients. RESULTS: Laparoscopy identified extrahepatic disease in 12% of patients, and intraoperative hepatic ultrasound identified additional lesions in 33% of patients, despite extensive preoperative imaging. Radiofrequency ablation alone or combined with resection or CSA resulted in reduced blood loss (P<.05), thrombocytopenia (P<.05), and shorter hospital stay compared with CSA alone (P<.05). Median ablation times for lesions greater than 3 cm were 60 minutes with RFA and 15 minutes with CSA (P<.001). Local recurrence rates for lesions greater than 3 cm were also greater with RFA (38% vs 17%). CONCLUSIONS: Laparoscopy and intraoperative ultrasound are essential in staging patients with hepatic malignant neoplasms. Radiofrequency ablation when combined with CSA reduces the morbidity of multiple freezes. Although RFA is safer than CSA and can be performed via different approaches (percutaneously, laparoscopically, or at celiotomy), it is limited by tumor size (<3 cm). Percutaneous RFA should be considered in high-risk patients or those with small local recurrences.

Immunology and adjuvant chemoimmunotherapy of breast cancer.

Antibody against a breast carcinoma antigen was present in patients with breast carcinoma and other cancer more often (P less than .05) than in normal women. The incidence of antibody in women with breast carcinoma correlated with the presence or absence of gross tumor, and the titer of antibody paralleled the clinical course. These results suggest importance of a host-immune response to breast carcinoma. Fifty-seven patients with stage II carcinoma of the breast were entered into a prospective randomized adjuvant chemoimmunotherapy program of cyclophosphamide, methotrexate, and fluorouracil, and BCG vaccine +/- an irradiated allogeneic tumor cell vaccine. After 24 months of study, metastases occurred in two patients (3.5%) and a new primary carcinoma developed in the contralateral breast in two others, for an overall treatment failure rate of 7%. Adjuvant chemoimmunotherapy can delay early recurrence. Long-term follow-up is needed to assess the significance of these results.

Infectious complications in liver transplantation.

Thirty-five patients received 42 liver homografts between February 1984 and August 1985. One or more infections developed in 23 patients (66%) some time after transplantation. An average of 2.5 infections per infected patient occurred. Of 37 bacterial infections, two thirds were either bacteremias or localized intra-abdominal infections. The median onset was 29 days after operation. Thirteen viral infections were identified, with a median onset of 18 days after operation. Nine fungal infections, six disseminated and three localized, were identified, with a median onset of nine days after operation. Infection was the primary cause of death in five (14%) of 35 patients. Fatal infections were evenly distributed among bacterial (two), fungal (three), and viral (two) pathogens. Despite advances in surgical techniques and the use of cyclosporine, infection after orthotopic liver transplantation is a serious problem. Certain patients can be identified as high risks for infection and require an aggressive diagnostic workup followed by early institution of antimicrobial therapy.

Systemic irinotecan or regional floxuridine chemotherapy prolongs survival after hepatic cryosurgery in patients with metastatic colon cancer refractory to 5-fluorouracil.

Most colorectal cancers metastatic to the liver are resistant to chemotherapy and are not amenable to surgical resection. This study evaluated our 6-year experience (July 1992-July 1998) in treating patients with unresectable hepatic colorectal metastases refractory to systemic 5-fluorouracil (5-FU). One hundred fifty-three patients underwent cryosurgical ablation (CSA) of 5-FU-resistant hepatic metastases. The patients then received either hepatic arterial floxuridine (FUDR), systemic CPT-11, or no postoperative adjuvant chemotherapy. Number, size, and location of hepatic metastases, carcinoembryonic antigen (CEA) levels, and type of postoperative treatment were analyzed. One to 15 lesions were frozen (median number, 3; median size, 6 cm), for a total of 73 synchronous and 80 metachronous lesions. Overall median survival was 28.4 months from the date of diagnosis of liver metastases and 16.1 months from the time of CSA. After cryosurgery alone, median survival was 13 months, which was significantly shorter than the post-CSA survival of 23.6 months with adjuvant CPT-11 and 21.2 months with hepatic FUDR (P = 0.007). Predictors of survival included preoperative CEA, postoperative reduction in CEA, and adjuvant chemotherapy (P < 0.05). Neither size, number of lesions, nor tumor location impacted survival. At a median follow-up of 13 months, 67% of patients have recurred (35% hepatic, 16% extrahepatic, and 49% both). Twenty percent of the recurrences were in the lobe of the CSA site. The 25 patients who underwent a second CSA had a median survival of 28.4 months from CSA and 40 months from the date of diagnosis of liver metastases. These data indicate that CSA offers an effective alternative for unresectable patients resistant to 5-FU. Systemic CPT-11 or regional FUDR may further prolong survival after CSA.

Repeat hepatic cryotherapy for metastatic colorectal cancer.

This study evaluated the risks and benefits of repeat hepatic cryotherapy for recurrent, unresectable hepatic metastases from colorectal carcinoma. Review of a prospective database identified 195 patients who underwent hepatic cryotherapy for metastatic colorectal carcinoma during a 7-year period. Of the 14 patients who underwent successful repeat cryotherapy for recurrences confined to the liver, 86% had Duke's stage D colorectal carcinoma at initial diagnosis. The median age of the 14 patients was 58 years (range 41 to 77 years). The median number of hepatic metastases was three at the first cryotherapy and two at the second cryotherapy. At a median follow-up of 71 months, the mean survival times from original diagnosis, first cryotherapy, and second cryotherapy were 53, 42, and 19 months, respectively. At the most recent follow-up, eight patients (57%) have died of their disease, four (29%) are alive with disease, and two (14%) have no evidence of disease. The mean interval between the first and second cryotherapies was 23 months. The complication rates after the first and second cryotherapies were 7% and 14%, respectively. One patient developed a wound dehiscence after the first cryotherapy. Following the second cryotherapy, one patient had a small bowel obstruction and another had a pleural effusion. There was no perioperative mortality. Repeat cryotherapy for recurrent, unresectable hepatic metastases from colorectal cancer is safe and improves survival. However, a prospective trial is needed to validate the efficacy of systemic therapy and to better define the indications for repeat hepatic cryotherapy.

Management of carcinoma of the rectum and anus without abdominoperineal resection.

Since 1979, 16 patients with cancer of the rectum and anus have been treated without abdominoperineal resection. All have received radiotherapy. Nine of these had local excision before receiving radiotherapy. There has been no evidence of recurrent cancer in 15 of the 16 patients with a median follow-up period of 24 months (range 14 to 52 months) for a recurrence rate of 6 percent. We conclude that limited excision, radiotherapy, or both are viable alternatives to abdominoperineal resection of small, early cancers of the rectum and anus.

Surgical management of extensive tracheal lesions.

Resection and end-to-end anastomosis has been effective in correcting localized tracheal obstruction. This procedure can be utilized in the definitive management of extensive tracheal lesions requiring the resection of at least eight tracheal rings. Important clinical considerations are the precise preoperative assessment of the lesion, careful planning of anesthetic management, choice of the appropriate incision, avoidance of circumferential dissection, and the construction of an anastomosis free of disruptive tension.

Surgical management and reconstruction of extensive chest wall malignancies.

Seven patients aged 8 to 77 years underwent massive resection for chest wall malignancies. Two had chondrosarcoma, one recurrent breast cancer, one malignant hemangioepithelioma, one embryonal cell sarcoma, one metastatic osteogenic sarcoma, and one lymphangiosarcoma. The smallest surgical defect was 17 by 19 cm, the largest 35 by 45 cm. Closure was done with Marlex mesh, full-thickness muscle flaps, or free island pectoralis or latissimus dorsi flaps. The rotation of myocutaneous island flaps (bilateral in two patients) greatly facilitated reconstruction. No infection, pulmonary compromise, or operative morbidity or mortality was encountered. The age of the patients and the location or size of the lesions were not significant factors. Designing a surgical strategy which provides adequate full-thickness margins and immediate reconstruction is critically important. Massive chest wall resection for malignancy should be pursued aggressively whenever these lesions are encountered. The operations can be performed safely and can be curative, and the benefits to patients in terms of comfort and prolonged survival justify this extensive surgery.