Kenneth P. Ramming

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 lesions Clark level of invasion and Breslow thickness and the patients 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.

Effect of a prior portasystemic shunt on subsequent liver transplantation.

Fifteen patients who had a prior portasystemic shunt underwent orthotopic liver transplantation. Shunt types were portacaval in six patients, H-graft mesocaval in six, distal splenorenal in two, and proximal splenorenal in one. Mean blood loss and hospital stay were highest in the portacaval group. Retransplants (two patients) and deaths (two patients) also were limited to this group. In this report, technical considerations, advantages, and disadvantages of the various shunt types are described. Management of patients with late stages of portal hypertension must include estimation of the effects of a portasystemic shunt on subsequent liver transplantation. It is concluded that portacaval shunts should be avoided in patients who may be considered for transplantation. Distal splenorenal shunts are best performed in younger patients with intractable variceal bleeding who are not expected to require transplantation in the near future. A mesocaval H-graft is the shunt of choice in patients who are current liver transplant candidates.

Pulmonary resection for metastatic sarcoma

Surgical resection plays an important role in the treatment of sarcoma that is metastatic to the lung. Multiple bilateral metastases are not contraindications to surgery. The rapidity of growth and the response to chemotherapy can be accurately determined by the tumor doubling time. Preoperative chemotherapy provides an in vivo measurement of tumor sensitivity, and the response to chemotherapy correlates with prognosis. Since residual microscopic pulmonary disease appears to be responsible for most failures after thoracotomy, attention should be directed toward delivering more effective adjuvant therapy to the lungs.

Fulminant hepatic failure: The role of liver transplantation as primary therapy

Fulminant hepatic failure is a clinical syndrome with a high mortality rate when traditional supportive therapy is used as treatment. Orthotopic liver transplantation has been proposed as a therapeutic option. Clinical and logistic difficulties include the rapid deterioration of the patients, unpredictable recovery, and the immediate need for a donor organs. Including this series, a total of 41 patients with fulminant hepatic failure have been transplanted, with a survival rate of 61 percent. We have reported eight liver transplantations carried out in six patients. Four of the patients survived (66 percent). Death was due to irreversible neurologic dysfunction in one patient and fungal sepsis in one patient. These results indicate that orthotopic liver transplantation is a practical therapeutic option for fulminant hepatic failure which should be considered early, before neurologic deterioration becomes irreversible.

Hepatic artery ligation and 5-fluorouracil infusion for metastatic colon carcinoma and primary hepatoma.

Nine patients with extensive bilateral hepatic metastases of colorectal cancer were treated with hepatic artery ligation and continuous infusion of 5-fluorouracil (5-FU). Silastic catheters were inserted into the hepatic artery at laparotomy, and continuous perfusion was effected by a Sigmamotor pump. There was no operative mortality or morbidity, and drug toxicity was acceptable. Dosage averaged 10 mg/kg/day and average time of infusion was sixty-three days. Liver function returned to preoperative values within two weeks in all patients, and four patients had improvement of preoperative liver function for three to six months after perfusion. Two patients had palpable regressions that lasted five months or more, and one patient had a slight palpable regression for two months. Five who are dead had a mean survival of 10.4 months after therapy, with a median survival of 11.5 months. Eight of the nine patients had significant clinical improvement following treatment. Seven patients with irresectable primary liver carcinoma were treated with continuous 5-FU infusion. A Silastic catheter was placed at laparotomy into the hepatic artery via the gastroduodenal artery. Ligation of the hepatic artery was not performed. There was no operative mortality or morbidity. Dosage averaged 10 mg/kg/day and the average time of infusion was 140 days. Significant clinical improvement was noted in six of the seven patients although this did not correlate with improvement of hepatic function. All six responding patients are still living (mean survival, 14 months). Prolongation of life with hepatic artery infusion of 5-FU has been significantly better than with any previously reported chemotherapy for this disease.

An Improved Operation for the Definitive Treatment of the Wolff-Parkinson-White Syndrome

Abstract As our experience increased with the definitive surgical treatment of patients with Wolff-Parkinson-White syndrome (WPW), an intraatrial method was devised that permits separation of the atria from the ventricles at any point along the annulus fibrosus. This technique depends on separating the atrium from the annulus fibrosus, using the fat about the coronary vessels and epicardial reflections from the aorta to the right atrial wall as the plane of dissection. This method allows easy approach to the septal area on the right. Successful results with 2 patients, one with Type A (left-sided) and the other with Type B (right-sided) WPW are recorded to illustrate the use of this method.

Interleukin 4 inhibits hepatocyte growth factor‐induced invasion and migration of colon carcinomas

Hepatocyte growth factor (HGF) is known to have a number of biological properties including promoting tumor progression of human carcinomas. Metastasis involves a number of events that are attributed to induction by paracrine factors such as HGF. Identification of natural inhibitors of these events would allow better control of tumor progression. Recently we demonstrated that interleukin 4 (IL‐4) can regulate proliferation of various human carcinoma cell lines. In the present study, we used established human colon carcinoma cell lines and primary colon carcinoma cell cultures to determine if IL‐4 could regulate HGF‐induced cell proliferation and other events of tumor progression such as MMP (matrix metalloproteinases)‐1, ‐2, and ‐9 production, cell migration and cell‐matrix invasive activity. All colon carcinoma cell lines expressed HGF and IL‐4 receptors. IL‐4 significantly inhibited HGF‐induced proliferation of one cell line. Cell‐matrix invasion was significantly enhanced by HGF (0.1–10 ng/ml); IL‐4 (1–10 U/ml) significantly inhibited HGF‐induced invasion in a dose‐dependent manner. IL‐4 also inhibited HGF‐induced cell‐matrix invasion of metastatic colon carcinoma cells and HGF‐induced cell migration. HGF enhanced MMP‐1, ‐2, and ‐9 production by cell lines. This effect could be inhibited by IL‐4. These findings indicate that IL‐4 is a potent inhibitor of HGF‐induced invasion and metastasis‐related functions of human colon carcinoma cells.

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.

Transfer of tumor immunity with ribonucleic acid.

The transfer of antitumor immunoreactivity to previously normal, nonimmune lymphoid cells was accomplished by incubating normal C3H mouse spleen cells with RNA extracted from the lymphoid organs of guinea pigs immunized with a chemically‐induced C3H fibrosarcoma. Injections of these cells into normal C3H mice significantly inhibited the development of subsequent isografts of the same tumor. RNA from pigs inmunized with normal C3H tissues was ineffective. RNAase treatment of the RNA preparations removed all activity. Within a completely syngeneic tumor‐host system, strain 2 guinea pig spleen cells were incubated with RNA extracted from the spleens of strain 2 guinea pigs previously immunized with a chemically‐induced strain 2 guinea pig liposarcoma, MCA‐A. Immunoreactivity of these cells was demonstrated by their ability to cause areas of specific immune cytolysis in monolayers of MCA‐A tumor cells in vitro. This reaction was found not to be PHA dependent. Again, treatment of the active RNA preparations with RNAase abolished their efficacy. RNA extracted from the spleens of guinea pigs stimulated nonspecifically by immunization with Freunds adjuvant, but not exposed to the tumor, was ineffective. Incubation of normal lymphoid cells with sol‐ubilized extracts of MCA‐A tumor tissue known to be rich in tumor‐specific transplantation antigens, but not containing RNA, did not reproduce the immune cytolysis produced by the active RNA preparations.

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.