Pharmacokinetics of 5-fluorouracil following different routes of intrahepatic administration in the canine model.

In an effort to achieve high concentrations of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure, several routes of intrahepatic administration were compared in the canine model. To ascertain these data, 5-FUra (30 mg/kg) was given as a bolus into either a systemic vein (femoral vein), hepatic artery, hepatic artery distal to its ligation after hepatic dearterialization, or through the portal vein. Three dogs were studied for each route with concomitant blood samples taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, and 60 min after injection. 5-FUra levels were determined in plasma by high-pressure liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data were best described by a multicompartmental model including the measured flows. Hepatic components of the model were separate arterial and portal compartments, with elimination from each described by linear kinetics. Analysis of the results indicated that the highest hepatic levels with the least systemic exposure, as indicated by drug levels in hepatic and peripheral vein, were realized following hepatic artery administration distal to its ligation after hepatic dearterialization.

Hepatic drug-metabolizing enzymes in primary and secondary tumors of human liver.

Significant increases in activities of epoxide hydrolase, UDP-glucuronosyltransferase, and glutathione S-transferase, and marked reductions in cytochrome P-450 mixed-function oxidase systems occur in hyperplastic nodules induced in rat liver by chemical mutagens. In contrast, activities of both oxidative (Phase I) and conjugative (Phase II) enzymes are decreased in hepatocellular carcinomas induced by peroxisome proliferators. The present work compares alterations induced by chemical mutagens or peroxisome proliferators with changes in enzyme activities that occur in primary and secondary hepatic tumors in man. The above activities, along with beta-glucuronidase and arylsulfatase, were measured in liver samples from 6 normal livers obtained at immediate autopsy, and liver specimens obtained by surgical biopsy from the following patients: 8 with hepatomas, 5 with nonmetastatic colorectal carcinomas, and 14 with metastatic colorectal carcinomas. Cytochromes P-450MP and P-450NF in addition to epoxide hydrolase were measured by immunoquantitation. Enzymes involved in conjugation reactions were either assayed fluorometrically (UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase) or spectrophotometrically (glutathione S-transferase) using umbelliferyl substrates or 1-chloro-2,4-dinitrobenzene. Secondary hepatic tumors showed no significant change in drug-metabolizing enzymes, in contrast to primary hepatomas, which displayed decreases in all of the measured drug metabolizing enzymes. Arylsulfatase was markedly depressed in primary hepatomas (14% of normal values). Thus, activities of drug-metabolizing enzymes in human primary tumors resemble those associated with altered hepatic foci induced by peroxisome proliferators such as ciprofibrate. The marked decreases in sulfatase that occurred in primary but not in secondary human tumors suggest that sulfation of endogenous compounds and xenobiotics may differ in patients with primary and secondary hepatic tumors.

Ethiodized oil emulsion 13 in computed tomography of hepatoma.

Six patients with biopsy-proven hepatoma were prospectively evaluated both by conventional computed tomography (CT) and by scans using ethiodized oil emulsion 13 (EOE 13) as a contrast agent. EOE 13 infusion resulted in marked improvement in the demonstration of the neoplasm in all cases and allowed more accurate definition of tumor extent than was possible with standard scanning techniques. In two cases EOE 13 enhancement was essential for complete radiographic depiction of tumor location, size, and extent. EOE 13 also proved to be of considerable value in assessment of therapeutic response in three patients, permitting more objective determination of tumor growth or regression. EOE 13--enhanced CT scanning provides a valuable means of staging patients presenting with hepatoma and is a reliable, accurate means of radiographic follow-up.

Reconstruction of sternal and abdominal wall defects in a case of desmoid tumor.

A case of desmoid tumor of the anterior chest and abdominal wall is presented. The entire body of the sternum along with the upper abdominal wall and inner parts of both breasts was resected. The resulting defect over the pericardium and abdomen was reconstructed by the omentum and Marlex mesh. The large skin defect was covered by bilateral thoracoabdominal tube pedicles. The patient had a stable chest wall with uncompromised respiratory function 1 week after the operation. Prevention of local recurrences of desmoid tumors requires wide excision of the involved soft tissues and bony structures. The principles of wide resection of soft tissue tumors, reconstruction of the anterior chest and abdominal wall defects, and planning the skin coverage over the resulting defect are discussed.

The surgical management of multiple lung metastases.

From 1970 to June, 1976, 56 patients who had multiple metastatic tumors of the lung were treated by lung resection. Most of the bilateral lung lesions were removed through a median sternotomy so as to avoid staged bilateral thoracotomy. The surgical mortality was 1.8%. A total of 26 patients are alive at 7 to 69 months (estimated median survival, 20.7 months). Patients with tumor doubling time of less than 40 days had lower survival results (median, 9.5 months), compared to patients with tumor doubling time of more than 40 days (median not yet reached). The type of primary tumor, tumor-free interval, number of lesions removed, and presence of unilateral as opposed to bilateral lung metastases did not seem to affect the therapeutic results.

Combination chemotherapy for advanced squamous cell carcinoma of the head and neck.

Fifty-one patients (32 previously untreated, 19 previously treated) with advanced squamous cell carcinoma of the head and neck received a single course of combination chemotherapy consisting of high dose cis-platinum (DDP), bleomycin (Bleo), +/- high dose methotrexate (MTX). Thirty-three (65%) patients responded to therapy; 5 (10%) of these patients had a complete response. Previously untreated patients and those who received the three drugs (DDP, Bleo and MTX) had the highest response rates. The duration of response was 8 to 12 weeks. Seven (15%) patients showed a two-year survival rate. All nonresponders were dead of disease within two years. Three (56%) of the five complete-response patients and 4 (21%) of the partial-response patients survived for two years. The role of preoperative chemotherapy in head and neck cancer is yet to be conclusively defined.

Hepatic resection using intermittent vascular inflow occlusion and low central venous pressure anesthesia improves morbidity and mortality.

Hepatic resection results in significant morbidity and mortality primarily related to intraoperative blood loss. Intermittent vascular inflow occlusion (VO) and low central venous pressure (CVP) during hepatectomy have been used to reduce blood loss. To determine the benefit of VO and low CVP, we reviewed the outcomes of 168 consecutive patients who underwent liver resection. The results of 78 patients who had undergone hepatic resection between 1993 and 1998 with the use of VO and low CVP (post-VO/CVP) were compared to the previous 90 patients who had undergone hepatectomy without VO and low CVP (pre-VO/CVP) between 1979 and 1992. Hepatectomies were performed for metastatic disease (65%), hepatoma (20%), and benign tumors (15%). Resections included 18 trisegmentectomies, 67 lobectomies, and 83 segmental resections. Patients in both groups were similar with regard to extent of resection. Post-VO/CVP patients had significantly lower median estimated blood loss (725 ml vs. 2300 ml, P <0.001), less postoperative morbidity (10.3% vs. 22. 2%, P = 0.038), lower in-hospital mortality (2.6% vs. 10%, P = 0. 050), fewer days in the intensive care unit (1.6 +/- 0.1 days vs. 5. 6 +/- 1.2 days, P = 0.003), and shorter overall length of stay (8.0 +/- 0.5 days vs. 15.0 +/- 1.6 days, P <0.001) than pre-VO/CVP patients. These data suggest that VO and low CVP during liver resection may improve patient outcomes.

Long-term results of a combined modality approach in treating inflammatory carcinoma of the breast.

Twenty-eight patients with inflammatory carcinoma of the breast were managed initially by induction chemotherapy consisting of 3 courses of a combination of cyclophosphamide, doxorubicin hydrochloride, and 5-fluorouracil. Twenty-two showed a partial response, and 21 underwent mastectomies. Histopathologic examination of the surgical specimens revealed no residual tumor in 2 breasts, but all 21 patients had residual metastases in their axillary lymph nodes. Postoperatively, they received the same chemotherapy. The other six patients who failed to respond to induction chemotherapy received radical radiation therapy followed by a combination chemotherapy regimen that consisted of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone. Any patient in whom chemotherapy failed during the follow-up period was treated by radiation therapy and/or a combination of mitomycin-C and vinblastine as necessary. At the time of diagnosis, 17 patients who had no evidence of distant metastasis, i.e., stage III B disease, had disease-free survival ranging from 5 to more than 84 months, with a median of 30 months, and an overall survival of 7 to more than 120 months with a median of 32 months. The 5-year survival rate was 18%. The other 11 patients who had distant metastases, i.e., stage IV disease, had an overall survival ranging from 4 to 14 months. The results of this approach of initial systemic chemotherapy followed by local-regional cytoreductive therapy, then systemic therapy, might suggest some survival benefits in patients with stage III disease.

Prognostic factors in squamous cell carcinoma of the larynx.

One hundred fifty-two patients with squamous cell carcinoma of the larynx were studied. The disease-free survival and overall survival rates were correlated to 12 variables. Seven of them seemed to affect survival. Poor prognosis was related to (1) advanced stage of disease at diagnosis, (2) cord fixation and massive local invasion, (3) ulceration of the primary tumor, (4) lymph node metastases at diagnosis, (5) glottic lesions had a poorer prognosis than supraglottic ones, (6) locoregional recurrences, and (7) male gender. However, most of these significant differences were in disease-free survival, and only primary tumor staging; lymph node status; and locoregional recurrences affected overall survival. On the other hand, the other five variables showed no effect on either disease-free or overall survival rates. These included age, race, cell differentiation, type of recurrence, and the initial definitive therapeutic modality.

Biologic behavior of ocular malignant melanoma and comparison with melanoma of the head and neck.

Ocular melanoma is the most common malignant tumor of the eye and accounts for 70 to 80 percent of all extracutaneous melanomas. Its biologic behavior differs from that of its cutaneous counterpart. To elucidate this, 62 patients with histologically proven melanoma of eye (58 uveal tract and 4 conjuntiva) at Roswell Park Memorial Institute from 1945 to 1977 were studied. The prominent contradistinctions from other head and neck melanomas were (1) a very high percentage of patients had either locally advanced or systemic disease at diagnosis, although the eye is the most sensitive organ; (2) regional lymph node involvement was absent even in the late stages of disease; (3) hematogenous spread involved single organs, most commonly the liver and the lung; (4) local recurrence was rare; (5) most recurrences occurred evenly in first 10 years after treatment; (6) regional resection, chemotherapy or both are advocated for distant metastases since they are confined to a single organ and are amenable to it; and (7) despite hematogenous spread and advanced disease at diagnosis, the overall prognosis of ocular melanoma is comparable to that of cutaneous melanoma.

Flow cytometric DNA analysis of primary and concurrent metastatic squamous cell carcinoma of the head and neck.

Adequate flow cytometric DNA analysis comparing primary and concurrent metastatic squamous cell carcinoma of the head and neck has not been done in the past. The purpose of this study was to define any differences between the primary and concurrent metastasis of each patient with respect to flow cytometric parameters and histologic grade. Paraffin-embedded archival specimens from 28 patients with primary and metastatic tumors were prepared into nuclei and analyzed by flow cytometry using human lymphocyte standards. The mean DNA index was 0.82 for primary tumors and 0.83 for the metastases. Aneuploidy was found in 68 percent of primary tumors and in 82 percent of metastases. The percentage of cells in the proliferative fraction was 40.4 in the primary tumors and 24.5 in the metastases. A direct correlation was found between the differentiation of the primary and metastatic tumors. No survival difference was discovered among the flow cytometric parameters and histologic grade. We conclude that there is no difference between the primary and concurrent metastasis in squamous cell carcinoma of the head and neck with regard to DNA index, aneuploidy, or histologic grade.

Problems in resection of chest wall sarcomas.

To illustrate the problems of reconstruction in major chest wall resection, five patients with a variety of soft tissue tumors of the chest wall, located at different sites, are presented. Patients, who underwent a lateral or posterolateral chest wall resection required removal of two to five ribs sequentially as well as the adjacent soft tissue. Those who underwent an anterior chest wall resection required resection of the manubrium or the body of sternum as well as of adjacent costal cartilages. To prevent instability of the chest, herniation, and to minimize flailing, the chest defect was bridged with the use of Marlex mesh. Whenever possible, the omentum was brought into the chest cavity to increase the vascularity of the reconstruction. Since, in most instances, the tumors involved the skin because of previous damage from radiation therapy, extensive skin coverage was planned well in advance of resection. Pedicle skin flaps or rotation flaps were used to cover the skin defect. Ventilatory support by volume respirator, was required for three to four days. In all patients, the chest wall was completeley stable after three to six weeks.