Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study.

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

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.

Pharmacokinetics of dacarbazine in the regional perfusion of extremities with melanoma.

BACKGROUND: The pharmacokinetics of dacarbazine (DTIC), which has been shown to be an effective therapeutic agent against metastatic melanoma, has not been extensively studied. However, to improve the clinical use of the drug, more information on the kinetics is required. METHODS: A pharmacokinetic study was undertaken in six patients with melanoma of an extremity who were undergoing hyperthermic isolation perfusion with DTIC in order to understand better its clinical pharmacokinetics. Plasma was sampled from the arterial and venous lines of an extracorporeal pump during the perfusion with the systemic vein and urine sampled postperfusion. Samples were analyzed for DTIC. 2-azahypoxanthine (2-AZA), and aminoimidazole carboxamide (AIC). 99(m)Tc (Technetium) human serum albumin (HSA) was used in the perfusion circuit to monitor the crossover of the perfusate into the systemic circulation during the procedure. The data were analyzed using a compartmental model of sampled body compartments incorporating the isolated extremity. RESULTS: High tissue DTIC levels were maintained throughout the perfusion, whereas in the systemic circulation, plasma DTIC concentrations, when observed, were 40-100-fold less than those in the perfusate. Almost 70% of the DTIC administered was not recovered in the perfusate after the washout of the extremity. CONCLUSIONS: High levels of DTIC can be maintained in an extremity (i.e., arm or leg) during perfusion.

Immediate mandibular stabilization following resection of advanced oral cavity carcinoma using the Joe Hall Morris external fixation device.

Internal mandibular fixation after resection of advanced oral cavity carcinoma with mandibulectomy has a significant complication rate. We placed the Joe Hall Morris (JHM) external mandibular appliance in 29 patients undergoing mandibulectomy for advanced oral cavity carcinoma. Fourteen patients received postoperative radiation therapy (RT). Three of 29 patients (10%) had complications associated with the JHM appliance: one patient had a broken connecting bar, a second had loosening of a single pin, and a third had loss of fixation requiring complete replacement of the appliance. Complications not associated with the appliance occurred in 8 patients (28%) including mandibular exposure (1), orocutaneous fistula (2), partial flap dehiscence (4), and flap necrosis (1). Oral continence was maintained in 26 patients, and occlusion was normal in 27. The appliance was removed in 12 weeks to 6 months in all patients. The JHM appliance allows for a reliable and rapid immediate fixation of the mandible with acceptable functional and aesthetic results, and no delay or interference with postoperative radiotherapy. Since the life expectancy of these patients is short, most do not require subsequent permanent fixation after removal of the appliance.

Use of an instrument-holding clip for deeply recessed anastomoses of the rectum and esophagus.

Posterior layer closure of deeply located anastomoses including those performed in the course of low anterior rectal resection, total gastrectomy, and esophagogastrectomy, are often difficult. Usually five to six seromuscular or through-and-through posterior wall sutures are inserted sequentially and the loop or cut end of bowel is advanced over these parallel sutures. The sutures are then tied down. Entanglement of these sutures in a deep surgical field with limited access can lead to tears in the bowel wall. In addition, uneven and nonsequential tying of these sutures may compromise the anastomosis itself. We have described here how manual anastomosis in deep, hard to reach surgical fields can be better accomplished with the use of an instrument-holding clip. Use of the described instrument-holding clip, to clearly delineate and anchor each suture in sequence, eliminates these problems. An easily available device, it can save operative time, facilitate a more even anastomosis, and decrease the chance of bowel wall tearing, thus enhancing the security of the anastomosis.

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.

A protocol for the safe administration of debrisoquine in biochemical epidemiologic research protocols for hospitalized patients.

The genetically determined ability to metabolize the antihypertensive drug debrisoquine has been proposed as a genetic risk factor for primary carcinomas of the lung. To test this hypothesis, the metabolism of the drug was evaluated in a case control study. The subjects were characterized by their ability to metabolize debrisoquine after receiving a test dose of the drug followed by the collection of an 8-hour urine sample. They were classified by laboratory analysis into one of the following three groups: extensive, intermediate, and poor metabolizers. Poor metabolizers comprise 10% of the population and are unable to hydroxylate the drug. This group was expected to be at highest risk for deleterious effects from this medication. A protocol was created that included patient education and blood pressure monitoring to administer this medication safely to a group of patients with cancer who were already compromised. Although poor metabolizers showed a small decrease in systolic and diastolic blood pressure, no significant hypotensive episodes or clinical sequelae were observed in any of the groups. These data suggest that debrisoquine can be administered safely in a controlled clinical setting and will be useful for the characterization of lung cancer patients in biochemical epidemiology studies.

Squamous cell carcinoma of the umbilicus associated with acquired immune deficiency syndrome.

A variety of malignancies, including hematologic malignancies, Kaposi's sarcoma, as well as adenocarcinomas and squamous cell carcinoma have been reported in association with acquired immune deficiency syndrome. Tumors of the umbilical area are unusual and can represent lesions of urachal origin. These may require extensive resection and are associated with a poor prognosis. We describe here a case of a young woman with AIDS who developed a squamous cell carcinoma of the umbilicus which suggests more than a casual relationship between these two conditions.

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.

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.

Influence of the routes of continuous intrahepatic infusion of 5-fluorouracil on its pharmacokinetics.

Continuous infusion chemotherapy via hepatic artery using newly available mechanical devices is frequently used to treat hepatic metastases to achieve a high concentration of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure. We compared four routes of intrahepatic administration to find out the best one in the canine model. To ascertain this data, 5-FUra (30 mg/kg) was given as a continuous infusion over a 3 hr period into either a systemic vein (femoral), portal vein, hepatic artery, or hepatic artery distal to its ligation after hepatic dearterialization. A total of eight dogs were studied. During 5-FUra infusion, concomitant blood samples were taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, 60, 120, and 180 min. 5-FUra levels were determined in plasma by high-performance liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data described by a multicompartmental model, including the measured flows, had separate hepatic arterial and portal compartments with elimination from each described by linear kinetics. Mean area under the curve values in microgram/ml X min and the ratios of the systemic/hepatic vein areas following 5-FUra infusion via systemic, portal vein, hepatic artery, or hepatic artery after dearterialization routes were: 975/539 (R = 1.80), 939/748 (R = 1.35), 211/454 (R = 0.46), and 562/1,424 (R = 0.39). The results indicated that the administration of 5-FUra via the hepatic arterial route distal to its ligation results in the highest hepatic vein drug levels with the smallest systemic/hepatic vein exposure ratio, followed by intra-arterial route, while systemic and portal vein routes were not nearly as advantageous as the intra-arterial routes.

Risk factors before hepatectomy, hepatic function after hepatectomy and computed tomographic changes as indicators of mortality from hepatic failure.

The mortality rate from hepatic failure after extensive resection should be negligible in the presence of normal results from preoperative liver function tests in patients without pre-existing hepatitis and cirrhosis. Despite conventionally acceptable results from preoperative hepatic function tests in 56 patients undergoing extensive hepatic resection for tumours (47 metastatic, six hepatomas and three adenomas), however, five patients died of hepatic failure. Among the many preoperative and intraoperative risk factors studied, the important factors in the group with hepatic failure were very high levels of serum alkaline phosphatase (p less than 0.05) in the presence of normal levels of bilirubin and large tumor, preoperative administration of chemotherapy, the presence of hepatomas rather than metastatic carcinoma (p = 0.083) and intraoperative blood loss of greater than 5,000 milliliters (p = 0.03). The patients receiving preoperative chemotherapy or those with hepatoma showed a minimal rise of alkaline phosphatase (p less than 0.03) and a minimal regeneration of liver on computed tomographic (CT) scan after hepatic resection. In the group with hepatic failure, a consistent postoperative pattern of increasing bilirubin with normal or subnormal alkaline phosphatase levels corresponded with lack of regeneration of liver on repeated CT scans. Conversely, the pattern of decreasing bilirubin with reciprocal increase in alkaline phosphatase corresponded with hepatic regeneration on CT scan in the group of survivors. Thus, we observe that alkaline phosphatase is a good indicator of hepatic regeneration in the absence of jaundice in patients after hepatectomy. To avoid postoperative hepatic failure, we recommend more discriminant tests than conventional hepatic function tests in patients with large tumors associated with high alkaline phosphatase levels, preoperative chemotherapy and hepatoma even without pre-existing cirrhosis or hepatitis.

Abstract renders the summary superfluous.

By definition, an abstract and summary must contain much the same content, as it is the purpose of each to provide a synopsis of the study or review. The journal Surgery Gynecology and Obstetrics requires both an abstract and a summary for its articles. We studied 83 reports from Surgery, Gynecology and Obstetrics, reviewing the similarities and differences in the abstracts and summaries based on six objective criteria: the number of words, the number of sentences, the number of repetitious sentences, the clarity of the abstract or summary without having to refer to the body of the article, the expression of conclusions and the introduction of new material that is not mentioned within the body of the article. Our results showed that, although abstracts were nearly one-third longer than the summaries, almost one-third of the sentences were repetitious. On the other hand, in one-fifth of the instances, the important conclusions of the article were included in either the abstract or summary but not both. We conclude that the quantitative and structural attributes of the summary and abstract are sufficiently similar to warrant that the abstract mandated by many publications has rendered the summary superfluous. Furthermore, when both the abstract and summary are included within an article, the omission of important conclusions can occur in one or the other. We recommend to retain the abstract or the summary in the conventional format in the articles rather than to have both in entirety or an altered format.

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.

Gerota's fascia flap for control of hemorrhage of the hepatic surface.

A technique of providing coverage with a Gerota's fascia flap coverage for the raw bleeding surface of the liver after major hepatic resection is described. It is most applicable in patients in whom conventional omental or falciform ligaments flaps are not available.

Computed tomography of the liver after dearterialization and intraarterial chemotherapy.

Hepatic dearterialization by ligation of the main hepatic artery followed by local intraarterial chemotherapy was performed in 24 patients with clinically isolated but unresectable hepatic metastasis after local resection of carcinoma of the colon. Computed tomography of the abdomen and laboratory parameters were used both to stage and follow-up these patients. Computed tomography changes following dearterialization and chemotherapy of the liver are described. Computed tomography is a valuable technique for both staging and follow-up this group of patients.