Philip D. Schneider

A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases.

Sixty-four patients were entered into a randomized trial that evaluated intra-arterial (I.A.) versus intravenous (I.V.) 5-fluorodeoxyuridine (FUDR) for colorectal liver metastases. There was a significant improved response rate for I.A. (62%) compared with I.V. (17%) treatment (p less than 0.003). However, the improved response rate for patients in whom I.A. therapy was used did not translate to a significantly improved survival rate. The 2-year actuarial survival rates for the groups for which I.A. and I.V. therapy was used were 22% and 15% respectively, with the survival curves not differing significantly (p = 0.27). These results may have been due to the inclusion of patients with tumor in draining hepatic lymph nodes. The presence of tumor in hepatic lymph nodes was associated with a poorer prognosis. Analysis of a subgroup of patients with negative hepatic lymph nodes suggested an improved actuarial survival rate in patients for whom I.A. versus I.V. therapy was used (p less than 0.03). The toxicity of I.A. FUDR was considerable, and side effects included chemical hepatitis (79%), biliary sclerosis (21%), peptic ulcers (17%), and gastritis/duodenitis (21%). The only major effect of toxicity of I.V. FUDR was severe diarrhea (59%). Regional I.A. FUDR allowed more drug delivery to liver tumors, which resulted in increased tumor responses when compared with use of systemic therapy. However, the small gain in survival seen in a select subgroup of patients with negative hepatic nodes appeared to be offset by the toxicity of I.A. FUDR.

Lymphatic dissemination of hepatic metastases. Implications for the follow-up and treatment of patients with colorectal cancer

Hepatic spread of colorectal cancer is a prominent cause of treatment failure, but selected patients with liver metastases may attain long‐term palliation or cure with liver resection. A review of the records of 81 patients seen at the National Cancer Institute for treatment of colorectal hepatic metastases revealed 7 instances of metastases discovered at operation within the hepatic lymphatic drainage in the absence of other extrahepatic tumor. These patients were studied with reference to location and stage of the primary colon cancer and location of metastases at the time of planned liver resection. All seven patients had their extrahepatic lymphatic disease limited to nodes draining the liver, implicating lymphatic dissemination from hepatic metastases as the mechanism of tumor spread. This pattern of spread rendered these patients unresectable for cure. If lymphatic metastases occur from hepatic tumor this implies a need for frequent and thorough follow‐up of patients following resection of a primary colon cancer, and indicates urgency in treatment of liver metastases.

Apolipoprotein B synthesis in humans: liver synthesizes only apolipoprotein B-100

Apolipoprotein (apo) B-100 and B-48 are prominent apolipoproteins in VLDL, IDL, and chylomicrons. Organ cultures of normal adult human liver were established to ascertain the form of apo B synthesized by hepatocytes in humans. Human liver was minced and incubated in 15 mL methionine-free RPMI-1640 medium with 10% dialyzed fetal calf serum plus 250 microCi 35S-methionine for eight hours at 37 degrees C. Lipoproteins secreted by the liver were isolated by ultracentrifugation and the content of newly synthesized apo B determined by quantitation of radioactivity in the apoB-100 and apoB-48 bands after separation by 3% NaDodSO4 gel electrophoresis. In the eight-hour period, 2.5% to 3.2% of added 35S-methionine was secreted in TCA-precipitable protein of which 0.34% was apo B. Ninety-nine percent of the apo B in VLDL, IDL, and LDL was in the apo B-100 electrophoretic band. No significant radioactivity was detected in the apo B-48 electrophoretic band. Eighty-nine percent of the total radioactivity of apo B-100 was in VLDL with 3% and 8% in IDL and LDL, respectively. These results establish that adult human liver in organ culture synthesizes apo B-100 but not apo B-48.

Ct Appearance of Enlarged Parathyroid Glands in the Posterior Superior Mediastinum

Enlarged ectopic parathyroid glands in the posterior superior mediastinum appear as rounded dense masses in the tracheoesophageal groove. Five of six surgically proven adenomas in the posterosuperior mediastinum were demonstrated by computed tomography.

Limiting ischemic liver injury by interfering with lysosomal autophagy

Two regimens designed to ameliorate hepatic injury from complete liver dearterialization (LD) by interfering with lysosome-mediated proteolysis were studied in 200-g Buffalo rats. Five rats received a lysosome membrane-stabilizing flavenoid, catechin, 200 mg/kg/day for 5 days pre-LD. Five others were infused with lysosome protease inhibitors (LPI), leupeptin and pepstatin, delivered in 0.22-micron multilamellar liposomes at 500 micrograms each per hour for 2 hr, beginning 20 min before LD. Control groups (n = 4 or 5) were untreated LD, and treated and untreated sham LD rats. Blood from an arterial catheter pre-LD and 2 hr (peak enzyme release), 2 days, and 4 days post-LD yielded beta-glucuronidase (BG), aspartate transaminase (AST), and alkaline phosphatase values for each rat. Liver histology was not different between groups at 4 days post-LD. Untreated controls and the catechin LD group had similar enzyme levels at all points. LPI treatment values were statistically similar to sham LD values and had peak values significantly lower (P less than 0.05) than untreated LD controls at 2 hr. BG, 75 +/- 10 (SD) units per liter versus 185 +/- 32 units per liter; AST, 134 +/- 47 units per liter versus 459 +/- 175 units per liter. The BG lowering persisted to day 2 (55 +/- 25 units per liter versus 93 +/- 40 units per liter). Other values remained normal or normalized by Day 2. Hepatic damage as measured by enzyme release was not diminished by the membrane stabilizer catechin but was diminished after ischemic injury by specific targeted lysosomal protease inhibitors.

Ultrasonic parathyroid localisation in previously operated patients

Sixty-two patients with hyperparathyroidism and failed prior neck surgery were examined by ultrasound before reoperation to localise abnormally enlarged glands. If mediastinal lesions are excluded, a total of 57 glands greater than 5 mm in size were removed from 48 patients. Ultrasound demonstrated only 18 of these for a true positive rate of 32%. There were 39/57 (68%) false negatives. In addition, there were 16 false positives. In our experience, the detection rate of ultrasound for enlarged parathyroid glands in patients with failed surgery is significantly less than that reported in previously unoperated patients (73%), or in the limited number of reported cases of patients with previous operations (75%). Our high false negative rate is probably partially due to the large number of posteriorly located small glands which cannot be adequately visualised by ultrasound. Nevertheless, because of its non-invasive nature, low cost and ready availability, ultrasound should be utilised as an initial screening procedure in patients with failed previous surgery.

Hepatic Arterial Infusion Chemotherapy: Clinical Trials with the Implantable Pump

Continuous infusion of chemotherapy agents into the arterial system of the liver has several theoretical advantages. The continuous administration of chemotherapy to the tumor prolongs drug exposure to the tumor cells undergoing DNA synthesis, thus increasing the cell-kill fraction. Previous anatomical studies in laboratory animals and humans have demonstrated that most hepatic tumors derive a majority of their blood supply from the hepatic artery as opposed to the portal vein.1,2 This phenomenon, along with the ability of the liver to metabolize certain chemotherapeutic drugs, allows a much higher local concentration of drug to reach the tumor, with reduced systemic effects. The extensive clinical experience with regional hepatic arterial therapy in the treatment of primary and metastatic liver tumors by means of extracorporeal pump devices is reviewed elsewhere in this volume. Suffice it to say that long-term ambulatory therapy with such systems remains inconvenient and has been associated with mechanical and infectious complications.3

Long-term hypolipidemic effect of portacaval transposition and distal intestinal resection without change in liver function tests☆

Partial ileal bypass and end-to-side portacaval shunt (PCS) have significantly reduced serum cholesterol levels in clinical use. PCS can cause deterioration of liver function. Portacaval transposition (PCT) may induce plasma cholesterol lowering equivalent to PCS without deleterious side effects. We have followed four dogs with PCT, two with 50% distal ileal resection (IR), and five with PCT + IR for 3 years, as well as four control animals for 1 year, and have measured their hepatic cholesterol synthesis, hepatic lipid concentration, and cholesterol turnover rates. The dogs at 3 years postoperatively are in good health without deterioration of liver function tests (BSP retention, bilirubin, GGT, SGOT, alkaline phosphatase) and BUN. Dogs with IR had 25% reduction of plasma cholesterol and 58% reduction of triglycerides; dogs with PCT had 36% reduction of plasma cholesterol (P < 0.01) and 39% reduction of triglycerides (P < 0.01); those with PCT + IR had 43% reduction of plasma cholesterol (P < 0.01) and 68% reduction of triglycerides (P < 0.001). Compared to normal dogs, IR dogs have increased cholesterol turnover rate (P < 0.05), hepatic total lipid (P < 0.02), free cholesterol (P < 0.01), and cholesterol esters (P < 0.01). PCT + IR dogs have increased hepatic cholesterol synthesis (P < 0.05), increased cholesterol turnover (P < 0.001), and increased hepatic free cholesterol (P < 0.05), and cholesterol ester (P < 0.05). Neither PCT nor IR alone affected the cholesterol-exchangeable pool sizes. However, the PCT + IR dogs, compared to normal dogs, have larger slowly (P < 0.05) and rapidly (P < 0.01) exchangeable cholesterol pool sizes. The rapidly exchangeable cholesterol pool size of PCT + IR was also larger than that after PCT alone (P < 0.01). In summary, there is significant and lasting 35+% reduction of plasma cholesterol and triglyceride for 36+ months after either PCT or PCT + IR without deterioration of liver function parameters. Combining the IR and PCT in euthyroid dogs does not significantly improve the cholesterol lowering and causes increased cholesterol pool sizes and hepatic cholesterol content. PCT dogs remained in good health, without deterioration of liver function, for 3 years. It is suggested that PCT may be an attractive clinical alternative to PCS, at least for lipid reduction.

Tumor stasis factor (TSF): a possible mechanism for the regulation of tumor cell proliferation.

A new class of factors that regulates tumor cell division in vitro can be isolated from fresh and cultured tumor cells by 3 M KCl extraction. Tumor stasis factors (TSF) inhibiting cultured tumor cell proliferation were extracted from 8 of 11 fresh human tumors and 2 cultured tumor cell lines. TSF inhibited [3H]Tdr incorporation by allogeneic and autologous cultured tumor cells in a dose-dependent manner. Extracts of normal human tissues and benign tumors did not demonstrate inhibition with the exception of liver. The mechanism of inhibition was cytostatic and not cytotoxic as demonstrated with trypan blue exclusion by tumor cells following TSF treatment, maintenance of intact tumor cell monolayers following addition of TSF, and lack of inhibition of Con A-mediated lymphocyte proliferation by TSF. TSF activity could be reversed by washing for up to 48 hr of incubation and was resistant to heat, pH alterations, reducing agents, proteases, and glycosidases. However, the active moiety bound to lentil lectin and could be purified 80-fold by preparative isoelectric focusing. These factors may represent a novel regulatory mechanism for tumor cell proliferation.

Quality of Life and Cost Effectiveness Issues in the Management of Patients with Hepatic Metastases from Colorectal Cancer

The intent of this chapter is to focus on relevant quality of life and cost effectiveness issues of new treatment strategies for patients who have colorectal cancer that has metastasized to the liver. At the present time, there is no potentially curative treatment except surgical excision of metastatic lesions. There is a danger of rediscovering limitations of old treatments by use of new technologies, unless carefully designed trials are performed. Unless treatment results in prolonged survival, the detrimental effects on quality of life that often accompany these chemotherapeutic regimens argue strongly against their use. It may be that the current strategy for clinical and research efforts in this field should be reexamined. The optimum management of the patient with hepatic metastases may not be part of routine cancer therapy and may still be an important area to investigate. Is it advisable that no more patients with hepatic metastases should be treated by infusion techniques unless they agree to participate in an experimental protocol? Also, should a no treatment control arm be required in all therapeutic trials? Only with a no treatment control arm can the survival, quality of life, and cost of these treatments be assessed properly.