John M. Daly

Resection of the liver for colorectal carcinoma metastases. A multi-institutional study of long-term survivors.

In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized.

Perfusion of colorectal hepatic metastases. Relative distribution of flow from the hepatic artery and portal vein

The importance of portal circulation in the delivery of drugs and nutrients to colorectal hepatic metastases is controversial. Using 13N (nitrogen 13) amino acids and ammonia with dynamic gamma camera imaging, we demonstrate, for the first time in human beings, a quantitative advantage of hepatic artery compared with portal vein infusion. Eleven patients were studied by hepatic artery injection, five patients were studied by portal vein injection, and two patients had injections through both routes. Data collected from the liver for 10 minutes after rapid bolus injection of 13N L‐glutamate, L‐glutamine, or ammonia were compared with 99mTc (technetium) macroaggregated albumin (MAA) images produced after injection through the hepatic artery or portal vein at the same session. Tumor regions defined from 99mTc sulfur colloid scans were compared with nearby liver areas of similar thickness. For the 13N compounds, the area‐normalized count rate at first pass maximum (Qmax) and the tissue extraction efficiency were computed. The tumor/liver Qmax ratios for MAA and 13N compounds were highly correlated. Both tumor and liver extracted more than 70% of the nitrogenous compounds. The tumor/liver Qmax ratios reflect the relative delivery of injected tracer per unit volume of tissue. After hepatic artery injection the Qmax ratio was 1.03 ± 0.33 (mean ± SD), significantly exceeding the Qmax ratio of 0.50 ± 0.34 after portal vein injection (P < 0.003). Therefore, (1) more than twice as much of a nutrient substrate is delivered per volume of tumor relative to liver by the hepatic artery as by the portal vein; (2) the high extraction efficiency demonstrates that the hepatic artery flow is nutritive; and (3) the delivery of substance in solution (such as nutrients or drugs) to tumor and liver tissue correlates with the distribution of colloids such as macroaggregated albumin after hepatic arterial and portal venous injection.

Nutritional support in the cancer-bearing host: Effects on host and tumor

Cancer patients have the highest prevalence of malnutrition of any group of hospitalized patients. The potential causes of this malnutrition are numerous, as elements of both starvation and stress are evident in the cancer‐bearing host. The presence of the tumor alone may lead to reduced intake of nutrients and treatment modalities of surgery, chemotherapy, and radiation therapy further exacerbate nutritional deficits. It is clear that the tumor requires energy substrates to grow, and that these substrates are exacted from the host. Animal studies identify progressive nutritional depletion concommitant with increasing tumor growth during ingestion of a regular diet. This appears predominantly due to reduced dietary intake in addition to host metabolic alterations. In animal/tumor models deliberate dietary protein depletion results in severe host weight loss, but also causes diminished tumor growth rates. Dietary manipulation in these animal/tumor models have demonstrated methods of improving tumor response to chemotherapy by manipulation of tumor growth rates. In addition, drug‐pharmacokinetics have been altered by dietary manipulation. However, data from animal/tumor models are not directly applicable to man since the tumor in animals usually results in the death of the host within six to eight weeks. Nevertheless, controlled laboratory studies in animals provide basic metabolic information which promotes understanding of host/tumor relationships in man. In cancer patients malnutrition has prognostic value, leads to a distortion of body composition with erosion of body protein and fat stores, and compromises the delivery of adequate therapy. There is no direct objective evidence of accelerated tumor growth in humans with cancer who receive nutritional support as part of their treatment regimen. The host benefits to the extent that body composition is at least maintained during the period of nutritional repletion. Thus, nutritional support provides support to the patient during periods of treatment and dietary deprivation. No improvement in the tumors response to therapy, however, has been demonstrated by this approach.

Effects of nutritional depletion and repletion on plasma methotrexate pharmacokinetics

Clinically, a relationship exists among nutritional status, drug responsiveness, and host toxicity, but the effects of nutrition on chemotherapy drug metabolism are relatively unknown. This article evaluates the effect of malnutrition and nutritional repletion on plasma methotrexate (MTX) pharmacokinetics. In Study I, 55 non‐tumor‐bearing rats were fed regular diet (RD) (N = 27) or protein‐free diet (PFD) (N = 28) for 10 days. On day 10, MTX 20 mg/kg was injected intraperitoneally and four to six animals in each group were killed at 30 minutes, 1, 2, 6, 24, and 48 hours following MTX administration. Plasma MTX was measured by dihydrofolate reductase enzyme inhibition assay and was found to be significantly elevated (P < 0.01) in PFD animals as compared with RD animals at 1 and 2 hours following MTX injection. In Study II, 87 tumor‐bearing rats were fed RD (N = 29) or PFD (N = 58) for 10 days. At this time, 27 PFD rats were switched to RD (PFD → RD), while 31 rats remained on PFD. MTX 20 mg/kg was injected intraperitoneally and six to eight rats in each group were killed at 1, 2, 6, and 24 hours post‐MTX injection. Mean levels were found to be significantly elevated at 2, 6, and 24 hours in PFD (P < 0.01) and PFD → RD (P < 0.05) compared with RD rats. Several investigators have shown that increased plasma MTX levels at 24 and 48 hours after drug administration correlates with host toxicity in patients receving chemotherapy. In this experimental study, malnutrition delayed plasma MTX clearance, and nutritional repletion for 2 days was insufficient to return MTX pharmacokinetics to normal. These results in experimental animals suggest an explanation for increased MTX toxicity in malnourished individuals.

Tracer priming in human protein turnover studies with [15N] glycine☆

Sixty-three studies in healthy normal volunteers (n = 29), malnourished cancer (n = 8) or non-cancer patients (n = 9), and postoperative radical cystectomy patients (n = 17) were conducted to evaluate the primed constant infusion labeling technique for the estimation of whole-body protein turnover under a variety of dietary conditions. [15N]Glycine was used as the tracer with a prime to infusion ratio of 1300 to 3300 min and a continuous-infusion rate of 0.11 to 0.33 micrograms 15N . kg-1 . min-1 for 24 to 36 hr. The isotopic steady-state enrichment was reached in all subjects both in urinary urea and ammonia between 10 and 26 hr (mean 18 +/- 2). During protein calorie fasting the attainment of isotopic steady state is much quicker (10 to 18 hr) with a primed constant infusion than with a constant infusion alone (approximately 38 hr). A P/I ratio greater or less than 1800 (min) usually resulted in a delay of plateau attainment without affecting the protein turnover values. Reliable estimates of protein kinetics in humans can be made in clinical conditions with a 26-hr infusion of glycine at the rate of 0.28 microgram 15N . kg-1 . min-1 with a P/I ratio of 1800 min, collecting six urine samples every 2 hr from 16 hr and analyzing for both urinary urea and ammonia enrichments.

Complications in Surgery of the Colon and Rectum

Postoperative complications after surgery of the colon and rectum are related most often to sepsis, anastomotic disruption, hemorrhage, urinary tract injury, bowel stoma, and sexual dysfunction. Improved safety in colorectal surgery requires comprehensive preparation of the patient with attention to associated diseases, clear surgical judgement, excellence in technical skill, and aggressive postoperative management of any complications that may develop.

Alteration of methotrexate toxicity in rats by manipulation of dietary components

Administration of a chemically defined, elemental diet to rats given 20 mg/kg of methotrexate intraperitoneally has consistently resulted in a 100% mortality from severe enteritis within 156 h. This study examined the importance of specific dietary components in the etiology of this enhanced toxicity. Rats were given their respective diets for 7 days, whereupon methotrexate (20 mg/kg) was given intraperitoneally, and percent of survivors was recorded. Varying the concentration of carbohydrate as polysaccharide (0%, 50%, 100%) (n = 30) had no effect on survival. An increase in the percent of protein as polypeptide (0%, 25%, 50%, 75%, 100%) (n = 50) in the elemental diet resulted in a progressively significant increase in percent survival. Addition of either fat or bulk to this elemental diet had no effect on survivorship. Serum and bile methotrexate levels of rats fed an elemental liquid diet (whether or not all of the protein was provided as polypeptide) were significantly increased from 12 to 72 h (p less than 0.03) compared with rats fed a regular Chow diet. When the protein content of the elemental liquid diet was provided as 100% polypeptide, serum and bile methotrexate levels were significantly lower at 48 h compared with the elemental diet group given 100% of protein as amino acid. Administration of methotrexate to rats fed an elemental liquid diet in which all of the protein is provided as amino acids is extremely toxic to the gastrointestinal tract, probably as a result of delayed clearance of the drug from the systemic circulation and from bile. This toxicity is alleviated by the provision of protein as polypeptide in the elemental diet. No toxicity to the drug is seen at this dose in rats fed a regular Chow diet. If these results are applicable to humans, the use of elemental liquid diets as the only source of enteral nutrition would appear contraindicated in patients receiving methotrexate.

Value of splenectomy in non‐Hodgkin's lymphoma

A retrospective review of patients with non‐Hodgkins lymphoma (NHL) who underwent palliative splenectomy for splenomegaly, hypersplenism, or autoimmune complications was done. From 1970 through 1981, 46 patients had palliative splenectomy for splenomegaly alone (n = 3) or various hematologic abnormalities with (n = 35) or without (n = 8) splenomegaly. Splenectomy was performed for life‐threatening (n = 7), severe (n = 15), or mild (n = 24) symptoms/signs. The most common hematologic abnormalities were thrombocytopenia (platelet count < 120,000/mm3; n = 38) and/or anemia (hemoglobin level < 11.0 g/mm3; n = 29). Response to splenectomy was defined as greater than a threefold increase in preoperative platelet count and/or an increase in hemoglobin levels to greater than 11.0 g/mm3 in the first postoperative month. Four patients with thrombocytopenia did not respond, whereas 33 patients responded with greater than a sevenfold increase in platelet count. All four nonresponders died of complications of thrombocytopenia or progressive disease. Eighteen of 28 (64%) patients with anemia responded to splenectomy. Larger spleens (2000 g versus 1410 g; P < 0.05) and lower platelet counts (42,000 versus 75,000; P < 0.05) were found in all nonresponding patients. Responders and nonresponders could not be distinguished on the basis of age, sex, race, duration of disease or splenic involvement, primary site of disease, histopathologic findings, bone marrow or lymphangiogram results, or prior chemotherapy and radiotherapy. Patients with mild symptoms/signs were more likely to respond hematologically than patients with life‐threatening or severe symptoms/signs (86% versus 54%; P = 0.06). For all patients, 2‐ and 5‐year survival from the time of splenectomy was 44% and 26%, respectively. Median survival was 18 months (range, 1–144 months). Inability to reverse hematologic abnormalities was associated with poor survival. All nonresponding patients died within 36 months of surgery, whereas 5‐year survival in responding patients was 40%. Nine of 30 patients (30%) who responded hematologically survived longer than 5 years, but this group of patients could not be distinguished from the remaining patients on the basis of age, sex, race, duration of disease or splenic involvement, primary site of disease, histopathologic features, bone marrow or lymphangiogram results, or prior chemotherapy and radiotherapy. Surgery was well‐tolerated (mortality, 9%; morbidity, 21%). All surgical mortalities and 78% of complications occurred in patients operated on for life‐threatening or severe symptoms/signs. For optimal hematologic response, palliative splenectomy should be considered in NHL patients before the spleen becomes excessively large, the platelet count becomes excessively low, or life‐threatening or severe symptoms/signs develop from progression of the disease. Cancer 55:1256‐1264, 1985. Cancer 55:1256‐1264, 1985.

Intravenous hyperalimentation: techniques and potential complications.

Use and care of subclavian, peripheral venous, and cuffed catheters are described. Potential complications are also considered.

Potassium depletion and malignant transformation of villous adenomas of the colon and rectum

Epidemiologic evidence suggests that a high potassium intake inhibits the development of cancer, and a high sodium intake increases the incidence of gastrointestinal malignancy. Once malignant transformation occurs the sodium/potassium ratio in the cancer cell increases to more than three times that of a normal cell. The ionic redistribution seen in the cancer cell is similar to that seen in the potassium‐depleted state. The relationship between potassium depletion and the size at which villous adenomas of the large bowel undergo malignant transformation was examined in 144 patients. Villous adenomas containing invasive carcinoma were 40% smaller in potassium‐depleted patients than in normal patients indicating that in the potassium‐depleted state earlier malignant transformation had occurred. Cancer 53:1260‐1264, 1984.