Murray F. Brennan

Abnormal liver function during parenteral nutrition: Relation to infusion excess

Abnormalities of liver function are frequently noted during the course of total parenteral nutrition (TPN) [6, 9, 14-171. While the functional significance of increases in “liver function tests” (LFTs) is unclear, a broad spectrum of histological changes including fatty infiltration [6, 9, 14, 15, 171, glycogen deposition [ 14, 151, and cholestasis [17] are reported to coincide with LFT abnormalities in adults. Among the proposed etiologies for such changes during TPN are excessive dextrose infusion [14, 15, 171, toxicity or imbalances of infused amino acids [6, 171, and concurrent essential fatty acid deficiency [ 111. A uniform finding among previous studies has been a temporal relationship of 1 to 3 weeks between the onset of parenteral feeding and the appearance of abnormal LFTs. This finding suggests that alterations in liver function and histology may be related to the rate of TPN infusion or to an excessive cumulative load of parenteral nutrition solutions. Parenteral Nutrition and Laboratory Methods

Divalent cation metabolism: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Abstract Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m 2 (mean ± 1 standard deviation [SD] p p p p p p p

A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk

Since 1977, 31 patients were entered in a randomized, prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment of high‐grade sarcomas of the head, neck, breast, and trunk (excluding retroperitoneal sarcomas). All patients had complete resection of gross tumor and underwent postoperative radiotherapy (6000–6300 rads over 7–8 weeks). Seventeen patients received adjuvant chemotherapy consisting of doxorubicin (⩽550 mg/m2), cyclophosphamide (⩽5500 mg/m2), and methotrexate (⩽1000 mg/kg). Three‐year actuarial disease‐free survival in the chemotherapy arm was 77%, compared to 49% in the no‐chemotherapy arm (P = 0.075). Three‐year overall actuarial survivals in the two treatment arms, however, were 68% and 58%, respectively (P = 0.38). Considering only patients with tumors of the trunk (22 patients), 3‐year actuarial disease‐free survival in the chemotherapy arm was 92%, compared to 47% in the no‐chemotherapy arm (P = 0.006). Actuarial 3‐year overall survival in the chemotherapy arm was 82%, compared to 61% in the no‐chemotherapy arm (P = 0.18). An additional 26 patients were treated in an identical fashion, but were not part of the randomized trial because of contraindications to chemotherapy, refusal to enter the randomized trial, or because they were treated before 1977 in a trial in which all patients received chemotherapy. Considering the entire group of 57 patients, follow‐up ranged from 10 to 86 months (median, 35 months). Local control was achieved in 46 patients (81%); 3‐year actuarial disease‐free and overall survivals were 67% and 77%, respectively. A tendency toward improved disease‐free survival was apparent among patients treated with chemotherapy (P = 0.018), but there was no statistically significant improvement in overall actuarial survival (P = 0.46). The subgroup of patients with sarcomas of the trunk (39 patients) demonstrated the greatest benefit from chemotherapy, with regard to disease‐free survival (P < 0.001). The most significant toxicity associated with chemotherapy was doxorubicin‐induced cardiomyopathy, which resulted in clinically apparent congestive heart failure in five patients. Thus, the use of chemotherapy when combined with aggressive local measures appears to improve disease‐free survival, but additional patients and longer follow‐up are necessary to determine if improved overall survival will result. Cancer 55:1206‐1214, 1985.

A controlled, prospective, randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient.

In order to evaluate the metabolic effects of enteral versus parenteral nutritional support in the cancer patient, patients with localized, squamous cell carcinoma of the distal esophagus were randomized to one of three nutritional regimens: oral feeding, jejunal feeding, or total parenteral nutrition (TPN). Patients were initially studied in the postabsorptive state and again two weeks after beginning, and while receiving, enteral or parenteral feedings. Radioisotopic tracer methods were utilized to evaluate parameters of glucose and alanine kinetics, and arterial substrate and hormone levels were measured. Arterial plasma glucose and blood lactate levels increased and plasma free fatty acid, serum triglyceride, and serum cholesterol levels decreased to comparable levels in patients receiving jejunal feedings or TPN. Changes in serum insulin, plasma glucagon, serum cortisol, serum growth hormone, and serum thyroxine were similar in patients receiving enteral and parenteral nutrition. Enteral and parenteral nutrition also had comparable effects on both alanine and glucose kinetics. In particular, both jejunal feedings and TPN were equally efficacious in markedly suppressing gluconeogenesis in the cancer patient. Our data would support the conclusion that there are few, if any, differences in the measured metabolic effects of enteral versus parenteral nutritional support in the group of cancer patients studied.

The quantitative and qualitative impairment of wound healing by adriamycin

Clinical impression suggests that Adriamycin (ADR) interferes with wound healing. To examine the effects of ADR on wound healing, male Fischer rats were subjected to a dorsal, midline, full‐thickness longitudinal incision (day 0). Wound clips were removed on day +7. Twenty animals per group were given intravenous ADR on day −7, day 0, day +3 and day +7. Twenty animals served as non‐treated, wounded controls (C). Five animals/group were sacrificed on days +7, +14 and +21, at which time two 9.5 mm wide strips were taken from each animal perpendicular to the wound axis and submitted for wound breaking strength (WBS) measurements and load‐extension curve analysis. WBS differed most markedly at Day 21 between C(1671 ± 59g) and ADR day −7(1360 + 71 g) p < 0.01; C and ADR day 0 (1051 ± 108 g) p < 0.001; C and ADR day +3(1134 ± 176 g) p < 0.02. No difference existed between C and day +7 (1790 ± 153 g). A point of inflection always occurred between 55–60% elongation in ADR treated animals only. This portion of the curve has been previously shown to represent collagen content. It is concluded that perioperative ADR administration (day −7 through day +3) significantly and substantially impairs skin wound healing in the rat. A form of collagen yielding underlies and may contribute to this defect. Cancer 43:932–938, 1979.

In vivo utilization of substrate by human sarcoma‐bearing limbs

Human sarcoma‐bearing limb substrate utilization was characterized by studying 10 otherwise healthy patients with extremity sarcomas (five osteosarcomas, five soft tissue sarcomas). All patients were studied in the postabsorptive state. Extremity blood flow was measured using a non‐invasive capacitance plethysmograph. Percutaneous arterial and venous effluent blood samples from the tumor‐bearing (TB) and control extremity were obtained and flux was calculated for free fatty acids (FFA), glucose, and amino acids. The control limb showed a release of amino acids similar to that reported previously. There was a dramatic difference in the TB extremity, which consistently released fewer amino acids. Both the TB and control limbs released FFA at the same rate. A significant difference in glucose uptake between TB and control limbs was noted for soft tissue sarcoma patients but not osteogenic sarcoma patients. The amount extracted correlated with excised tumor size and gluconeogenic amino acid release from the contralateral normal limb. This study suggests that the tumor‐bearing limb ignores the inherent conservation mechanisms in the postabsorptive state and continues to utilize substrate, apparently at the expense of host tissues.

A controlled, randomized trial evaluating the effects of enteral and parenteral nutrition on protein metabolism in cancer-bearing man

To characterize the effects of enteral versus parenteral nutritional support on protein metabolism in the cancer patient, patients with localized, squamous cell carcinoma of the distal esophagus were randomized to receive nutritional support as follows: (1) if there was a loss of less than 20% of the preillness body weight, patients were randomized to continue eating ad libitum (group I) versus receiving total parenteral nutrition (TPN) (group II); (2) if there was a loss greater than 20% of the preillness body weight and/or the patient was unable to swallow, patients were randomized to jejunostomy feedings (group III) versus TPN (group IV). Patients were initially studied in the postabsorptive state and again 2 weeks after beginning, and while receiving, enteral or parenteral feedings. Stable isotopic tracer methods utilizing constant infusion of [15N]glycine were used to determine whole-body protein turnover (flux), synthesis, and catabolism. Skeletal muscle catabolism was determined by measuring the urinary excretion of 3-methylhistidine and lean tissue mass was evaluated by determining total-body potassium by 40K whole-body scanning. Positive nitrogen balance was obtained in groups II and IV associated with significant weight gain in both; the changes in weight were not significant in groups I and III. Whole-body protein flux increased in all groups, but significantly only in group II. Synthesis increased in groups II and IV and decreased in I and III, but not significantly. Catabolism tended to decrease in all groups but group I. Urinary 3-methylhistidine excretion decreased in groups II and IV signifying decreased skeletal muscle catabolism, but increased in groups I and III. Total body potassium tended to increase in groups II and IV. In this group of patients with localized squamous cell carcinoma of the esophagus, both TPN and jejunal feedings tended to stabilize nutritional status and whole-body protein economics. TPN appeared to be slightly more efficacious, although the differences between enteral and parenteral nutritional support in this study were slight.

The development of gene therapy for the treatment of cancer

ObjectiveThe authors sought to develop new treatments for patients with cancer based on the genetic modification of immune lymphocytes and tumor cells designed to increase the host immune reaction against growing cancers. MethodsRetroviral-mediated gene transduction was used to introduce genes into tumor-infiltrating lymphocytes (TIL), and these genetically altered TIL were administered to patients with cancer. Genes coding for cytokines were introduced into tumor cells, and these cells were used to immunize patients against their autologous cancers. ResultsIn initial studies, the gene for neomycin phosphotransferase was introduced into the TIL of ten patients with advanced cancer to study the survival and distribution of TIL in humans. These studies showed that retroviral gene transduction is a safe and practical method for adding genes to human cells and led to clinical trials in which the gene for tumor necrosis factor (TNF) was inserted into TIL in an effort to increase their therapeutic effectiveness. Phase I trials are currently underway using TIL that secrete up to 100 times the normal level of TNF. More recently, animal experiments have revealed that transduction of tumor cells with cytokine genes can enhance tumor immunogenicity and, thus, increase the recognition of the tumor as foreign by the host. Clinical trials based on these observations have begun in which patients are immunized against their own autologous tumors that were transduced with the genes for TNF or interleukin-2. ConclusionsAttempts at gene therapy for cancer are underway and have opened new possibilities for the development of cancer treatments.

The influence of tumor-bearing on protein metabolism in the rat.

Abstract The effects of tumor on protein metabolism in F344 male rats in three different nutritional states (baseline, fasting, and refeeding) were studied. Nitrogen intake and output were measured and [ 15 N]glycine was infused intravenously. Urine was analyzed for [ 15 N]urea enrichment to measure whole body protein turnover, and 15 N tissue enrichment was analyzed to determine tissue fractional synthesis rates (FSR). Urinary 3-methylhistidine was measured as an indicator of muscle catabolism. Nitrogen balance data were similar in control (C) and tumor-bearing (TB) animals. Whole-body protein turnover was increased in TB animals. Liver fractional synthesis rates were increased in TB animals. Muscle FSR were decreased in TB animals. Urinary 3-methylhistidine was increased in TB animals. Tumor FSR remained the same despite different nutritional states. These findings indicate that TB protein cachexia begins insidiously. Despite normal nitrogen balance, the TB animal has increased protein turnover and liver FSR. Tumor tissue protein synthesis continues undisturbed, while muscle protein synthesis is reduced and muscle catabolism is increased.

Autotransplantation of cryopreserved parathyroid tissue in man

Human eryopreserved parathyroid autografts have been performed in six patients following reoperative parathyroid surgery. All patients were rendered hypoparathyroid by their most recent reoperation. Parathyroid tissue was successfully autotransplanted after as long as eighteen months of cryopreservation. Viability and expected in vivo function of cryopreserved parathyroid tissue may be predicted by in vitro testing of parathyroid hormone secretion in response to varying ambient calcium concentration. Parathyroid cryopreservation with subsequent autotransplantation is a practical solution to the problem of permanent hypoparathyroidism that may follow multiple surgical procedures for persistent hyperparathyroidism.