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J H Shaw

Publications and source records attributed to J H Shaw.

At least 19 recordsLinked to original sources
PubMed1992

Microculture-based chemosensitivity testing: a feasibility study comparing freshly explanted human melanoma cells with human melanoma cell lines.

BACKGROUND: The culture of cancer cells has many applications in chemosensitivity testing and new drug development. PURPOSE: Our goal was to adapt simple semiautomated microculture methods for testing the chemosensitivity of melanoma cells freshly recovered from patients' tumors. METHODS: Cells were cultured on a substrate of agarose and exposed continuously to cytotoxic drugs, the effects of which were measured by determining the uptake of [3H]thymidine 4-7 days later. RESULTS: Immunocytochemical staining of cells cultured with 5-bromo-2'-deoxyuridine demonstrated that tumor cells were responsible for the measured thymidine incorporation. The effects of cytotoxic drugs were calculated as logarithmic 50% inhibitory concentrations and expressed as divergences from the mean in a log-mean graph. The inhibitory effects of amsacrine, etoposide, doxorubicin, cisplatin, mitomycin C, and fluorouracil were tested. Tumors differed widely in their sensitivity to these drugs, although sensitivity to the three topoisomerase-II-directed agents was highly correlated. Cells from two non-neoplastic hematopoietic progenitor cell lines (FT and 32D) showed chemosensitivity patterns distinct from those in the melanoma cells, indicating tissue selectivity. Two established melanoma cell lines, MM-96 and FME, were tested under the same conditions and showed sensitivity typical of at least some fresh specimens. CONCLUSIONS: These results support the validity of melanoma cell lines as models of freshly resected melanoma cells. If successfully applied to other tumor types, such semiautomated approaches could find wide application in routine hospital laboratories for the chemosensitivity testing of patients' tumor cells.

Animals↗
PubMed1992

The effect of tumor bulk on the metabolic response to cancer.

The derangements in energy/substrate metabolism seen in oncology patients are similar regardless of the tumor's site of origin, and in advanced disease these metabolic derangements can be manifested as cancer cachexia. The relationship between tumor size and the degree of metabolic abnormality, however, remains unclear. Using primed constant infusions of stable and radiolabeled isotopes and indirect calorimetry, the authors have determined the rates of net protein catabolism (NPC), glucose oxidation, Cori cycling of glucose, and oxygen consumption in 85 patients with cancer. They have assessed the association between bulk of tumor and metabolic abnormality using regression analysis. A positive correlation was found between tumor bulk and the rates of NPC (r2 = 0.8), plasma glucose appearance (r2 = 0.72), plasma glucose clearance (r2 = 0.70), the percentage of tissue glucose uptake recycled to lactate (r2 = 0.62), and oxygen consumption (r2 = 0.79). The percentage of tissue glucose uptake oxidized was negatively correlated with tumor bulk (r2 = 0.75). The data indicate that the degree of metabolic abnormality seen in cancer patients is closely related to the quantity of malignant tissue present. Progressive increase in tumor size is associated with an increase in peripheral substrate mobilization, an increase in the rate of hepatic glucose production, an increase in tissue glucose uptake, an increase in energy-expensive glucose cycling to lactate, and an increase in protein loss.

Adolescent↗
PubMed1992

A possible role for IGE-II: evidence in sheep for in vivo regulation of IGF-I mediated protein anabolism.

Using primed constant infusions of [14C]urea we assessed the effects in castrate male lambs of insulin-like growth factor (IGF) II infusion on protein metabolism during concurrent IGF-I infusion. A 300 minute infusion of IGF-I at 15 micrograms/kg.hour (n = 4) increased (p less than 0.001) the plasma IGF-I concentration from 72.5 +/- 6.4 ng/ml to 213.6 +/- 17.4 ng/ml and decreased (p less than 0.01) the rate of net protein catabolism (NPC) from 1.48 +/- 0.28 g/kg.day to 1.02 +/- 0.18 g/kg.day. Infusion of IGF-II at a dose of 50 micrograms/kg.hour concurrently with IGF-I at 15 micrograms/kg.hour (n = 4) was associated with a similar rise (p less than 0.01) in plasma IGF-I concentration from 79.4 +/- 4.1 ng/ml to 225.2 +/- 32.8 ng/ml. Plasma IGF-II increased (p less than 0.05) from 350.6 +/- 41.6 ng/ml to 746.7 +/- 165.5 ng/ml over the infusion. Coadministration of IGF-II completely blocked (p less than 0.01) the anabolic effect of IGF-I and the rate of NPC remained unchanged throughout the combined IGF-I and IGF-II infusion at a level comparable to saline infused controls (n = 4). This study suggests that IGF-II may play a physiological role as a circulating modulator of the anabolic effects of IGF-I.

Animals↗
PubMed1992

Synergistic effect of insulin-like growth factor-I administration on the protein-sparing effects of total parenteral nutrition in fasted lambs.

Using primed constant isotopic infusions, we investigated the effects of recombinant human insulin-like growth factor-I (IGF-I) infusion on protein kinetics in both fasted and parenterally fed (TPN) lambs. Infusion of IGF-I at a dose of 50 micrograms/kg.h in fasted animals increased (P less than 0.005) the mean plasma IGF-I concentration from 77.5 +/- 9.7 to 454.4 +/- 51.4 ng/ml. During IGF-I infusion the rate of net protein catabolism (NPC) was decreased (P less than 0.005) by 17% from 3.5 +/- 0.2 to 2.9 +/- 0.2 g/kg.day, and the rate of appearance (Ra) of leucine in plasma decreased (P less than 0.01) from 5.0 +/- 0.4 to 3.4 +/- 0.4 mumol/kg.min. In addition, the fractional synthetic rate of protein in cardiac and diaphragmatic muscle increased by 100% (P less than 0.05) during the same period. After 3 h of TPN, the rate of NPC was decreased (P less than 0.01) in the TPN animals compared to that in their fasted counterparts (1.89 +/- 2.27 vs. 4.1 +/- 0.2 g/kg.day, respectively). The rate of NPC was further decreased after another 300 min of TPN to 0.76 +/- 0.27 g/kg.day. However, the Ra of leucine was not changed compared to the initial value. Infusion of IGF-I concurrently with TPN reversed (P less than 0.001) the rate of NPC from 1.02 +/- 0.21 g/kg.day after 180 min of TPN alone to a state of net protein gain of 0.14 +/- 0.19 g/kg.day after a further 300 min of combined IGF-I and TPN infusion. The Ra of leucine decreased (P less than 0.01) from 3.9 +/- 0.8 to 2.5 +/- 0.47 mumol/kg.min during IGF-I and TPN infusion. Similarly, the fractional synthetic rates of protein in cardiac muscle, diaphragm, adductor muscle, psoas muscle, and hepatic tissue were increased (P less than 0.05) compared to those in animals that received only TPN. The protein-sparing effects of IGF-I and TPN were synergistic, and the infusion of both agents resulted in the induction of a protein anabolic state within 60 min of commencing IGF-I infusion. In contrast, neither IGF-I nor TPN alone resulted in a state of net protein anabolism, and neither had an effect on protein kinetics until 120 min into the infusion. Consequently, IGF-I shows considerable potential as an anticatabolic agent when used synergistically with nutritional support.

Animals↗
PubMed1992

Passive immunization against circulating insulin-like growth factor-I (IGF-I) increases protein catabolism in lambs: evidence for a physiological role for circulating IGF-I.

Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1.69 +/- 0.16 g/kg per day from a baseline value of 1.45 +/- 0.22 g/kg per day (P < 0.05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1.31 +/- 0.20 to 1.59 +/- 0.16 g/kg per day (P < 0.05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved.

Animals↗
PubMed1991

Merkel cell tumour: clinical behaviour and treatment.

We have reviewed 30 reports of Merkel cell tumour and described a further five cases in order to establish a database and from this more clearly define the biology of this tumour, prognostic factors that govern outcome, and optimal management. After excision alone of the primary lesion, local recurrence occurred in 39 per cent of patients and regional failure occurred in 46 per cent. In contrast, in patients treated by excision plus prophylactic treatment (adjuvant node dissection and/or adjuvant radiation), local recurrence occurred in 26 per cent and regional failure in 22 per cent. Locoregional recurrence carried an ominous significance with 67 per cent of patients subsequently dying of the disease. For patients who either presented with regional disease or later developed regional disease, the best outcome (44 per cent survival with mean follow-up of 40 months) was obtained following treatment by therapeutic node dissection with or without radiation. In contrast, treatment of regional disease with radiation alone was associated with only a 20 per cent survival rate. Unfavourable prognostic factors included young age, lesions sited in the head and neck or trunk, male sex, and the presence of locoregional failure and/or systemic disease. We conclude that Merkel cell tumours behave in a similar manner to the aggressive variants of melanoma and that minimal treatment consists of wide surgical resection of the primary lesion (with a margin of 2.5-3 cm) coupled with resection and probably also radiation of regional disease if present. In addition, consideration should be given to prophylactic node dissection in node negative patients, especially in those patients with unfavourable prognostic factors.

Adult↗
PubMed1991

The circulating molecular weight forms of infused recombinant insulin-like growth factor-I and effects on glucose and fat metabolism in lambs.

We have investigated the relationship between the plasma distribution of infused recombinant insulin-like growth factor-I across the insulin-like growth factor binding proteins and the resultant effects on glucose and fat metabolism. The studies were performed in 24-h fasted ram lambs which received primed constant infusions of 3H labelled glucose tracer. When isotopic equilibrium had been reached, the animals received 90-min infusions of human insulin-like growth factor-I at various doses (2.5, 20, 40 and 120 micrograms.kg-1.h-1, n = 3 for each dose). Total plasma insulin-like growth factor-I was significantly elevated by infusion at a rate of 40 micrograms.kg-1.h-1 (from 185 +/- 14 micrograms/l to 442 +/- 41 micrograms/l, p less than 0.05) and 120 micrograms.kg-1.h-1 (from 181 +/- 2 micrograms/l to 953 +/- 39 micrograms/l, p less than 0.005). The plasma concentrations of insulin-like growth factor-I not associated with binding proteins remained undetectable (less than 15 micrograms/l) at the end of the 2.5 and 20 micrograms.kg-1.h-1 doses, but were significantly elevated at the end of the 40 and 120 micrograms.kg-1.h-1 infusions (to 71 +/- 14 micrograms/l, p less than 0.05 and 176 +/- 55 micrograms/l, p less than 0.01 respectively). The infused insulin-like growth factor-I associated primarily with 35-60 kilodalton binding proteins. Glucose kinetics were significantly altered only by the highest dose infusion, during which there was a fall in plasma glucose concentration from 3.5 +/- 0.2 mmol/l to 1.9 +/- 0.2 mmol/l (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of recombinant IGF-I on protein and glucose metabolism in rTNF-infused lambs.

Achieving nitrogen accretion in patients with critical surgical illness or cancer cachexia is often not possible by the simple provision of calories and nitrogen. Cachexia may result from the metabolic derangements caused by release of inflammatory mediators such as tumor necrosis factor (TNF). We wished to determine whether recombinant human insulin-like growth factor I (rhIGF-I) preserves its protein-sparing effects in the face of high plasma TNF concentrations. Primed constant infusions of [15N]urea and [6-3H]glucose tracers were used to measure protein and glucose kinetics in fasted lambs. The lambs were divided into four groups: two groups received normal saline infusions of 480 min, and two groups received recombinant TNF (rTNF) infusions of 1 microgram.kg-1.h-1. During the last 300 min, one of the normal saline and one of the rTNF-infused groups were infused with rhIGF-I at a dose of 50 micrograms.kg-1.h-1. rTNF infusion resulted in the lambs becoming febrile and significantly increased plasma cortisol, glucagon, and insulin levels. rhIGF-I infusion in the control animals reduced the rate of loss of protein by 15% (P less than 0.01) and increased the rate of peripheral glucose clearance by 55% (P less than 0.01). rhIGF-I infusion in the rTNF-treated animals reduced the rate of net protein loss by 15% (P less than 0.01) and caused similar changes in glucose kinetics, as were observed in the control animals. We conclude that as rhIGF-I preserves its protein anabolic action in the face of high rTNF levels, further investigation into a possible clinical role for rhIGF-I in severe surgical illness is warranted.

Animals↗
PubMed1991

The effects of infusion of insulinlike growth factor (IGF) I, IGF-II, and insulin on glucose and protein metabolism in fasted lambs.

In vivo effects of 300-min infusions of recombinant insulinlike growth factor I (IGF-I) and IGF-II on glucose and protein metabolism have been investigated in awake, fasted lambs. Two doses of recombinant human (rh) IGF-I were infused: 6.7 nmol/kg.h, which induced hypoglycemia, and 2.0 nmol/kg.h, which did not. The effects were compared with an insulin infusion (0.17 nmol/kg.h) that had the same hypoglycemic potential as the high dose rhIGF-I infusion. rhIGF-II was infused at a rate of 6.7 nmol/kg.h. Primed constant infusions of isotopically labeled glucose, urea and leucine tracers were used to determine glucose and protein kinetics. rhIGF-I lowered blood glucose by increasing the rate of glucose clearance (P less than 0.01), in contrast to insulin, which both increased clearance and reduced glucose production. Net protein loss was reduced after infusion of low and high dose rhIGF-I and insulin by 11% (P less than 0.05), 15% (P less than 0.01), and 12% (P less than 0.05), respectively. rhIGF-II infusion did not alter the rate of net protein loss. In contrast to insulin, high dose rhIGF-I infusion increased the rate of protein synthesis in skeletal (P less than 0.05) and cardiac muscle (P less than 0.01) and in hepatic tissue (P less than 0.05). We conclude that (a) protein metabolism is more sensitive than glucose metabolism to rhIGF-I infusion, as protein loss was reduced by an rhIGF-I infusion that did not alter glucose kinetics; (b) protein synthesis is increased by rhIGF-I infusion but not by insulin infusion; and (c) rhIGF-II is a less effective anabolic agent than rhIGF-I. We speculate that the effects of rhIGF-I on protein metabolism are not mediated by insulin receptors.

Animals↗
PubMed1991

Gastropod availability and habitat utilization by wapiti and white-tailed deer sympatric on range enzootic for meningeal worm.

Gastropod occurrence and the utilization of habitat by sympatric populations of wapiti (Cervus elephus) and white-tailed deer (Odocoileus virginianus) on range enzootic for meningeal worm (Parelaphostrongylus tenuis) were studied on Cookson Hills Wildlife Management Area (WMA) in eastern Oklahoma. Visual observations and fecal pellet group transect data indicated that wapiti spent the majority of their time in open fields and meadows where we recovered the least numbers of gastropods. Although deer were frequently observed in open areas, visual sightings and transect data indicated that they spent more time in forested areas where we recovered the most gastropods. Gastropods harbored low numbers of P. tenuis larvae (0.00 to 0.06 larvae/gastropod) in all habitat types with the greatest recovery from red oak white oak-hickory forests (0.34 larvae/gastropod). Our results indicate that the reason a viable wapiti herd exists on Cookson Hills WMA in a P. tenuis enzootic area is at least partially because of the habitat preference by wapiti and the reduced availability of infected gastropods in the selected areas prefered by the wapiti. We were not able to detect any free-ranging wapiti that were shedding P. tenuis larvae nor were we able to detect past or sub-clinical infections with P. tenuis in wapiti.

Animals↗
PubMed1991

Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support.

We have performed intraoperative isotopic infusions of carbon 14-labeled leucine in 65 patients to define the abnormalities in protein metabolism at both the whole-body and tissue level in patients with weight-losing and non-weight-losing cancer. Eighteen patients had benign disease, 26 had non-weight-losing cancer, and 21 had cancer cachexia. Samples of plasma and expired breath were taken to determine rates of whole-body protein synthesis (WBPS), whole-body protein catabolism (WBPC), net protein catabolism, and albumin fractional synthetic rates. Tissue samples were taken to determine the fractional synthetic rates (FSR) of protein in muscle, liver, cancer, and the tissue in which the cancer arose. In addition, in 14 patients the effect of nutritional support on protein metabolism was assessed. In all parameters examined we were unable to detect any significant differences between patients with no cancer and the patients with non-weight-losing cancer. In contrast, patients with cancer cachexia had a significant elevation (p less than 0.005) in WBPC compared with the other two groups. WBPS was also elevated (to a lesser extent) in the patients with cancer cachexia, and the rate of net protein catabolism was increased significantly (p less than 0.05). Patients with cancer cachexia also had significantly higher values of FSR of protein in muscle (p less than 0.05), liver (p less than 0.05), and albumin (p less than 0.01) compared with the other two groups. In addition, the protein FSR in the cancer rose progressively when the values for the primary cancer were compared with those for nodal and systemic metastases. Further, although nutritional support resulted in an increase in host muscle protein synthesis (p less than 0.04), there was no promotion of FSR of protein in cancer. We conclude that patients with cancer cachexia are actively losing protein as a result of an increase in WBPC that is only partially compensated for by an increase in WBPS. There are compensatory increases in protein synthesis in muscle and liver, but these increases in host protein synthesis are insufficient to keep pace with the combined effect of the accelerated rate of protein synthesis in the cancer per se and the accelerated rate of net protein catabolism at the whole-body level. In response to nutritional support, there is a significant increase in the muscle protein synthesis, but we could not demonstrate any increase in cancer protein synthesis.

Adult↗
PubMed1990

Metabolic effects of cancer.

The potential causes of deranged metabolism in cancer are discussed with emphasis on changes in energy metabolism of glucose, fat and protein. The implications of these changes for the treatment of cachexia are then considered.

Cachexia↗
PubMed1990

Complications and local recurrence following lymphadenectomy.

We have retrospectively reviewed the case notes of 208 patients undergoing either cervical, axillary, or inguinal lymphadenectomy with a view to determining the factors that predispose to complications and local recurrence. The most frequent complications were wound infection, seroma formation, paraesthesiae and lymphoedema. The main predisposing factor for complications was anatomical site; wound complications occur with twice the frequency in the inguinal lymphadenectomy group than in the two other sites. Preresection biopsy was also associated with an almost twofold increase in complications, while fine needle aspiration cytology was not. The two major factors influencing the incidence of local recurrence were the stage of the disease process and the use of preresection biopsy. There was a steady increase in the incidence of local recurrence with increasing stage of regional disease. In addition, local recurrence was almost twice as common in patients who had undergone biopsy before resection when compared with patients who either did not have tissue sampling before resection or had fine needle aspiration cytology alone. We conclude that fine needle aspiration cytology is safe and the investigation of choice in patients undergoing lymphadenectomy. In contrast, preresection biopsy should be avoided as it promotes both complications and local recurrence. In addition, wound complications and lymphoedema are frequent following lymphadenectomy, especially following inguinal dissection.

Adolescent↗
PubMed1990

Metabolic effects of recombinant human growth hormone: isotopic studies in the postabsorptive state and during total parenteral nutrition.

We have performed a series of isotopic studies in 25 adult patients with sepsis and/or trauma in order to determine the metabolic effects of recombinant human growth hormone (rHGH) administration. Twelve of the patients were receiving total parenteral nutrition, and 13 were eating a normal ward diet and were studied postabsorption. Energy and protein kinetics were quantified isotopically before rHGH administration and following a 3-day course of rHGH (20 units subcutaneously daily). In the total parenteral nutrition group the rate of net loss of protein decreased from 0.82(0.17) g kg-1 day-1 to 0.43(0.20) g kg-1 day-1 (P less than 0.02) following the administration of rHGH. The rate of appearance of leucine was not altered, suggesting that the improvement in nitrogen balance following rHGH was because of an increased rate of protein synthesis rather than reduced catabolism. In the postabsorptive group, rHGH treatment significantly increased the rate of appearance of free fatty acids (from 7.4(2.2) mumol kg-1 min-1 to 11.1(2.6) mumol kg-1 min-1, P less than 0.03) and free fatty oxidation (from 1.3(0.4) mumol kg-1 min-1 to 1.7(0.4) mumol kg-1 min-1, P less than 0.06), while the rate of leucine oxidation was reduced (from 0.44(0.05) mumol kg-1 min-1 to 0.26(0.03) mumol kg-1 min-1, P less than 0.005). Glucose appearance and oxidation remained unchanged. These results suggest that fat was being oxidized in preference to protein, which resulted in a reduction in the net rate of loss of protein of 0.3 g kg-1 day-1 (P less than 0.05). We conclude that rHGH administration is capable of significantly reducing net protein loss in septic or injured surgical patients. Recombinant HGH may be clinically useful in supporting critically ill surgical patients who require intensive nutritional support.

Adult↗
PubMed1990

Carcinoma of the thyroid gland in Auckland, New Zealand.

We have reviewed the Auckland experience (1969 to 1987) of 212 instances of carcinoma of the thyroid gland. Females outnumbered males by 4:1, the average age of the patients was 46 years and differentiated cancer was more common (180) than either anaplastic (20) or medullary carcinoma (12). The incidence was higher in the Polynesian patients, most of whom were born outside of New Zealand, than in Maori or European patients, most of whom were born in New Zealand. Patients with papillary carcinoma fared well with greater than 90 per cent of the patients alive at the time of the study, while the corresponding figure for follicular carcinoma was 70 per cent. For both types of differentiated carcinoma of the thyroid gland, the best results, in terms of outcome and morbidity, occurred after total ipsilateral lobectomy and partial contralateral lobectomy (TL + CLPL). In neither type of operation was the use of an adjuvant radioiodine therapy of any obvious benefit. The incidence of permanent complications was twice as high after total thyroidectomy than for TL + CLPL. In contrast with the situation regarding adjuvant radioiodine, patients who presented with systemic follicular carcinomatosis responded well to therapeutic radioiodine, and if thyroidectomy could also be accomplished, the outcome was good. Most patients with anaplastic carcinoma presented with unresectable disease and no regimen used made any impact on the biologic factors of the disease. All but one of the patients with medullary carcinoma had the sporadic variant, and the results were similar after performing either unilateral operation or total thyroidectomy. Carcinoma of the thyroid is more common in Polynesians born in Pacific Islands than in Caucasians or Maoris born in New Zealand. For differentiated carcinoma of the thyroid gland, a satisfactory combination of outcome and morbidity is accomplished with TL + CLPL. Although therapeutic radioiodine is effective in patients with metastatic differentiated carcinoma of the thyroid, we could not show that surgical treatment plus adjuvant radioiodine yielded better results than surgical treatment alone. The major prognostic factors governing the outcome were the histologic type (most patients with papillary carcinoma survive; most patients with anaplastic carcinoma die irrespective of treatment, and patients with follicular and medullary lesions have an in-between outlook) and the presence of systemic disease. The presence of regional disease did not appear to influence the outcome.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma↗