Phenytoin intoxication associated with omeprazole administration in a child with defective CYP2C9.

Adverse drug reactions occur at a high rate in hospitalized children, frequently due to antiepileptic drug administration. Phenytoin is a commonly used drug, and its metabolism is mediated by a specific cytochrome-P450 isoform, CYP2C9, which is encoded by a polymorphic gene. It is worth noting that very frequently administered drugs, such as proton pump inhibitors, compete with phenytoin for CYP2C19-mediated metabolism. Here we describe a case of phenytoin intoxication in a child with defective CYP2C9, after omeprazole administration.

Pharmacokinetic effects of endoscopic gastric decontamination for multidrug gastric pharmacobezoars.

Introduction: Intentional multiple drugs overdose is an often-encountered method of self-harm in adolescence. Treatments include supportive therapy, antidotes (when available) and decontamination techniques with the aim of reducing drugs absorption by the gastrointestinal system to minimize toxicity. Nevertheless, the decontamination techniques currently used, such as gastric lavage (GL), activated charcoal or whole-bowel irrigation, have a questionable effectiveness. Endoscopic gastric decontamination (EGD) treatment for massive ingestion of drugs or formation of pharmacobezoars is currently described only in anecdotal cases. Here we describe the management of an intentional drug overdose in an adolescent patient treated with EGD and the effects of this therapy on drugs pharmacokinetics. Case report: A 15-year-old boy was admitted in an unconscious state (Glasgow Coma Scale: 7-8) to the pediatric intensive care unit after assuming an unspecified amount of quetiapine, aspirin, bisoprolol, fluoxetine, furosemide, alprazolam, and pregabalin pills. Rapid sequence intubation was immediately performed and then the patient was treated with symptomatic therapy and GL with minimal removal of gastric material. Accounting for the type of drugs, the time elapsed from oral assumption and the unknown quantity assumed, EGD was attempted with aim of removing potential aggregate of the drugs. Serial blood samples were taken before and after EGD to measure the plasma level of the drugs. A pharmacobezoar was found and was immediately removed with EGD. The results of the drug monitoring showed that quetiapine exceeded the toxic level reported in literature indicating that it may have been the drug assumed in higher quantity by our patient. PICU stay was uneventful, and the patient was transferred to the psychiatric ward after extubation. Discussion: Our case shows how GL is not effective in mitigating multidrug absorption especially drugs potentially inducing pharmacobezoars. Furthermore, based on our plasma drug monitoring, we believe that early EGD should be considered in all cases of massive pill intake, prolonged release drugs that can form pharmacobezoars or in cases where a life-threatening dose cannot be excluded.

Induced pluripotent stem cell production (CSSi019-A)(14432) from an asymptomatic subject carrying a expansion of C9orf72 gene.

One of the genetic mutations most associated with the onset of amyotrophic lateral sclerosis, both in sporadic and familial cases, is the expansion of the C9orf72 gene. The presence of more than 30 repeats (GGGGCC) correlates with uncertain ALS symptomatology. Here we collected a dermal biopsy from a subject carrying 36 hexanucleotide repeats and reprogrammed it into an induced pluripotent stem cell line. Despite the number of repeat elements, the subject had no symptoms at the age of the biopsy (76 years), thus resulting in a healthy carrier of the mutation.

Acute toxic exposures in children: analysis of a three year registry managed by a Pediatric poison control Center in Italy.

INTRODUCTION: Acute pediatric poisoning is an emerging health and social problem. The aim of this study is to describe the characteristics of a large pediatric cohort exposed to xenobiotics, through the analysis of a Pediatric Poison Control Center (PPCc) registry. METHODS: This study, conducted in the Pediatric Hospital Bambino Gesù of Rome, a reference National Pediatric Hospital, collected data of children whose parents or caregivers contacted the PPCc by phone (group "P"), or who presented to the Emergency Department (group "ED"), during the three-year period 2014-2016. Data were prospectively and systematically collected in a pre-set electronic registry. Comparisons among age groups were performed and multivariable logistic regression models used to investigate associations with outcomes (hospital referral for "P", and hospital admission for "ED"group). RESULTS: We collected data of 1611 children on group P and 1075 on group ED. Both groups were exposed to both pharmaceutical and non-pharmaceutical agents. Pharmaceutical agent exposure increased with age and the most common route of exposure was oral. Only 10% among P group were symptomatic children, with gastrointestinal symptoms. Among the ED patients, 30% were symptomatic children mostly with gastrointestinal (55.4%) and neurologic symptoms (23.8%). Intentional exposure (abuse substance and suicide attempt), which involved 7.7% of patients, was associated with older age and Hospital admission. CONCLUSIONS: Our study describes the characteristics of xenobiotics exposures in different paediatric age groups, highlighting the impact of both pharmacological and intentional exposure. Furthermore, our study shows the utility of a specific PPCc, either through Phone support or by direct access to ED. PPCc phone counselling could avoid unnecessary access to the ED, a relevant achievement, particularly in the time of a pandemic.

Antibiotic Usage After Procalcitonin-Guided Therapy Algorithm Implementation In A Burn Intensive Care Unit.

The study investigated antibiotic utilization after the implementation of a procalcitonin (PCT)-guided antibiotic algorithm in the burn intensive care unit (BICU) to minimize antibiotic exposure appropriately. An algorithm established the ordering of an initial procalcitonin level, an additional level following 48 hours post-admission, and upon suspicion of sepsis. The primary endpoint was the percent of days on antibiotics in the BICU. Secondary endpoints were the percent of patients reinitiated on antibiotics, length of BICU and hospital stay, and 30-day mortality. Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) methodology aided in antibiotic usage evaluation. The retrospective and prospective phases involved five and seven patients in the final analysis, respectively. The median percent of days on antibiotics in the BICU was 33.3% versus 14.3% in the retrospective and prospective phases, respectively (p=0.222). Secondary outcomes evaluated were percent of patients reinitiated on antibiotics at 80.0% versus 28.6% (p=0.242), the median length of BICU stay at 38 days versus 31 days (p=0.465), the median duration of hospital stay at 39 days versus 37 days (p=0.624) and 30-day mortality of one versus zero cases (p=0.417) in the retrospective and prospective group, respectively. The probability of better DOOR with a PCT-guided antibiotic algorithm versus the control group was 95.7% (95% CI, 81.4-99.5%). The benefit of a PCT-guided antibiotic algorithm implementation cannot be determined based on the small sample size producing a lack of internal validity. Future studies warrant utilizing DOOR/RADAR to evaluate antibiotic stewardship strategies in the burn patient population.

Cette étude a pour but d'étudier les consommations d'antibiotiques après mise en place dans une réanimation pour brûlés d'un algorithme guidant les antibiothérapies selon la procalcitonine (PCT). En cas de suspicion de sepsis, des dosages de PCT sont réalisés le jour même et à 48 h. Le critère de jugement principal était le pourcentage de jours sous antibiotiques durant l'hospitalisation en réanimation. Les critères de jugement secondaires étaient le pourcentage de patients remis sous antibiotiques, la durée de séjour en réanimation et la mortalité à J30, en utilisant un design avant/après. L'évaluation de l'utilité de l'antibiothérapie a utilisé les méthodes DOOR (Desirability Of Outcome Ranking et RADAR (Response Adjusted for Duration of Antibiotic Risk). Les phases pré (1)- et post (2)- interventionnelles ont concerné 5 et 7 patients, respectivement. En phase 1, la durée sous antibiotiques représentait 33,3% du séjour contre 14,3% en phase 2 (p= 0,222). Quatre vingts pour cent des patients en phase 1 avaient eu une réintroduction d'antibiotiques, contre 28,6% en phase 2 (p=0,242). Les durées médianes d'hospitalisation en réanimation étaient de 38 jours en phase 1, 31 en phases 2 (p=0,465), de 39 et 37 jours à l'hôpital (p=0,624). À J30, un patient du groupe 1 était décédé, aucun du groupe 2 (p=0,417). La probabilité d'un meilleur DOOR en utilisant l'algorithme basé sur la PCT était de 95,7% (IC 95% 81,4-99,5%). Toutefois, l'intérêt de cet algorithme ne peut pas être affirmé sur une si petite série et des études plus solides sont indispensables.

The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans.

The in vivo alterations in organ-specific substrate processing and endogenous mediator production induced by endotoxin were investigated in healthy volunteers. An endotoxin bolus (20 U/kg) produced increased energy expenditure, hyperglycemia, hypoaminoacidemia, and an increase in circulating free fatty acids. These changes included increased peripheral lactate and free fatty acid output, along with increased peripheral uptake of glucose. Coordinately, there were increased splanchnic uptake of oxygen, lactate, amino acids, and free fatty acids, and increased splanchnic glucose output. There were no changes in circulating glucagon, or insulin and transient changes in epinephrine and cortisol were insufficient to explain the metabolic changes. Plasma cachectin levels peaked 90 min after the endotoxin infusion, and hepatic venous (HV) cachectin levels (peak 250 +/- 50 pg/ml) were consistently higher than arterial levels (peak 130 +/- 30 pg/ml, P less than 0.05 vs. HV). No interleukin 1 alpha or 1 beta was detected in the circulation. Circulating interleukin 6, measured by B.9 hybridoma proliferation, peaked 2 h after the endotoxin challenge (arterial, 16 +/- 2 U/ml; HV, 21 +/- 3 U/ml). The net cachectin efflux (approximately 7 micrograms) from the splanchnic organs demonstrates that these tissues are a major site for production of this cytokine. Hence, splanchnic tissues are likely influenced in a paracrine fashion by regional cachectin production and may also serve as a significant source for systemic appearance of this cytokine.

Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia.

The present study was undertaken to evaluate the extent to which an endogenous interleukin-1 (IL-1) response contributes to the hemodynamic and metabolic consequences of sublethal endotoxemia or lethal Gram-negative septic shock. Young, healthy baboons received either a sublethal dose of lipopolysaccharide (LPS) or an LD100 of live Escherichia coli bacteria, and one half of the animals in each group were continuously infused with IL-1 receptor antagonist (IL-1ra). Plasma IL-1 beta was not detected in this model of endotoxemia. Administration of IL-1ra had only minimal effects on the modest hemodynamic and metabolic responses to sublethal endotoxemia, and did not attenuate the plasma cytokine response. In contrast, high circulating levels of IL-1 beta (range 300-800 pg/ml) were seen during lethal E. coli septic shock. IL-1ra treatment significantly attenuated the decrease in mean arterial blood pressure (MAP) (from -72 +/- 8 to -43 +/- 6 mm Hg; P less than 0.05) and cardiac output (from -0.81 +/- 0.17 to -0.48 +/- 0.15 liter/min; P less than 0.05), and significantly improved survival from 43 to 100% at 24 h (P less than 0.05). The plasma IL-1 beta and IL-6 responses to lethal E. coli septic shock were also significantly diminished by IL-1ra treatment (P less than 0.05), whereas tumor necrosis factor-alpha (TNF alpha) concentrations were unaffected. We conclude that an exaggerated systemic IL-1 beta response is characteristic of lethal E. coli septic shock, and contributes significantly to the hemodynamic and metabolic consequences of E. coli septic shock. IL-1ra can significantly attenuate the cytokine cascade and improve survival.

Assessing bradykinesia in Parkinson's disease using gyroscope signals.

Parkinson's disease (PD) is a neurodegenerative brain disorder that slowly brings on the dopaminergic neurons death. The depletion of the dopaminergic signal causes the onset of motor symptoms such as tremor, bradykinesia and rigidity. Usually, neurologists regularly monitor motor symptoms and motor fluctuations using the MDS-UPDRS part III clinical scale. Nevertheless, to have a more objective and quantitative evaluation, it is possible to assess the cardinal motor symptoms of PD using wearable sensors and portable robotic devices. Unfortunately while there are several research papers on the use of these devices on PD patients, their use is not so common in clinical practice. In this work we recorded specific MDS-UPDRS motor tasks using magneto-inertial devices, worn by seven PD subjects and seven age-matched controls, in order to deeply analyze the kinematic and dynamic characteristics of goal-directed movements of upper limb, in addition to extract quantitative indices (peak velocity, smoothness, etc) useful for the assessment of motor symptoms. Using only gyroscope signals we looked at those parameters useful to assess bradykinesia. We observed parameters changes from OFF to ON phase congruent with the MDS-UPDRS changes, especially in the frequency domain. Our results suggest the prono-supination task is the more consistent to describe the bradykinesia symptom with the gyroscopes. Probably because of the amplitude of the movement performed. Moreover the peak power looks appropriate for bradykinesia symptom evaluation. We can conclude that, similar to the studies in which tremor symptom is evaluated, it is possible to monitor the bradykinesia using few wearable sensors and few simple parameters.

Comparative bioavailability of different formulations of levothyroxine and liothyronine in healthy volunteers.

OBJECTIVE: To evaluate the relative bioavailability of T4 sodium and liothyronine sodium (T3), administered in single doses as oral solution (drops) and tablet forms, according to two separate study protocols. METHODS: Twenty-four healthy, male volunteers were included in both studies. Two test drugs containing T4 or T3 (T4-Ibsa and T3-Ibsa, respectively) were compared to two reference drugs, ie Eutirox 100 and Ti-tre tablets, respectively. A single oral dose of 100 microg (1 ml or 1 tablet) of T4 and 20 microg (1 ml or 1 tablet) of T3 were administered with an open, randomized, crossover design. T4 and T3 serum concentrations were determined by a validated immunoassay in electro-chemo-luminescence method. RESULTS: Study 1: after administration of T4-Ibsa oral solution, Cmax was 14.26+/-0.61 microg/dl, AUC0-t was 282.70 +/-14.29 microg/dl/h, Tmax was 2.71+/-0.25 h. After administration of Eutirox 100 tablets, Cmax was 14.34+/-0.59 microg/dl, AUC0-t was 279.42+/-9.59 microg/dl/h and Tmax was 2.65+/-0.23 h. The 90% confidence interval ratios between test/reference drugs were 1.01 for AUC0-t and 0.99 for Cmax. Study 2: after administration of T3-Ibsa oral solution, Cmax was 3.19+/-0.25 ng/ml, AUC0-t was 44.79+/-2.15 ng/ml/h and Tmax was 2.31+/-0.25 h. After administration of Ti-tre tablets, Cmax was 3.16+/-0.23 ng/ml, AUC0-t was 45.19+/-2.19 ng/ml/h and Tmax was 2.44+/-0.34 h. The 90% confidence interval ratios between test /reference drugs were 0.99 for AUC0-t and 1.01 for Cmax. CONCLUSIONS: The bioavailability of the two oral solutions (T4-Ibsa and T3-Ibsa oral solutions) and the corresponding tablet forms (Eutirox 100 and Ti-tre tablets) were confirmed and they can be considered bioequivalent and therapeutically interchangeable.

Kidney injury owing to Streptococcus pneumoniae infection in critically ill infants and children: report of four cases.

Streptococcus pneumoniae sepsis has high morbidity, particularly if complicated by renal injury. Four patients with S. pneumonia invasive infections complicated by renal disorders are presented. The first case was an 18-month-old girl with pneumococcal empyema complicated by haemolytic uraemic (HUS) syndrome. She made a full recovery after mechanical ventilation, inotropic support and haemodiafiltration. The second was a 4-year-old boy who presented with acute post-infectious glomerulonephritis associated with bilateral pneumococcal pneumonia. He too made a complete recovery. The third was a newborn girl with pneumococcal meningitis complicated by acute respiratory distress syndrome and acute renal failure. The fourth patient was an 8-month-old boy with pneumococcal pneumonia and meningitis complicated by HUS and with fulminant thrombotic thrombocytopenic purpura. Despite full support including mechanical ventilation and haemodiafiltration, he died 4 days after admission. On follow-up, all three survivors recovered completely from their pulmonary symptoms and had normal renal function and cardio-circulatory status in the mid-term.

Recombinant human growth hormone enhances the metabolic efficacy of parenteral nutrition: a double-blind, randomized controlled study.

This multicenter, randomized, double-blind study was performed to investigate whether recombinant GH improves the efficacy of total parenteral nutrition (TPN). Fifteen stable patients requiring parenteral feeding due to gastrointestinal/pancreatic disease were studied. Constant maintenance TPN providing approximately 30 kcal/kg day and approximately 1.6 g protein/kg.day was administered during an initial 7-day baseline period. After randomization, daily sc injections of saline (control, n = 9) or GH (10 mg/day, n = 6) were administered a 14-day treatment period as nutrient intake remained constant. Elemental balances for nitrogen (N), potassium (K), phosphorus (P), and sodium (Na) were determined daily and serial blood indices, vital signs, and other clinical parameters were monitored. Nutrient balances approached equilibrium during the baseline week in both groups. With GH administration, a significant increase in N, K, and P balance occurred; in contrast, nutrient balances did not change significantly from baseline values in control patients. The cumulative change (delta) in nutrient balances from the baseline week was also significantly greater in the GH-treated patients (delta N: control+2 +/- 7 g vs. GH+36 +/- 6. g, P less than 0.005; delta K:+57 +/- 45 mmol vs.+199 +/- 19 mmol, P less than 0.03; delta P: -27 +/- 30 mmol vs. +91 +/- 69 mmol, P less than 0.02). Plasma insulin-like growth factor-I concentrations rose 5-fold and serum cholesterol rose slightly with GH; no other significant change in group mean blood values occurred. One patient receiving GH and chronic prednisone therapy developed moderate hyperglycemia and mild peripheral edema; no other deleterious effects attributable to GH were observed. GH was well tolerated and significantly enhanced nutrient retention compared to standard parenteral feeding alone. GH improves the efficacy of parenteral nutrient utilization in patients requiring TPN.

Analysis of gene expression in human bullous keratopathy corneas containing limiting amounts of RNA.

PURPOSE: To validate the use of polymerase chain reaction (PCR)-amplified full-length cDNA as a substitute for mRNA in nucleic acid array and gene expression analysis. METHODS: Total RNA was isolated from age-matched normal autopsy corneas and pseudophakic bullous keratopathy (PBK) corneas. Full-length cDNA was generated and PCR amplified using the Smart cDNA synthesis technology. Southern blot analysis of this cDNA was compared with Northern blot analysis of the RNA. Amplified cDNA was used to probe a commercial gene array. By immunohistochemistry, the expression pattern of several adhesion molecules represented on the array was assessed. RESULTS: The cDNA produced by the Smart cDNA system gave results very similar to those of northern blot analysis when examined for beta2-microglobulin, Rab geranylgeranyl transferase, and tenascin-C. This cDNA obtained from normal or PBK corneas was labeled and used to probe a 588 gene array (Clontech). Among other differences, beta6 integrin was detected only with the PBK probe, beta-catenin was markedly elevated in PBK, and beta4 integrin appeared to be reduced in PBK. Immunohistochemical patterns of these proteins were consistent with the hybridization signals on the gene array. CONCLUSIONS: Smart cDNA synthesis and nucleic acid arrays were combined and validated for the first time to identify differential gene expression in normal and diseased corneas. These techniques require very little RNA such as that equivalent to a half of a single cornea, which is useful when the amount of tissue is limiting. Altered expression of adhesive proteins beta6 integrin and beta-catenin may be related to the formation of epithelial bullae and microcystic changes in PBK patients.

Current estimates from the National Health Interview Survey, 1995.

OBJECTIVES: This report presents data on national estimates of the incidence of acute conditions, percent of medically attended acute conditions, number of disability days (including restricted activity and bed days, and work- or school-loss days), number of episodes of persons injured and associated activity restriction, prevalence of selected chronic conditions, number of activity limitations due to chronic conditions, number of restricted activity days associated with acute and chronic conditions, respondent-assessed health, number of physician contacts, and short-stay hospitalizations. METHODS: The National Health Interview Survey (NHIS) is a complex, multi-stage, probability sample survey conducted annually by trained interviewers of the U.S. Bureau of the Census for the National Center for Health Statistics. Information is collected during in-home interviews of the civilian noninstitutionalized U.S. population on a variety of health issues. RESULTS: The NHIS estimates that in 1995, there were 174.4 acute conditions per 100 persons. Of these, 67.3 percent were medically attended and this resulted in 674.6 days of restricted activity per 100 persons. Of acute injuries, 91.2 percent were medically attended. The most frequently reported rates for chronic conditions per 1,000 persons included sinusitis (141.3), arthritis (124.7), and deformity and orthopedic impairment (121.4). Some degree of activity limitation due to chronic conditions was reported by 14 percent of persons. There were about six physician contacts per person per year and 7.5 percent of the population had at least one hospitalization in the past year.

Current estimates from the National Health Interview Survey, 1996.

OBJECTIVES: This annual report presents national estimates, based on data from the National Health Interview Survey (NHIS), on the incidence of acute conditions, percent of medically attended acute conditions, number of disability days, episodes of persons injured and associated activity restriction, persons with activity limitation due to chronic conditions, restricted activity days associated with acute and chronic conditions, physician contacts and short-stay hospitalizations, as well as prevalence of chronic conditions and respondent assessed health status. This edition includes a section on trends in health statistics for 1982-96. SOURCE OF DATA: NHIS is a multistage probability sample survey conducted annually by interviewers of the Bureau of the Census for the National Center for Health Statistics. Data is collected during in-home interviews of the civilian noninstitutionalized U.S. population. Data collection procedures were similar from 1982 through 1996, but were changed after 1996. HIGHLIGHTS: In 1996 there were 163.5 acute conditions per 100 persons, (67.9% were medically attended) and 624.0 associated days of restricted activity per 100 persons. Of acute injuries, 91.4% were medically attended. The highest rates for chronic conditions per 1000 persons included arthritis (127.3), sinusitis (125.5), deformity and orthopedic impairment (111.6), and high blood pressure (107.1). Activity limitation due to chronic conditions was reported by 14.4% of persons. There were six physician contacts per person per year and 7.3% of the population had a hospitalization in the past year. During 1982-96, the prevalence of asthma increased and the rate and duration of hospitalizations decreased.

Identification of a novel tumor necrosis factor alpha/cachectin from the livers of burned and infected rats.

Tumor necrosis factor alpha (TNF-alpha)/cachectin is a monocyte/macrophage-derived cytokine implicated as a proximal mediator of many of the catastrophic host responses to infection or endotoxin. However, circulating levels of TNF-alpha/cachectin have only been episodically detected in hospitalized patients with life-threatening bacterial infections. In the present report, increased quantities of immune-reactive TNF-alpha/cachectin were recovered from the livers of rats 3 days following a lethal burn and infection. Two species of TNF-alpha/cachectin were detected, one of approximately 29 kd and the other 17 kd, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In murine peritoneal macrophages and rat Kupffer cells stimulated in vitro with endotoxin, a 29-kd cell-associated and 17-kd secreted form were also detected. We conclude that the increased appearance in vivo of a 29-kd form of TNF-alpha/cachectin from the livers of lethally burned and infected rats represents a novel cell-associated form of the protein.

Cachectin/TNF production in experimental burns and Pseudomonas infection.

Burn injury and infection result in significant losses of lean tissue. The cytokine cachectin/tumor necrosis factor has been implicated in this process but is not uniformly detected during infection. We sought to determine the relationship between body composition changes and in vivo hepatic levels of pretranslational message for cachectin (messenger RNA) in a burn and infection rodent model. Adult Wistar rats were grouped as follows: (1) freely fed, (2) 30% burn, (3) 30% burn with Pseudomonas aeruginosa infection, (4) pair fed, and (5) 30% burn and infection with recombinant cachectin. Compared with controls or animals only burned, burned and infected rats had a 100% increase in hepatic cachectin messenger RNA content, lost carcass protein, and exhibited muscle loss with sparing of liver mass. Tissue production of cachectin as well as other cytokines may be sufficient to mediate several body composition changes observed in response to injury and infection.

Tumour location influences local cytokine production and host metabolism.

To determine whether the location of tumour growth influences host cytokine and metabolic responses, experimental subcutaneous (SQ) and liver (LIV) tumours were compared in Buffalo rats. An LIV tumour that was only 1 +/- 1% (P < 0.05 versus SQ) of body weight produced similar anorexia, weight loss, acute phase response, and systemic cytokine responses as are SQ tumour that was 10 +/- 2% of body weight. Neither tumour-bearing group had abnormal liver function tests or evidence of obstructive biliary pathology. Tumour necrosis factor (TNF) was detected by western analysis in both tumour as well as histologically normal liver remote from the tumour in the LIV group but not in livers of animals in freely fed and SQ groups. The proximity of the tumour to competent tissue macrophage populations, such as hepatic Kupffer cells, may be sufficient to induce cachexia. Hence, tumour location may be as important as tumour burden in determining the host's response to cancer.