Changes in nutritional status associated with unresectable pancreatic cancer.

Weight loss is common in patients with pancreatic cancer; however, the nature and progress of their nutritional depletion are not well documented. In this study, pre-illness weight and duration of weight loss were recorded in 20 patients with histologically confirmed unresectable cancer of the pancreas. Patients then underwent nutritional analysis at monthly intervals until death. The median period of assessment was 27 weeks (interquartile range 22.5-38.0 weeks). At the time of diagnosis, all patients had lost weight [median 14.2% (10.0-20.0%) of pre-illness stable weight], and this weight loss was progressive, increasing to a median of 24.5% by the time of the last assessment (P =0.0004). Body mass index was significantly reduced from a pre-illness median value of 24.9 kg m-2 (22.4-27.4 kg m-2) to 20.7 kg m-2 (19.5-23.6 kg m-2) at the time of diagnosis and further to 17.7 kg m-2 (16.6-23.1 kg m-2) just before death (P =0.0003). Further evidence of tissue depletion was evident from the significant reductions in lean body mass [43.4 kg (36.9-53.0 kg) to 40.1 kg (33.5-50.7 kg) P =0.008] and fat mass [12.5 kg (8.9-17.8 kg) to 9.6 kg (6.3-15.1 kg) P =0.03). This study confirms that the majority of patients with unresectable pancreatic cancer have already undergone significant weight loss by the time of diagnosis and that the natural history of this process is one of inexorable progression. These results highlight the need for selective non-toxic therapeutic intervention to attenuate cachexia and indicate that such interventions should be instituted early in the course of the disease

Ibuprofen reduces energy expenditure and acute-phase protein production compared with placebo in pancreatic cancer patients.

The aim of this study was to investigate the effect of the cyclo-oxygenase inhibitor ibuprofen on the acute-phase protein response and resting energy expenditure (REE) of weight-losing patients with pancreatic cancer. Patients with irresectable pancreatic cancer (n = 16) were treated with either ibuprofen (1200 mg day-1 for 7 days (n = 10) or placebo (n = 6). A group of 17 age-related non-cancer subjects were also studied. Indirect calorimetry, anthropometry, multifrequency bioelectrical impedence analysis and serum C-reactive protein (CRP) estimation were performed immediately before and after treatment. Before treatment, total REE was significantly elevated in the pancreatic cancer patients compared with healthy controls (1499 +/- 71 vs 1377 +/- 58 kcal) (P < 0.02). Following treatment the mean REE of the ibuprofen group fell significantly (1386 +/- 89 kcal) compared with pretreatment values (1468 +/- 99 kcal) (P < 0.02), whereas no change was observed in the placebo group. Serum CRP concentration was also reduced in the ibuprofen-treated group (pre-ibuprofen, 51 mg l-1; post-ibuprofen, 29 mg l-1; P < 0.05). These results suggest that ibuprofen may have a role in abrogating the catabolic processes which contribute to weight loss in patients with pancreatic cancer

Lattice-dynamics of a Disordered solid-solid Interface

Generic properties of elastic phonon transport at a disordered interface are studied. The results show that phonon transmittance is a strong function of frequency and the disorder correlation length. At frequencies lower than the van Hove singularity the transmittance at a given frequency increases as the correlation length decreases. At low frequencies, this is reflected by different power-laws for phonon conductance across correlated and uncorrelated disordered interfaces which are in approximate agreement with perturbation theory of an elastic continuum. These results can be understood in terms of simple mosaic and two-colour models of the interface.Comment: 17 pages, 5 figures, submitted to PR

Expression of the proteolysis-inducing factor core peptide mRNA is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy

Gastro-oesophageal cancer is associated with a high incidence of cachexia. Proteolysis-inducing factor (PIF) has been identified as a possible cachectic factor and studies suggest that PIF is produced exclusively by tumour cells. We investigated PIF core peptide (PIF-CP) mRNA expression in tumour and benign tissue from patients with gastro-oesophageal cancer and in gastro-oesophageal biopsies for healthy volunteers. Tumour tissue and adjacent benign tissue were collected from patients with gastric and oesophageal cancer (n=46) and from benign tissue only in healthy controls (n=11). Expression of PIF-CP mRNA was quantified by real-time PCR. Clinical and pathological information along with nutritional status was collected prospectively. In the cancer patients, PIF-CP mRNA was detected in 27 (59%) tumour samples and 31 (67%) adjacent benign tissue samples. Four (36%) gastro-oesophageal biopsies from healthy controls also expressed PIF-CP mRNA. Expression was higher in tumour tissue (P=0.031) and benign tissue (P=0.022) from cancer patients compared with healthy controls. In the cancer patients, tumour and adjacent benign tissue PIF-CP mRNA concentrations were correlated with each other (P<0.0001, r=0.73) but did not correlate with weight loss or prognosis. Although PIF-CP mRNA expression is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy, expression does not relate to prognosis or cachexia. Post-translational modification of PIF may be a key step in determining the biological role of PIF in the patient with advanced cancer and cachexia

A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss

The use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the combination of megestrol acetate and placebo with megestrol acetate and ibuprofen in the treatment of weight loss in such patients. At baseline, 4–6 weeks and 12 weeks, patients underwent measurements of anthropometry, concentrations of albumin and C-reactive protein and assessment of appetite, performance status and quality of life using EuroQol-EQ-5D and EORTC QLQ-C30. Thirty-eight and 35 patients (median weight loss 18%) were randomized to megestrol acetate/placebo or megestrol acetate/ibuprofen, respectively, for 12 weeks. Forty-six (63%) of patients failed to complete the 12-week assessment. Of those evaluable at 12 weeks, there was a decrease in weight (median 2.8 kg) in the megestrol acetate/placebo group compared with an increase (median 2.3 kg) in the megestrol acetate/ibuprofen group (P < 0.001). There was also an improvement in the EuroQol-EQ-5D quality of life scores of the latter group (P < 0.05). The combination of megestrol acetate/ibuprofen appeared to reverse weight loss and appeared to improve quality of life in patients with advanced gastrointestinal cancer. Further trials of this novel regimen in weight-losing patients with hormone-insensitive cancers are warranted. © 1999 Cancer Research Campaig

Functional identity of receptors for proteolysis-inducing factor on human and murine skeletal muscle

Background: Cachexia in both mice and humans is associated with tumour production of a sulphated glycoprotein called proteolysis-inducing factor (PIF). In mice PIF binds with high affinity to a surface receptor in skeletal muscle, but little is known about the human receptor. This study compares the human PIF receptor with the murine. Methods: Human PIF was isolated from the G361 melanoma and murine PIF from the MAC16 colon adenocarcinoma. The human PIF receptor was isolated from human skeletal muscle myotubes. Protein synthesis and degradation induced by human and murine PIF was studied in human and murine skeletal muscle myotubes. Results: Both the human and murine PIF receptors showed the same immunoreactivity and Mr 40 000. Both murine and human PIF inhibited total protein synthesis and stimulated protein degradation in human and murine myotubes to about the same extent, and this was attenuated by a rabbit polyclonal antibody to the murine PIF receptor, but not by a non-specific rabbit antibody. Both murine and human PIF increased the activity of the ubiquitin-proteasome pathway in both human and murine myotubes, as evidenced by an increased 'chymotrypsin-like' enzyme activity, protein expression of the 20S and 19S proteasome subunits, and increased expression of the ubiquitin ligases MuRF1 and MAFbx, and this was also attenuated by the anti-mouse PIF receptor antibody. Conclusions: These results suggest that the murine and human PIF receptors are identical

The presence of the proteolysis-inducing factor in urine does not predict the malignancy of a pancreatic tumour

BACKGROUND: The proteolysis-inducing factor (PIF) was identified as a tumour product in various gastrointestinal cancers. A previous study in pancreatic cancer patients suggested PIF expression as a tumour marker, which is not related to tumour size. We hypothesized that PIF could be a useful marker to exclude benign pancreatic tumors, as chronic pancreatitis with a pancreatic mass. METHODS: Urine of patients with a pancreatic mass of uncertain malignancy was investigated for PIF expression by Western blot. Sufficient urine protein for analysis was available in 59 patients. The diagnosis was established by histology in 54 patients and by follow up in five patients with chronic pancreatitis. In addition, serum CA19-9 was measured. RESULTS: The sensitivity (specifity) for the detection of a malignant pancreatic tumour was 90% (75%) and 54% (71%) for CA19-9 and PIF, respectively. The sensitivity (specifity) for the distinction of pancreatic cancer from chronic pancreatitis was 89% (80%) and 57% (63%) for CA19-9 and PIF, respectively. CONCLUSION: Evaluation of PIF in urine is of no diagnostic value in patients with a pancreatic mass of unknown malignancy