ANTICANCER RESEARCH 24: 2515-2518 (2004)

Pancreatic Polypeptide is Increased in Patients with Advanced Malignant Disease

AUDHILD HJALMARSEN1, ROY M. BREMNES2, ULF AASEBØ1, ROLF JORDE3

Divisions of 1Pulmonary Medicine and 3Endocrinology, Department of Medicine and 2Department of Oncology, University Hospital of Northern Norway, N-9038 Tromsø, Norway

Abstract. Background: Augmented secretion of pancreatic dysfunction in patients with severe chronic obstructive polypeptide (PP) has been demonstrated in patients with severe pulmonary disease as well as in patients with systemic lupus systemic diseases or endocrine tumors. The aim of this study was to erythematosus (3,4). PP secretion has been localized to a evaluate PP and autonomic neuropathy in patients with advanced specific population of human islet cells and has also been malignant disease. Materials and Methods: Basal PP assessments shown to be produced and released by pancreatic endocrine and five cardiovascular tests for autonomic function were used. tumors (5). PP-producing tumors are mostly located in the Twenty patients, including 11 patients with lung cancer (69 yrs±11, pancreas and may present as three pathological lesions: pure mean±SD) and 10 healthy age-matched controls, were studied. PP-omas, mixed tumors with minor PP cell population and Results: PP levels were significantly higher in the patients than in PP-cell hyperplasia. Numerous types of extrapancreatic the controls (pmol/L 107.0±111.4 versus 28.2±13.4, p<0.05). In endocrine tumors are able to synthesize and secrete PP (5,6). the parasympathetical tests, the patients showed significantly The aim of this study was to assess serum PP concentrations decreased heart rate response to the Valsalva manoeuvre (ratio in patients with advanced malignant disease including lung 1.20±0.19 versus 1.46±0.23, p<0.005). Also, in the sympathetical cancer. We also assessed autonomic neuropathy as an indirect tests, the blood pressure response to standing up was significantly measure of vagal stimulation (7-10). Since all these test results decreased (mmHg –3.84±17.53 versus 10.80±8.89, p<0.05). The may be age-dependent, an age-matched control group was heart rate response to standing up and deep breathing, as well as included (6,11). the blood pressure response to sustained handgrip, did not differ significantly between the groups. In spite of the apparent Materials and Methods autonomic dysfunction among cancer patients with advanced malignant disease, PP levels were significantly higher in these Patients. Twenty patients with advanced malignant disease including patients when compared with healthy controls. Conclusion: PP 11 patients with lung cancer, were enrolled in the study. The mean levels were significantly higher in patients with advanced cancer age was 69 years (range 38-82) and 65% of the patients were male. The cancer diagnosis was based on histological examination and than controls, regardless of autonomic dysfunction in the cancer disease extension was confirmed by CT-scan and/or whole body patients. This finding supports the hypothesis that PP may, in some scintigraphy. The tests were performed before the start of chemo- or cancer patients, be a marker of advanced malignant disease. radiotherapy. Ten age-matched healthy subjects served as controls. Informed consent was obtained from all the subjects. The study was Previous studies have shown that pancreatic polypeptide (PP) approved by the regional Ethics Committee. is reduced in diabetic patients with autonomic neuropathy (1,2). PP consequently has been considered a useful marker Methods. The Performance Status was assessed according to a 5-point scale by WHO (12). of vagal efferent integrity (1,2). However, other studies have shown augmented PP secretion regardless of autonomic Basal pancreatic polypeptide. Prior to cytotoxic treatment, fasting blood samples for basal serum PP were collected, stored and analyzed as previously described (13).

Correspondence to: A. Hjalmarsen, Department of Medicine, Tumor markers. Fasting blood samples for carcinoembryonal antigen University Hospital of Northern Norway, N-9038 Tromsø, (CEA), neuron-specific enolase (NSE) and prostate-specific antigen Norway. Tel: +47 776 26000, Fax: +47 776 2686, e-mail: (PSA) were analyzed prior to treatment start. [email protected] Cardiovascular tests. Five cardiovascular tests of autonomic function Key Words: Malignant disease, cardiovascular tests, pancreatic were employed as previously described (7,8,14,15) in the following polypeptide. order: heart rate response to Valsalva manoeuvre; heart rate

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Table I. Characteristics of patients and controls. Table II. Pancreatic polypeptide (PP), carcinoembryonal antigen (CEA), neuron specific enolase (NSE) and prostate specific antigen (PSA) in Patients Controls p values patients and controls.

Number 20 10 Diagnosis PP, CEA, NSE, PSA in males, Sex, m/f 13 /7 8/2 pmol/L microg/L microg/L microg/L Age, yrs 69.1±10.7 70.6±3.1 NS NSCLC 250 4.8 19 2.6 BMI, kg/m2 24.0±2.6 23.7±2.0 NS NSCLC 40 3.1 49 0.1 Performance status* 1.7±0.9 0.0±0.0 < 0.0001 NSCLC 398 0.7 5 0.8 Hb, g/L 12.1±1.7 14.8±0.8 < 0.001 NSCLC 72 7.9 7 2.5 Creatinin, mmol/L 81.1±24.2 83.1±11.6 NS NSCLC 332 0.7 6 0.8 Albumin, g/L 35.4±4.0 41.3±2.8 < 0.001 NSCLC 16 3.6 7 1.4 NSCLC 44 1.1 5 0.6 WHO, grades 0 – 4. NS = non significant, BMI = body mass index, NSCLC, Hb = hemoglobin. *Performance status: grade 0 = able to carry out adenocarcinoma 87 40.4 6 5.5 all normal activity without restriction; grade 1 = restricted in physically strenuous activity but ambulatory and able to carry out light work; NSCLC, grade 2 = ambulatory and capable of all self-care but unable to carry adenocarcinoma 31 140.1 21 out any work; up and about more than 50% of waking hours; grade 3 = capable of only limited self-care; confined to bed or chair more than NSCLC, 50% of waking hours; grade 4 = completely disabled; cannot carry out adenocarcinoma 12 2.3 5 any self-care; totally confined to bed or chair. SCLC 68 2.6 106 1.2 Ca. coli cum met. 151 7.1 10 2.9 Ca. coli cum met. 206 156.1 10 1.5 variation during deep breathing; immediate heart rate response to Ca. ventriculi cum met. 25 0.8 5 standing up; blood pressure response to standing up; and blood Ca. prostatae cum met. 28 2.5 6 397.4 pressure response to sustained handgrip. The tests were performed Ca. prostatae cum met. 126 0.9 16 20.1 in the same order in all subjects. Ca. mammae cum met. 37 1.2 7 Ca. mammae cum met. 160 14.1 10 Statistical analysis. Results are given as means±SD. At first the Ca. mammae cum met. 33 0.9 9 Student’s t-test for unpaired data was used to compare results between Malignt schwannom 23 0.5 5 the groups. Then, for selected tests we used analysis of variance Patients, mean±SD, (ANOVA) and the Mann-Whitney test when comparing test results n=20 107.0±111.4 19.6±44.9 15.7±23.5 31.3±105.5 between the groups. p<0.05 was considered statistically significant. Controls, mean±SD, Correlations between the tests and pulmonary function characteristics n=10 28.2±13.4 1.8±0.8 5.9±0.8 2.2±1.2 p, patients versus were performed using the Spearman’s rank correlation coefficient. controls < 0.05 NS NS NS

Results Abbreviations: NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer Patient characteristics. Characteristics for patients and controls are given in Table I. The patients’ performance status was significantly reduced when compared to age-matched controls. Autonomic tests. The data are given in Table III. In individual According to the WHO performance status (grades 0-4), the autonomic tests, the patients had significantly decreased heart majority of patients were ambulatory and capable of self-care rate response to the Valsalva manoeuvre and blood pressure but unable to carry out any work. Haemoglobin and serum response to standing up compared to controls. The heart rate albumin were significantly decreased. Sex, age and body mass response to deep breathing and standing up, as well as the index (BMI) did not differ significantly between patients and blood pressure response to sustained handgrip, did not differ controls. The distribution regarding diagnoses was as follows: significantly between the groups. lung cancer 11 patients; squamous cell carcinoma 7, Correlations. There were no significant correlations between adenocarcinoma 3, small cell lung carcinoma 1, three breast patient characteristics, PP values, tumor markers and cancers, two prostate cancers, two colon cancers, one gastric autonomic tests in the patient group, and no significant cancer and one malignant schwannoma. All the patients had a difference in PP levels between lung cancer patients compared stage III-IV malignant disease. to patients with other malignant diseases.

Biochemical markers. The patients’ PP levels were significantly Discussion higher than in the controls (p<0.05) (Table II). Tumor markers such as CEA, NSE and PSA (males) were In the present study, patients with advanced malignant disease not significantly increased in patients when compared to had a higher basal serum PP value than healthy controls. To controls (Table II). our knowledge, this finding has not been reported before.

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Table III. Autonomic function in patients and controls.

Cardiovascular testsa Patients, n=20 Controls, n=10 p values

Heart rate response to Valsalva manoeuvre (ratio) 1.20±0.19 1.46±0.23 < 0.005 Heart rate response to deep breathing (ratio) 6.89±4.56 6.50±3.50 NS Heart rate response to standing up (ratio) 0.97±0.24 1.09±0.13 NS Blood pressure response to standing up (mmHg) -3.84±17.53 10.80±8.89 < 0.05 Blood pressure response to sustained handgrip (mmHg) 10.32±11.80 16.90±14.22 NS aHigher score = better performance

When evaluated with tests for cardiovascular reflexes, References patients with advanced malignant disease demonstrated dysautonomia when compared with controls. This is in 1 Schwarts T W: Pancreatic polypeptide: A hormone under vagal agreement with results reported previously. Paraneoplasic control. Gastroenterology 85: 1411-25, 1983. 2 Rasmussen M H, Carstensen H, List S, Schwarts TW and Hilsted dysautonomia is associated with cancer of the lungs (16). J: Impaired pancreatic polypeptide response to a meal in type I Previous studies have shown that the PP levels decrease in diabetic patients: Vagal neuropathy or islet cell dysfunction? Acta diabetic patients with autonomic neuropathy (2). The PP level, Endocrinologica 128: 221-4, 1993. therefore, has been considered as a marker for vagal tone. 3 Hjalmarsen A, Aasebø U, Aleksandersen G and Jorde R: Consequently, the increased PP levels in the advanced cancer Cardiovascular responses to tests for autonomic dysfunction in patients were unexpected. However, a similar finding of patients with chronic obstructive pulmonary disease with and without continuous long-term oxygen therapy, J Autonom Nerv augmented PP secretion inspite of autonomic dysfunction has Syst 60: 169-74, 1996. also been seen in patients with severe chronic obstructive 4 Omdal R, Jorde R, Mellgren S L and Husby G: Autonomic pulmonary disease, as well as in patients with systemic lupus function in systemic lupus erythematosus. Lupus 3: 413-17, 1994. erythematosus (3,4). 5 Bordi C, Azzoni C, D’Adda T and Pizzi S: Pancreatic polypeptide- PP has been reported to be produced and released by related tumors. Peptides 23: 339-48, 2002. pancreatic endocrine tumors, but in most cases PP cells 6 Schwartz TW: Pancreatic-polypeptide (PP) and endocrine tumors of the pancreas. Scand J Gastroent 14 Suppl 53: 93-100, 1979. represent a subpopulation in tumors with heterogeneous 7 Clarke BF and Ewing DJ: Autonomic neuropathy: its diagnosis multihormonal cell composition. Pure PP cell tumors have and prognosis. Clin Endocrinol Metab 15: 885-89, 1986. also been identified (5,6). PP-producing cells may also occur 8 Fuqua M, Peter M and Pfeifer MA: Clinical manifestations and as a minor population in non-functional tumors with tests for cardiovascular autonomic neuropathy. Clin Diabetes 10- predominance of the non-hormone-producing cells (5,6). This 12, 1988. 9 McLeod JG and Tuck RR: Disorders of the autonomic nervous previous finding is supported by our study. system: Part 1. Pathophysiology and clinical features. Ann Neurol The PP concentrations observed in our study are remarkably 21: 419-30, 1987. elevated. It would be interesting to know whether some of the 10 McLeod JG and Tuck RR: Disorders of the autonomic nervous malignant tumors actually express PP or whether it is the system: Part 2. Investigation and treatment. Ann Neurol 21: 519- pancreatic secretion of the peptide that is increasead. It cannot 29, 1987. be excluded that PP should enter the panel of tumor markers. 11 Borst C, van Brederode JFM, Dunning AJ, de Rijk LG and Wieling W: Reflex control of heart rate in normal subjects in With regards to its relation to autonomic neuropathy, it is relation to age: a data base for cardiac vagal neuropathy. probably irrelevant to look at fasting concentrations; instead Diabetologia 22: 163-66, 1982. the first phase response to a meal should have been examined. 12 World Health Organization: Handbook for Reporting Results of In addition, it might have been informative to examine the Cancer Treatment. WHO offset publication no. 48. Geneva: fasting concentrations after the administration of atropine. WHO, 1979. In conclusion, the PP levels were significantly higher in 13 Jorde R and Burhol PG: Effects of jejunoileal bypass operation and Billroth II resection on postprandial plasma pancreatic patients with advanced cancer than controls, regardless of polypeptide release. Scand J Gastroenterol 17: 613-17, 1982. autonomic dysfunction in the cancer patients. This finding 14 Benn J, Dyrberg T, Hilsted J, Nerup J and Sandahl Christiansen supports the hypothesis that PP may, in some cancer patients, J: Prevalence of diabetic autonomic neuropathy measured by be a marker of advanced malignant disease. simple bedside tests. Diabetologia 20: 190-94, 1981. 15 Stewart AG, Waterhouse JC and Howard P: Cardiovascular autonomic nerve function in patients with hypoxaemic chronic Acknowledgements obstructive pulmonary disease. Eur Respir J 4: 1207-14, 1991. 16 Kaufmann H: The most common dysautonomias. Rev Neurol (1- We wish to thank Tordis Arild and the Department of Clinical 15)36: 93-96, 2003. Research, University Hospital of Northern Norway, Tromsø, Norway, Received March 15, 2004 for skillful technical assistance. Accepted June 2, 2004

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