Substance P Serum Degradation in Complex Regional Pain Syndrome - Another Piece of the Puzzle?

In a previous study, we demonstrated that the serum peptidase system might be less efficient in complex regional pain syndrome (CRPS). Since the neuropeptide substanc P (SP) contributes to inflammation in CRPS, we now investigated the metabolism of SP in CRPS specifically. An SP metabolism assay was performed in 24 CRPS patients, which constitute a subgroup of our previous investigation on BK degradation. In addition, we included 26 healthy controls (24 newly recruited plus 2 from our previous investigation), and 13 patients after limb trauma, who did not fulfil the CRPS diagnostic criteria (trauma controls, TC) were included. We adapted a thin layer chromatography assay (TLC) to quantify SP disappearance after incubation with 7.5 µL of serum. These results were compared with bradykinin (BK) metabolization to BK1-8 and BK1-5 fragments from our previous study. In addition, TC were clinically and quantitative sensory testing (QST) phenotyped; the phenotyping of CRPS patients was retrieved from our existing database. SP metabolism was less efficient in CRPS and TC patient serum vs human control (HC) serum (P < .03) suggesting reduced activity of the neutral endopeptidase (NEP) and/or the angiotensin converting enzyme (ACE). Together with the decreased occurrence of BK1-5 fragment in CRPS and TC, this suggests a reduced activation of the angiotensin converting enzyme (ACE). There was no clear clinical phenotype related to impaired SP degradation; duration of disease and gender were also not associated. Most importantly, results in TC did not differ from CRPS. Collectively, our current and previous experimental results suggest that limb trauma reduces serum peptidase metabolism of SP ex vivo, specifically serum ACE activity. However, this finding is not CRPS-specific and seems to be rather a long-term consequence of the trauma itself. PERSPECTIVE: The experimental data from this study further support the hypothesis that impaired metabolism of inflammatory peptides potentially contribute to the development of posttraumatic pain in CRPS or limb trauma patients.

Labeled substance P as a neuropeptide reporter substance for enzyme activity.

Recently, we developed a bradykinin reporter assay and demonstrated the differing protease activity in Complex Regional Pain Syndrome patients vs. controls. In order to further characterize CRPS pathophysiology, the neuropeptide substance P was evaluated as possible reporter substance, here. It was labeled with a chromophore at the lysine residue and generated two major fragments following incubation with serum (amino acid residues 3-8 and 3-11) which were reproducibly separated by thin-layer chromatography. Dabsylated substance P was shown to be a substrate of angiotensin-converting enzyme. The combination of both bradykinin and substance P reporter substances with specific enzyme inhibitors will shed more light on biochemical pathways in inflammatory processes and pain. Comparative clinical studies are now needed to define the application range of both assays in more detail.

Impact of haemoglobin levels during adjuvant chemotherapy on the survival of patients with primary breast cancer.

Tumour anaemia is a common symptom in cancer patients, particularly in those receiving chemotherapy. The aim of the current study was to analyse the impact of haemoglobin levels on the prognosis of patients with primary breast cancer receiving adjuvant chemotherapy. A total of 129 patients were available for analysis. The estimated median five-year overall survival rate was 76.6%. Mean Hb prior to primary surgery was 13.8 g/dl (SD 1.09), pre-chemotherapy Hb 12.8 g/dl (SD 1.2), and nadir Hb during chemotherapy 11.0 g/dl (SD1.1), respectively. Hb values were analysed as continuous variables in the Cox model. Survival analyses did not show a correlation between preoperative and pre-chemotherapy Hb levels with patient outcome. However, univariate analysis identified low nadir Hb (p=0.008), larger tumours (p=0.042), and hormone-receptor-negative tumours (p=0.022) to be significantly associated with poor patient survival. This result was persistent when analysis was adjusted for relevant prognostic factors in a multivariate Cox proportional hazards model. Nadir Hb, 1.54-fold increased risk for death (95% CI 1.03-2.32), and tumour size, 3.2-fold increased risk (95% CI 1.17-8.77) remained as independent variables, whereas hormone-receptor status failed to retain significance. The present data showed anaemia during adjuvant chemotherapy to be associated with poor survival in patients with primary breast cancer. Prospective randomized trials are warranted to examine the value of correcting anaemia with regard to improve disease control and survival.

Incidence of anaemia in breast cancer patients receiving adjuvant chemotherapy.

Anaemia is frequent in breast cancer patients but often remains undiagnosed and untreated. To determine the incidence of anaemia a prospective survey of primary non-metastatic breast cancer patients who received at least four cycles of adjuvant, non-platinum multi-agent chemotherapy was conducted at 47 centres in Austria. Two hundred and forty seven patients were prospectively included between October 1999 and December 1999. Haemoglobin (Hb) levels were determined after surgery and prior to each cycle of chemotherapy. Treatment of anaemia (blood transfusion or epoetin alfa) during the observation period was at the physician's discretion. For the purpose of this study, patients were considered to be anaemic if their Hb was below 12 g/dl. At baseline (after surgery and before the first cycle of chemotherapy), 28.7% of all patients were anaemic. The only significant differentiating factor was the type of surgery. 37.9% of patients who underwent mastectomy were anaemic, whereas only 22.8% of patients who underwent breast conserving surgery were anaemic. Forty two percent of 176 patients with a Hb level of > or = 12 g/dl at baseline developed anaemia during adjuvant chemotherapy. The only factor that significantly influenced the development of anaemia during chemotherapy was the Hb level at baseline. The total incidence of anaemia in patients with primary breast cancer who underwent surgery followed by adjuvant multi-agent chemotherapy was 58.7%. Forty nine patients (20.2%), 48 patients (19.2%) and 48 patients (19.2%) showed a decrease in Hb levels by 1 g/dl, 1-2 g/dl and > 2 g/dl, respectively. Only 18.6% of the patients who were found to be anaemic received anaemia treatment. The two most important factors for developing anaemia are the kind of surgery and the Hb level prior to chemotherapy.