[Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer. Its relation with molecular subtypes]. / La biopsia del ganglio centinela después de quimioterapia neoadyuvante en el cáncer de mama. Relación con los subtipos moleculares.

OBJECTIVE: To evaluate the influence of the molecular subtype (MS) in the Sentinel Node Biopsy (SNB) technique after neoadjuvant chemotherapy (NAC) in women with locally advanced breast cancer (BC) and a complete axillary response (CR). MATERIAL AND METHODS: A prospective study involving 70 patients with BC treated with NAC was carried out. An axillary lymph node dissection was performed in the first 48 patients (validation group: VG), and in case of micro- or macrometastases in the therapeutic application phase (therapy group:TG). Classified according to MS: 14 luminal A; 16 luminal B HER2-, 13 luminal B HER2+, 10HER2+ non-luminal, 17 triple-negative. RESULTS: SNB was carried out in 98.6% of the cases, with only one false negative result in the VG (FN=2%). Molecular subtype did not affect SN detection. Despite the existence of axillary CR, statistically significant differences were found in the proportion of macrometastasis (16.7% vs. 35.7%, p=0.043) on comparing the pre-NAC cN0 and cN+. Breast tumor response to NAC varied among the different MS, this being lowest in luminal A (21.5%) and highest in non-luminal HER2+ group (80%). HER2+ and triple-negative were the groups with the best axillary histological response both when there was prior clinical involvement and when there was not. CONCLUSIONS: Molecular subtype is a predictive factor of the degree of tumor response to NAC in breast cancer. However, it does not affect SNB detection and efficiency. SNB can also be used safely in women with prior node involvement as long as a complete clinical and radiological assessment is made of the node response to NAC.

Intraoperative ultrasound in conservative surgery for non-palpable breast cancer after neoadjuvant chemotherapy.

AIMS: A complete clinical response after neoadjuvant chemotherapy (NACT) in breast cancer patients hinders the localization of the residual lesion and the removal of a minimum amount of breast tissue. The aim of the present work is to report our single-centre experience with intraoperative ultrasound-guided (IOUS) excision performed by surgeons in these patients. PATIENTS AND METHODS: From January 2008 to December 2012, IOUS excisions were performed on 58 patients with a previous intralesional ultrasound-detectable metallic marker and non-palpable breast cancer after NACT. The specimen margins were estimated by ultrasonography and macroscopic pathologic examination. Successful lesion removal, specimen weight, and analysis of the results as regards margins were evaluated, and the need for breast-conserving re-excision and mastectomy was considered. RESULTS: After NACT the average ultrasound/mammography and MRI diameters were 11.7 mm (0-30) and 9.1 mm (0-40) respectively. In all cases, the residual lesion or tissue around the marker was removed. The average weight of the specimens was 26.4 g (6-84), being lower in cases of complete response according to ultrasound (p < 0.05). In 4 patients (6.8%), breast-conserving re-excision was carried out, and in 3 patients (5.2%) a secondary mastectomy was performed, two of which had invasive lobular carcinoma. CONCLUSIONS: The emplacement of a readily echodetectable metal marker before NACT makes IOUS excision feasible in an increasing number of complete clinical responses, with the excision of small amounts of breast tissue and a high percentage of conservative breast surgery. This technique requires surgeons to be trained, but has the advantage of a reduced use of other hospital services, better planning of operating theatres, and less discomfort for patients, which means that it is attractive and indeed recommendable.

[Incidence of axillary recurrence after a negative sentinel lymph node result in early stages of breast cancer: a 5-year follow-up]. / Incidencia de recurrencia axilar tras un ganglio centinela negativo en cáncer de mama en estadios iniciales: seguimiento de 5 años.

UNLABELLED: The sentinel lymph node (SLN) biopsy is currently the procedure of choice for axillary node staging in initial stages of breast cancer. The purpose of this study is to establish our false negative rate within a 5-year follow-up period in 258 patients with breast cancer staged with this procedure. METHODS: A retrospective study on 258 consecutive T1-T2<3 cm pN0 staged breast carcinomas treated from January 1, 2001 to December 31, 2005 was performed. The combined technique of isotope plus blue dye was used for detection. The subjects underwent a minimum follow-up of 5 years, mean 81 months, with an end of follow-up at December 31, 2010. Evidence of axillary recurrence, tumor recurrence in the breast and signs of disease progression or death were the events collected and analyzed. RESULTS: Of the 258 patients, 3 false negatives (1.1%) with axillary recurrence were detected at 10, 11 and 29 months of the surgery. This did not have a significant repercussion in the survival analysis on the contrary to the existence of breast recurrence or the appearance of distant metastasis in 4.7% and 6.2% patients, respectively. Global survival related with the cancer was 93.0 (240/258) and disease free survival was 89.1% (230/258). CONCLUSION: The risk of developing axillary recurrence after a negative SLN without axillary node dissection is low enough to consider the SLN procedure to be the best approach for axilla staging in early breast cancer. This staging technique also makes it possible to achieve local disease control without diminishing the survival of the patients.

Incidencia de recurrencia axilar tras un ganglio centinela negativo en cáncer de mama en estadios iniciales: seguimiento de 5 años / Incidence of axillary recurrence after a negative sentinel lymph node result in early stages of breast cancer: a 5-year follow-up

La biopsia selectiva del ganglio centinela (GC) es en la actualidad el procedimiento de elección en la estadificación axilar en cánceres de mama en estadios iniciales. El objetivo de este trabajo es establecer nuestra tasa de falsos negativos a lo largo de un período mínimo de 5 años de seguimiento de 258 pacientes con cáncer de mama estadificados mediante este procedimiento. Método. Estudio retrospectivo de 258 pacientes con cáncer de mama consecutivos T1-T2<3cm estadificados como pN0 mediante GC entre enero-2001 y diciembre-2005.Se empleó la técnica combinada isotópica y colorante para la detección. Fueron sometidos a seguimiento con un período mínimo de 5 años, la media fue 81 meses, siendo el punto final del seguimiento el 31 de diciembre de 2010. La evidencia de recurrencia axilar, recidiva tumoral en la mama, presencia de enfermedad a distancia, y muerte fueron los eventos recogidos y analizados. Resultados. De las 258 pacientes, se detectaron 3 falsos negativos (1,1%), con recurrencia axilar a los 10, 11 y 29 meses de la cirugía. En el análisis de supervivencia este hecho no tuvo repercusión significativa, a diferencia de la existencia de recidiva mamaria o la aparición de metástasis a distancia que ocurrieron en un 4,7 y un 6,2% de las pacientes. La supervivencia global relacionada con el cáncer fue de un 93,0% (240/258) y la supervivencia libre de enfermedad del 89,1% (230/258). Conclusión. El riesgo de recurrencia axilar tras un ganglio centinela negativo sin vaciamiento linfático completo es lo suficientemente bajo como para considerar a este procedimiento como de elección en la estadificación axilar del cáncer de mama en estadios iniciales. Además, permite alcanzar un adecuado control local de la enfermedad sin disminuir la supervivencia de los pacientes(AU)

The sentinel lymph node (SLN) biopsy is currently the procedure of choice for axillary node staging in initial stages of breast cancer. The purpose of this study is to establish our false negative rate within a 5-year follow-up period in 258 patients with breast cancer staged with this procedure. Methods. A retrospective study on 258 consecutive T1-T2<3cm pN0 staged breast carcinomas treated from January 1, 2001 to December 31, 2005 was performed. The combined technique of isotope plus blue dye was used for detection. The subjects underwent a minimum follow-up of 5 years, mean 81 months, with an end of follow-up at December 31, 2010. Evidence of axillary recurrence, tumor recurrence in the breast and signs of disease progression or death were the events collected and analyzed. Results. Of the 258 patients, 3 false negatives (1.1%) with axillary recurrence were detected at 10, 11 and 29 months of the surgery. This did not have a significant repercussion in the survival analysis on the contrary to the existence of breast recurrence or the appearance of distant metastasis in 4.7% and 6.2% patients, respectively. Global survival related with the cancer was 93.0 (240/258) and disease free survival was 89.1% (230/258). Conclusion. The risk of developing axillary recurrence after a negative SLN without axillary node dissection is low enough to consider the SLN procedure to be the best approach for axilla staging in early breast cancer. This staging technique also makes it possible to achieve local disease control without diminishing the survival of the patients(AU)

[Sentinel node biopsy in T2 breast cancers larger than 3 cm and clinically negative axilla compared with the T1-T2 <3 cm standard indication]. / La biopsia del ganglio centinela en cáncer de mama de más de 3 cm y axila clínicamente negativa frente a la indicación estándar T1-T2 < 3 cm.

OBJECTIVE: To present our experience in the application of sentinel node (SN) biopsy in patients with breast cancer T > 3 cm without clinical evidence of axillary metastasis. MATERIAL AND METHOD: Retrospective study of 393 cases in the period 2001--2006, divided into group (A) 47 patients with 3-5 cm T2N0 tumours and group (B) 346 patients T < 3 cm, N0. We employed the combined technique with 99mTc-colloidal rhenium sulphide and isosulfan blue dye. Preoperative lymphoscintigraphy was performed and the SN was located intraoperatively with a gamma ray detection probe and the blue dye. Axillary lymph node dissection was completed only when the SN was positive for metastasis in the histopathology analysis or not located. RESULTS: The SN detection rate for T2 > 3 cm was 94 % in the scintigraphy and 96 % with the probe, with no statistically significant differences between T < 3 cm (97 % and 98 %). In T2 > 3 cm, the final staging was 45 % pN0, 8 % pN1mi, 34 % pN1a, 11 % pN2a and 2 % pN3a. We found statistically significant differences (p < 0.05) when compared with palpable T < 3 cm and non-palpable cancer (62 % pN0 and 74 % pN0, respectively). In the follow-up of T2 > 3 cm (median 42.88 months) we did not find any axillary relapse which could be considered a false negative of the technique. CONCLUSION: The detection of sentinel lymph nodes is feasible and safe in tumours larger than 3cm with clinically negative axilla. Axillary lymph node dissection can be avoided in 45 % of these patients and therefore, we consider that they should be included as a general indication in breast cancer SN detection.

Staging the axilla with selective sentinel node biopsy in patients with previous excision of non-palpable and palpable breast cancer.

PURPOSE: To present our experience in the therapeutic approach of the sentinel node biopsy (SNB) in patients with previous excision of the breast cancer, divided in non-palpable and palpable lesions, in comparison with time treatment and stagement of breast cancer. METHODS: In the period 2001-2006, 138 patients with prior diagnostic excisional biopsy (96 non-palpable and 42 palpable breast cancer) and 328 without previous surgery (32 non-palpable; 296 palpable cancer) were treated. The combined technique ((99m)Tc-colloidal rhenium and isosulfan blue dye) was the approach for sentinel lymph node (SLN) detection. Axillary lymph node dissection (ALND) was completed only when the SLN was positive for metastasis or not located. RESULTS: Detection rate, if there was prior surgery, was 95% for non-palpable and 98% for palpable cancer, and 99% for one-time treatment group. Metastasis rate in the SLN was 15% in non-palpable cancer (14/91), significantly smaller than in palpable breast cancer (39% if prior surgery and 37% in one-time surgery). According to tumoral size, ALND metastasis rate was similar for T1 and T2 tumors (43-44%). In the follow-up of the groups with prior diagnostic biopsy or surgery of the breast cancer we have not found any false negative in the axilla. CONCLUSION: The detection of the SLN is also feasible in patients with previous surgery of breast cancer. Because SLN metastasis rates are significantly smaller in non-palpable lesions, the effort in screening programs for early detection of breast cancer and also in improving histopathological confirmation of malignancy with ultrasound or stereotactic guided core biopsies must continue.

Down-regulation of matrix metalloproteinase-9 (MMP-9) expression in the myocardium of congestive heart failure patients.

UNLABELLED: Matrix metalloproteinases (MMPs) are proteolytic enzymes responsible for extracellular matrix protein degradation. They have an important role in tissue remodeling processes. Their activity is regulated at the transcriptional, translational, and posttranslational level and by tissue inhibitors (TIMPs). Our aim was to analyze whether expression changes in MMPs that degrade collagens and their inhibitors in the myocardium have an impact on ventricular remodeling and the fibrogenesis in congestive heart failure. METHODS: We analyzed left ventricle biopsies from 18 patients with idiopathic dilated cardiomyopathy (iCDM) and severe congestive heart failure (HF) and 13 biopsies from organ donors. mRNA expression was quantified by real-time PCR, and fibrosis levels measured with picrosirius red staining. RESULTS: The patients mean age was 53 +/- 3 years. Expression levels of MMP-1, MMP-2, MMP-3, and TIMP1 did not show differences in pathological hearts compared to control hearts. Expression levels of MMP-1 and MMP-3 were low. MMP-9 expression levels were down-regulated in the cardiomyopathic hearts (49.77 +/- 7.6 ng equivalents of cDNA [ng-eq]) compared to controls (91.24 +/- 10.8 ng-eq, P < .005). MMP-2 expression levels correlated with the fibrosis levels (P < .05, R2 = 0.33, n = 18). CONCLUSION: MMP-9 mRNA expression down-regulation suggested that the protein levels were regulated at the posttranscriptional level. The correlation between MMP-2 expression levels and the collagen fraction in the pathological hearts indicated a putative role of MMP-2 in the fibrosis that takes place in congestive heart failure.

Correlation between mast cell density and myocardial fibrosis in congestive heart failure patients.

UNLABELLED: Besides the well-established role of mast cells in allergic reactions as an important source of vasoactive and proinflammatory products, they have been related to tissue fibrosis and remodelling processes. In a heart failure (HF) animal model, mast cells were shown to synthesize transforming growth factor beta1 and basic fibroblast growth factor in myocardial tissue and were localized to an area with fibrosis. Our objective was to quantify mast cell density in left ventricles from patients with congestive heart failure who were candidates for transplantation and to analyze whether they showed a correlation with the fibrosis level of the same area. METHODS: We obtained myocardial biopsies from 20 patients with end-stage HF secondary to idiopathic dilated cardiomyopathy (iDCM) undergoing heart transplantation and 15 controls (donors without cardiopathy). Mast cells were detected by immunohistochemistry with a human mast cell chymase antibody and fibrosis levels measured with picrosirius red staining of collagen fibrils with later quantification by morphometry. RESULTS: The patients mean age was 51 +/- 3 years. Fibrosis levels in the myocardial sections from patients with congestive HF was three-fold higher than those in control myocardium (12.41 +/- 1.7% vs 3.98 +/- 0.63%, P < .001). Mast cell density correlated with the collagen fraction and could be fitted to a linear regression curve: collagen fraction = 0.78 + 0.05 mast cell density (n = 33, P < .005, R2 = 0.28). CONCLUSION: The elevated collagen fraction present in failing hearts may be the cause of increased stiffness and loss of elasticity that is detected in patients with end-stage HF. Due to the mast cells capacity to synthesize vasoactive and fibrogenic products and the correlation between their density and fibrosis levels, they probably play a role in the ventricular remodelling in HF.

Value of NT-proBNP determinations in the follow-up of heart transplantation.

BACKGROUND: The N-terminal pro-brain natriuretic peptide (NT-proBNP) has been useful in the diagnosis and follow-up of heart failure. Whether it can be useful in the detection of acute rejection (AR) after heart transplantation (HT) has not been addressed. Our aim was to assess the prognostic value of NT-proBNP determinations after HT. METHODS: We analyzed 137 endomyocardial biopsies (EMB) performed in 51 patients as assessment of AR and correlated them with NT-proBNP determinations. The value of NT-proBNP in the early follow-up of the novo HT was also assessed. RESULTS: AR grade > or =3A was diagnosed in 10 of the 137 performed biopsies. There were no significant differences in NT-proBNP values between patients with or without AR (1047 +/- 629 versus 1886 +/- 3026 pg/mL, P = NS). There were 24 de novo HT, in these patients increased NT-proBNP levels showed an inverse significant correlation with time since HT (r = -0.40, P = .0001). During follow-up, 15 of the novo HT had a descending NT-proBNP curve over time, and in the remaining 9 (37%) a late increase of NT-proBNP values were observed. Those 9 patients had the following complications: AR > or =3A in 5 cases, 1 death, 2 required a permanent pacemaker, and in the last patient a significant EMB could not be obtained. CONCLUSIONS: NT-proBNP values follow a descending curve early after HT. During the first months, a late increase of NT-proBNP value was associated with HT complications, with AR being the most frequent. Isolated increased NT-proBNP levels were not useful for the detection of AR. More studies are needed to establish the prognostic value of NT-proBNP after HT.

Impairment in forearm endothelium-dependent vasodilation after heart transplantation.

BACKGROUND: Endothelial dysfunction has been found in the peripheral circulation of patients with severe heart failure. However, whether the endothelial dysfunction improves after heart transplantation remains unknown. Our aim was to assess the forearm endothelium-dependent vasoreactivity one and six months after heart transplantation. METHODS: We studied 12 patients using high resolution brachial artery ultrasound to assess flow-mediated dilation induced by reactive hyperemia and nitroglycerin induced dilation (NTGdil). RESULTS: One month after heart transplantation, endothelium-dependent vasodilation was significantly impaired in 10 patients (83%), while it was preserved in the remaining two (17%) (0.4%+/-2.4% vs 9.9%+/-4.6%, respectively, P=.001). NTGdil was normal in both groups (12%+/-10% vs 23%+/-5%, respectively, P=NS). At six months, endothelial dysfunction was present in all patients including the two patients without endothelial dysfunction at the first study. CONCLUSIONS: The present study demonstrates that peripheral endothelial dysfunction is present after heart transplantation despite the improvement in left ventricular function. More studies are needed to prove if endothelial dysfunction reversion may improve survival in heart transplantation.

Acute quadriplegic myopathy with loss of thick (myosin) filaments following heart transplantation.

Acute quadriplegic myopathy with loss of thick (myosin) filaments (AQM-LTF) is an acute toxic myopathy observed in critically ill patients and is characterized by proximal or diffuse weakness of extremities and difficulty in weaning from mechanical ventilation. In recent years, this myopathy has been described in transplanted patients, although only 5 cases have been reported following heart transplantation. We present 3 new cases and review the previous literature. We conclude that the clinical picture and outcome of AQM-LTF in heart-transplanted patients do not differ from those observed in other critically ill patients (transplanted and non-transplanted). Therefore, because AQM-LTF is often clinically suspected muscle biopsy should be quickly performed to confirm the diagnosis so that physical therapy may begin as soon as possible.

Prognostic value of serum cytokines in patients with congestive heart failure.

BACKGROUND: Increased levels of circulating cytokines have been previously reported in patients with congestive heart failure; however, whether they have prognostic implications is still unknown. The aim of this study was to assess the prognostic implications of elevated serum cytokines in patients with heart failure and to identify the predictors of cytokine activation. METHODS AND RESULTS: We assessed neurohormonal determinations, circulating cytokines, ejection fraction (EF) and end-diastolic and end-systolic left ventricular lengths in 87 patients (aged 57 +/- 9 years) with left ventricular dysfunction (EF 24% +/- 6%). In 48 patients, we also assessed cytokine receptors. During follow-up (mean, 14 +/- 9 months), 8 patients died and 12 had new heart failure episodes that required hospital admission, 5 of whom underwent heart transplantation. The univariate predictors of these events were serum interleukin-6 (IL-6) (p = 0.00001), New York Heart Association (NYHA) functional class (p = 0.0004), tumor necrosis factor-soluble receptor I (p = 0. 001), atrial natriuretic peptide (p = 0.002), tumor necrosis factor-soluble receptor II (p = 0.004), angiotensin II (p = 0.006), serum interleukin-1 beta (p = 0.01), and plasma renin activity (p = 0.02). Increased serum interleukin-6 (>10 pg/ml) was a significant predictor of death or new heart failure episodes according to the Kaplan-Meier survival method by log-rank test (p = 0.004). By Cox regression analysis, serum IL-6 (p = 0.0005) and the NYHA functional class (p = 0.005) were identified as independent predictors of prognosis. CONCLUSIONS: In patients with congestive heart failure, increased serum IL-6 was identified as a powerful independent predictor of the combined end point: death, new heart failure episodes, and need for heart transplantation.

Nitric oxide synthase II mRNA expression in cardiac tissue of patients with heart failure undergoing cardiac transplantation.

OBJECTIVES: To examine whether inducible nitric oxide synthase is expressed in myocardial tissue of patients with heart failure. BACKGROUND: There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiologic importance in heart failure. Nitric oxide (NO) can exert negative inotropic and cytotoxic effects on cardiomyocytes. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS III), but there is little information on the role of NOS II. Expression of NOS II could lead to excessive production of NO in the myocardium and affect cardiac contractility. METHODS: NOS II mRNA expression in myocardial tissue of 18 patients with idiopathic dilated cardiomyopathy (DCM), 7 patients with ischemic cardiopathy and severe ventricular dysfunction (ISCH), 4 patients with acute myocardial infarction (AMI) and 11 controls. Serum concentration of NO2-/NO3- (NOx) was also measured. RESULTS: NOS II gene expression occurred in all the patients with DCM, in 1 out of the 7 ISCH patients, in 2 out of the 4 patients with AMI and in none of the controls. Moreover, DCM patients showed a significant 6-fold increase in NOx concentration (253+/-47 nm/ml) as compared to controls (40+/-2 nm/ml) P < 0.001, a phenomenon not observed in ISCH patients (56+/-3 nm/ml). CONCLUSIONS: NOS II expression occurs in failing human cardiac myocytes and can play an specific role in the pathogenesis of DCM.

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy.

OBJECTIVE: To study the mitochondrial respiratory chain enzyme activities in patients with idiopathic dilated cardiomyopathy (IDC). METHODS: Mitochondrial respiratory chain enzyme activities were assessed spectrophotometrically in left ventricular tissue of 17 patients with IDC undergoing cardiac transplantation, as well as in two groups of controls: a group of six patients suffering from ischemic dilated cardiomyopathy (IC) also undergoing cardiac transplantation, and a group of 17 organ donors considered normal from a cardiac point of view. Cytochrome b gene from three IDC patients whose complex III activity was particularly low and from three controls was also sequenced. RESULTS: We found that complex III enzymatic activity was lower not only in IDC but also in IC patients when compared with normal controls. When analysing cytochrome b gene we only found neutral polymorphisms previously described. CONCLUSIONS: In view of such results, we believe that the decrease of respiratory chain complex III activity found in some cases of IDC is a secondary phenomenon, and not due to a primary mitochondrial disease.

Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure.

AIMS: The aim of the study was to assess the incidence and clinical implications of increased plasma angiotensin II despite chronic ACE inhibitor therapy in patients with heart failure. METHODS AND RESULTS: The studied population consisted of 70 patients (mean age 59+/-9 years). Plasma renin activity and plasma concentration of aldosterone, norepinephrine, atrial natriuretic peptide, angiotensin II, tumour necrosis factor, interleukin-6 and interleukin-1B were assessed at 6 months of ACE inhibitor therapy. Mean left ventricular ejection fraction was 24+/-5% and the end-systolic and end-diastolic diameters were 59+/-9 and 71+/-8 mm, respectively. Despite chronic enalapril or captopril therapy, 35 patients (50%) had increased plasma angiotensin II (median 33 pg. ml(-1), range 17-84), while it was in the normal range in the remaining 35 patients (median 10 pg. ml(-1), range 5-15). Plasma renin activity (P=0.005), interleukin-6 (P=0.004), New York Heart Association functional class III-IV (P=0. 006), furosemide dose (P=0.01), lack of beta-blocker therapy (P=0. 04) and norepinephrine (P=0.04) were univariately associated with increased angiotensin II. Multivariate regression analysis identified the plasma renin activity (0.0004), norepinephrine (0.02) and interleukin-6 (0.03) as independent predictors of plasma angiotensin II. During follow-up (35+/-29 months), nine (12.8%) patients died and 13 had new heart failure episodes. Increased plasma angiotensin II, despite ACE inhibitor therapy, was a significant predictor of death or heart failure according to the Kaplan-Meier survival method by log rank test (P=0.002). CONCLUSION: Fifty per cent of patients with heart failure, ha increased plasma angiotension II despite chronic ACE inhibitor therapy. These patients had higher neurohormonal activation and poor prognosis.

Serum interleukin-6 in congestive heart failure secondary to idiopathic dilated cardiomyopathy.

Increased serum interleukin-6 (IL-6) was associated with a higher incidence of New York Heart Association functional classes III to IV and worse left ventricular function during follow-up. Patients with elevated serum IL-6 had poor prognosis. These results reinforce the concept that increased serum IL-6 may also play an important role in disease progression.