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Cytokines, thyroid disease and thyroid cancer
Cytokines are molecules that influence activation, growth, and differentiation of several target cells. They are roinflammatory mediators, regulate the systemic inflammatory response, playing a crucial role in autoimmune thyroid diseases, and modulate development and growth of both normal and neoplastic thyroid cells. In addition cytokines, as well as chemokines, have been shown to generate antitumor
response. In patients with thyroid cancer, cytokines are useful as serum biomarkers, and should be a part of multi-analyte assay in the clinical evaluation of patients with ndeterminate fine-needle aspiration cytology. Finally, several cytokines, such as interleukin-6 (IL-6), leukemia inhibiting factor (LIF), and thyroid transcription factor-1 (TTF-1) are expressed in thyroid cancer cell lines, and they can be used for evaluating the inhibitory effects of several drugs in redifferentiation therapies. This review reports the latest advances in defining the actions of cytokines, and resumes the relationship between cytokines, thyroid diseases and thyroid cancer
Chromogranin A, NSE, and 5-hydroxyindolacetic acid measurements in patients with malignant carcinoids.
Background: Neuroendocrine tumors (NET) of the gastro-entero-pancreatic
(GEP) system, which comprise nonfunctioning neuroendocrine pancreatic
tumors, pancreatic islets tumors, and carcinoids, are a heterogeneous group of
cancers more common in the small intestine. NET have extremely varying clinical
pictures, and it has been estimated a global incidence between 2.5-5 cases/100,000
per year. Each NET, depending on its anatomical site, arises from a different
neuroendocrine cell, exhibiting different functionality and biological behavior.
The neuroendocrine system of the GEP has at least 16 different types of endocrine
cells, that produce more than 50 amines or peptides, being the widest NET system
of the whole body. The NET of the small intestine are rare, and usually
asymptomatic. Gastric carcinoids accounts for 4-5% of all carcinoids, originate
from enterochromaffin-like cells, which are the source of several hormonal
substances, including histamine, serotonine, and chromogranin A (CgA). Because
of widespread and long-term use of proton pump inhibitors, and subsequent
chronic hypergastrinemia, in the last decades an increased risk of gastric carcinoids
have been reported. Appendiceal endocrine tumors, found incidentally in about
0.1% of appendicectomies, are often very small and benign. Colorectal carcinoids
are usually discovered on colonscopy in less than 0.1% of patients. In patients with
malignant carcinoids a number of prognostic parameters have been considered,
such as age, clinical symptoms related to the neoplasm, TNM staging, histological
grade, as well as urinary 5-hydroxyindolacetic acid (5-HIAA), and CgA, and
neuron-specific enolase (NSE) serum levels. 5-HIAA is a metabolite of serotonine,
and thus it is a specific marker of carcinoids producing serotonine.With the aim of
discriminating between well-differentiated and poorly differentiated malignant
carcinoids, the immunohistochemical expression of Ki-67 proliferation index,
which is associated with higher histologic grade and overall survival, should also be
measured. Unfortunately, the sensitivity of each tumor marker (TM) largely
depends on disease extent and the presence of functioning tumors, and thus their
usefulness is still debated. The aim of this study was to found a relationship
between TMs 5-HIAA, CgA, and NSE and survival in patients with gastrointestinal
carcinoids.
Patients and Methods: We retrospectively reviewed data regarding 14 patients (8
men, 6 women, median age 56 years, range 33-72) with histologically confirmed
gastric (N=8), ileal (N=1), colorectal (N=4) and appendiceal (N=1) malignant
carcinoids. All patients underwent surgery, and 4 had liver metastases at the time of
diagnosis.
Results: The specificity of TMs was 86%, 86%, and 93%, and the sensitivity was 64%,
36%, and 36% for CgA, NSE, and 5-HIAA, at a cut-off of 5 UI/L, 12lg/mL, and 50
lmol/24 h, respectively. In patients with liver metastases all TMs were above the cutoff.
The overall survival was 35.5±41.4 months (median 18, range 4-132 months),
while the 5-year survival was 28.6%. There was no relationship between survival and
both CgA (R=0.22, p=0.21) and NSE (R=0.12, p=0.76) serum levels.
Conclusions: The sensitivity of TMs is low, and they are not useful in predicting
outcome of patients with gastrointestinal malignant carcinoids
C-reactive protein in predicting survival of patients with colorectal cancer
Background: Colorectal cancer is the second most common cause of cancer death in
Western Countries. Overall survival is poor and only half patients, of those treated
with curative intent, survive 5 years. Cancer progression depends on a complex interaction
of both tumour’s characteristics and host inflammatory response. Circulating
levels of C-reactive protein (CRP) has been found to be related to survival in cancer
patients. The aim of this study was to analyze whether relationship exists between
age, gender, stage of the disease, and CRP serum levels in patients with colorectal
cancer.
Patients and Methods: Forty-five patients (25 men, 20 women, median age 69 years,
range 49-88 years) who underwent curative surgery for colorectal cancer were enrolled
in the study. The TNM stage was the following: Stage I: 2 (4.5%), Stage II: 24 (53.3%),
Stage III: 19 (42.2%) patients. Overall, preoperative PRC level was 9.737.13 mg/L (median
11, range 1-27 mg/L).
Results: The overall survival was 38.113.0 months (median 41 months, 95% CI: 34.4-
47.6months).Asignificant (c21⁄413.4, Log rank p<0.001) difference between Stage II and
III patients (43.61.7 vs. 38.11.9 months), and between patients with PRC>10 mg/L
and those with PRC<11 mg/L (33.02.9 vs. 44.11.7 mg/L; c21⁄44.8, Log rank
p<0.03) was found, while there was no difference according to gender (c21⁄40.41, Log
rank p<0.52). Using the multivariate Cox model analysis (forward stepwise method), adjusted
for age, both PRC and stage of the disease were independently related to survival.
The relative risk (RR) was 3.5 (95%CI: 1.5-8.2), and 8.1 (95% CI: 3.0-21.3), respectively.
Conclusions: Our results suggest that systemic inflammatory response, as shown by
raised circulating levels of CRP, is an independent prognostic factor in patients with
colorectal cancer, allowing to a better clinical stratification of patients
Sentinel node biopsy and axillary node sampling in women with breast cancer undergoing breast conserving surgery. Preliminary results of a prospective study
Background: Axillary dissection still represents the most accurate means of determining axillary lymph node status in patients with breast cancer (BC), but at the expense of significant morbidity. However, sentinel node biopsy (SNB) technique does not reach 100% sensitivity in detecting (or excluding) axillary node metastases, especially in the presence of unsuspected micrometastases. The aim of this study was to asses the accuracy of axillary node sampling (ALNS) in addition to SNB in patients with BC undergoing curative surgery.
Patients and Methods: Sixty-seven consecutive women (median age 54 years, range 28-68 years) with pT1 primary BC undergoing breast conserving surgery were enrolled in the study. Patients were prospectively randomizes to undergo SNB alone (Group A, 35 patients) or ALNS in addition to SNB (Group B, 32 patients), followed by level I-II axillary dissection. In all cases, a combined method using radioisotope and blue dye was used for SNB. Patients with positive SNB were excluded.
Results: The age of the patients (54.8±8.2 vs. 54.1±9.2, p=0.74) and the number of the removed nodes (median 19, range 16-25 in each Group) did not differ significantly (p=NS) between Groups. A median of 7 lymph nodes (range 6-9) was removed in Group B patients. In all patients intraoperative frozen section examination did not show positive nodes, whilst final histopathology showed micometastases in six (8.9%) patients. The sensitivity of SNB technique alone (false-negative rate: 14.3%) and SNB in addition to ALNS (false-negative rate: 3.1%) was 85.7% and 96.9%, respectively.
Conclusions: SNB alone in inaccurate in detecting axillary node micrometastases, and ALNS should be performed in all patients with macroscopically suspicious nodes and negative SNB
CT-guided fine-needle aspiration cytology and CDX2 immunostaining of pulmonary nodules in patients with colorectal cancer.
BACKGROUND:
Colorectal cancer (CRC) is the second most common cause of cancer death. The 5-year survival rate varies widely according to the stage of the disease, ranging from 80% to 60% in patients with localized and regional disease, respectively. Unfortunately, 20-25% of patients initially considered free of regional lymph-node involvement, present occult nodal metastases. Similarly, despite the use of CT-scan of the thorax with intravenous contrast with Hounsfield Units measurement and 18F-FDG-PET or PET/CT, more than 20% of metastatic nodules are not detectable preoperatively. Moreover, false-positive images of lung metastases (LM) from CRC are not infrequent, especially in patients at risk of lung cancer. Several alternative strategies have been suggested, enclosed radiotracer-guided biopsy and image-guided navigation. However, the routinely use of CT-guided fine-needle aspiration cytology (FNAC) represents the most sensitive diagnostic tool, especially when immunohistochemical staining of smears is performed. The aim of this study was to evaluate the usefulness of image-guided FNAC in patients with CRC who had undergone colonic resection and developed suspicious pulmonary nodules during follow-up.
PATIENTS & METHODS:
We studied a group of 12 patients (8 men, 4 women, median age 65 years, range 48-73 years) with primary CRC who underwent routine postoperative staging CT-scan of the liver and the thorax and MRI scan of the pelvis in case of rectal cancer. All the patients showed one or two suspicious pulmonary nodules, and had specific risk factors for another primary cancer, such as smoking history or dangerous chronic chemical substances exposure, with the aim of determining the tissue origin. They underwent CT- guided FNAC for standard cytological evaluation, and immunohistochemical staining for both thyroid transcription factor 1 (TTF1) and caudal type homeobox transcription factor 2 (CDX2), using anti-TTF1 (clone SPT 249) and anti-CDX2 (clone CDX2-88) monoclonal antibodies.
RESULTS:
TTF1 was positive in 5 specimens (CRC=2, LC=3), while CDX2 was positive in 11 specimens (CRC=10, LC=1). Thus, the sensitivity and positive predictive value (PPV) were 75.0% and 60.0%, and 83.3% and 90.9% for TTF1 and CDX2, respectively (χ2= 4.75, p=0.11). TTF1 and CDX2 together were 100% sensitive (χ2=11.11, p=0.001).
IN CONCLUSION, CT-guided FNAC and TTF1+CDX2 immunostaining in combination have a high sensitivity in differentiating between LMs from CRC and other malignancies such as lung cancer. It should be suggested in all patients with CRC and suspicious pulmonary nodules revealed during follow-up
Prognostic significance of circulating tumor cells in patients with colorectal cancer and liver metastases.
BACKGROUND:
Despite the reduction in colorectal cancer (CRC) incidence rates in recent years, this tumor remains the most common gastrointestinal cancer in Western countries. CRC is a systemic disease (stage IV) in about 20% of patients, and metastases are most commonly found in the liver and lung. Unfortunately, patients undergoing surgery for CRC liver metastases are at risk for tumor recurrence. Several prognostic criteria have been proposed to improve patient selection for liver resection and adjuvant or neoadjuvant chemotherapy, including specific molecular or genetic assay and circulating tumor cells (CTC) dissemination detection. CTC can be revealed by reverse transcription-polymerase chain reaction (RT-PCR) based on mRNA detection. Since blood contains RNAse able to rapidly destroy extracellular RNA, the detection of mRNA can be accepted as an indicator of the presence of CTC. The aim of this study was to evaluate whether the presence of CTC in blood may predict tumor recurrence in patients who underwent resection for CRC liver metastases (LMs). The Fisher exact probability test, relative risk (RR) and associated 95% confidence interval (CI) calculation were used to analyze results.
PATIENTS & METHODS:
Preoperative blood samples were obtained form 12 patients (8 men, 4 women, median age 67 years, range 58-72 years) with stage IV CRC and LMs. Blood samples were examined by immunomagnetic enrichment with RT-PCR technique based on specific molecular biological markers to detect CTC. The results were expressed as CTC-positive or CTC-negative samples. Patients underwent both spiral CT-scan and MRI to better define the size e number of metastases. CT-scan of the chest and whole-body 99mTc-MDP scintigraphy were also performed to exclude pulmonary and bone metastases, respectively. 18F-FDG-PET was used only in selected patients. Intraoperative ultrasound of the liver was performed in all patients. The chi-square test was used to analyze results.
RESULTS:
Nine patients showed CTC positivity, while three were CTC-negative. At 12-month follow-up, 9 patients developed relapse of the disease (CTC-positive=8, CTC-negative=1), and 3 were disease-free (CTC-positive=1, CTC-negative=2). A significant relationship between CTC-positivity and recurrence (chi-square=3.7, p=0.05) was found. The risk ratio (RR) was 2.66 (95%CI 0.53-13.43).
CONCLUSIONS:
In patients with CRC and LMs who underwent surgery, CTC detection by RT-PCR represents a reliable tool for selecting those at risk of relapse, and should be suggested in all patients with advanced CRC
Circulating PTH, vitamin D and IGF-I levels in relation to bone mineral density in elderly women.
Age and reduced bone mineral density (BMD) represent major risk factors for vertebral fracture risk, especially in postmenopausal women, and measurement of BMD is currently considered of value in estimating bone mineralization. BMD correlates with demographics and anthropometric parameters, as well as with several markers of bone metabolism and calcium-regulating hormones, such as leptin, osteoprotegerin, parathyroid hormone (PTH), vitamin D, insulin-like growth factor-I (IGF-I) and sex steroid hormones. The aim of this study was to evaluate the relationship between PTH, 25(OH) vitamin D [25(OH)D], IGF-I and BMD in a selected group of elderly women. Thirty-one postmenopausal women over age 65, who were not estrogen, vitamin D or bisphosphonate users and did not have a history of fracture, bone disease or malignancy, were prospectively enrolled in the study. All the patients underwent lumbar spine dual-energy x-ray absorptiometry (DXA) and serum calcium, creatinine, PTH, 25(OH)D and IGF-I measurements. As expected, a weakly inverse correlation between age and 25(OH)D (R= –0.50, p=0.020), and between BMD and PTH (R= –0.48, p=0.027) was found. There was a strong relationship between IGF-I and BMD (R=0.64, p=0.0016), and between age and IGF-I (R= –0.70, p<0.001), while IGF-I did not correlate with 25(OH)D (R= –0.16, p=0.48) or BMI (R= –0.089, p=0.70). In conclusion, in this selected group of elderly women, we found a strong relationship of increased bone resorption, expressed as BMD, to calcium-regulating hormones PTH and IGF-I, while 25(OH)D and BMI seem to be independent of bone mineralization status
Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer.
The early diagnosis of non-small cell lung carcinoma (NSCLC) is difficult, and 30-40% of patients with NSCLC develop bone metastases (BMs) during the course of their disease. Because the delayed demonstration of skeletal involvement may seriously affect survival, there is a need for early diagnosis of BMs. Unfortunately, the sensitivity of common serum tumor markers is low and they are used mainly for monitoring the efficacy of therapy and detection of recurrence. The aim of this study was to evaluate the utility of a panel of serum biomarkers in patients with NSCLC and BMs. Sixteen patients (11 males, five females; median age=64 years, range 54-68 years) with NSCLC and BMs (cases), and 18 age- and stage-matched patients without BMs (controls) underwent measurement of serum carboxy-terminal telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform type 5b (TRAP5b) and amino-terminal propeptide of type I collagen (PINP), carcinoembryonic antigen (CEA) and fragments of cytokeratin 19 (CYFRA 21-1. CTX (443.7±945.1 vs. 402.7±28.4 pg/ml, p=0.003) and PINP (75.9±11.4 vs. 64.1±7.5 μg/l, p=0.001) were significantly higher in patients with BMs, while the mean value of the other markers did not differ (p=NS) between cases and controls. The sensitivity, specificity and accuracy were 73.3%, 86.7% and 79.4% for CTX; 55.5%, 62.5% and 58.8% for CEA; 65.0%, 78.6% and 70.6% for CYFRA; 30.4%, 76.2% and 67.6% for TRAP5b; and 72.2%, 81.2% and 76.5% for PINP, respectively. The area under the receiver operating characteristic curve (AUC) for CTX was 0.68. In conclusion, CTX and PINP measurement can be useful in monitoring patients with NSCLC during follow-up, with the aim of detecting BMs early
Relationship between bone remodeling serum markers and BMD in premenopausal women with advanced breast cancer
Relationship between Bone Formation Markers Bone Alkaline Phosphatase, Osteocalcin and Amino-terminal Propeptide of Type I Collagen and Bone Mineral Density in Elderly Men. Preliminary Results.
Bone remodeling is altered in all metabolic bone diseases, especially in post-menopausal women and in the elderly. Predicting changes in bone mineral density (BMD) is useful to manage the progression of such diseases and to potentially provide interventions in reducing fracture risk. Continuous bone formation and resorption processes can be monitored by measuring biochemical markers of bone turnover (BTMs) and a relationship between BMD and BTMs has been known for long. The aim of this study was to evaluate the relationship between BMD and serum BTMs bone alkaline phosphatase (BAP), osteocalcin and amino-terminal propeptide of type I collegen (PINP) in elderly (>65 years) men. We prospectively studied 18 elderly men (median age=69, range=65-77 years) with no history of fractures, angina, stroke, myocardial infarction or diabetes mellitus. Patients who had undergone corticosteroid, calcitonin, androgen or bisphosphonate therapy were excluded from the study, as well as those who were vitamin D and calcium supplementation users. All the patients underwent lumbar-spine (L2-L4) dual-energy x-ray absorbtiometry and BMD, BAP, osteocalcin and PINP measurements. The mean BMD and body mass index (BMI) were 0.963±0.04 g/cm(2) and 24.4±1.2 kg/m(2), respectively. BAP, osteocalcin and PINP were 27.8±11.3 U/l, 25.6±7.1 ng/ml and 36.0±7.5 ng/ml, respectively. No correlation was found between BMD and BAP (R=-0.28, p=0.25), osteocalcin (R=-0.18, p=0.48) and PINP (R=-0.21, p=0.39), nor between BMI and both age (R=0.05, p=0.83) and BMD (R=0.10, p=0.67). In conclusion, we did not find any relationship between bone formation markers BAP, osteocalcin and PINP and bone density. Thus, our preliminary data suggest that BTMs are not useful in monitoring the bone mineral status of elderly me
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