Predictors of Malignancy in Children with Thyroid Nodules.

OBJECTIVE: To evaluate the diagnostic accuracy of clinical, laboratory, and ultrasound (US) imaging characteristics of thyroid nodules in assessing the likelihood of malignancy. STUDY DESIGN: Data from 184 children and adolescents with thyroid nodules were evaluated and compared with respective cytologic/histologic outcomes. A regression model was designed to assess the predictors associated with malignancy and to calculate ORs. RESULTS: Twenty-nine malignant neoplasms (25 papillary, 1 medullary, 3 Hurtle-cell carcinomas), 8 follicular adenomas, and 147 goitrous nodules (92 based on cytology, 55 on follow-up) were diagnosed. Fine-needle aspiration biopsy diagnostic accuracy, sensitivity, and specificity were 91%, 100%, and 88%, respectively. Male sex, compression symptoms, palpable lymphopathy, thyroid stimulating hormone concentration, microcalcifications, indistinct margins, hypoechoic US pattern, pathologic lymph node alterations, and increased intranodular vascularization were associated with malignancy. Regular margins, mixed echoic pattern, and peripheral-only vascularization were associated with benignity. During follow-up, nodule growth was associated with malignant disease, especially with levothyroxine therapy. A multivariate analysis confirmed that microcalcifications, hypoechoic pattern, intranodular vascularization, lymph node alterations, and thyroid stimulating hormone concentration were independent predictors of malignant outcome. For each predictor, we provide sensitivity, specificity, and positive/negative predictive values. CONCLUSIONS: Clinical, laboratory, and US features of nodules can be used as predictors of malignancy in children. Although none has diagnostic accuracy as high as that of fine-needle aspiration biopsy, these predictors should be considered in deciding the diagnostic approach of children with thyroid nodules.

Diagnostic performance of elastography in cytologically indeterminate thyroid nodules.

Cytological examination of material from fine-needle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4-20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p < 0.0001) with a OR of 21.9 (95 % CI 7.1-76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7-106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up.

Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness.

INTRODUCTION: Cyclooxygenase-2 (COX-2) is overexpressed in several malignancies and is implicated in breast cancer progression. OBJECTIVES: We investigated whether changes in COX-2 expression may affect epithelial-to-mesenchymal transition (EMT) and then invasive potential of human breast cancer cells, in relationship with hypoxia. COX-2-null MCF-7 human breast cancer cells, MCF-7 cells transiently expressing COX-2 and COX-2-expressing MDA-MB-231 cells were employed. RESULTS: COX-2 overexpression resulted in downregulation of E-cadherin and ß-catenin, upregulation of vimentin, N-cadherin and SNAI1, suggesting EMT occurrence. COX-2-overexpressing MCF-7 cells were also characterized by increased invasiveness and release of matrix-metalloproteinase-9. The above-mentioned characteristics, homologous to those detected in highly invasive MDA-MB-231 cells, were reverted by treatment of COX-2-overexpressing MCF-7 cells with celecoxib, a COX-2-specific inhibitor, partly through the inhibition of COX-2-related intracellular generation of reactive oxygen species. Hypoxia further exacerbated COX-2 expression, EMT changes and invasive ability in both COX-2-overexpressing MCF-7 cells and MDA-MB-231 cells. Finally, immunohistochemistry performed on samples from normal and neoplastic human breast tissues revealed that COX-2-positive malignant cells were also positive for EMT-related antigens, hypoxia-inducible factor (HIF)-2α and the oxidative stress marker heme oxygenase. CONCLUSIONS: These findings support the existence of a direct link between COX-2 overexpression, EMT and invasiveness in human breast cancer cells, emphasizing the role of hypoxic microenvironment.

BRAF (V600E) associates with cytoplasmatic localization of p27kip1 and higher cytokeratin 19 expression in papillary thyroid carcinoma.

The genetic alterations are responsible for the altered protein expression in tumors. The knowledge of the link between the altered protein expression and genetic alterations may provide potentially important biological and clinical information. In this study, the expression of some protein markers (Gal-3, p21Kip1, CK19) known to be associated to the papillary thyroid carcinoma (PTC) was assessed in a series of surgical samples by immunohistochemistry, and the association between expression of these markers and the BRAF (V600E) mutation was investigated. Gal-3 positive staining was evident in 26 % of benign nodules. The BRAF (V600E) mutation and Gal-3 expression, were found in 55.5 and 87 % of PTC respectively, and were unlinked. The expression of CK19 in benign nodules was weak and limited to scattered follicular cells. Diffuse cytoplasmatic expression of CK19 was present in malignant tumors in a variable percentage of cells. A higher percentage of CK19 expressing cells was associated with BRAF (V600E) (P ≤ 0.001). All benign nodules displayed nuclear p27kip1 in more than 15 % of the cells. Twenty-nine PTC showed a cytoplasmatic staining with negative nuclei. PTC with cytoplasmatic or 0-5 % of cells with nuclear staining, 6-15 % or >15 % of cells with nuclear staining were 72 (66.7 %), 24 (22.2 %), and 12 (11.1 %) respectively. In BRAF (V600E) positive tumors, the cytoplasmatic localization of p27kip1 was significantly more frequent (P = 0.024). In conclusion, we provide evidences that BRAF (V600E) is non-associated with Gal-3 expression, whereas it is associated with cytoplasmatic localization of p27kip1 and higher CK19 expression in PTC.

Prospective evaluation of accuracy of liver biopsy findings in the identification of chemotherapy-associated liver injuries.

OBJECTIVE To evaluate the accuracy of liver biopsy findings in preoperative assessment of chemotherapy-associated liver injuries (CALIs). DESIGN Prospective study. SETTING Tertiary care referral hospital. PATIENTS From July 1, 2007, to January 31, 2011, all patients with colorectal metastases receiving preoperative oxaliplatin- and/or irinotecan-based chemotherapy (≥4 cycles) were considered for the present study. Patients underwent parenchymal biopsy before liver resection. Blinded CALI evaluation was performed on biopsy and resection specimens. INTERVENTION Liver resection. MAIN OUTCOME MEASURES Sensitivity, specificity, and accuracy of liver biopsy in CALI evaluation. RESULTS We included 100 patients. At specimen analysis, grade 2 or 3 steatosis was diagnosed in 30 patients; grade 2 or 3 sinusoidal dilatation, in 28; grade 2 hepatocellular ballooning, in 3; grade 2 or 3 lobular inflammation, in 25; and steatohepatitis in 19. Obesity was associated with grade 3 steatosis (20.8% vs 5.3%; odds ratio [OR], 4.74 [P = .03]) and steatohepatitis (33.3% vs 14.5%; OR, 2.96 [P = .04]). Oxaliplatin administration was associated with higher sinusoidal dilatation grade (P = .049). Mortality (2 cases) was increased among patients with steatohepatitis (10.5% vs 0; OR, 13.67 [P = .04]). Biopsy findings correctly predicted steatosis (sensitivity, 88.9%; accuracy, 93.0%) but had low sensitivity and accuracy for sinusoidal dilatation (21.4% and 63.0%, respectively), hepatocellular ballooning (16.0% and 69.0%, respectively), lobular inflammation (20.0% and 78.0%, respectively), and steatohepatitis (21.1% and 79.0%, respectively). Biopsy accuracy did not improve regarding specific chemotherapy regimens or prolonged treatments. CONCLUSIONS Liver biopsy cannot be considered a reliable tool in assessing CALIs except for steatosis. The procedure should not be recommended during preoperative workup.

High diagnostic accuracy and interobserver reliability of real-time elastography in the evaluation of thyroid nodules.

Elastography is a new diagnostic tool in the evaluation of thyroid nodules. Aim of the study was to evaluate the accuracy and reliability of elastography in discriminating thyroid lesions and the interobserver variability. One hundred thirty-two nodules in 115 patients selected for thyroid surgery underwent conventional ultrasound and elastographic evaluation. Elastography score was divided in four categories (totally elastic nodule, mainly elastic, mainly rigid and totally rigid) according to signal distribution. Three independent operators conducted the study. Final histology showed 92 benign nodules and 40 malignant. On elastography, 77/92 benign nodules were classified as score 1 or 2 and 34/40 malignant nodules as score 3 or 4 (sensitivity 85%, specificity 83.7%, positive predictive value [PPV] 69.3%, negative predictive value [NPV] 92.7%). Rate of concordance between operators was good (K test: 0.64, p < 0.0001). Simple to use, with good interobserver agreement, elastography has all the requisites to become an important complement of conventional US examination in the near future.

High growth rate of benign thyroid nodules bearing RET/PTC rearrangements.

CONTEXT: Benign thyroid nodules display a broad range of behaviors from a stationary size to a progressive growth. The RET/PTC oncogene has been documented in a fraction of benign thyroid nodules, besides papillary thyroid carcinomas, and it might therefore influence their growth. OBJECTIVE: The aim of the present work was to evaluate whether RET/PTC in benign thyroid nodules associates with a different nodular growth rate. STUDY DESIGN: In this prospective multicentric study, 125 subjects with benign nodules were included. RET rearrangements were analyzed in cytology samples; clinical and ultrasonographic nodule characteristics were assessed at the start and at the end of the study. RESULTS: RET/PTC was present in 19 nodules. The difference between the mean baseline nodular volume of the RET/PTC- and RET/PTC+ nodules was not significant. After 36 months of follow-up, the RET/PTC+ group (n = 16) reached a volume higher than the RET/PTC- group (n = 90) (5.04 ± 2.67 vs. 3.04 ± 2.26 ml; P = 0.0028). We calculated the monthly change of nodule volumes as a percentage of baseline. After a mean follow-up of 36.6 months, the monthly volume increase of nodules bearing a RET rearrangement was 4.3-fold that of nodules with wild-type RET (1.83 ± 1.2 vs. 0.43 ± 1.0% of baseline volume; P < 0.0001). CONCLUSIONS: Benign thyroid nodules bearing RET rearrangements grow more rapidly than those with wild-type RET. Searching for RET rearrangements in benign thyroid nodules might be useful to the clinician in choosing the more appropriate and timely therapeutic option.

Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application.

Fine-needle aspiration cytology (FNAC) is the primary means to distinguish benign thyroid nodules from malignant ones. About 20% of FNAC yields indeterminate results leading to unnecessary or delayed surgery. Many studies of tissue samples, the majority of which are retrospective advocate testing for RET rearrangements as a diagnostic adjunctive tool in thyroid nodules with indeterminate cytological findings. Because of the uncertain prevalence of RET rearrangements, its utility as a tumor marker is still controversial. The goal of this study was to establish the prevalence and the utility of testing for RET rearrangements in FNAC suspicious of cancer in a clinical setting. In this prospective study, we analysed a large series of thyroid aspirates by RT-PCR only and Southern blot on RT-PCR products for type 1 and 3 RET rearrangements. Results were compared with clinical findings, cytological diagnosis and final histopathology. By the higher sensitive Southern-blot on RT-PCR method, RET rearrangements were present in 36% of papillary thyroid carcinomas (RET/PTC-1, 12%; RET/PTC-3, 20%; both, 4%) and of 13.3% of benign nodules. By means of RT-PCR only, RET rearrangements were disclosed only in 14.3% of PTC and in 3.6% of benign nodules. No significant correlation was found between RET rearrangements and clinicopathological features of patients. These results indicate that molecular testing of thyroid nodules for RET/PTC must take into account of its high prevalence in benign nodules, inducing false positive diagnoses when the highly sensitive assay Southern-blot on RT-PCR is used. Its searching by means of RT-PCR only, has a specificity superior of conventional cytology and can be used to refine inconclusive FNAC.

Growing thyroid nodules with benign histology and RET rearrangement.

Some benign thyroid nodules are stationary in size over time while others grow progressively, indicating that there is a broad individual variability within benign nodules. To date, it is very difficult to predict if a benign thyroid nodule will grow in size and which will be its trend over time. While BRAF(V600E) is a highly specific marker of thyroid cancer, RET rearrangements have been disclosed also in non malignant thyroid lesions and their biological significance is debated. We compared the clinical history of three histologically benign thyroid nodules harboring RET rearrangements with that of 6 benign nodules bearing wild type RET. The nodules negative for RET rearrangements were followed for 10 years by ultrasonographic evaluation, showing a slow, constant enlargement. Three patients with benign nodules diagnosed at FNAC, were followed for 11, 9 and 7 years by annual ultrasonographic evaluation. After several years of latency, the nodules had an unexpected and gradual increase in their dimensions, reaching a large final size. A second FNAC confirmed the previous cytologic diagnosis of benign lesion. Because of the increasing size of the nodules, the patients were advised to surgery. Before undergoing thyroidectomy, we performed molecular diagnostic tests that revealed the absence of BRAF(V600E) and the presence of RET/PTC-1 in one nodule and RET/PTC-3 in the two others. Despite the presence of this oncogene, the samples were histologically classified as benign hyperplastic nodules. These findings lead us to speculate that histologically benign hyperplastic thyroid nodules containing RET rearrangements might represent a subgroup of nodules with a rapid size increase.

Diagnostic value of a cytomorphological subclassification of follicular patterned thyroid lesions: a study of 927 consecutive cases with histological correlation.

BACKGROUND: Fine-needle aspiration cytology (FNAC) has proved to be an effective diagnostic tool in patients with thyroid nodules. Several reporting schemes have been suggested to define the risk of malignancy and consequent clinical management. To date, however, among lesions showing a follicular pattern, FNAC is still unable to differentiate between benign and malignant ones. The aim of our study was to evaluate whether a subclassification of follicular cytologic specimens, based on cytoarchitectural patterns, could differentiate categories with a different risk of malignancy, thus improving the clinical management of patients harboring follicular nodules. METHODS: We report a cohort of 927 consecutive cases who underwent thyroid surgery in our hospital between 2000 and 2008. Each patient underwent FNAC before surgery. All the cytologic specimens were divided into five categories (Thy 1: inadequate material, Thy 2: benign, Thy 3: indeterminate, Thy 4: suspicious for malignancy, Thy 5: malignant). Thy3 specimens were further divided into three subcategories (Thy 3a, or "follicular lesions of indeterminate significance": scant colloid, microfollicular pattern, or small clusters of thyrocytes with round nuclei usually without, but sometimes with, minimal cellular pleomorphism; Thy 3b, or "follicular neoplasm": absence of colloid, small clusters, or microfollicles of medium-large sized cell populations arranged in cohesive groups with nuclear overlapping, crowding, and pleomorphisms; and Thy 3c or "Hurthle-cell neoplasm": scant colloid, sheets or clusters of oxyphilic cells). RESULTS: Thy 1 specimens (51 cases on the whole) proved to be malignant in 5.88% (3 cases), Thy 2 specimens (319) in 3.45% (11 cases), Thy 4 specimens (91) in 84.62% (77 cases), and Thy 5 specimens (172) in 98.84% (170 cases). Thy 3 specimens (294 cases) proved to be malignant in 17.35% as a whole, but when divided into the three subcategories, the percentage of malignant cases was significantly different between the Thy 3a group (4.95%) and the Thy 3b and Thy 3c groups (25.0% and 22.77% respectively). CONCLUSIONS: This study supports the National Cancer Institute consensus showing a different risk of malignancy for "follicular lesions of undetermined significance" compared with "follicular neoplasms" and "Hurthle cells neoplasms," which are more suspect for malignancy. This subclassification could improve clinical management of thyroid nodules, helping to better select patients for surgery or follow up.

COX-2 expression in human breast carcinomas: correlation with clinicopathological features and prognostic molecular markers.

OBJECTIVE: COX-2 is implicated in carcinogenesis and tumour progression in many cancers, including breast cancer. Recently, it has been reported that human breast carcinomas aberrantly express COX-2, and that raised tissue levels of COX-2 may have prognostic value. Patients expressing high levels of COX-2 can develop local recurrence, and have reduced disease-free and disease-related overall survival. The aim of this study was to investigate COX-2 expression in human ductal and lobular breast cancers and its possible association with clinicopathological features and prognostic molecular markers. RESEARCH DESIGN AND METHODS: Cytoplasmic COX-2 expression was detected by means of immunohistochemistry in a series of 91 breast carcinomas with ductal (n = 60) and lobular (n = 31) patterns. COX-2 expression was investigated by multivariate analyses and compared with clinicopathological features. RESULTS AND CONCLUSIONS: COX-2 immune positivity and percentage of positive cells correlated significantly with the size, grading, extent of primary tumour and vascular invasion of carcinoma but not with biological parameters (estrogen receptor, progesterone receptor and human EGF receptor 2). The findings of the present study suggest that COX-2 overexpression in lobular and ductal breast cancers, which correlates with traditional clinico-pathological parameters, may be considered as a negative prognostic marker.

Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases.

BACKGROUND: The optimal duration, safety, and benefit of preoperative chemotherapy in patients with colorectal liver metastases (CLM) are unclear. We evaluated the association between the duration of preoperative chemotherapy with 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX) ± bevacizumab, pathologic response, and hepatotoxicity after hepatic resection for CLM. METHODS: A total of 219 patients underwent hepatic resection following FOLFOX with or without bevacizumab and were divided into 2 groups according to the chemotherapy duration: 1-8 cycles (short duration [SD]; N = 157) and ≥9 cycles (long duration [LD]; N = 62). The frequency of complete or major pathologic response, sinusoidal injury, and major postoperative morbidity were compared. RESULTS: Treatment consisting of ≥9 cycles was not associated with an increase in complete or major pathologic response (SD vs. LD, 57% vs. 55%; P = .74). The incidence of sinusoidal injury was higher in the LD group (26% vs. 42%; P = .017). The incidence of liver insufficiency was higher in the LD group (4% vs. 11%; P = .035). Sinusoidal injury did not predict postoperative liver insufficiency; multivariate analysis revealed ≥9 cycles was the only independent predictor of postoperative liver insufficiency (P = .031; odds ratio = 3.90). Chemotherapy including bevacizumab was associated with a significantly higher frequency of complete or major response in both SD and LD groups. CONCLUSIONS: Extended preoperative chemotherapy increases the risk of hepatotoxicity in CLM without improving the pathologic response. The type of chemotherapy (FOLFOX with bevacizumab) has more impact on pathologic response than the duration of chemotherapy.

Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. RESULTS: We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. CONCLUSION: In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

Combined analysis of galectin-3 and BRAFV600E improves the accuracy of fine-needle aspiration biopsy with cytological findings suspicious for papillary thyroid carcinoma.

Ten to fifteen percent of fine-needle aspiration biopsy (FNAB) of thyroid nodules are indeterminate. Galectin-3 (Gal-3) and the oncogene BRAFV600E are markers of malignancy useful to improve FNAB accuracy. The objective of this study was to determine whether the combined analysis of Gal-3 and BRAFV600E expression in thyroid aspirates could improve the diagnosis in FNAB with suspicious cytological findings. Two hundred and sixty-one surgical thyroid tissues and one hundred and forty-four thyroid aspirates were analyzed for the presence of the two markers. In surgical specimens, Gal-3 expression was present in 27.4% benign nodules, 91.9% papillary (PTC) and 75% follicular (FTC) thyroid carcinomas. BRAFV600E was not detected in 127 benign nodules, as well as in 32 FTCs, while was found in 42.9% PTC. No correlation was found between BRAF mutation and Gal-3 expression. Forty-seven consecutive FNAB suspicious for PTC were analyzed for the presence of the two markers. Of these nodules, 23 were benign at histology, 6 were positive for Gal-3, none displayed BRAFV600E, and 17 were negative for both the markers. Twenty suspicious nodules were diagnosed as PTC and four FTCs at histology. Of these 24 carcinomas, 9 resulted positive for BRAFV600E, 17 for Gal-3, and 22 for one or both the markers. The sensitivity, specificity, and accuracy for the presence of Gal-3 and/or BRAFV600E were significantly higher than those obtained for the two markers alone. Notably, the negative predictive value increased from 70.8 to 89.5%. In conclusion, the combined detection of Gal-3 and BRAFV600E improves the diagnosis in FNAB with cytological findings suspicious for PTC and finds clinical application in selected cases.

Warning nonrespiratory symptoms in asthma: catastrophic abdominal involvement in a case of Churg-Strauss syndrome.

BACKGROUND: Churg-Strauss syndrome (CSS) is a systemic vasculitis that occurs in the setting of asthma or allergic rhinitis with eosinophilia. The development of systemic manifestations in these allergic patients needs to be recognized as a likely sign of CSS. OBJECTIVE: To describe a patient with limb paresthesia and abdominal complaints related to CSS. METHODS: Blood leukocyte count, nerve conduction study, ultrasound and computed tomography of the abdomen, laparoscopic cholecystectomy and ileum resection, and histopathologic examination of ileum and gallbladder samples. RESULTS: A 55-year-old man with chronic asthma and rhinosinusitis had acute acalculous cholecystitis after he experienced lower limb paresthesia subsequently recognized as being due to mononeuritis multiplex. His eosinophil count was 1,860/microL. Three days after laparoscopic cholecystectomy the patient developed sudden severe diffuse abdominal pain with hypotension due to perforation of the ileum. The peripheral eosinophil count increased to 14,000/microL. Ileal resection was performed. Histopathologic examination showed necrotizing vasculitis with eosinophilic infiltration of the ileum and granulomatous vasculitis with eosinophilic infiltration of the gallbladder. He was treated with pulse intravenous methylprednisolone, 1 g for 3 consecutive days, followed by pulse intravenous cyclophosphamide, 750 mg/m(2), and recovered uneventfully. He received 6 additional monthly infusions of cyclophosphamide, and oral prednisone was tapered. When last seen, 2 years later, the patient was in good clinical condition, continuing alternate-day use of oral prednisone (10 mg). CONCLUSIONS: Nonrespiratory symptoms, such as paresthesia and acalculous cholecystitis, in a patient with asthma should alert the physician to consider CSS. If the neuropathic complaints had prompted the consideration of vasculitis, medical management might have avoided one or both surgical procedures.

Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) is the primary means to distinguish benign from malignant nodules and select patients for surgery. However, adjunctive diagnostic tests are needed because in 20-40% of cases the FNAB result is uncertain. OBJECTIVE: We investigated whether a search for the oncogenes RET/PTC, TRK and BRAF(V600E) in thyroid aspirates could refine an uncertain diagnosis. PATIENTS AND METHODS: A total of 132 thyroid aspirates, including colloid nodules, inadequate samplings, indeterminate and suspicious for malignancy were analysed by reverse transcription polymerase chain reaction (RT-PCR) and mutant allele-specific amplification techniques for the presence of oncogenes. RESULTS: No oncogenes were detected in 48 colloid nodules, 46 inadequate and 19 indeterminate FNABs, then confirmed to be benign at histology. No oncogenes were detected in one follicular thyroid cancer (FTC) with indeterminate cytology. Five out of six papillary thyroid cancers (83%) with FNAB suspicious for malignancy were correctly diagnosed by the presence of oncogenes. Among these, four (67%) contained the BRAF mutation and one (17%) contained RET/PTC-3. On final analysis, no false-positive results were reported in 131 samples and five out of seven carcinomas (71%) were correctly diagnosed. The finding of oncogenes in FNAB specimens suspicious for malignancy guided the extent of surgical resection, changing the surgery from diagnostic to therapeutic in five cases. CONCLUSIONS: Detection of RET/PTC, TRK and BRAF(V600E) in FNAB specimens is proposed as a diagnostic adjunctive tool in the evaluation of thyroid nodules with suspicious cytological findings.

Intratumoral microvessel density in advanced epithelial ovarian cancer and its use as a prognostic variable.

BACKGROUND: The aim of this retrospective study was to assess whether the intratumoral microvessel density (IMD) in primary tumour specimens had any impact on the clinical outcome of patients with advanced epithelial ovarian cancer treated in two Italian departments of gynaecological oncology. MATERIALS AND METHODS: The study was conducted on 101 patients who underwent initial surgery followed by platinum-based chemotherapy (37) or paclitaxel/platinum-based chemotherapy (64) for International Federation of Gynecology and Obstetrics (FIGO) stage III-IV epithelial ovarian cancer. The median follow-up of survivors from initial surgery was 65 months (range, 27 to 132 months). Paraffin-embedded sections of primary tumour specimens were analysed for IMD by immunohistochemistry using anti-CD34 antibodies. RESULTS: Progression-free survival and overall survival were significantly better in patients with IMD > or =40 microvessels/field compared with those with lower IMD (p = 0.0105 and p = 0.0065, respectively). Cox model showed that IMD was the strongest independent prognostic variable for both progression-free survival (p = 0.0267) and overall survival (p = 0.0189). CONCLUSION: An elevated IMD was associated with a significantly better progression-free survival and overall survival in patients with stage III-IV epithelial ovarian cancer who underwent initial surgery followed by chemotherapy, mainly consisting of a paclitaxel/platinum-based regimen.

Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns: a clinicopathologic study of 183 patients.

BACKGROUND: The term poorly differentiated (PD) carcinoma was proposed 20 years ago to define aggressive, follicular-derived thyroid carcinomas with behavior intermediate between follicular/papillary and anaplastic carcinomas. Among the variable histologic patterns recognized in such tumors, trabecular-insular-solid (TIS) areas usually are predominant. Conversely, some authors pointed out that PD carcinomas are characterized by unequivocal, high-grade histology with atypias, high mitotic counts, and necrosis rather than by a specific growth pattern. METHODS: The clinicopathologic features of a series of 183 thyroid carcinomas with predominant (n = 165 tumors) or focal (n = 18 tumors) TIS growth patterns were studied by univariate and multivariate overall survival analyses and were compared with clinical outcomes. Subgroups included tumors with predominant oxyphilic features (n = 66 tumors) and (residual) papillary carcinoma features (n = 24 tumors). Control groups of papillary (n = 68 tumors), follicular (n = 71 tumors), and anaplastic (n = 35 tumors) carcinomas also were included for overall survival analysis. RESULTS: TIS carcinomas had an intermediate behavior between papillary/follicular and anaplastic carcinomas (P < 0.0001). Univariate and multivariate statistical analyses demonstrated that age > 45 years (P = 0.007), the presence of necrosis (P < 0.0001), and a mitotic count > 3 per 10 high-power fields (P = 0.01) were associated with poor outcome. A simplified scoring system based on statistically significant parameters allowed the identification of three prognostic subgroups (P < 0.0001). CONCLUSIONS: PD TIS carcinomas overall followed a more aggressive course compared with differentiated thyroid carcinomas, irrespective of the extent of the TIS component. However, a numeric scoring system applied to specific clinicopathologic parameters further may identify three prognostic categories of patients who have significantly different survival rates at 5 years and 10 years.