Thyroid hormone autoantibodies: are they a better marker to detect early thyroid damage in patients with hematologic cancers receiving tyrosine kinase inhibitor or immunoregulatory drug treatments?

BACKGROUND: Unlike cytotoxic agents, novel antineoplastic drugs can variably affect thyroid function and so impair patient outcomes. However, the widely used standard thyroid tests have demonstrated low sensitivity for detecting early thyroid damage that leads to dysfunction of the gland. To find a more reliable thyroid marker, we assessed the presence of antibodies binding thyroid hormones (thAbs) in a cancer population undergoing potentially thyrotoxic treatment. METHODS: From April 2010 to September 2013, 82 patients with hematologic malignancies treated with tyrosine kinase inhibitors or immunoregulatory drugs were recruited. Healthy volunteers (n = 104) served as control subjects. Thyroid function, autoimmunity tests, thAbs, and thyroid sonography were assessed once during treatment. RESULTS: Overall, thAb positivity was recorded in 13% of the entire cohort. In most cases, the thAbs were of a single type, with a predominance of T3 immunoglobulin G. More specifically, thAbs were detected in 11 cancer patients; and abnormal levels of thyroid-stimulating hormone, thyroglobulin antibody, and thyroperoxidase antibody were detected in 6 (p = 0.05), 0 (p = 0.0006), and 2 cancer patients (p = 0.001) respectively. Ultrasonographic alterations of the thyroid were observed in 12 cancer patients. In contrast, of the 104 healthy control subjects, only 1 was positive for thAbs (1%). CONCLUSIONS: We have demonstrated for the first time that thAbs are a reliable marker of early thyroid dysfunction when compared with the widely used standard thyroid tests. A confirmatory prospective trial aiming at evaluating thAbs at various time points during treatment could clarify the incidence and timing of antibody appearance.

Cervical follicular dendritic cell sarcoma: a case report and review of the literature.

Follicular dendritic cell (FDC) sarcoma is a rare tumour with a low-to-intermediate grade of malignancy. It frequently occurs in cervical, mediastinal and axillary lymph nodes. In approximately 30% of cases an extranodal localization has been reported (tonsils, oral cavity, mediastinum, liver, and spleen). Very little is known about possible treatment options and overall prognosis. This case reports a 66 year-old patient, who underwent surgical removal of a persistently enlarged right cervical lymph node. The histopathological examination revealed a spindle cell tumour with lymphocyte and plasma cell infiltrates. Neoplastic cells stained positive for CD21, CD23 and CD35, thus confirming the diagnosis of FDC sarcoma. The neoplasm recurred two years later and partial regression was achieved by IGEV rescue therapy. We briefly discuss clinical history, histopathological differential diagnosis and treatment options of FDC sarcoma.

Increased annual frequency of Hashimoto's thyroiditis between years 1988 and 2007 at a cytological unit of Sicily.

Like other auto-immune diseases, Hashimoto's thyroiditis (HT) results from the interaction of genetic with environmental factors. Only few studies have evaluated the year-to-year change in frequency of HT over a wide period of time. The endocrine division of our Hospital has reported a great increase in the annual frequency of HT between 1975 and 2005, and a progressive decrease in both age at presentation and female to male (F/M) ratio starting in the mid-1990s. Between years 1988 and 2007, we have collected 8397 adequate examinations by fine needle aspiration cytology (FNAC) on 8397 persons referred for the evaluation of a solitary or dominant thyroid nodule (total FNAC and persons=8520) with a 14-fold increase in 2007 over 1988. In this 20-year period, cases of HT, De Quervain's thyroiditis (DQT) and Riedel's thyroiditis (RT) were 490, 36 and two, respectively. HT cases were one in 1988 but 90 in 2007, with a significant upward temporal trend (r=0.919, P<0.001) and significant downward trend for age at FNAC (r=-0.466, P<0.05). In contrast, DQT cases were zero and one, respectively, with no significant temporal trend (r=0.29, P=0.21). The HT increase in frequency started in 1996 (+350% over 1995). Until 1995 there was only one man, but there were 22 men in 2005-2007. These FNAC data provide independent confirmation to the data from the endocrine division of the same hospital, further supporting the conclusion that only environmental modifications can explain these marked changes that have occurred in such a relatively short period of time.

Multiple paraneoplastic diseases occurring in the same patient after thymomectomy.

Thymoma-associated paraneoplastic diseases include myasthenia gravis (MG), neuromyotonia (NMT), Morvan's syndrome, and several non-neurological paraneoplastic manifestations, including glomerulonephritis. Paraneoplastic syndromes often precede the occurrence of thymoma, but cases occurring after thymomectomy, which sometimes herald the recurrence of thymoma, have also been described. We report on a patient who developed MG after thymomectomy for a malignant thymoma. After MG remission, NMT and Morvan's syndrome occurred, which heralded a mediastinic recurrence, as demonstrated only by autopsy findings.

Evaluation of quality of life of patients submitted to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis of gastrointestinal and ovarian origin and identification of factors influencing outcome.

BACKGROUND: The prognosis of patients with peritoneal tumors has been improved by the association of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, though still with an unclear impact on patients' quality of life. The purpose of our study was to evaluate the quality of life in 18 cases submitted to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and particularly to identify the factors that influence it. PATIENTS AND METHODS: Quality of life was evaluated using the functional assessment of cancer therapy; the results were correlated with 25 parameters. RESULTS: The study demonstrated that the patients'quality of life was not modified by treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy; the dose of mitomycin C, the site of the primary tumor, gastrointestinal, renal and neurological toxicity, adjuvant chemotherapy, the patients' age and leukopenia were factors that influenced the quality of life. CONCLUSION: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy allows conservation of preoperative quality of life.

Anticancer activity of an adenoviral vector expressing short hairpin RNA against BK virus T-ag.

The human polyomavirus BK (BKV) is oncogenic in rodents and induces malignant transformation of rodent cells in vitro. Although its role in human tumorigenesis is still debated, BKV represents an excellent model to evaluate molecularly targeted antineoplastic approaches. Here, we have tested whether stable suppression of the T antigen (T-ag) oncogene expression could inhibit the in vitro and in vivo malignant phenotype of BKV-transformed mouse cells. An adenovirus vector system that expresses small hairpin RNAs (shRNAs), which are converted into active small interfering RNAs (siRNA) molecules against the BKV T-ag, was developed. This vector was able to inhibit the expression of BKV T-ag through a highly efficient in vitro and in vivo delivery of the siRNA molecule. In addition, it allowed a stable expression of siRNA for a period of time sufficient to elicit a biological effect. Inhibition of T-ag expression results in reduction of the in vitro growth rate of BKV-transformed cells, which is, at least in part, caused by restoration of p53 activity and induction of apoptosis. In vivo studies proved that adenovirus vectors expressing anti-T-ag siRNA were able to suppress tumorigenicity of BKV-transformed cells. Moreover, adenovirus vector direct treatment of growing tumors resulted in a significant reduction of tumor growth. This study indicates that siRNAs delivery via a viral vector have a potential usefulness as in vivo anticancer tool against viral and cellular oncogenes.

[186Re]HEDP in the palliation of painful bone metastases from cancers other than prostate and breast.

AIM: Palliative therapy using [186Re]hydroxyethylidene diphosphonate (HEDP) has been widely tested in patients with bone metastases from prostate and breast cancers. Whereas, to the best of our knowledge, only few cases of bone metastases from tumors other than prostate and breast treated with [186Re]HEDP have been reported. The aim of this paper is to report our experience with 186Re-HEDP in the palliation of painful bone metastases from tumors other than prostate and breast. METHODS: In this study 41 patients (17 non-small cell lung cancer-NSCLC, 1 small cell lung cancer, 1 lung neuroendocrine tumor, 8 bladder cancer, 3 kidney cancer, 3 gastric cancer, 1 uterine carcinoma, 1 colon cancer, 1 rhinopharynx carcinoma, 1 medullary thyroid carcinoma, 1 ovarian cancer, 1 esophagus cancer, 2 carcinoma of unknown origin) are evaluated. All patients had lesions with increased [99mTc]MDP uptake and none had radiological findings of mainly osteolytic lesions. A total of 46 therapeutic cycles were performed using a [186Re]HEDP activity of 1 295 MBq for each administration. After treatment, patients were followed up for 3 months or to the time of pain recurrence (if longer than 3 months). Responses were evaluated using a validated method considering the modifications of pain index, analgesic intake and performance status. RESULTS: Treatment efficacy was complete in 49% (20/41) of patients, partial in 36% (15/41) and negative in 15% (6/41). Namely, we observed 35% (6/17) complete, 41% (7/17) partial and 24% (4/17) negative responses in patients with NSCLC and 63% (5/8) complete, 25% (2/8) partial and 12% (1/8) negative responses in patients affected by bladder cancer. The median duration of pain relief in responder patients was 10 weeks. A mild platelet toxicity occurred in 32% (13/41) of patients. CONCLUSIONS: Pain palliation with [186Re]HEDP seems highly effective and safe also in patients with bone metastases from cancers other than prostate and breast. Patients who can benefit from the treatment with [186Re]HEDP can be selected on the basis of [99mTc]MDP bone scan and radiological examination findings.

Significance of P16INK4A hypermethylation gene in primary head/neck and colorectal tumors: it is a specific tissue event? Results of a 3-year GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Methylation of the p16 promoter is one of the most frequent mechanisms of gene inactivation; its incidence is extremely variable according to the type of tumor involved. Our purpose was to analyze the hypermethylation of the p16 promoter in laryngeal squamous cell carcinomas (LSCC), salivary gland (SG) tumors and in colorectal cancer (CRC), to detect any possible association with the clinicopathological features and to determine the prognostic significance of the p16 gene in the tumors analyzed. PATIENTS AND METHODS: The hypermethylation of the p16 promoter was prospectively analyzed, by MSP, in a consecutive series of 64 locally advanced LSCC patients, in a consecutive series of 33 SG tumor patients and in a consecutive series of 66 sporadic CRC patients. RESULTS: Hypermethylation was observed in 9% of the LSCC cases, in all cases of SG cancer and in 21% of the CRC cases. No significant association was observed between p16 hypermethylation and clinicopathological variables in all the tissue samples analyzed. Moreover at univariate analysis p16 mutations were not independently related at disease relapse and death in LSCC and CRC. CONCLUSIONS: The results of this study suggest that the lack of p16 function could happen in advanced stage of SG tumors.

Shift from Conn's syndrome to Cushing's syndrome in a recurrent adrenocortical carcinoma.

OBJECTIVE: Adrenocortical tumors may originate from the zona glomerulosa, zona fasciculata, or zona reticularis and be associated with syndromes due to overproduction of mineralocorticoids, glucocorticoids, or androgens respectively. We report an unusual case of recurrent adrenocortical carcinoma (ACC), which seems to contradict the paradigm of functional adrenal zonation. CASE REPORT: A male patient presented with severe primary aldosteronism due to an ACC, which relapsed after adrenalectomy and adjuvant mitotane therapy. After removal of the tumor recurrence and eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin, the patient presented again with ACC masses, but in association with overt Cushing's syndrome and normal aldosterone levels. METHODS AND RESULTS: Extensive pathologic examination showed that this shift in steroid hormone production was paralleled by an attenuation of tumor cell atypia and polymorphism, whereas gene expression profile analysis demonstrated a change in expression of adrenal steroidogenic enzymes. Moreover, cancer progression was associated with overexpression of the inhibin-alpha subunit, which could have contributed to the phenotypic changes. CONCLUSIONS: This case of recurrent ACC demonstrates that adrenocortical cells can reverse their differentiation program during neoplastic progression and change their specific hormone synthesis, as a consequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a consequence of chromosome amplification induced by chemotherapy. These findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis in order to dissect thoroughly the biology of cancer.

Adrenal incidentaloma in pregnancy: clinical, molecular and immunohistochemical findings.

Adrenal incidentalomas detected during pregnancy are very rare, and the natural history of these tumors during gestation is unknown. We report a case of a pregnant woman with an adrenal mass discovered serendipitously, who was followed-up during gestation and underwent adrenalectomy shortly after delivery. This allowed the evaluation of both the clinical outcome and the molecular/immunohistochemical correlates. Estrogens may indeed influence the function and proliferation of human adrenal cells, and a state of circulating estrogen excess can represent an in vivo model to test their effect on the adrenals. No evidence of adrenal change in morphology and function was found in our patient throughout pregnancy, as shown by adrenal ultrasound imaging and adrenal hormone measurements. Four months after delivery, the patient underwent laparoscopic right adrenalectomy, and pathologic analysis revealed a 2.7 cm benign adrenocortical adenoma. The diameter of the adrenal mass at ultrasonography correlated highly with post-partum mass diameter measured by abdominal computed tomography (CT). Quantitative expression of both ERalpha and ERbeta by real-time RT-PCR analysis and Western blotting findings did not differ among adenoma, normal adjacent adrenal and normal adrenal control tissues. This case of an adrenal incidentaloma discovered during pregnancy shows that a close observation with endocrine investigations and ultrasonography could be an appropriate approach, delaying the decision of surgical intervention after delivery. Estrogen receptor mRNA levels in the adrenal mass similar to those observed in normal adrenals suggest that estrogen oversecretion during pregnancy was not a risk factor for tumor progression.

Tumour staging, morphology and p53 overexpression concur in predicting survival in hepatocellular carcinoma.

BACKGROUND/AIMS: The prognosis of hepatocellular carcinoma (HCC) on cirrhosis is hard to predict as it depends on tumour stage, underlying liver disease, type of treatment and, possibly, biological factors of the tumour itself. METHODS: We prospectively evaluated the survival of 91 consecutive patients with HCC on cirrhosis, diagnosed between January 1998 and December 1999. Clinical features and histological/biological aspects, including histotype, grade, p53 overexpression, cytoproliferation and apoptotic markers were analysed. RESULTS: Child-Pugh (P = 0.01), Okuda (P < 0.0001), Cancer of the Liver Italian Program (CLIP) staging (P < 0.0001) and type of treatment (P = 0.0001) were significantly related to survival. In the Cox model, CLIP staging was included as independent predictor of survival at step 1 (P < 0.0001) with Okuda at step 2 (P = 0.013). Amongst the biological factors, p53 overexpression and histotype were significantly related with survival (P = 0.0044 and 0.017 respectively). When clinical and biological variables were examined together in the Cox model, CLIP and Okuda were confirmed as being statistically related with survival (P < 0.0001 and =0.012) followed by histotype and p53 overexpression (P = 0.019 and 0.02). CONCLUSIONS: CLIP, Okuda, histotype and p53 overexpression are the strongest predictors of survival in this series of patients. These data confirm that staging of the tumour and underlying liver disease are strictly related to prognosis but support the concurrent role of clinical and biological factors in upgrading our capacity of predicting the fate of HCC patients.

Prevalence of liver tumours in HIV-1 tat-transgenic mice treated with urethane.

The human immunodeficiency virus type 1 (HIV-1) Tat protein stimulates cell proliferation, inhibits apoptosis, displays angiogenic functions and is believed to be involved in the pathogenesis of Kaposi's sarcoma (KS) and other tumours arising in AIDS patients. Tat-transgenic (TT) mice, which constitutively express Tat in all tissues and organs, may therefore be predisposed to tumorigenesis. To test this hypothesis, we treated TT mice with urethane, a general carcinogen inducing tumours of various organs. The results indicate that, after injection of urethane, the incidence of lung tumours and lymphomas is not significantly different in the TT and control (CC) mice, whereas liver preneoplastic lesions and tumours show a significantly greater incidence in TT than in CC mice. This remarkable carcinogenic effect of urethane for the liver may be due to a tat-induced predisposition, manifested as a liver cell dysplasia (LCD), spontaneously affecting most of the TT mice. LCD may exert a promoting effect by stimulating proliferation of cell clones initiated by the mutagenic effect of urethane. In addition, LCD, which is associated with aneuploidy and chromosome instability, may enhance the progression to malignancy of the preneoplastic lesions induced by urethane. Interestingly, a significantly greater incidence of vascular ectasias and haemangiomas was detected in the liver of urethane-treated TT mice, most likely due to the marked angiogenic properties of Tat. This study suggests a role for Tat in the promotion and progression of tumours initiated by exogenous and endogenous carcinogens in HIV-1-infected patients, thereby contributing to the tumorigenesis in the course of AIDS.

CD44v10: an antimetastatic membrane glycoprotein for pancreatic cancer.

AIMS: The aims of this study were 1) to investigate the mRNA pattern of CD44 variants in three primary (MIA PaCa 2, PANC-1, PSN-1) and two metastatic (CAPAN-1, SUIT-2) pancreatic cancer (PC) cell lines; 2) to ascertain whether the genetic transfer of CD44s and CD44v10 modifies the adhesion of PC cells to the extracellular matrix (ECM) in vitro and their metastatic behavior in vivo. METHODS: CD44 mRNA analysis was done by means of RT-PCR. Adhesion to ECM the was assessed using coated microtiter plates. For the study of CD44v10 insertion in the CAPAN-1 line, liposome-mediated DNA transfer was used. SCID mice were employed for in vivo experiments. RESULTS: CD44v10 mRNA was not expressed by the CAPAN-1 nor by four of the six SUIT-2-derived clones. The stable expression of CD44v10 by modified CAPAN-1 significantly enhanced fibronectin adhesion. Mice without either liver or pancreatic metastases were more frequently found among the animals injected with modified (CD44v10 expressing) than with non-modified CAPAN-1. CONCLUSIONS: 1) It is possible to differentiate between metastatic and non-metastatic PC cells on the basis of CD44v10 expression; 2) CD44v10 seems to be involved in mediating fibronectin adhesion in vitro and in counteracting metastases in vivo.

Venous damage prevention by defibrotide in vinorelbine-treated patients.

GOALS: The aim of our study was to evaluate the incidence of venous toxicity induced by vinorelbine administration in patients who received a preventive therapy with defibrotide. PATIENTS AND METHODS: From July 1996 to July 2002 we treated 203 patients with vinorelbine, 51 with vinorelbine alone and 152 with vinorelbine in combination with other drugs via peripheral vein infusion. Of the 203 patients, 123 were male and 80 female with a median age of 67 years (range 18 to 82 years), and 118 were chemotherapy-naive. Defibrotide was delivered i.v. at a dose of 400 mg in 250 ml normal saline. After infusion of 125 ml over about 15 min, vinorelbine mixed with 10 ml normal saline was delivered as quick brief repeated pulses over 5 min through the plastic tube, followed by infusion of the remaining defibrotide. The specific Rittenberg scale was used to assess venous irritation episodes. RESULTS: Among a total of 1336 vinorelbine infusions, with a median of five infusions per patient, the incidence of venous irritation episodes graded according to Rittenberg scale was 1.1% (15), of which 0.6% (8) were grade 2 and 0.5% (7) grade 1. Globally, 15 patients (7.3%) developed venous toxicity after a median of 3 infusions (range 1-14), but no patient had more than one event. CONCLUSION: Our findings support the use of defibrotide as an effective, safe and low-cost means for preventing vinorelbine-related venous damage.

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m(2) days 1 and 8 plus cisplatin 75 mg/m(2) day 2 every 21 days (GC arm), or paclitaxel 225 mg/m(2) (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL x min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m(2)/wk for 12 weeks then every other week plus cisplatin 100 mg/m(2) day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P <.001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P <.001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P <.05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

Validation of a LC method for the analysis of oxaliplatin in a pharmaceutical formulation using an experimental design.

A rapid and sensitive RP-HPLC method with UV detection for routine control of oxaliplatin in a pharmaceutical formulation (Eloxatin) was developed. Quantitation was accomplished with the internal standard method. The procedure was validated by linearity (correlation coefficient=0.999948), accuracy, robustness and intermediate precision. Experimental design was used during validation to calculate method robustness and intermediate precision. For robustness test three factors were considered: percentage v/v of acetonitrile, flow rate and temperature; an increase in the flow rate results in a decrease of the drug found concentration, while the percentage of organic modifier and temperature have no important effect on the response. For intermediate precision measure the considered variables were: analyst, equipment and days. The RSD value (2.27%, n=24) indicated a good precision of the analytical method.

Brain resistance to HSV-1 encephalitis in a mouse model.

Brain resistance to intracerebral superinfections develops after a peripheral inoculation of neurovirulent viruses. Superinfection resistance combines specificity, toward the virus used for the peripheral inoculum, and short-term duration after the inoculum. In order to study this unusual combination, neurovirulent superinfections were made on albino Swiss mice previously infected with a nasal inoculum. A herpesvirus strain SC16, or a homologue recombinant virus carrying the reporter lac Z gene or a vesicular stomatitis virus (VSV) (a virus taxonomically unrelated to Herpesviridae) were used. The mice underwent a neurological examination and their survival rate was recorded. The brains superinfected with the reporter virus were stained for the beta-galactosidase reaction to trace the virus spread and the inflammatory infiltrates were characterized immunocytochemically. The results confirm and extend previous observations about virus specificity and short-term duration of superinfection resistance. They show, moreover, an enhanced brain inflammation with T-cells and macrophages infiltrating the tissue around microvessels, at a time when both neurovirulence and the spread of herpesvirus in the brain are reduced. The results suggest that the immune response to superinfection in the nervous tissue is enhanced by blood-brain barrier mechanisms that promote the timely extravasation of immune cells.