Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

Metronomic and metronomic-like therapies in neuroendocrine tumors - Rationale and clinical perspectives.

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings.

Menstrual and reproductive history and use of exogenous sex hormones and risk of thyroid cancer among women: a meta-analysis of prospective studies.

PURPOSE: Thyroid cancer has a higher incidence in women than in men, and it has been hypothesized that hormonal factors may explain such disparity. We performed a meta-analysis of observational prospective studies to investigate the association between menstrual and reproductive variables and exogenous hormone use and the risk of thyroid cancer among women. METHODS: We calculated summary relative risks and 95% confidence intervals (95% CI) using random effect models. RESULTS: Overall, 5,434 thyroid cancer cases from twenty-four papers were included. Increasing age at first pregnancy/birth (SRR 1.56, 95% CI 1.01-2.42) and hysterectomy (SRR 1.43, 95% CI 1.15-1.78) were associated with thyroid cancer risk. Women that were in menopause at enrolment had a reduced thyroid cancer risk (SRR 0.79, 95% CI 0.62-1.01). No other menstrual, reproductive, and hormonal variable was associated with thyroid cancer risk. CONCLUSIONS: Menstrual and reproductive factors may play a role in the etiology of thyroid cancer, possibly through the mediation of estrogen receptors.

Role of hemithyroidectomy in differentiated thyroid cancer.

PURPOSE OF REVIEW: The incidence of differentiated thyroid cancer (DTC), especially among small tumors, is increasing worldwide, despite the fact that the mortality rate from thyroid cancer remains stable. Total thyroidectomy with or without radioiodine therapy is actually the standard treatment. In the last 2 decades, several studies have shown that lobectomy could be an alternative to total thyroidectomy in low-risk DTC without compromising overall survival. The aim of this article was to assess the role of conservative surgery (hemithyroidectomy) in DTC reviewing the literature data. RECENT FINDINGS: Recent advances in diagnostic techniques allow treatment to be tailored to patients' needs. The latest consensus guidelines suggest that patients with high-risk tumors should undergo total thyroidectomy, whereas patients with small, low-risk, node-negative DTC may be candidates for conservative surgery. Careful risk evaluation and stratification makes it possible to individualize treatment, avoid overtreatment and guarantee a good long-term prognosis with low recurrence risk. Excellent prognosis of DTC would require large sample sizes and long-term follow-up for prospective trials comparing the outcomes of total thyroidectomy vs. lobectomy; however, there are several remarkable retrospective studies. SUMMARY: Based on current clinical data, a conservative surgery might be appropriate for patients with low-risk DTC.

Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer.

The purpose of this study is to determine if there are differences in the expression of estrogen-regulated genes (ERGs), proliferation-associated genes and the progesterone effector RANKL, in premenopausal ER+ breast cancer as a result of the major changes in hormone levels that occur through the menstrual cycle. Primary ER+ tumours from 174 patients were assigned to one of three menstrual cycle windows: W1 (days 27-35 + 1-6), W2 (days 7-16) and W3 (days 17-26). RNA expression of 42 genes, including 24 putative genes associated with plasma E2 levels, seven proliferation genes and RANKL was measured. Expression of PGR, TFF1, GREB1 and PDZK1 followed the previously reported pattern: a higher level in W2 compared to W1 while W3 had an intermediate value, mirroring changes in plasma estradiol. Of the other 20 ERGs, four (RUNX1, AGR2, SERPINA3 and SERPINA5) showed significant differences (p = 0.009-0.049) in expression across the menstrual cycle. The expression of six of seven proliferation-associated genes varied across the cycle but differently from the ERGs, being 20-35 % lower in W3 compared to W1 and W2 (p = 0.004-0.031). Expression of RANKL was 2.5 to 3-fold highest in W3 (p = 0.0001) and negatively correlated to the expression of the proliferation-associated genes (r = -0.37; p < 0.0001). Expression of proliferation-associated genes and RANKL in ER+ breast tumours varies across the menstrual cycle showing a different rhythm to that of ERGs. This may affect the interpretation of gene expression profiles but may be exploitable as an endogenous test of endocrine responsiveness.

Expression of key oestrogen-regulated genes differs substantially across the menstrual cycle in oestrogen receptor-positive primary breast cancer.

Plasma estradiol (E2) and progesterone vary markedly through the menstrual cycle. Data on whether these differences in hormone levels affect gene expression in oestrogen receptor-positive (ER+) tumours are inconsistent. We wished to determine whether there are substantial changes in the expression of oestrogen-regulated genes (ERGs) in ER+ breast cancer through the menstrual cycle. One hundred and seventy five paraffin-embedded ER+ breast carcinomas from premenopausal patients were analysed. Timing of the ovarian cycle was confirmed using serum progesterone levels. Patients were ascribed to one of three pre-defined menstrual cycle windows: 1 (days 27-35 + 1-6), 2 (days 7-16) and 3 (days 17-26). The RNA expression of ESR1, four ERGs (PGR, GREB1, TFF1 and PDZK1), and three proliferation genes (MKI67, TOP2A and CDC20) were compared between the windows. Gene expression of the four ERGs was 53-129 % higher in window 2 than window 1 (p = 0.0013, 0.0006, 0.022 and 0.066 for PGR, GREB1, TFF1 and PDZK1, respectively) and lower (9-41 %) in window 3 compared to window 2 (p = 0.079, 0.31, 0.031 and 0.065 for PGR, GREB1, TFF1 and PDZK1, respectively). Their average expression (AvERG) was 64 % higher in window 2 than window 1 (p < 0.0001) and 21 % lower in window 3 than window 2 (p = 0.0043). There were no significant differences between the windows for ESR1 and proliferation genes. In agreement with the gene expression data, progesterone receptor protein levels measured by immunohistochemistry (IHC) were 164 and 227 % higher in windows 2 and 3, respectively, compared to window 1 (30.7 and 37.9 % cells positive vs. 11.6 %; p = 0.0003 and 0.0004, respectively), while no difference in ER IHC score was observed. In conclusion, we observed significant differences in the expression of ERGs in ER+ breast tumours across the menstrual cycle. This variability may affect the interpretation of gene expression profiles incorporating ERGs and may be exploitable as an endogenous test of endocrine responsiveness.

Surgical management of thyroid cancer.

Thyroid cancer is the most common endocrine neoplasm; however, it only accounts for less than 1% of all human malignances. Thyroid cancers are divided into well differentiated and non-well differentiated cancers, according to their histology and behavior. The surgical management options of well-differentiated thyroid cancer include total or near-total thyroidectomy, subtotal thyroidectomy and lobectomy plus isthmusectomy. The extent of surgery for thyroid cancer continues to be an area of controversy. Complications associated with thyroid surgery are directly proportional to the extent of thyroidectomy and inversely proportional to the experience of the operating surgeon. They occur less frequently with good surgical technique and better understanding of surgical anatomy, and include wound healing and infections (seroma, hematoma and wound infection), nerve injury, hypoparathyroidism, hypothyroidism, postoperative hemorrhage and respiratory obstruction.

Thyroid disorders in patients treated with radiotherapy for head-and-neck cancer: a retrospective analysis of seventy-three patients.

PURPOSE: To evaluate the incidence of thyroid disorders and dose distribution to the thyroid in patients treated with radiotherapy for head-and-neck carcinomas. METHODS AND MATERIALS: A retrospective evaluation of data from 73 patients treated for head-and-neck cancers in our department was performed. Thyroid function was evaluated mainly by the measurement of thyrotropin (thyroid stimulating hormone [TSH]). A retrospective analysis of treatment plans was performed for 57 patients. Percentages of thyroid glandular volume absorbing 10, 30, and 50 Gy (V10, V30, and V50 respectively) were considered for statistical analysis. RESULTS: A majority of patients (61%) had a normal thyroid function whereas 19 patients (26%) had hypothyroidism. Mean thyroid volume was 30.39 cc. Point 3 (located at isthmus) absorbed lower doses compared with other points (p < 0.0001). Median values of V10, V30, and V50 were 92% (range, 57-100%), 75% (range, 28.5-100%), and 35% (range, 3-83%) respectively. Gender was associated with toxicity (presence of any kind of thyroid disorders) (p < 0.05), with females displaying higher levels of TSHr (relative TSH = patient's value/maximum value of the laboratory range) (p = 0.0005) and smaller thyroid volume (p = 0.0012) compared with male population. TSHr values were associated with thyroid volume, and the presence of midline shielding block in the anterior field was associated with relative free thyroxine (FT4r = patient's value/maximum value of the laboratory range) values. CONCLUSIONS: Gender and thyroid volume seem to play an important role in the occurrence of thyroid toxicity, but further studies on dose-effect relationship for radiotherapy-induced thyroid toxicity are needed.

Radiotherapy-induced thyroid disorders.

Despite their specific functional consequences, radiotherapy-induced thyroid abnormalities remain under-estimated and underreported. These sequelae may include primary or central hypothyroidism, thyroiditis, Graves' disease, euthyroid Graves' ophthalmopathy, benign adenomas, multinodular goitre and radiation-induced thyroid carcinoma. Primary hypothyroidism, the most common radiation-induced thyroid dysfunction, affects 20-30% of patients administered following curative radiotherapy to the neck region, with approximately half of the events occurring within the first 5 years after therapy. The relative risk of radiation-induced cancer (mainly well-differentiated tumours) is 15-53-fold higher than in non-irradiated population. The aetiology of radiation-induced thyroid injury includes vascular damage, parenchymal cell damage and auto-immune reactions. Total radiotherapy dose, irradiated volume of the thyroid gland, and the extent of prior thyroid resection are among the most important factors associated with the risk of hypothyroidism. The contribution of other treatment modalities (chemotherapy, endocrine therapy) as well as patient- and tumour-related factors is less clear. Reduction in radiation dose to the thyroid gland and hypothalamic/pituitary complex should be attempted whenever possible. New radiotherapy techniques, such as stereotactic radiosurgery, three-dimensional conformal irradiation, intensity modulated radiotherapy and proton therapy allow generally better dose distribution with lower dose to the non-target organs. The diagnostic approach to thyroid radiation injury includes baseline thyroid function assays in all patients undergoing thyroid or parasellar irradiation. Recommended follow-up procedures include at least annual evaluation with a history for symptoms of thyroid dysfunction, clinical examination, and measurement of thyroid hormones and thyrotropin. Management of overt hypothyroidism is based on hormone replacement therapy. Thyroid hormone therapy is also recommended in cases of subclinical hypothyroidism. Treatment of other radiation-induced thyroid disorders (thyroiditis, Graves' disease, thyroid cancer) is similar to that employed in spontaneously occurring conditions. Further improvements in radiotherapy techniques and progress in endocrine diagnostics and therapy may allow better prevention and management of radiation-related thyroid injury.