Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity.

In the last decade, a large amount of research has focused on elucidating the mechanisms that account for homing disseminated cancer cells (DCCs) from solid tumours to distant organs, which successively progress to overt metastatic disease; this is currently incurable. A better understanding of DCC behaviour is expected to allow detectable metastasis prevention by more effectively targeting 'metastatic seeds before they sprout'. As DCC biology co-evolved with that of the primary tumour, and due to the many similarities between them, the term 'niche' has been borrowed from normal adult stem cells (ASCs) to define the site of DCC metastatic colonisation. Moreover, heterogeneity, survival, protection, stemness and plasticity as well as the prolonged G0-G1 dormant state in the metastatic niche have been the main aspects of intense investigation. Consistent with these findings, in solid cancers with minimal residual disease (MRD), it has been proposed to prolong adjuvant therapy by targeting specific molecular pathway(s) involving DCC dormancy. However, so far, few disappointing clinical data have been reported. As an alternative strategy, because immune-surveillance contributes to the steady state of the DCC population and likely to the G0-G1 state of cancer cells, we have used prolonged immune-modulatory cytostatic chemotherapy, active immune stimulation with an INF-ß/IL-2 sequence or drugs inhibiting myeloid-derived suppressor cell (MDSC)/Treg-mediated immune suppression. This strategy, mainly aimed at boosting the immune response, is based on recent findings suggesting the downregulation of immune escape mechanisms as well as other principal hallmarks during the G0-G1 state and/or in MRD. Preliminary clinical and/or laboratory data suggest the efficacy of this strategy in gastrointestinal and some endocrine-dependent cancers. Following this, we propose therapeutic schedules to prevent DCC activation and proliferation in solid cancers at a high risk of relapse or as maintenance therapy in metastatic patients after complete response (CR) to conventional treatment.

Treatment of Metastatic or High-Risk Solid Cancer Patients by Targeting the Immune System and/or Tumor Burden: Six Cases Reports.

This article summarizes the histories of six patients with different solid tumors treated with a new strategy based on tumor burden reduction and immune evasion as potential targets. All six patients were at a high risk of relapse and were likely to have a minimal residual disease following conventional therapy: biochemical recurrence (BCR) following radical prostatectomy (RP) (two prostate cancers patients), removal of distant metastases (one colorectal and one breast cancer), and complete response (CR) of distant metastases to conventional therapy (one breast cancer and one esophageal-gastric junction cancer). Four of the patients, two after RP and BCR, one after removal of a single pulmonary metastasis from breast cancer, and one after CR to chemotherapy of peritoneal metastases and ascites from an esophageal-gastric junction primary cancer, regularly received cycles of a new drug schedule with the aim of inhibiting immune suppression (IT). In these four patients, preliminary laboratory tests of peripheral blood suggested an interleukin (IL)-2/IL-12 mediated stimulation of cellular immune response with a concomitant decrease in vascular endothelial growth factor (VEGF) immune suppression. The fifth case was a breast cancer patient with distant metastases in CR, while receiving beta-interferon and interleukin-2 in addition to conventional hormone therapy. To date, all five patients are alive and doing well and they have been unexpectedly disease-free for 201 and 78 months following BCR, 28 months following the removal of a single pulmonary metastases, 32 months following CR to chemotherapy of peritoneal metastases and ascites, and 140 months following diagnosis of multiple bone metastases, respectively. The sixth patient, who had colorectal cancer and multiple synchronous liver metastases and underwent nine surgical interventions for metastatic disease, although not disease-free, is doing well 98 months after primary surgery. Our six cases reports can be interpreted with the hypothesis that immune manipulation and/or a concomitant low tumor burden favored their clinical outcome.

Alterations of Signaling Pathways Related to the Immune System in Breast Cancer: New Perspectives in Patient Management.

In recent years, immune manipulation for cancer treatment, including breast cancer, has been increasingly gaining consent, and many attempts have been made, mainly by either strengthening the immune response (IR) or by inhibiting immune evasion. Therefore, elucidating the related mechanisms is of importance due to the potential to improve the management of cancer patients by immunotherapy. This review article summarized some recent experimental studies, which have discovered novel alterations of signaling pathways related to the immune system in breast cancer. These altered signaling pathways have been grouped according to the general biological mechanism involved: tumor-initiating cells (TICs), cancer stem cells (CSCs), immune evasion, tumor growth and progression, prediction of clinical outcome and prediction of response, or resistance to chemotherapy. These altered pathways related to the immune system open clinical opportunities for the prognosis or treatment of patients. Many of these pathways are related to the origin of breast cancer and immune evasion. We recommended development of new drugs which act on these molecular pathways, and the designing of clinical trials to be carried out mainly in breast cancer patients who required adjuvant treatment.

Recent Advances in Comprehending the Signaling Pathways Involved in the Progression of Breast Cancer.

This review describes recent advances in the comprehension of signaling pathways involved in breast cancer progression. Calcium sensing receptor (CaSR), caveolae signaling, signaling referred to hypoxia-inducing factors and disturbances in the apoptotic machinery are related to more general biological mechanisms and are considered first. The others refer to signaling pathways of more specific biological mechanisms, namely the heparin/heparin-sulfate interactome, over-expression of miRNA-378a-5p, restriction of luminal and basal epithelial cells, fatty-acid synthesis, molecular pathways related to epithelial to mesenchimal transition (EMT), HER-2/neu gene amplification and protein expression, and the expression of other members of the epithelial growth factor receptor family. This progress in basic research is fundamental to foster the ongoing efforts that use the new genotyping technologies, and aim at defining new prognostic and predictive biomarkers for a better personalized management of breast cancer disease.

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy.

Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed.

Overexpression of estrogen receptor-α in human papillary thyroid carcinomas studied by laser- capture microdissection and molecular biology.

The expression pattern of estrogen receptor (ER) isoforms in normal and tumor thyroid tissues is still controversial and poor defined, therefore, a more detailed study of the distribution of these molecules is needed. Most discrepancies might be due to the methods utilized. We studied the expression of ER isoforms in human papillary thyroid carcinoma (PTC), in fine-needle aspiration biopsy-derived specimens, and in cells, using more accurate techniques, such as laser-capture microdissection, real-time quantitative PCR, and Western blot. Laser-capture microdissection allowed us to isolate homogeneous cell populations from human PTC surgical samples. Tumor, peritumor, or normal host tissue of the same sample were separately dissected and analyzed by RT-PCR and Western blot. Estrogen receptor-α mRNA was more expressed in cancer-microdissected cells from human PTC, as compared with microdissected cells obtained from surrounding normal host tissue (450 vs 12, P = 0.001). A similar pattern was observed with Western blot for the ER-a protein. By contrast, ER-ß mRNA expression was not detected among the microdissected tissue fractions. Fine-needle aspiration biopsy-derived specimens showed a similar expression pattern to ER. Moreover, human PTC cell line BCPAP and cancer stem cells from PTC, analyzed under hypoxic conditions, showed a hypoxia-driven increase in ER-α expression. In conclusion, ER-α might have an important role in human PTC, and its overexpression can be studied in routine needle aspirate as a possible marker of malignancy.

Large needle aspiration biopsy histology for preoperative selection of Hürthle cell thyroid nodules.

AIMS: To assess whether the large needle aspiration biopsy (LNAB) histological distinction between pure microfollicular nodules and mixed micro-macrofollicular nodules can assist preoperative selection of a Hürthle cell nodule (HCN) discovered by fine needle aspiration cytology (FNAC). METHODS AND RESULTS: In 24 HCN identified by preoperative FNAC, preoperative LNAB histology was compared with postoperative pathology. FNAC demonstrated seven benign HCN (negative), eight HCN with atypia (positive); seven suspected cancers with HC (positive); and two cancers with Hürthle cells (positive). LNAB showed mixed micro-macrofollicular hyperplastic features in 12 nodules (negative) and a microfollicular structure in 12 nodules (positive), two of which included findings of papillary cancer. Postoperative findings were benign (negative) in 16 patients and malignant (positive) in eight patients. The sensitivity and specificity for FNAC were 87.5% [seven of eight, 95% confidence interval (CI): 47.3-99.7%) and 37.5% (six of 16, 95% CI: 15.2-64.6%], respectively, and for LNAB were 87.5% (seven of eight, 95% CI: 47.3-99.7%) and 68.8% (11 of 16, 95% CI: 41.3-89.0%), respectively. FNAC results were significantly different from postoperative results (McNemar's test, exact two-sided P=0.012), while LNAB results were not (McNemar's test, exact two-sided P=0.219). CONCLUSIONS: These data suggest that LNAB histology is more accurate than FNAC cytology for the preoperative selection of HCN.

Thyroid tumor marker genomics and proteomics: diagnostic and clinical implications.

Two systems biology concepts, genomics and proteomics, are highlighted in this review. These techniques are implemented to optimize the use of thyroid tumor markers (TTM). Tissue microarray studies can produce genetic maps and proteomics, patterns of protein expression of TTM derived from preoperative biopsies and specimens. For instance, papillary and medullary thyroid cancers harbor RAS, RET, and BRAF genetic mutations. Follicular thyroid cancers harbor translocations and fusions of certain genes (PAX 8 and PPAR-gamma). Proteomic analysis from various tissue sources can provide useful information regarding the overall state of a thyroid cancer cell. Understanding the molecular events related to these genetic and protein alterations can potentially clarify thyroid cancer pathogenesis and guide appropriate molecular targeted therapies. However, despite the realization that these emerging technologies hold great promise, there are still significant obstacles to the routine use of TTM. These include equivocal thyroid nodule tissue morphologic interpretations, inadequate standardization of methods, and monetary costs. Interpretative shortcomings are frequently due to the relative scarcity of cellular material from fine-needle aspiration biopsy (FNAB) specimens. This can be rectified with large needle aspiration biopsy (LNAB) techniques and is exemplified by the favorable performance of galectin-3 determinations on LNAB specimens.

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect.

In metastatic colorectal and other locally advanced gastrointestinal cancers, the mechanisms of tumor growth and/or immune escape by residual cancer cells after curative resection often provoke tumor recurrence. Current adjuvant therapy is based on pharmacological administration up to 6-8 months after surgery. We hypothesized that the long-term, cytostatic action from repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles, as a result of the downregulation of the above-mentioned cellular mechanisms, could halt tumor progression. An active prospective cohort, including 19 patients (study group) at high risk of relapse, was considered. All patients received repeated post-adjuvant administration of 5-FU-LV cycles for up to 52-60 months following curative surgery (total cumulative dose of about 90 g and mean follow-up of 70.6 ± 49.7 months). The 5-year disease-free interval (DFS) and overall survival (OS) were 80.4 ± 10.2% and 87.1 ± 8.6%, respectively, which is very different from the recent literature that has reported 5-year DFS and OS values of 31.8% and 40.1%, respectively. These findings suggest that this new pharmacological approach based on the long-term maintenance of a cytostatic effect with 5-FU-LV can produce a relevant improvement in the outcome of this population.

A new immunotherapy schedule in addition to first-line hormone therapy for metastatic breast cancer patients in a state of clinical benefit during hormone therapy.

Acquired resistance occurs in metastatic hormone receptor-positive breast cancer patients. The addition of interferon beta/interleukin-2 immunotherapy to first-line salvage hormone therapy (HT) prolonged progression-free (PFS) and overall survivals (OS) in 26 patients, as compared with 30 historical controls and literature data. This was a 2 : 1 ratio case-control retrospective observational study. The cases were from an open pilot study, started in 1992, and controls were recruited in 2006. The planned mean follow-up time was the time at which more than 80% of controls progressed. The median PFS was significantly longer in the cases than that in controls, 33.1 (95% CI 24.5-41.8) vs 18 (95% CI 12.1-23.8) months (p < 0.0001). Also, median OS was significantly longer in the cases, 81 vs 62 (95% CI 48.1-75.9) months (p < 0.0029). When analysis of the 2 groups was adjusted for the disease-free interval (DFI), hormone receptor status, HER2, site of metastases and molecular-targeted therapies, the hazard ratio for PFS and for OS in the cases increased from 2.347 to 3.090 and from 1.874 to 2.147, respectively. This occurred in spite of the higher proportion of controls (82% vs 7.1%) treated with aromatase inhibitors (AIs), while selective oestrogen receptor modulators (SERMs) were given to 92.9% of the cases and to 18% of the control group (p < 0.0001). Immunotherapy significantly prolonged PFS and OS during conventional first-line HT. A multi-centre randomised clinical trial is advised to enter this immunotherapy into clinical practice. KEY MESSAGES: • Acquired resistance occurs in metastatic endocrine-dependent breast cancer patients. • Interferon beta-interleukin-2 immunotherapy added to first-line salvage hormone therapy prolonged progression-free (PFS) and overall (OS) survivals in 26 patients of a pilot study as compared with 30 historical controls. • In this 2:1 ratio case-control prospective observational study, the PFS median time was significantly longer in the study group than that in controls, 33.1 (95% CI 24.5-41.8) vs 18 (95% CI 12.1-23.8) months (p < 0.0001). • Also, the OS median time was significantly longer in the study group, 81 vs 62 (95% CI 48.1-75.9) months (p < 0.0029).

Immune manipulation of advanced breast cancer: an interpretative model of the relationship between immune system and tumor cell biology.

This review summarizes some recent clinical immunological approaches with cytokines and/or antibodies for therapy of advanced breast cancer. It considers the recent advances in genetics and molecular tumor biology related to impaired immunosurveillance involving cytokines and growth factors to explain clinical results. Evasion of the host immune attack might be induced by the following groups of mechanisms: (a) tumor dependent (genomic instability, HLA class I antigen abnormalities, upregulation of fetal type nonclassical HLA class I molecules, epitope immunodominance, apoptosis inhibition by defective death receptor signaling, apoptosis of activated T cells, tumor cannibalism and constitutive activation of signal transducer, and activator of transcription-3 (Stat 3) and nuclear factor-kappaB (NF-kappaB) signaling); (b) host dependent (CD4+CD25+ regulatory T cells (T reg), CD4+ T cells anergy, Th2 antitumor immunity diversion and myeloid suppressor cells); (c) tumor and host dependent (lack of co-stimulation molecules, immunosuppressive cytokines (vascular endothelial growth factor (VEGF), interleukin (IL)-10, prostaglandin (PG)E2, transforming growth factor (TGF)-beta)). Cytokines and growth factors are involved in virtually all three types of mechanisms. These mechanisms are integrated with the current knowledge of tumor growth and inhibited apoptosis primarily mediated by cytokines and growth factors to propose an interpretation of the relationships among tumor cells, tumor stroma, and tumor-infiltrating lymphocytes. Tumor growth, defective immunorecognition and immunosuppression are the three principal effects considered responsible for immune evasion.

Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study.

BACKGROUND: In the USA, about 30 200 well-differentiated thyroid carcinomas were diagnosed in 2007, but the prevalence of thyroid nodules is much higher (about 5% of the adult population). Unfortunately, the preoperative characterisation of follicular thyroid nodules is still a challenge, and many benign lesions, which remain indeterminate after fine-needle aspiration (FNA) cytology are referred to surgery. About 85% of these thyroid nodules are classified as benign at final histology. We aimed to assess the diagnostic effect of galectin-3 expression analysis in distinguishing preoperatively benign from malignant follicular thyroid nodules when FNA findings were indeterminate. METHODS: 544 patients were enrolled between June 1, 2003, and Aug 30, 2006. We used a purified monoclonal antibody to galectin-3, a biotin-free immunocytohistochemical assay, and a morphological and phenotypic analysis of FNA-derived cell-block preparations. Galectin-3-expression analysis was applied preoperatively on 465 follicular thyroid proliferations that were candidates for surgery, and its diagnostic accuracy was compared with the final histology. FINDINGS: 31 patients were excluded because they had small galectin-3-negative thyroid nodules; we did not have data for 47 patients; and one patient with an oncocytic nodule was excluded. 331 (71%) of the assessable 465 preoperative thyroid FNA samples did not express galectin-3. 280 (85%) of these galectin-3-negative lesions were classified as benign at final histology. Galectin-3 expression was detected, instead, in 134 of 465 (29%) thyroid proliferations, 101 (75%) of which were confirmed as malignant. The overall sensitivity of the galectin-3 test was 78% (95% CI 74-82) and specificity was 93% (90-95). Estimated positive predictive value was 82% (79-86) and negative predictive value was 91% (88-93). 381 (88%) of 432 patients with follicular thyroid nodules who were referred for thyroidectomy were correctly classified preoperatively by use of the galectin-3 test. However, 29 (22%) of 130 cancers were missed by the galectin-3 method. INTERPRETATION: Our findings show that if the option of surgery was based theoretically on galectin-3 expression alone, only 134 thyroid operations would have been done in 465 patients; therefore a large proportion (71%) of unnecessary thyroid surgical procedures could be avoided, although a number of galectin-3-negative cancers could be potentially missed. The galectin-3 test proposed here does not replace conventional FNA cytology, but represents a complementary diagnostic method for those follicular nodules that remain indeterminate.

The Use of Immunotherapy to Treat Metastatic Breast Cancer.

This article reviews the principal attempts of immune-modulation or immune therapy in metastatic breast cancer. It considers their rationale and reports on results from the relevant key clinical trials. Immune-modulatory or immune-stimulating cytokines used alone or combined with conventional therapies is among the principal approaches of immune manipulation in breast cancer. As this issue has recently been reviewed by us, the aim of the current article is to discuss our updated and unpublished data on this topic. Overall survival in luminal (28 patients) and non-luminal (9 patients) molecular subtypes is 91 and 59 months respectively that is about two and half or three times longer than expected. Thereafter, we focus on monoclonal antibodies (mAb) based-therapies including novel strategies to overcome resistance to anti-HER2 mAb. The main vaccine platforms in different molecular subtypes and immune therapies in triple negative metastatic breast cancer (m-TNBC) are discussed in the last sections. Some phase III investigations have already changed the current clinical practice. In fact, pertuzumab plus trastuzumab and docetaxel is the recommended first line regimen in HER2 positive locally recurrent or metastatic breast cancer and bevacizumab plus paclitaxel or docetaxel is a reasonable option for m-TNBC. In some other observational or phase I/II studies on first-line trastuzumab plus chemotherapy and hormonal therapy and in that on HER2 peptide/protein vaccines promising although preliminary findings have been reported to be further validated. In the remaining studies, results were disappointing. In the future, finding new predictive biomarkers and exploring more suitable synergizing combinations, time and dose-dependent-scheduled sequences of currently and further investigated immunological approaches are main challenges.

Carotid integrated backscatter analysis in patients with subclinical hypothyroidism.

OBJECTIVE: The aim of the present study was to determine whether integrated backscatter (IBS) analysis combined with conventional ultrasonography could differentiate the tissue characteristics of carotid artery intimal hyperplasia in patients with subclinical hypothyroidism (SH). METHODS: Forty-one patients with SH, as judged by elevated serum TSH levels and free thyroid hormones within the normal range, and 31 sex- and age-matched euthyroid volunteers underwent two-dimensional conventional ultrasonography and IBS analysis of the carotid wall. Carotid intima-media thickness (IMT) and corrected IBS (C-IBS), an index of arterial wall degeneration and fibrosis, were evaluated. RESULTS: Mean IMT as well C-IBS values were higher in SH than in controls (P < 0.0001 for both), whereas the carotid diameter was not significantly different between the two groups. The distribution of C-IBS values in each group showed that regions with higher C-IBS values were found more frequently in SH patients than in control subjects. The percentage of regions that could be considered as fibromatous (C-IBS value from -18 to -21 dB) was 28% in SH and 9% in euthyroid subjects (P < 0.0001). In the SH group, C-IBS values were significantly and positively associated with plasma TSH (r = 0.32, P < 0.05 and r = 0.59, P < 0.0001, respectively) and with both total cholesterol (r = 0.46, P = 0.01) and low density lipoprotein (LDL)-cholesterol (r = 0.55, P = 0.001). CONCLUSIONS: Carotid IMT in subclinically hypothyroid patients is higher than that in euthyroid controls. This is characterized by increased IBS values, which are related to the collagen content of the arterial wall. The severity of this remodelling process seems to be related to TSH and cholesterol levels.

Thyroid cancer: the impact of emerging technologies on clinical practice guidelines.

Clinical practice guidelines are available for the evaluation and management of thyroid nodules and thyroid cancer. Nevertheless, there are uncertainties associated with these protocols due to genomic variations among patients and an incomplete evidence base. In addition, deviations from these protocols are due to physician bias and different levels of training. These shortcomings may eventually disappear as emerging technologies enter mainstream medicine. These interventions include (1) better risk stratification with the routine use of diagnostic molecular marker panels in the cytological analysis of thyroid fine-needle aspiration specimens as well as hybridized imaging modalities, (2) less aggressive therapies in low- and intermediate-risk thyroid cancer patients, and (3) molecular targeted therapy, pretargeted radioimmunotherapy, and novel minimally invasive surgical techniques in high-risk thyroid cancer patients.

Lifestyle and testicular dysfunction: a brief update.

The incidence of testicular cancer, cryptorchidism and defective spermatogenesis is increasing probably due to environmental and lifestyle-related factors. The aim of this review is to briefly describe and comment on the principal lifestyle factors. The recent findings that the electromagnetic waves following the use of the cell phone and the prolonged exposure to the noise stress cause relevant testicular dysfunction in man or animals reinforce the hypothesis of the importance of lifestyle-related factors.

Bioactive calcium silicate ceramics and coatings.

CaO-SiO2 based ceramics have been regarded as potential candidates for artificial bone due to their excellent bone bioactivity and biocompatibility. However, they cannot be used as implants under a heavy load because of their poor mechanical properties, in particular low fracture toughness. Plasma spraying CaO-SiO2 based ceramic coatings onto titanium alloys can expand their application to the hard tissue replacement under a heavy load. Plasma sprayed wollastonite, dicalcium silicate and diopside coatings have excellent bone bioactivity and high bonding strength to titanium alloys. It is possible that these plasma sprayed CaO-SiO2 based ceramic coatings will be applied in clinic after they are widely and systematically researched.

Hemodynamic parameters regulating vascular inflammation and atherosclerosis: a brief update.

Atherosclerosis is a chronic lipid-driven inflammatory disease of the arteries. Early lesions (fatty streaks) contain monocytes and T lymphocytes which are recruited from the circulation by adhesion to activated vascular endothelial cells (EC). This process is described as the leukocyte adhesion cascade. Atherogenesis occurs predominantly at branches and bends of the arterial tree that are exposed to relatively low or re-circulating blood flow. Here we briefly review the effects of blood flow and shear stress on the leukocyte adhesion cascade and endothelial cell function.

Vascular endothelial growth factor and its soluble receptor in benign and malignant ovarian tumors.

An imbalance between pro-angiogenic and anti-angiogenic factors is hypothesized in the pathogenesis of ovarian cystic disease. The aim of the following study was to explore the possible role of free vascular endothelial growth factor receptor 1 (sVEGFR-1), a soluble regulator of vascular endothelial growth factor (VEGF) action, in ovarian cystoadenoma, endometriomata and cystoadenocarcinoma. Forty-eight women, of whom fourteen had ovarian serous cysts, twenty-eight had stage III-IV ovarian endometriomata, and six had stage IIIB-IIIC ovarian carcinoma, were included. Sampling of serum, peritoneal and ovarian cystic fluids and of tumor tissue was performed before, during and following surgery, respectively. Levels of VEGF and sVEGFR-1 were measured in serum, peritoneal and cystic fluid. VEGF and sVEGFR-1 expression was evaluated in tumor tissue. There were no differences in serum VEGF and sVEGFR-1 levels nor in VEGF/VEGFR-1 ratio between study groups. Peritoneal fluid VEGF levels were higher in cystoadenocarcinoma patients than in endometriosis and in cystoadenoma patients, while sVEGFR-1 peritoneal fluid concentrations were significantly higher only in endometriosis-affected women. VEGF/VEGFR-1 ratio was highest in the peritoneal fluid of cancer patients with respect to the other two groups of women. Cystic fluid VEGF and VEGFR-1 concentrations were higher in endometriomata and in cystoadenocarcinomas than in cystadenomas but the VEGF/VEGFR-1 ratio was highest in cancer patients. Western blot evidenced a marked expression of VEGF and soluble VEGFR-1 in endometriosis tissue with respect to benign cyst tissue but a lower expression of both molecules, contrary to that expected, in cancer tissue. In conclusion, all in all, our data indicate that an excess of local VEGF with respect to its soluble receptor VEGFR-1 may be a key factor in the onset and maintenance of pathological neo-angiogenesis in ovarian cyst formation.

Dedifferentiated thyroid cancer: a therapeutic challenge.

Human papillary dedifferentiated thyroid cancer (HPDTC) represents a therapeutic dilemma. Targeted therapy (RET proto-oncogene or BRAF-targeting drugs) are promising treatments for HPDTC. Also PPARg agonists are another exciting field for redifferentiating therapy of HPDTC. However, even if many new approaches for the therapy of HPDTC are emerging, until now a significant clinical impact on survival by the use of these drugs is still lacking. In the future, the identification of patients who are likely to benefit from each therapeutic option will be important. In this view particular importance should be given to development of primary cells from the single patient by fine needle aspiration samples, as recently observed in anaplastic thyroid cancer. In fact, chemosensitivity tests in primary tumoral cells may help in detecting responsive patients and in preventing the administration of inactive drugs to those unresponsive.