Steroid Hormones as Modulators of Emotional Regulation in Male Urogenital Cancers.

BACKGROUND: Tumors develop within an organism operating in a specific social and physical environment. Cortisol and dehydroepiandrosterone (DHEA), two of the most abundant steroid hormones in humans, are involved in both emotional regulation and the tumor progression. Several studies reported preclinical findings that DHEA can have preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, although the mechanisms of action are not yet defined. The main aim of current study was to investigate the relationship between psychological and physiological emotional regulation and cancer development. METHOD: This study assessed the quality of life of urogenital cancer male patients using several validated tools, including the Functional Assessment of Cancer Therapy-General and the Profile of Mood States. Saliva samples were collected to monitor peripheral activity of both cortisol and DHEA. It was hypothesized that patients with a better quality of life would have higher levels of the DHEA/cortisol ratios. RESULTS: We found that the quality of life was positively related to DHEA, but not cortisol levels. Negative mood increases were related to lower levels of DHEA. Logistic regression of the predictors of metastases indicated three main independent factors involved: DHEA, age, and cortisol. In other words, the higher the DHEA levels in comparison to cortisol levels, controlling for age, the lower the probability of metastases. CONCLUSION: Our results appear to support the hypothesis that emotional dysregulation mediated by DHEA/cortisol activity is a key factor in the probability of metastasis in urogenital cancers.

Proposal for a New Diagnostic Histopathological Approach in the Evaluation of Ki-67 in GEP-NETs.

INTRODUCTION: Studies have shown that the Ki-67 index is a valuable biomarker for the diagnosis, and classification of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). We re-evaluated the expression of Ki-67 based on the intensity of the stain, basing our hypothesis on the fact that the Ki-67 protein is continuously degraded. BACKGROUND: The aim was to evaluate whether a new scoring method would be more effective in classifying NETs by reducing staining heterogeneity. METHODS: Patients with GEP-NET (n = 87) were analyzed. The classification difference between the two methods was determined. RESULTS: The classification changed significantly when the Ki-67 semiquantal index was used. The percentage of G1 patients increased from 18.4% to 60.9%, while the G2 patients decreased from 66.7% to 29.9% and the G3 patients also decreased from 14.9% to 9.2%. Moreover, it was found that the traditional Ki-67 was not significantly related to the overall survival (OS), whereas the semiquantal Ki-67 was significantly related to the OS. CONCLUSIONS: The new quantification was a better predictor of OS and of tumor classification. Therefore, it could be used both as a marker of proliferation and as a tool to map tumor dynamics that can influence the diagnosis and guide the choice of therapy.

Gastrin-Releasing Peptide Receptor in Low Grade Prostate Cancer: Can It Be a Better Predictor Than Prostate-Specific Membrane Antigen?

The aim of the present study was to evaluate whether prostate cancer (PC) patients can be accurately classified on the bases of tissue expression of gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA). This retrospective study included 28 patients with PC. Formalin-fixed paraffin-embedded samples were used for diagnosis. Immunohistochemistry staining techniques were used to evaluate PSMA and GRPR expression (both number of cells expressed and % of area stained). To assess the independent associations among selected variables, a multi-dimensional scaling (MDS) analysis was used. It was found that the PSMA expression was inversely correlated with GRPR expression. Only the number of cells expressing GRPR was significantly related to the Gleason score. Both the percentage of area expressing GRPR and the number of cells expressing PSMA were close to reaching significance at the 0.05 level. MDS provided a map of the overall, independent association confirming that GRPR and PSMA represent inversely correlated measures of the same dimension. In conclusion, our data showed that GRPR expression should be evaluated in prostate biopsy specimens to improve our ability to detect PC with low grades at the earliest phases of development. Considering that GRPRs appear to be directly involved in the mechanisms of tumor proliferation, advancements in nuclear medicine radiotherapy can focus on this receptor to improve the therapeutic approach to PC. Further studies in our laboratory will investigate the molecular mechanisms of activation based on GRPR.

Prompt and sustained response of a steroid-refractory autoimmune hemolytic anemia to a rituximab-based therapy in a chronic lymphocytic leukemia patient.

INTRODUCTION: Autoimmune hemolytic anemia (AIHA) is a rare and potentially life-threatening event which may complicate the course of chronic lymphocytic leukemia (CLL) at any time and steroid-refractory AIHA of CLL poses a therapeutic challenge for physicians. Here, we report the safety and efficacy of a rituximab-containing regimen in a CLL patient with steroid- and IVIg-refractory AIHA. CASE REPORT: A 57-year- old man affected by CLL, presented with fatigue, dyspnoea, tachycardia and jaundice. His physical examination revealed overt jaundice, hepato- and splenomegaly, and enlargement of lymph nodes in all superficial sites. The blood chemistry showed severe anemia (Hb value 3.9 g/dL), high white blood cell count (89 x 10(9)/L), altered hemolysis markers and direct antiglobulin test (DAT) was positive for both complement and IgG. The patient failed to respond to both a 4-day course of high-dose dexamethasone IV (40 mg/day) and intravenous immunoglobulin (IVIg) (1 g/kg/day x 2 days). Thus, a schedule containing rituximab (375 mg/m(2) day +1), cyclophosphamide (750 mg/m(2) day +2) and prednisone (60 mg/m(2) from day +1 to day +7) (R-CP) were administered. Four cycles, repeated every 4 weeks, were administered. After 4 days from the infusion of this schedule, the patient showed a marked reduction of the lymphocytosis, and the hemoglobin level started to increase. No rituximab-related side effects were recorded. At the end of treatment DAT became negative and patient achieved a nodular Partial Remission (nPR). CONCLUSION: Our data showed the safety and efficacy of a rituximab-containing regimen in a life-threatening CLL-related AIHA, refractory to steroid and IVIg therapy. This schedule has allowed the patient to obtain a prompt and dramatic rise in hemoglobin level and a response to both AIHA and CLL.

PDGFRalpha/FIP1L1-positive chronic eosinophilic leukemia presenting with retro-orbital localization: efficacy of imatinib treatment.

INTRODUCTION: The fusion protein between the platelet-derived growth factor receptor alpha (PDGFRalpha, P) gene and the Fip1-like1 (FIP1L1, F) may be identified in 14 to 60% of HES and it indicates a clonal hypereosinophilic syndrome called F/P-positive CEL. We herein report a case of F/P-positive CEL with retro-orbital localization, who was successfully treated with imatinib. CASE REPORT: A 53-year-old male presented an absolute eosinophil count of 25,000/mm(3), anemia (Hb 10.2 g/dl) and a moderate increase in the platelet count (571,000/mm(3)). A clinical examination revealed left exophthalm, associated with diffuse hypoesthesia and diplopia. A CT scan of orbits showed a lesion located in the lachrymal fossa of the left orbit with intra- and extra-conical extension. Molecular analysis excluded the presence of bcr/abl transcript while a F/P fusion tyrosine kinase signal was documented. Imatinib mesylate (IM) was started and, after 7 days of treatment eosinophil count significantly declined along with a dramatic reduction of the left exophthalm. IM dosage was increased up to 300 mg/day. The drug was well tolerated with an initial modest haematological toxicity. The left exophthalm, as well as hypoesthesia and diplopia, disappeared after IM therapy. MRI showed a clear reduction of the intra- and extra-conical growth process. BM molecular signal of the F/P fusion gene resulted undetectable after 4 weeks of treatment. CONCLUSION: In our case, the diagnosis of FIPIL1-PDGFRA-positive CEL and IM therapy has allowed the patient to experience an excellent clinical therapeutic result, avoiding surgical treatment of the retro-orbital mass.

Epigenetic regulation in myelodysplastic syndromes: implications for therapy.

INTRODUCTION: Myelodysplastic syndromes (MDS), characterized by ineffective hematopoiesis and dysplasia in one or more lineages, produce life-threatening cytopenias and progress to acute myeloid leukemia (AML). Growing evidence suggests that targeting epigenetic mechanisms improves MDS/AML pathophysiology. AREAS COVERED: This review provides an understanding of studies investigating novel agents published up to January 2011 aimed at normalizing and monitoring the epigenetic profile of the MDS cancer cell. The authors discuss how non-intensive epigenetic therapy can 're-programme' gene expression patterns of abnormal hematopoiesis in MDS. Recently FDA-approved DNA-methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine or decitabine, represent frontline nonablative treatments, while combinations with histone deacetylase inhibitors show promising synergism in preclinical and Phase I/II trials in tumor suppressor gene re-expression and overall survival. Additional epigenetic mechanisms including non-encoding transcripts with inhibitory posttranscriptional regulatory functions, such as microRNAs, though not fully understood, present novel molecular and clinical implications in these disorders. EXPERT OPINION: Alongside current single-agent epigenetic regimens, combination therapies represent potentially effective options for intermediate-2 and high-risk MDS. Methylation profiles and gene mutation predictors provide promising areas of development for monitoring MDS disease progression and outcome, while targeting microRNA dysregulation represents an important therapeutic goal.

Lenalidomide in the treatment of chronic lymphocytic leukemia.

INTRODUCTION: insights into the role of the tumor microenvironment and of immune dysfunction in chronic lymphocytic leukemia (CLL) have opened the way for further augmenting the therapeutic armamentarium for CLL patients. In this respect, lenalidomide represents an exciting drug since it is able to eliminate CLL cells without immunosuppression. AREAS COVERED: mechanism of action and clinical trials of lenalidomide in CLL, and suggestions for its future utilization are reviewed. The most relevant papers and the meeting abstracts published up to July 2010 were used as sources for this review. This review will help readers understand the mechanism of action of lenalidomide and will provide a comprehensive summary regarding efficacy and safety of this drug in CLL patients. EXPERT OPINION: lenalidomide shows good activity against CLL. However, the toxicity profile is significant and can result in serious and potentially life-threatening side effects. Definitive data from ongoing trials will aid better definition of its status in CLL therapy. Moreover, clarification of the exact mechanism(s) of action in CLL will allow more precise use of lenalidomide and design of more efficacious combination therapies.

Janus kinase 2 inhibitors in myeloproliferative disorders.

IMPORTANCE OF THE FIELD: JAK2 is an obligatory kinase for the proliferation and differentiation of erythroid cells and megakaryocytes thus representing a relevant therapeutic target for agents that specifically inhibit its activity particularly in myeloproliferative disorders (MPD) harboring JAK2(V617F) mutations. AREAS COVERED IN THIS REVIEW: We discuss the physiopathology of the JAK2 signaling pathway and review clinical trials of JAK2 inhibitors for the treatment of MPD using papers and meeting abstracts published up to September 2010. WHAT THE READER WILL GAIN: This review helps in understanding the potential role of JAK2 inhibitors in MPD clinical trials and provides a comprehensive review regarding their efficacy and safety in these disorders. TAKE HOME MESSAGE: JAK2 inhibitors may prove to be useful only for suppressing disease manifestations. However, unlike drugs such as IFN which are capable of eliminating the malignant clone, JAK2 inhibitors are unable to eradicate the disease. In fact, results to date indicate that although these inhibitors reduce splenomegaly and alleviate constitutional symptoms irrespective of JAK2 mutational status, most have only a modest impact on the JAK2(V617F) allele burden. Considering the relevant risk of serious complications in patients undergoing splenectomy, these drugs could find a suitable indication in patients with myelofibrosis awaiting bone marrow transplantation.

The incidence of JAK2 V617F mutation in bcr/abl-negative chronic myeloproliferative disorders: assessment by two different detection methods.

A recurrent specific JAK2 V617F mutation has been reported in bcr/abl-negative chronic myeloproliferative diseases (cMPD), including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). The mutation is detectable in a variable proportion of neoplastic clones, depending on the molecular methods employed. In this study, we attempted to establish the JAK2 V617F mutation frequency in two partially overlapping cMPD patient series by two different PCR-based techniques. Using an allele-specific polymerase chain reaction assay (AS-PCR), the JAK2 V617F mutation was detected in 124/158 (78.5%) cMPD patients; in particular, 90.2, 72.1, 63.2 and 50% of PV, ET, IMF and unclassified (U)-MPD cases, respectively, showed the mutation. Employing a semiquantitative 5' fluorogenic TaqMan assay, the JAK2 V617F mutation was identified in a much larger percentage of cMPDs patients (118/127: 92.9%). Rates of mutation in PV, ET, IMF and U-MPD cases were 95.9, 85.7, 91.7 and 92.9%, respectively. Furthermore, a statistically higher percentage of JAK2 mutated alleles was detected by TaqMan assay in PV (68+/-3.5, mean value+/-SEM) and IMF (64+/-9.3) cases as compared with ET (35+/-5.4). Finally, a significant correlation between JAK2 V617F mutational status and hematocrit (Ht), white blood cell and platelet counts in PV patients, and Ht values in ET cases, was observed by AS-PCR. Overall, these data indicate that TaqMan technology significantly improved sensitivity in detecting the JAK2 mutation in cMPD patients and may be worth of further evaluations as a clinically useful tool for detection of small amounts of mutated clones.