M. Federico

Male breast cancer.

Male breast cancer (MaleBC) is a rare disease, accounting for <1% of all male tumors. During the last few years, there has been an increase in the incidence of this disease, along with the increase in female breast cancer (FBC). Little is known about the etiology of MaleBC: hormonal, environmental and genetic factors have been reported to be involved in its pathogenesis. Major risk factors include clinical disorders carrying hormonal imbalances, radiation exposure and, in particular, a positive family history (FH) for BC, the latter suggestive of genetic susceptibility. Rare mutations in high-penetrance genes (BRCA1 and BRCA2) confer a high risk of BC development; low-penetrance gene mutations (i.e. CHEK-2) are more common but involve a lower risk increase. About 90% of all male breast tumors have proved to be invasive ductal carcinomas, expressing high levels of hormone receptors with evident therapeutic returns. The most common clinical sign of BC onset in men is a painless palpable retroareolar lump, which should be evaluated by means of mammography, ultrasonography and core biopsy or fine needle aspiration (FNA). To date, there are no published data from prospective randomized trials supporting a specific therapeutic approach in MaleBC. Tumor size together with the number of axillary nodes involved are the main prognostic factors and should guide the treatment choice. Locoregional approaches include surgery and radiotherapy (RT), depending upon the initial clinical presentation. When systemic treatment (adjuvant, neoadjuvant and metastatic) is delivered, the choice between hormonal and or chemotherapy (CT) should depend upon the clinical and biological features, according to the FBC management guidelines. However great caution is required because of high rates of age-related comorbidities.

R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair

BackgroundCDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly upregulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDK-inhibitor R-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms.ResultsWe found that R-Roscovitine alone was unable to alter cyclin A1 transcriptional levels, however it was able to reduce protein expression through a proteosome-dependent mechanism. When combined with DNA damaging agents, R-Roscovitine was able to prevent the DNA damage-induced upregulation of cyclin A1 on a transcriptional and post-transcriptional level. This, moreover resulted in a significant decrease in non-homologous end-joining (NHEJ) paired with an increase in DNA DSBs and overall DNA damage over time. Furthermore, microarray analysis demonstrated that R-Roscovitine affected DNA repair mechanisms in a more global fashion.ConclusionsOur data reveal a new mechanism of action for R-Roscovitine on DNA repair through the inhibition of the molecular switch between cyclin A family members under genotoxic conditions resulting in reduced NHEJ capability.

Palliative splenic irradiation in primary and post PV/ET myelofibrosis: outcomes and toxicity of three radiation schedules

Splenectomy and splenic irradiation (SI) are the sole treatment modalities to control drug resistant splenomegaly in patients with myelofibrosis (MF). SI has been used in poor surgical candidates but optimal total dose and fractionation are unclear. We retrospectively reviewed 14 MF patients with symptomatic splenomegaly. Patients received a median of 10 fractions in two weeks. Fraction size ranged from 0.2–1.4 Gy, and total dose varied from 2–10.8 Gy per RT course. Overall results indicate that 81.8% of radiation courses achieved a significant spleen reduction. Splenic pain relief and gastrointestinal symptoms reduction were obtained in 94% and 91% of courses, respectively. Severe cytopenias occurred in 13% of radiation courses. Furthermore patients were divided in three groups according to the radiation dose they received: 6 patients in the low-dose group (LDG) received a normalized dose of 1.67 Gy; 4 patients in the intermediate-dose group (IDG) received a normalized dose 4.37 Gy; the remaining 4 patients in the high-dose group (HDG) received a normalized dose of 9.2 Gy. Subgroup analysis showed that if no differences in terms of treatment efficacy were seen among dose groups, hematologic toxicity rates distributed differently. Severe cytopenias occurred in 50% of courses in the HDG, and in the 14.3% and in 0% of the IDG and LDG, respectively. Spleen reduction and pain relief lasted for a median of 5.5 months in all groups. Due to the efficacy and tolerability of the low-dose irradiation 4 patients from the LDG and IDG were retreated and received on the whole 12 RT courses. Multiple retreatments did not show decremental trends in terms of rates of response to radiation nor in terms of duration of clinical response. Moreover, retreatment courses did not cause an increased rate of adverse effects and none of the retreated patients experienced severe hematologic toxicities. The average time of clinical benefit in retreated patients was much longer (21 months, range 44–10) than patients who were not retreated (5.75 months, range 3–6).

EP-1072: EBRT after radical prostatectomy in localized prostate cancer: a 5-years single-institution experience

Background: Local recurrence is a major problem after rectal cancer surgery. Local recurrence rates historically vary between 15% and 45%. The introduction of total mesorectal excision (TME) as treatment for patients with rectal cancer has led to an improved local control and survival when compared with historical controls. Purpose: To analyze local recurrence rates in our patients treated with preoperative radiotherapy with/without chemotherapy followed by TME or non TME surgery. Materials and Methods: Two hundred fifty patients(pts) were enrolled between January 2004 and December 2010. Median age was 62 years (min=26, max=83). There were 83 female and 167 male. To be eligible, patients had to have histologically confirmed adenocarcinoma of the rectum, without evidence of distant metastases, and the inferior margin of the tumor had to be located not farther than 15 cm from the anal verge. Initially, 96% of patients had locally advanced stage of disease (T3/T4N0, any TN+). All patients had preoperative radiotherapy (RT) with/without chemotherapy (5fluorouracil or capecitabine). The patients assigned to preoperative RT received a total dose of 45-50.4Gy in 25-28 fractions for 5 to 5.5 weeks followed by TME (118 pts) or non TME surgery (132 pts). The overall recurrence rate and the recurrence rates from different surgical approaches were calculated in our retrospective analysis. Also, we evaluated influence of tumor distance from the anal verge, dose of irradiation, type of chemotherapy, postoperative stage of disease, resection margins, presence of lymph–angioinvasion and KRAS mutation status on the rate of local recurrence (LR). Results: Median follow-up time was 48 months (range, 12 to 96months). The cumulative proportion of local recurrence was 6.8% for all group of patients (0.8% in the group with TME and 6% in the group with non TME, p=0.0022, Fisher‘s exact test). The 5 year DFS was 86% in the group of pts with TME and 71% in the group with non TME (p=0.0025). The 5 year OS was 87% in the group of pts with TME and 77% in the group with non TME (p=0.0012). There was very statistically significant difference between two groups of pts regarding DFS and OS. Conclusions: Radiotherapy followed by TME has been shown to significantly reduce local recurrence rates in our patients. The strong criteria for identifying low risk group of pts for LR were: TME and negative resection margins (p=0.0009).

Cancer Stem Cells and Microenvironment

The theory of the cancer stem cell (CSC) is fairly recent and has both challenged and disrupted the previous understandings of cancer biology. From the initial findings of cancer-driving cellular sub-populations, the interest in the CSC theory has flourished. Here we discuss the biology behind both embryonic and adult stem cells and how this biology is the basis for our understanding of CSCs. Furthermore, we elaborate on findings demonstrating the importance of the microenvironment on the stem cell and how changes in the microenvironment alone may direct stem cell differentiation or possibly tumorigenesis. Cancer research has taken a new fork in the road towards the involvement of CSCs and this road has been productive. However, the challenge remains in understanding and identifying CSCs independently from the embryonic and adult stem cell models of the past. Moving beyond the preconceived understanding of stem cells will allow researchers to be able to fully explore the complexity and role of CSCs in cancer and hopefully provide the knowledge necessary to combat cancer from that first initiating cell.