Risk Differences Between Prediabetes And Diabetes According To Breast Cancer Molecular Subtypes.

Hyperglycemia and hyperinsulinemia may play a role in breast carcinogenesis and prediabetes and diabetes have been associated with increased breast cancer (BC) risk. However, whether BC molecular subtypes may modify these associations is less clear. We therefore investigated these associations in all cases and by BC molecular subtypes among women living in Southern Italy. Cases were 557 patients with non-metastatic incident BC and controls were 592 outpatients enrolled during the same period as cases and in the same hospital for skin-related non-malignant conditions. Adjusted multivariate logistic regression models were built to assess the risks of developing BC in the presence of prediabetes or diabetes. The analyses were repeated by strata of BC molecular subtypes: Luminal A, Luminal B, HER2+, and Triple Negative (TN). Prediabetes and diabetes were significantly associated with higher BC incidence after controlling for known risk factors (OR = 1.94, 95% CI 1.32-2.87 and OR = 2.46, 95% CI 1.38-4.37, respectively). Similar results were seen in Luminal A and B while in the TN subtype only prediabetes was associated with BC (OR = 2.43, 95% CI 1.11-5.32). Among HER2+ patients, only diabetes was significantly associated with BC risk (OR = 3.04, 95% CI 1.24-7.47). Furthermore, when postmenopausal HER2+ was split into hormone receptor positive versus negative, the association with diabetes remained significant only in the former (OR = 5.13, 95% CI 1.53-17.22). These results suggest that prediabetes and diabetes are strongly associated with BC incidence and that these metabolic conditions may be more relevant in the presence of breast cancer molecular subtypes with positive hormone receptors. J. Cell. Physiol. 232: 1144-1150, 2017. © 2016 Wiley Periodicals, Inc.

Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015.

The fifth "Melanoma Bridge Meeting" took place in Naples, December 1-5th, 2015. The main topics discussed at this meeting were: Molecular and Immuno advances, Immunotherapies and Combination Therapies, Tumor Microenvironment and Biomarkers and Immunoscore. The natural history of cancer involves interactions between the tumor and the immune system of the host. The immune infiltration at the tumor site may be indicative of host response. Significant correlations were shown between the levels of immune cell infiltration in tumors and patient's clinical outcome. Moreover, incredible progress comes from the discovery of mutation-encoded tumor neoantigens. In fact, as tumors grow, they acquire mutations that are able to influence the response of patients to immune checkpoint inhibitors. It has been demonstrated that sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. The road ahead is still very long, but the knowledge of the mechanisms of immune escape, the study of tumor neo-antigens as well as of tumor microenvironment and the development of new immunotherapy strategies, will make cancer a more and more treatable disease.

Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial.

BACKGROUND: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. PATIENTS AND METHODS: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. RESULTS: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). CONCLUSIONS: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.

Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial.

BACKGROUND: Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. PATIENTS AND METHODS: We carried out a multicenter, randomized phase III study. Women aged 65-79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m(2) days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. RESULTS: From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83-1.76, P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80-2.22, P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. CONCLUSIONS: Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. CLINICALTRIALSGOV: NCT00331097.

Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial.

BACKGROUND: Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information. PATIENTS AND METHODS: In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer. RESULTS: Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect. CONCLUSIONS: This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort.

BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.

Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study.

BACKGROUND: To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. PATIENTS AND METHODS: A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. RESULTS: Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). CONCLUSIONS: In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

Efficacy of two Ni-Ti systems and hand files for removing gutta-percha from root canals.

AIM: To compare the effectiveness of two Ni-Ti systems and hand files for removing gutta-percha and sealer from root canals. METHODOLOGY: The root canals of 60 single-rooted human teeth were prepared, filled with gutta-percha and sealer (Pulp Canal Sealer; SybronEndo, Orange, CA, USA). Specimens were then divided into three groups (n=20), and root filling material was removed using MTwo Retreatment Files (group 1); R-Endo (group 2); K-files and Gates-Glidden drills (group 3). After retreatment, the efficacy of each technique was assessed using radiographs that were later digitized and the images analysed using AutoCAD 2004. The percentage of residual gutta-percha was calculated for the whole canal as well as for the coronal, middle and apical thirds. Time required, apically extruded debris and the number of fractured instruments were also recorded. Data were statistically analysed using Kruskal-Wallis and Mann-Whitney U-tests. RESULTS: All instrumentation techniques left gutta-percha and sealer remnants inside the root canals. Ni-Ti systems were significantly faster (P < 0.05) than the manual technique and significantly more effective (P < 0.05) in removing gutta-percha particularly from the middle and apical thirds of the root canal. R-Endo instrumentation was significantly more effective (P < 0.05) than MTwo retreatment files in removing gutta-percha from the middle and apical thirds. R-Endo instruments were associated with the least number of cases of apical extrusion. One MTwo instrument fractured. CONCLUSIONS: The Ni-Ti systems were more effective and faster than hand files, although all techniques left gutta-percha and sealer remnants on the root canals.

Can high-resolution ultrasound avoid the sentinel lymph-node biopsy procedure in the staging process of patients with stage I-II cutaneous melanoma?

PURPOSE: The objective of our study was to define the diagnostic accuracy of high-resolution ultrasound (US) in detecting nodal involvement before sentinel lymph node biopsy (SLNB) in patients with cutaneous melanoma, to define the sonographic criteria used to assess nodal metastases, and to establish if high-resolution US can directly select patients to radical lymphadenectomy, sparing selective lymphadenectomy. MATERIALS AND METHODS: 623 patients underwent high-resolution US of the regional lymph nodes, 24 hours prior being submitted to the sentinel lymph node biopsy procedure. The US findings were compared with histological findings. RESULTS: In 14.7 % out of 122 excised lymph nodes, high-resolution US showed sonographic features consistent with malignant involvement before the surgical step. US scan sensitivity and specificity were 15 and 100 %, respectively, since positive and negative predictive values were 100 and 87 % respectively. CONCLUSION: US is an effective modality in the presurgical detection of subclinical deposits within sentinel lymph nodes. However, preoperative staging work-up with high-resolution US cannot substitute the SLNB, mainly because of low sensitivity due to missing many micrometastases.

Expression and functional role of CRIPTO-1 in cutaneous melanoma.

BACKGROUND: CRIPTO-1 (CR-1) is involved in the pathogenesis and progression of human carcinoma of different histological origin. In this study we addressed the expression and the functional role of CR-1 in cutaneous melanoma. METHODS: Expression of CR-1 protein in melanomas and melanoma cell lines was assessed by immunohistochemistry, western blotting and/or flow cytometry. Levels of mRNA were evaluated by real-time PCR. Invasion assays were performed in Matrigel-coated modified Boyden chambers. RESULTS: Expression of CR-1 protein and/or mRNA was found in 16 out of 37 primary human cutaneous melanomas and in 12 out of 21 melanoma cell lines. Recombinant CR-1 protein activated in melanoma cells c-Src and, at lesser extent, Smad signalling. In addition, CR-1 significantly increased the invasive ability of melanoma cells that was prevented by treatment with either the ALK4 inhibitor SB-431542 or the c-Src inhibitor saracatinib (AZD0530). Anti-CR-1 siRNAs produced a significant inhibition of the growth and the invasive ability of melanoma cells. Finally, a close correlation was found in melanoma cells between the levels of expression of CR-1 and the effects of saracatinib on cell growth. CONCLUSION: These data indicate that a significant fraction of cutaneous melanoma expresses CR-1 and that this growth factor is involved in the invasion and proliferation of melanoma cells.

Human papillomavirus (HPV) genotypes and HPV16 variants and risk of adenocarcinoma and squamous cell carcinoma of the cervix.

OBJECTIVE: Human papillomavirus (HPV) genotypes have been extensively studied in uterine cervix squamous cell carcinoma and HPV16 variants have been found to be associated with increased cancer risk, but few reports have been published on genotype distribution and HPV16 variant prevalence in adenocarcinoma tumors. The objective of this study was to analyze viral genotypes and HPV16 intratypic variants in cervical adenocarcinoma and squamous cell carcinoma of Italian women. METHODS: A total of 39 invasive adenocarcinoma and 132 squamous cell carcinoma were reviewed and classified according to the modified WHO classification. HPV sequences were detected by nested PCR, using the broad spectrum consensus-primer pairs MY09/MY11 and the GP5+/GP6+ system, and genotyped by nucleotide sequence analysis. The HPV16-positive cases were amplified with E6-specific oligonucleotides and amplimers subjected to direct nucleotide sequence for variant identification. RESULTS: The prevalence rate of any HPV infection was 72% in adenocarcinoma, and 85% in cervical squamous cell carcinoma. Among the 140 HPV-positive cancer cases, a total of nine mucosal HPV genotypes (HPV16, 18, 31, 33, 35, 39, 45, 58, 82) epidemiologically classified as carcinogenic or probably carcinogenic viruses were identified. The HPV type 16 was the most common viral type representing 64% and 73% of all infections in adenocarcinoma and squamous cell carcinoma, respectively. The E6 nucleotide sequence analysis of HPV16 isolates allowed the identification of Asian American (AA) variants in 33% of adenocarcinoma and in 20% of squamous cell carcinoma suggesting their stronger association with cancer of glandular origin. CONCLUSION: These results suggest that HPV16 has a high prevalence in both invasive adenocarcinoma and squamous cell carcinoma from Italian patients. Moreover this study confirms previous observations, summarized in a systematic review of the literature, on the increased cancer risk of HPV16 AA class in adenoglandular cancer, possibly related to their more oncogenic behavior compared to HPV16 European variants.

Parallel determination of NeuroD1, chromogranin-A, KI67 and androgen receptor expression in surgically treated prostate cancers.

PURPOSE: Neuroendocrine differentiation is a hallmark of prostate cancer. The aim of our study was the detection of the parallel expression of neuroendocrine related markers using a prostate tissue microarray (TMA). MATERIALS AND METHODS: Our study was aimed at detecting the parallel expression of NeuroD1, Chromogranin-A (ChrA), Androgen Receptor (AR) and Ki-67 by immunohistochemistry on prostate cancer tissue microarray. The data was analyzed using SAS version 8.2 (SAS Inc, Cary, NC). The relationships between NeuroD1, ChrA and AR expressions and patients' characteristics were investigated by multivariate logistic regression analysis. Progression and Overall Survival (OS) distributions were calculated using Kaplan-Meier method. RESULTS: Tissue reactivity for NeuroD1, ChrA and AR concerned 73%, 49% and 77% of the available cases, respectively. Regarding overall survival, there were 87 deaths and 295 patients alive/censored (6 years of median follow-up). Seventy-seven disease progressions occurred at the median follow-up 5.4y. A significant correlation between NeuroD1, ChrA and AR expression was observed (p < 0.001 and p < 0.03, respectively). Additionally, ChrA was strongly associated in multivariate analysis to Gleason score and Ki67 expression (p < 0.009 and p < 0.0052, respectively). Survival analysis showed no association between markers neither for overall nor for cancer-specific survival. CONCLUSIONS: The results highlight that NeuroD1, Chromogranin-A and Androgen Receptor are strongly associated, however their expression does not correlate with overall survival or disease progression.

Reasons why COVID-19 survivors should follow dietary World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations: from hyper-inflammation to cardiac dysfunctions.

The World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) advise cancer survivors to follow their lifestyle recommendations for cancer prevention.  Recent research indicates that a proper diet could exerts beneficial metabolic and immune effects in humans through the involvement of several, not yet properly known, metabolic pathways. Here, we argue that following WCRF/AICR recommendations could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients during follow-up post COVID-19 infection. We discuss the metabolic effects of a WCRF/AICR based diet, highlighting on the involved cardio-metabolic pathways related on NLRP3 inflammasome-cytokines axis aimed to improve prognosis of COVID-19, especially in patients with cancer.

SARS-CoV-2 infection: NLRP3 inflammasome as plausible target to prevent cardiopulmonary complications?

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.

Low doses of Bisphenol A have pro-inflammatory and pro-oxidant effects, stimulate lipid peroxidation and increase the cardiotoxicity of Doxorubicin in cardiomyoblasts.

Endocrine disrupters are strictly associated to cancer and several cardiovascular risk factors. Bisphenol A (BPA) is an endocrine disrupter commonly used in the manufacturing of plastics based on polycarbonate, polyvinyl chloride and resins. Our study aims to investigate whether BPA may cause pro-oxidative and pro-inflammatory effects on cardiomyoblasts, thus exacerbating the Doxorubicin (DOXO)-induced cardiotoxicity phenomena. We tested the metabolic effects of BPA at low doses analyzing its affections on the intracellular calcium uptake, oxidative stress, lipid peroxidation and production of nitric oxide and interleukins. Co-incubation of BPA and DOXO significantly reduced the cardiomyoblast viability, compared to only DOXO exposure cells. The mechanisms underlying these effects are based on the stimulation of the intracellular calcium accumulation and lipid peroxidation. Notably, BPA increase the production of pro-inflammatory interleukins involved in cardiovascular diseases as well as in DOXO-Induced cardiotoxicity phenomena. This study provides a rationale for translational studies in the field of cardio-oncology.

Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab.

BACKGROUND: The immunotherapy has revolutionized the world of oncology in the last decades with considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiac toxicity has not been properly studied. PURPOSE: We studied, for the first time, the putative cardiotoxic and pro-inflammatory effects of Pembrolizumab associated to Trastuzumab. METHODS: Cell viability, intracellular calcium quantification and pro-inflammatory studies (analyses of the production of Interleukin 1ß, 6 and 8, the expression of NF-kB and Leukotriene B4) were performed in human fetal cardiomyocytes. Preclinical studies were also performed in C57BL6 mice by analyzing fibrosis and inflammation in heart tissues. RESULTS: The combination of Pembrolizumab and Trastuzumab leads to an increase of the intracellular calcium overload (of 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the Interleukins expression of 40-50% compared to the single treatments; the expression of NF-kB and Leukotriene B4 was also increased. CONCLUSION: Pembrolizumab associated to Trastuzumab leads to strong cardiac pro-inflammatory effects mediated by overexpression of NF-kB and Leukotriene B4 related pathways.

Metastases to the breast: role of fine needle cytology samples. Our experience with nine cases in 2 years.

BACKGROUND: The increased survival due to the introduction of effective antineoplastic regimens has caused a modification of the natural history of numerous malignancies. Follow-up of neoplastic patients often includes the evaluation of masses in various body sites by fine needle cytology (FNC) in order to rule out cancer recurrence. Besides primary neoplasms, the breast can host a number of metastases: these rarely do have a typical presentation, so FNC is requested for their cytomorphological assessment. PATIENTS AND METHODS: This report describes nine consecutive cases in which a cytopathological diagnosis of metastasis to the breast was carried out on FNC samples. RESULTS: Primary sites were identified on cytomorphological and immunocytochemical bases and were represented by the ovary (three cases), melanoma (two cases), endocervix (one case), endometrium (one case), lung (one case) and prostate (one case). CONCLUSION: The cytopathological diagnosis of metastatic neoplasms to the breast is not always straightforward, especially in the absence of a clinical history of cancer. The usage of improved cytopathological criteria combined with immunocytochemistry may be of great diagnostic help in the identification of breast metastases.

Patients with advanced stage breast carcinoma immunoreactive to biotinylated Herceptin are most likely to benefit from trastuzumab-based therapy: an hypothesis-generating study.

BACKGROUND: Biotin-labeled trastuzumab (BiotHER) can be used to test for HER2 by immunohistochemistry. We previously showed that BiotHER immunoreactivity is highly correlated with HER2 amplification and indicated that it could be associated with better clinical outcome in advanced breast cancer patients receiving trastuzumab. PATIENTS AND METHODS: Tumor specimens and clinical information from 234 patients who received trastuzumab-based treatments were collected from 10 institutions. HER2 amplification and BiotHER immunoreactivity were assessed centrally. The effect of BiotHER positivity on response rate (RR), time to progression and survival were studied by univariate and multivariate analysis in patients presenting HER2-amplified breast cancer. The pathologic reviews of the assays were blinded to patient outcomes. RESULTS: BiotHER was positive in 109/194 (56%) HER2-amplified breast cancers and in one not amplified tumor. RRs were 74% [95% (confidence interval) CI 64%-81%] and 47% (95% CI 36%-58%) in BiotHER-positive and -negative tumors, respectively (P < 0.001). BiotHER immunoreactivity was independently associated with increased probability of tumor response (odds ratio 3.848; 95% CI 1.952-7.582), with reduced risk of disease progression [hazard ratio (HR) 0.438; 95% CI 0.303-0.633] and with reduced risk of death (HR 0.566; 95% CI 0.368-0.870) by multivariate analysis. CONCLUSION: The results support a role for BiotHER testing in better tailoring trastuzumab-based treatments in patients with advanced HER2-amplified breast cancers.

Salivary epithelial-myoepithelial carcinoma: clinical, morphological and molecular features.

Epithelial-myoepithelial carcinoma (EMC) is a rare biphasic tumor accounting for less than 2% of all salivary gland malignancies. It presents as a slowly growing, asymptomatic small size mass, with ulceration of overlying mucosa in some cases. Microscopically, it is characterized by glands lined by the simultaneous presence of two different cell components, inner epithelial cells and outer myoepithelial cells. Immunohistochemical staining of myoepithelial cells is variably positive for vimentin, Smooth Muscle Actin (SMA), Muscle Specific Actin (MSA), S100, Smooth Muscle Myosin Heavy Chain I(SM-MHC), calponin and p63. Several molecular alterations, mainly point mutations, have been described. Mutations of HRAS, AKT1, CTNNB1 and PIK3CA were highlighted in variable percentage of EMC samples. EMC is considered a low-grade malignant tumor with a 5-year survival rate of 94% that may commonly recur locally after resection in 30-50% of cases. At the moment, adequate resection with negative margins is the minimum recommended and necessary treatment.

Epigenetic Changes Induced by Green Tea Catechins a re Associated with Prostate Cancer.

Prostate cancer is one of the most difficult cancers to treat especially when it becomes hormone resistant such as castrate resistant prostate cancer (CRPC) and subsequent metastatic CRPC. Apart from the genetic alterations in prostate cancer, epigenetic modifications also play an important role in the development and neoplastic progression of this disease. These include DNA methylation, histone modifications, and non-coding microRNAs. miRNAs are a novel class of small endogenous single-stranded non-coding RNAs of 19-25 nucleotides in length that typically silence gene expression. Considering the reversibility of epigenetic alterations in early carcinogenesis process, reversion (correction) of these modifications by green tea catechins could be a promising strategy for cancer chemoprevention and therapy. Recent evidence suggests that green tea catechins such as epigallocatechin gallate (EGCG) not only act as epigenetic modulators but can also modify miRNA expression and their target mRNAs, consistently contributing to the inhibition of prostate carcinogenesis. Various studies also indicate that several green tea polyphenols (GTPs) exert synergistic effects with other cancer chemotherapeutic agents. Therefore, the use of appropriate combinations of green tea catechins with the existing chemotherapeutics will lead to a reduction in side effects without decreasing the chemotherapeutic effects. This review will summarize the key results from recent studies detailing the effects of green tea catechins such as EGCG on epigenetic alterations and miRNA expression in prostate cancer.