Mitotic rate as an important prognostic factor in cutaneous malignant melanoma.

BACKGROUND: Recently, the quantification of mitoses in cutaneous melanoma has been discharged from the main prognostic variables of the TNM classification. OBJECTIVE: To investigate the prognostic value of the presence of mitoses in primary cutaneous melanoma and to establish the number of mitoses per mm2 that may have prognostic significance. METHODS: A retrospective observational study was performed on 141 patients treated for cutaneous melanoma, who were assessed by the same pathologist, and who had a minimum follow-up of 2 years. Clinical, epidemiological, histopathological and follow-up variables were gathered and compared with the number of mitoses to distinguish the significance of differences by means of univariate, multivariate, and survival analyses. RESULTS: The cut-off level related to a better sensitivity and specificity was 1.50 mitoses per mm2. The presence of two or more mitoses/mm2 showed a better relationship with prognostic variables and both the overall and disease-free survival than the presence of 1 or more mitoses/mm2. This happens especially in melanomas thicker than 0.8 mm and it could affect the staging in cases with Breslow between 1 and 2 mm. CONCLUSIONS: A mitotic rate of two or more mitoses per mm2 in cutaneous melanoma should be considered as a more accurate prognostic factor than one or more mitoses per mm2, particularly in tumors equal or greater than 0.8 mm in thickness.

Usefulness of lymphocyte-to-monocyte, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT. METHODS: A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS). RESULTS: Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P = 0.048 and P = 0.015, respectively) and, above all, NLR was associated with a better survival (P = 0.024), being those factors that predict a good progress. CONCLUSION: High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT.

Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis.

During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial-mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy.

Targeting the epigenetics of the DNA damage response in breast cancer.

Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Because the epigenetic factors involved in the DNA damage response are regulated by multiple elements, therapies to target specific components of the epigenetic machinery can be inefficient. In contrast, therapies aimed at inhibiting the methionine cycle can indirectly inhibit both DNA and protein methylation, and the wide variety of genes and pathways that are affected by these methylations make this global strategy very attractive. In the present study, we propose an adjuvant therapy that targets the epigenetics of the DNA damage response in breast cancer cells and that results in efficient apoptosis and a reduction in distant metastases in vivo. We observed that a combined therapy designed to uncouple adenosine metabolism using dipyridamole in the presence of a new synthetic antifolate, 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin, simultaneously and efficiently blocked both the folic cycle and the methionine cycle in breast cancer cells and sensitized these cells to radiotherapy. The treatment impeded the recruitment of 53BP1 and BRCA1 to the chromatin regions flanking DNA double-strand breaks and thereby avoided the DNA damage responses in breast cancer cells that were exposed to ionizing radiation. In addition, this hypomethylating therapy was also efficient in reducing the self-renewal capability of breast cancer-initiating cells and induced reversion of mesenchymal phenotypes in breast cancer cells.

Superparamagnetic iron oxide as a tracer for sentinel node biopsy in breast cancer: A comparative non-inferiority study.

AIMS: The gold standard for detection of Sentinel Lymph Nodes (SLN) is a combined radioisotope and blue dye breast injection, using a gamma probe (GP). A new, non-radioactive method was developed, using a tracer (Sienna+(®)) of superparamagnetic iron oxide (SPIO) nanoparticles and a manual magnetometer (SentiMag(®)) (SM). The IMAGINE study was designed to show the non-inferiority of SM compared to GP, for the detection of SLN in breast cancer patients with SLN biopsy indication. METHODS: From November 2013 to June 2014, 181 patients were recruited, and 321 nodes were excised and assessed ex-vivo. Readings from both SM and GP devices were recorded during transcutaneous, intraoperative, and ex-vivo detection attempts. RESULTS: At the patient level, ex-vivo detection rates (primary variable) with SM and GP were 97.8% and 98.3% (concordance rate 99.4%). Transcutaneous and intraoperative detection rates were 95.5% vs 97.2%, and 97.2% vs 97.8% for SM and GP respectively (concordance rates > 97%). At the node level, intraoperative and ex-vivo detection rates were 92.5% vs 89.3% and 91.0% vs 86.3% for SM and GP respectively. In all cases the non-inferiority of SM compared to SM was shown by ruling out a predefined non-inferiority margin of 5%. CONCLUSIONS: Our study showed the non-inferiority of SM as compared to GP. Moreover, the ex-vivo and intraoperative detection rates at the node level were slightly higher with SM.

[Selective sentinel node biopsy in melanoma using preoperative lymphoscintigraphy location and intraoperative detection gamma probe]. / Biopsia selectiva del ganglio centinela en el melanoma mediante localización con linfogammagrafía preoperatoria y sonda de detección gamma intraoperatoria.

BACKGROUND: The experience in detection of sentinel lymph node in melanoma using preoperative scintigraphy and intraoperative gamma probe is referred. PATIENTS AND METHODS: We studied 60 patients with stage I-II melanoma who underwent sentinel lymph node biopsy performed using 99m-Tc-labelled sulphur colloid as radioactive tracer. A preoperative scintigraphy was performed and intraoperative gamma probe was used to localize the sentinel node in all cases. Scintigraphy results, effectiveness of intraoperative detection (technical efficacy), pathological results, and follow-up have been studied. RESULTS: Preoperative detection was 98.3% and the mean basin detected was 1.17. There were multiple basins especially when melanomas were on the trunk. Technical efficacy was 98.4% and intraoperative detection was more difficult in parotid gland region. HMB-45 immunohistochemical staining was essential in pathological studies, in whom 10% were positives. Lymphadenectomy could be avoided in 90% of the patients. Recurrences were not detected during follow-up and metastases were found only in non biopsied cases. Sentinel node biopsy morbidity was significative lesser than that of lymphadenectomy. CONCLUSIONS: Preoperative scintigraphy and intraoperative gamma probe use to localize sentinel node in melanoma have a high efficacy. They can reveal multiple basins and they allow a more selective surgical approach and a minimal dissection.