Correlation between ferromagnetic and isotopic tracers for sentinel lymph node detection in cutaneous melanoma: IMINEM study.

BACKGROUND: The usefulness of sentinel lymph node biopsy (SLNB) in staging cutaneous melanoma has been proven. Therefore, different tracers have been used to identify the sentinel lymph nodes (SLNs). The use of isotopic tracers together with radioactivity detectors allowed a much more precise and direct approach to the SLNs. However, not all centres have access to a Nuclear Medicine department hindering sentinel lymph node detection (SLND) and consequently, other markers such as ferromagnetic tracers have been evaluated looking for the same advantages and effectiveness as isotopic tracers. Ferromagnetic tracers have proven their usefulness in other cancer entities such as breast, prostate and thyroid cancer. The objective was to assess the detection and concordance rates between isotopic and ferromagnetic techniques for SLNB in cutaneous melanoma. METHOD: Isotopic SLNB technique and ferromagnetic tracer were compared for cutaneous melanoma in a non-inferiority multicentre prospective study carried out in six Spanish hospitals. RESULTS: A total of 60 patients were recruited and 133 lymph nodes removed. The detection rate was slightly higher with ferromagnetic tracer in head-neck and trunk melanomas, and with isotopic tracer in limbs. The patients' and nodes' concordance rates between both techniques for ex vivo samples were 95% and 86% for head-neck and trunk tumours and 97% and 93% for limbs tumours, respectively. The concordance rates for involved nodes were 100% and 88.2% for patients and nodes, respectively. CONCLUSION: The intraoperative detection and biopsy of SLN in cutaneous melanoma using a ferromagnetic was a reliable alternative method to the isotopic technique in cutaneous melanomas.

External validation of a prognostic model based on total tumor load of sentinel lymph node for early breast cancer patients.

BACKGROUND: A prognostic model based on the results of molecular analysis of sentinel lymph nodes (SLN) is needed to replace the information that staging the entire axilla provided. The aim of the study is to conduct an external validation of a previously developed model for the prediction of 5-year DFS in a group of breast cancer patients that had undergone SLN biopsy assessed by the One Step Nucleic Acid Amplification (OSNA) method. METHODS: We collected retrospective data of 889 patients with breast cancer, who had not received systemic treatment before surgery, and who underwent SLN biopsy and evaluation of all SLN by OSNA. The discrimination ability of the model was assessed by the area under the ROC curve (AUC ROC), and its calibration by comparing 5-years DFS Kaplan-Meier estimates in quartile groups of model predicted probabilities (MPP). RESULTS: The AUC ROC ranged from 0.78 (at 2 years) to 0.73 (at 5 years) in the training set, and from 0.78 to 0.71, respectively, in the validation set. The MPP allowed to distinguish four groups of patients with heterogeneous DFS (log-rank test p < 0.0001). In the highest risk group, the HR were 6.04 [95% CI 2.70, 13.48] in the training set and 4.79 [2.310, 9.93] in the validation set. CONCLUSIONS: The model for the prediction of 5-year DFS was successfully validated using the most stringent form of validation, in centers different from those involved in the development of the model. The external validation of the model confirms its utility for the prediction of 5-year DFS and the usefulness of the TTL value as a prognostic variable.

Prospective randomized controlled study to assess the value of a hemostatic and sealing agent for preventing seroma after axillary lymphadenectomy.

BACKGROUND AND OBJECTIVES: Postoperative seroma after axillary lymphadenectomy leads to an increased use of resources and an impaired quality of life of patients. This randomized clinical trial was designed to assess the value of a hemostatic and sealing agent for decreasing seroma occurrence after axillary lymphadenectomy. METHODS: A prospective, randomized, blind study was conducted on 91 axillary lymphadenectomies distributed into a control group (n = 47) and a test group in which a collagen sponge coated with human coagulation factors was used (n = 44). Primary end-points were number of days before removal of axillary drainage, axillary drainage output, and occurrence of seroma, wound infection, haematoma, or wound dehiscence, within 8 weeks of surgery. Bivariate and multivariate analyses on seroma occurrence were performed. RESULTS: Seroma occurred in 29 patients (31.86%). A significant direct relationship (P = 0.002) was only noted between use of the hemostatic and sealing agent and nonoccurrence of seroma. In the multivariate study, the only variable found to be significantly related to seroma occurrence was use of the above agent (P = 0.046; odds ratio: 3.365 [95%CI: 1.024-11.060]). CONCLUSIONS: Use of a collagen sponge coated with human coagulation factors following axillary lymphadenectomy was associated to a lower incidence of postoperative seroma. J. Surg. Oncol. 2016;114:423-427. © 2016 Wiley Periodicals, Inc.

Selective sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: results of the GEICAM 2005-07 study.

INTRODUCTION: A controversial aspect of breast cancer management is the use of sentinel lymph node biopsy (SLNB) in patients requiring neoadjuvant chemotherapy (NCT). This paper discusses the detection rate (DT) and false negatives (FN) of SLNB after NCT to investigate the influence of initial nodal disease and the protocols applied. METHODS: Prospective observational multicenter study in women with breast cancer, treated with NCT and SLNB post-NCT with subsequent lymphadenectomy. DT and FN rates were calculated, both overall and depending on the initial nodal status or the use of diagnostic protocols pre-SLNB. RESULTS: No differences in DT between initial node-negative cases and positive cases were found (89.8 vs. 84.4%, P=.437). Significant differences were found (94.1 vs. 56.5%, P=0,002) in the negative predictive value, which was lower when there was initial lymph node positivity, and a higher rate of FN, not significant (18.2 vs. 43.5%, P=.252) in the same cases. The axillary study before SLNB and after the NCT, significantly decreased the rate of FN in patients with initial involvement (55.6 vs 12.5, P=0,009). CONCLUSIONS: NCT means less DT and a higher rate of FN in subsequent SLNB, especially if there is initial nodal involvement. The use of protocols in axillary evaluation after administering the NCT and before BSGC, decreases the FN rate in these patients.

Melanoma coordinates general and cell-specific mechanisms to promote methotrexate resistance.

Melanoma, the most aggressive form of skin cancer, is notoriously resistant to all current modalities of cancer therapy, including to the drug methotrexate. Melanosomal sequestration and cellular exportation of methotrexate have been proposed to be important melanoma-specific mechanisms that contribute to the resistance of melanoma to methotrexate. In addition, other mechanisms of resistance that are present in most epithelial cancer cells are also operative in melanoma. This report elucidates how melanoma orchestrates these mechanisms to become extremely resistant to methotrexate, where both E2F1 and checkpoint kinase 1 (Chk1), two molecules with dual roles in survival/apoptosis, play prominent roles. The results indicated that MTX induced the depletion of dihydrofolate in melanoma cells, which stimulated the transcriptional activity of E2F1. The elevate expression of dihydrofolate reductase and thymidylate synthase, two E2F1-target genes involved in folate metabolism and required for G(1) progression, favored dTTP accumulation, which promoted DNA single strand breaks and the subsequent activation of Chk1. Under these conditions, melanoma cells are protected from apoptosis by arresting their cell cycle in S phase. Excess of dTTP could also inhibit E2F1-mediated apoptosis in melanoma cells.

Lower limb cutaneous melanoma surgery: location matters.

The anatomical location of cutaneous melanoma is a relevant independent prognostic factor in melanoma. The aim of the study is to know the prognosis of lower limb cutaneous melanoma related to their location within the limb, regardless of the histological type, and if there are any other influencing variables. A real-world data observational study was developed. The lesions were divided depending on the location of the melanoma (thigh, leg and foot). Bivariate and multivariate analysis were performed, and melanoma-specific survival and disease-free survival rates were calculated. When these analysis were done, the results showed that, in melanomas of the lower limb, location on the foot presented a lower melanoma-specific survival rate compared to more proximal locations, and only the anatomical location presents statistical significance to discriminate cases with a higher mortality risk and a lower disease-free survival rate among distal melanomas (mainly on the foot). In conclusion, this study confirms that a more distal location of lower limb cutaneous melanoma is a relevant prognostic factor.Trial registration number NCT04625491 retrospectively registered.

MITF induces escape from innate immunity in melanoma.

BACKGROUND: The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. METHODS: By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. RESULTS: Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. CONCLUSION: Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

Cavity shaving for invasive breast cancer conservative surgery: Reduced specimen volume and margin positive rates.

INTRODUCTION: The cavity shaving (CS) technique was described in breast conserving surgery to reduce the rate of reoperation avoiding the need for intraoperative margin analysis. This study assesses differences in the rates of involvement of the surgical margin (requiring further surgery) and volume of surgical specimens, depending on the use or not of this technique. MATERIAL AND METHODS: A retrospective cohort study was conducted in patients with breast carcinoma who underwent breast conserving surgery between 2013 and 2019. They were divided into two groups depending on whether the cavity shaving technique was used or not. Primary outcomes of the study included presence of final margin involvement, requiring need for further surgery, and the volume of excised tissue comparing the study groups. RESULTS: A total of 202 cases were included: 92 in the control group and 110 in the cavity shaving group. Significant differences were found regarding involvement of the final margin (19.57% control group vs. 4.55% cavity shaving group; p = 0.010). The volume of additional surgical specimens were significantly greater in the traditional technique group than in the shaving technique (46.43 vs 13.32 cm3; p = 0.01) as was total specimen volume (143.40 vs 100.63 cm3; p = 0.022). CONCLUSIONS: CS can reduce the positive margin and re-excision rates without larger-volume resections and should therefore be considered a routine technique in BCS for early-stage breast cancer.

PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation.

The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation. In this study, we observed that irradiation of breast cancer cells was accompanied by an overproduction in S-adenosylmethionine, which increases the activity of cellular methylases. We found that by activating PRMT1, irradiation triggers a BRCA1-dependent program that results in efficient DNA repair and inhibition of apoptosis. Depletion of PRMT1 in irradiated cells resulted in a switch of BRCA1 functions from repair and survival in the nucleus to activation of cell death signals in the cytoplasm. We conclude that by modulating the cellular localization of BRCA1, PRMT1 is an important regulator of the oncogenic functions of BRCA1, contributing to the epigenetic defense of breast cancer cells against ionizing radiation.

A New Treatment for Mammillary Fistulas Using Ultrasound-Guided Percutaneous Needle Electrolysis.

The aim of this study was to investigate the efficacy of ultrasound-guided percutaneous needle electrolysis (PNE) in mammillary fistulas (MFs). A prospective study was performed in 18 patients with MF who were treated with the PNE technique. The technique was repeated in the case of no response or recurrence. The results obtained show that MFs revealing an elongated appearance with the ultrasound (US) are generally resolved with two sessions of PNE, whereas ovoid MFs require several sessions of PNE for complete resolution and they tend to recur. Success of the treatment with PNE was observed in 88.8% of the patients (16/18), and failure, after five or six sessions in two cases (11.2%), which were referred for surgery. Conclusions: To the best of our knowledge this is the first study to reveal that the PNE technique is safe, effective, quick, and well-tolerated by patients.

A New Therapeutic Application of Platelet-Rich Plasma to Chronic Breast Wounds: A Prospective Observational Study.

The aim of this study was to investigate the usefulness of platelet-rich plasma (PRP) treatment for chronic wounds (CWs) of the breast. A prospective study was performed in 23 patients with CW of the breast who were treated with PRP. The procedure was repeated until the wound was closed completely. The study included patients with a history of breast cancer (n = 8) and patients without cancer (n = 15). The treatment with PRP was successful in all cases and observed in ≤4 weeks in 82.6% (19/23) of patients. The patients without breast cancer showed significantly less time for wound closure than the patients with a history of breast cancer. Moreover, a greater number of PRP treatments were necessary to achieve wound closure in patients undergoing conservative breast treatment. No patients had complications associated with the application of PRP. Conclusions: To the best of our knowledge, this is the first study to reveal that PRP treatment for CWs of the breast is safe, simple, useful and well-tolerated by patients.

PET-CT gamma probe-guided lymph node biopsy: a new diagnostic surgical approach.

PURPOSE: The higher sensitivity of new diagnostic tools makes it easier to detect relapse in asymptomatic stages when classic procedures of lymph node biopsies are difficult to perform. The aim of this article is to describe the combination of gamma probe and 18F-FDG positron emission tomography-computed tomography (PET-CT) images in combination with sentinel lymph node biopsy technique for detection of nonpalpable lymph nodes. METHODS: After a dose of 18F-FDG was administered and PET-CT images that showed the location of suspected pathologic lymph nodes were obtained, transcutaneous localization of the lymph nodes with the highest captation of the tracer was done. The gamma probe was programmed to detect the radioactive signal from the F18, instead of the Tc99m that is usual in the sentinel node biopsy technique. Once the hottest point was detected, a short incision was made on this area, and suspicious nodes with the highest uptake registered by the gamma probe were localized and removed. After the surgical removal from the operating field, the surgical pieces stood positive to the gamma probe. Lymph node involvement, and subsequent relapse, was diagnosed before their clinical manifestation. CONCLUSIONS: This methodology confirms new horizons for the surgical approach of lymph node biopsies in patients with previous tumors with 18F-FDG avidity and suspicion of relapse.

[Hypoparathyroidism and hypocalcemia following thyroid surgery of multinodular goiter. Multivariant study of the risk factors]. / Hipoparatiroidismo e hipocalcemia en el postoperatorio de la cirugía del bocio multinodular. Estudio multivariante de los factores de riesgo.

BACKGROUND AND OBJECTIVE: The hypoparathyroidism is one of the most important complications in the patients submitted to thyroid surgery. The aim is to analyze across a multivariate statistical analysis the risks factors for the development of transient and permanent hypoparathyroidism following the multinodular goiter (MG) surgery. PATIENTS AND METHOD: Between 1970 and 1999, 672 thyroidectomies by MG were reviewed. It was considered transient hypoparathyroidism when the calcemia was minor of 7.5 mg/dl or when being minors of 8.5 mg/dl the patient was presenting symptomatology for the hipocalcemia. The hypoparathyroidsm was considered permanent when the calcemia was minor of 8.5 mg/dl to the year of the surgery. RESULTS: The hypoparathyroidism appeared in 75 patients (11.2%), 20 with symptomatology (3%), persisting like permanent 6 cases (0.9%). The risk factors for the development of this were the hyperthyroidism (p = 0.0370), and the surgical technique (p < 0.00001) (unilateral versus bilateral surgery), persisting in the multivariate analysis both variables. With respect to the permanent hypoparathyroidism, the risk factor was the toxic MG (p = 0.0109), persisting as independent risk factor in the multivariate analysis (RR = 2.3). CONCLUSIONS: The principal risk factor of permanent hypoparathyroidism in the MG surgery is the presence of hyperthyroidism.

Tumoral load quantification of positive sentinel lymph nodes in breast cancer to predict more than two involved nodes.

AIM: One-Step Nucleic Acid Amplification (OSNA) can detect isolated tumour loads in axillary lymph nodes of breast cancer patients. We investigated the predictability of the non-sentinel lymph node (SLN) metastatic involvement (MI) based on the OSNA SLN assessment in surgical invasive breast cancer. METHODS: We studied surgical breast invasive carcinoma patients, not taking neoadjuvant chemotherapy, having SLN positive by OSNA and having received axillary lymphadenectomy. Age, basic histopathological, immunohistochemical, SLN biopsy and lymphadenectomy data were compared between patients with or without MI of more than 2 non-SLN in both univariate and multivariate analyses. The discriminating capacity of the multivariate model was characterized by the ROC AUC. RESULTS: 726 patients from 23 centers in Spain aged 55.3 ± 12.2 years were analysed. The univariate analysis comparing patients with or without MI of more than 2 non-SLN detected statistically significant differences in primary tumour size, multifocality, presence of lymphovascular infiltration, positive proliferation index with ki67, immunophenotype and logTTL (Tumour Total Load). The multivariate logistic analyses (OR (95% CI)) confirmed multifocality (2.16 (1.13-4.13), p = 0.019), lymphovascular infiltration (4.36 (2.43-7.82), p < 0.001) and logTTL (1.22 (1.10-1.35), p < 0.001) as independent predictors, and exhibit an AUC (95% CI) of 0.78 (0.72-0.83) with an overall fit (Hosmer-Lemeshow test) of 0.359. A change in the slope of both sensitivity and specificity is observed at about 10,000 copies/µL, without relevant changes in the Negative Predictive Values. CONCLUSIONS: Using OSNA technique, the MI of more than 2 non-SLN can be reliably predicted.