Late Shoulder-Arm Morbidity Using Ultrasound Scalpel in Axillary Dissection for Breast Cancer: A Retrospective Analysis.

BACKGROUND: We aimed to assess whether the use of the harmonic scalpel (HS) in axillary dissection would reduce long-term shoulder-arm morbidity compared to traditional instruments (TIs). MATERIALS AND METHODS: A retrospective analysis on 180 patients who underwent standard axillary dissection for breast cancer between 2007 and 2015 was carried out. All patients were evaluated for postoperative pain, impairment of shoulder-arm mobility, seroma formation in axilla, frozen shoulder, and lymphedema. RESULTS: HS procedure on average was 50% shorter compared to the TI technique. HS reduced by 4.5 times the risk of axillary seroma. TIs were associated with 4 times higher risk of developing a painful frozen shoulder. CONCLUSIONS: Use of the HS was associated with reduced costs and a positive long-term effect on shoulder-arm morbidity. Axillary seromas are not the only reason of later postoperative shoulder-arm morbidity: other mechanisms are hypothesized in the onset of this very disabling disorder.

Suture thread check test for detection of surgical site contamination: a prospective study.

BACKGROUND: Surgical site infection (SSI) is a common complication of surgical procedures. AIM: Our study aimed at investigating a new method based on assessment of suture thread colonization to identify patients developing an SSI. MATERIALS AND METHODS: We prospectively enrolled 119 patients undergoing elective surgery. For each patient, a synthetic absorbable thread in Lactomer 9-1 (Polisorb Gauge 2) inserted in the surgical site at the end of surgery was sent to the microbiology laboratory after 48 h to assess colonization of its inner tract. RESULTS: Forty (33.6% of cases) patients had a colonized thread. Antibiotic prophylaxis was administered to 66 of 79 patients who did not display a colonized thread and to 20 of the 40 patients with a colonized thread (83.5% versus 50%, respectively, P = 0.0002). An SSI was observed only in patients with a colonized thread (10% versus 0, P = 0.02). The microorganisms identified in colonized threads were the same identified in SSIs. CONCLUSIONS: Since an SSI was found only in patients with colonized threads, the method described here may be valuable for identifying patients developing an SSI. Moreover, the method can also be useful for targeting efficient antibiotic therapy to the culprit microorganisms.

Early Breast Cancer: Could Combined LOCalizerTM and Ultrasound Localization Replace the Metallic Wire? A Multicentric Study.

Background: Breast localization plays a key role in early breast cancer (BC) surgery. The current gold standard is wire-guided localization (WGL), despite the known disadvantages. The patients often experience anxiety and discomfort due the metallic wire placed in the breast, and surgeons are compelled to perform the surgery on the same day as the radiological release of the wire to prevent migrations or breakages. Various wireless systems have been proposed as alternative to WGL. LOCalizerTM offers the advantage of providing the exact distance from the marker called Tag. The combined technique using LOCalizerTM and US allows for determining the distance from the BC margin, a critical surgical goal for oncological radicality. Methods: Patients referred for breast surgery to two Italian hospitals were enrolled and divided into two groups: Group A, including patients undergoing a combined approach, and group B, including patients treated with conventional WGL. Results: The combined approach with LOCalizerTM and US was associated with better outcomes in terms of oncological radicality, cosmetic results, and patients' satisfaction. Conclusions: In the current study, LOCalizerTM associated with US could be considered an excellent approach for localizing non-palpable BC. Further larger comparative studies are needed to address this issue.

Large renal lymphoma in a patient with horseshoe kidney: A case report.

Horseshoe kidney (HSK) is the most common renal fusion anomaly. It frequently consists of kidney fusion in the lower pole across the midline and occurs during embryogenesis. The incidence of malignancies in HSKs can be 3-4 times higher than that in normal kidneys. A 69-year-old man with a voluminous right kidney neoplasm in HSK and a single omolateral axillary lymphadenopathy underwent complete excision of right axillary lymphadenopathy and ultrasound-guided percutaneous biopsy of the right kidney expansive lesion. The diagnosis of non-Hodgkin's B cell lymphoma both in HSK and right axilla was made. We report this case to raise awareness among physicians regarding the importance of a correct clinical evaluation and diagnostic workup so as to avoid surgery, which is not easy and without complications, in patients with this kidney anomaly. Primary renal lymphoma should also be included among possible neoplasms of HSK. Renal biopsy should always be recommended in cases where atypical findings are obtained from imaging techniques and when its outcome can impact clinical decision-making. In the present case, biopsy was performed, and thus, nephrectomy was avoided and specific medical therapy was quickly started.

Post-Irradiation Breast Angiosarcoma: All the Possible Treatments and Electrochemotherapy. Case Report and Literature Review.

Breast angiosarcoma is a rare malignancy, accounting for less than 1% of all soft tissue cancers. It comprises primitive and secondary subtypes, such as radiogenic breast angiosarcoma (RAS). Despite multimodal treatment, angiosarcomas represent an incurable disease for many patients and a significant cause of deterioration in their quality of life. Surgery is a cornerstone in management, but high recurrence rates are reported. Electrochemotherapy (ECT) is a practicable locoregional treatment for patients with advanced angiosarcoma as part of a multimodal therapeutic strategy. The palliative benefits of ECT include optimal patient compliance, good local hemostasis control, and positive local responses. Since only 22 cases are described in the literature, we reported a rare case of RAS treated with ECT after a multidisciplinary approach, including Next Generation Sequencing (NGS). A literature review on the feasibility of ECT in RAS management was also performed.

Rare axillary cancer of unknown primary originating from the breast of a 64­year­old male patient: A case report and literature review.

Cancers of unknown primary (CUPs) are a heterogeneous group of tumors characterized by a difficult diagnosis. The primitive tumor remains unknown, whereas metastases are the most common manifestation. Occult male breast cancers are very rare types of CUPs. The present study describes the case of a 64-year-old man affected by a CUP of presumed mammary origin. The aim of the article and the present review was to focus on their management. To the best of our knowledge, only thirteen cases have been reported in the literature. Because no specific guidelines are available, various approaches have been applied, influencing the treatment and the prognosis of patients with CUP.

One Anastomosis Gastric Bypass vs. Sleeve Gastrectomy in the Remission of Type 2 Diabetes Mellitus: A Retrospective Analysis on 3 Years of Follow-Up.

Background. Obesity is a prevalent condition associated with various comorbidities, impacting mortality, fertility, and quality of life. Its relationship with type 2 diabetes mellitus (DMII) is well established, with nearly 44% prevalence. Bariatric surgery has proven crucial for treating both obesity and DMII. The comparison between surgical techniques, such as sleeve gastrectomy (SG) and one anastomosis gastric bypass (OAGB), remains controversial in terms of glycemic control efficacy. This retrospective study aimed to assess DMII remission efficacy between SG and OAGB after 36 months. Methods. From January 2016 to September 2020, 201 patients who underwent SG and OAGB for morbid obesity associated with DMII were accurately followed-up with for 36 months, focusing on %HbA1c, DMII remission, anthropometric results, and nutrient deficiency. Results. Although DMII remission did not exhibit statistical significance between the groups (82% vs. 93%, SG vs. OAGB, p = 0.051), OAGB demonstrated a more robust association with glycemic control (Odds Ratio 0.51) throughout the entire follow-up and yielded superior anthropometric outcomes. Notably, nutrient deficiencies, excluding cholecalciferol, iron, and riboflavin, did not show significant intergroup differences. Conclusions. This study contributes valuable insights into the extended-term efficacy of SG and OAGB in DMII remission. The nuanced findings underscore the multifaceted nature of metabolic outcomes, suggesting that factors beyond weight loss influence diabetes resolution. Larger comparative studies are warranted to comprehensively address this issue.

The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma.

Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a patients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.

Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease.

BACKGROUND: An ulcer is a trophic lesion with loss of tissue that often has a multifactorial genesis. It typically diverges from the physiologic processes of regeneration because it rarely tends to heal spontaneously. In this study, we used purified adipose-derived stem and regenerative cells (ADRCs) extracted from autologous fat, for the care of chronic ulcers of the lower limbs of arteriopathic patients. The primary objective of this study was complete re-epithelization of chronic ulcers; the secondary objective was a decrease in diameter and depth. METHODS: From January 2010 to January 2012, 20 patients with peripheral arterial disease, with an ankle-brachial index between 0.30-0.40, in the age range 60-70 y (14 men and six women), with chronic ulcers of the lower limb, were involved in the study. Only 10 arteriopathic patients (seven men and three women) with chronic ulcers of the lower limb were surgically treated. Using the Celution system, we isolated a solution of ADRCs in about 150 min. The isolated cells were injected through a 10-mL syringe into the edges of the ulcer, taking care to spread it in all directions. Using a small amount of Celution extract, we performed cell characterization by flow cytometry analysis and cell viability assay. RESULTS: We monitored patients treated with ADRC or untreated at 4, 10, 20, 60, and 90 d. In all cases treated with ADRC, we found a reduction in both diameter and depth of the ulcer, which led to a decrease in pain associated with the ulcer process. In six of 10 cases there was complete healing of the ulcer. Characterization of the cells by FACS clearly showed that the ADRC cells contained adipose-derived stem cells. Viability assays demonstrated that partial or total closure of the ulcer was attributable exclusively to ADRC cells present in the Celution extract, and not to growth factors extracted during the process of purification of the Celution and injected together with the cells. CONCLUSIONS: For the first time, the Celution method has been applied for the care of chronic ulcers in the lower extremity of patients with peripheral arterial disease. Our results demonstrate that the technique is feasible for autologous cell application and is not associated with adverse events. Moreover, the transplantation of autologous stem cells extracted with Celution may represent a valuable method for the treatment of chronic ulcers in lower limbs of arteriopathic patients.

Advanced Localization Technique for Non-Palpable Breast Cancer: Radiofrequency alone VS Combined Technique with Ultrasound.

Breast conservative surgery is the primary therapeutic choice for non-aggressive early breast cancers, and a minimally-invasive approach is strongly recommended. The breast localization represents a modern challenge for surgery. Wire-guided localization is still the gold standard technique, but new wireless systems have been proposed, such as radiofrequency identification with LOCalizerTM (Hologic, Santa Carla, CA, USA), which reports encouraging results. The current study aimed to evaluate the accuracy and efficacy of the combined use of LOCalizerTM and ultrasound compared with the results obtained using LOCalizerTM alone for the detection of non-palpable breast cancer. Ninety-six patients who were candidates for breast localization were enrolled. Group A received a combined localization with LOCalizerTM and US, while group B underwent only LOCalizerTM identification. Oncological radicality was reached in 100% of the patients in Group A and in 89.2% of the patients in Group B, with p = 0.006. The mean specimens' volume was 13.2 ± 0.6 cm3 for Group A and 16.1 ± 1.4 cm3 for Group B, while mean specimen weights were 21.8 ± 2.2 and 24.4 ± 1.8 g, respectively (p = 0.003 and p = 0.004, respectively). LOCalizerTM with ultrasound, in the current series, has resulted in the preferred option for the localization of non-palpable breast cancer, allowing limited resection (in weight and volume), guaranteeing excellent oncological outcomes, and great satisfaction for patients and physicians.

Automated 3D Ultrasound as an Adjunct to Screening Mammography Programs in Dense Breast: Literature Review and Metanalysis.

Purpose: The purpose of this meta-analysis is to investigate the effectiveness of supplementing screening mammography with three-dimensional automated breast ultrasonography (3D ABUS) in improving breast cancer detection rates in asymptomatic women with dense breasts. Materials and Methods: We conducted a thorough review of scientific publications comparing 3D ABUS and mammography. Articles for inclusion were sourced from peer-reviewed journal databases, namely MEDLINE (PubMed) and Scopus, based on an initial screening of their titles and abstracts. To ensure a sufficient sample size for meaningful analysis, only studies evaluating a minimum of 20 patients were retained. Eligibility for evaluation was further limited to articles written in English. Additionally, selected studies were required to have participants aged 18 or above at the time of the study. We analyzed 25 studies published between 2000 and 2021, which included a total of 31,549 women with dense breasts. Among these women, 229 underwent mammography alone, while 347 underwent mammography in combination with 3D ABUS. The average age of the women was 50.86 years (±10 years standard deviation), with a range of 40-56 years. In our efforts to address and reduce bias, we applied a range of statistical analyses. These included assessing study variation through heterogeneity assessment, accounting for potential study variability using a random-effects model, exploring sources of bias via meta-regression analysis, and checking for publication bias through funnel plots and the Egger test. These methods ensured the reliability of our study findings. Results: According to the 25 studies included in this metanalysis, out of the total number of women, 27,495 were diagnosed with breast cancer. Of these, 211 were diagnosed through mammography alone, while an additional 329 women were diagnosed through the combination of full-field digital mammography (FFDSM) and 3D ABUS. This represents an increase of 51.5%. The rate of cancers detected per 1000 women screened was 23.25‱ (95% confidence interval [CI]: 21.20, 25.60; p < 0.001) with mammography alone. In contrast, the addition of 3D ABUS to mammography increased the number of tumors detected to 20.95‱ (95% confidence interval [CI]: 18.50, 23; p < 0.001) per 1000 women screened. Discussion: Even though variability in study results, lack of long-term outcomes, and selection bias may be present, this systematic review and meta-analysis confirms that supplementing mammography with 3D ABUS increases the accuracy of breast cancer detection in women with ACR3 to ACR4 breasts. Our findings suggest that the combination of mammography and 3D ABUS should be considered for screening women with dense breasts. Conclusions: Our research confirms that adding 3D automated breast ultrasound to mammography-only screening in patients with dense breasts (ACR3 and ACR4) significantly (p < 0.05) increases the cancer detection rate.

Expression of c-MET in Estrogen Receptor Positive and HER2 Negative Resected Breast Cancer Correlated with a Poor Prognosis.

Introduction: The mesenchymal-epithelial transition factor (c-MET) receptor is overexpressed in about 14−54% of invasive breast cancers, but its prognostic value in clinical practice is still unclear. Methods: In order to investigate the relationship between c-MET expression levels and prognosis, we retrospectively reviewed the clinical features and outcomes of 105 women with estrogen receptor positive HER2 negative (ER+/HER2-) resected breast cancer. We used the Kaplan Meier method to estimate Disease Free Survival (DFS) and Breast Cancer Specific Survival (BCSS) in the subgroups of patients with high (≥50%) and low (<50%) c-MET expression. Univariate and multivariate Cox proportional regression models were performed to assess the prognostic impact of clinicopathological parameters for DFS an BCSS. Results: High c-MET values significantly correlated with tumor size, high Ki67 and low (<20%) progesterone receptor expression. At a median follow up of 60 months, patients with high c-MET tumor had significantly worse (p = 0.00026) and BCSS (p = 0.0013). Univariate analysis showed a significant association between large tumor size, elevated Ki67, c-MET values and increased risk of recurrence or death. The multivariate COX regression model showed that tumor size and high c-MET expression were independent predictors of DFS (p = 0.019 and p = 0.022). Moreover, large tumor size was associated with significantly higher risk of cancer related death at multivariate analysis (p = 0.017), while a trend towards a poorer survival was registered in the high c-MET levels cohort (p = 0.084). Conclusions: In our series, high c-MET expression correlated with poor survival outcomes. Further studies are warranted to validate the clinical relevance and applicability of c-MET as a prognostic factor in ER+/HER2- early BC.

Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer.

The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.

MRI in Pregnancy and Precision Medicine: A Review from Literature.

Magnetic resonance imaging (MRI) offers excellent spatial and contrast resolution for evaluating a wide variety of pathologies, without exposing patients to ionizing radiations. Additionally, MRI offers reproducible diagnostic imaging results that are not operator-dependent, a major advantage over ultrasound. MRI is commonly used in pregnant women to evaluate, most frequently, acute abdominal and pelvic pain or placental abnormalities, as well as neurological or fetal abnormalities, infections, or neoplasms. However, to date, our knowledge about MRI safety during pregnancy, especially about the administration of gadolinium-based contrast agents, which are able to cross the placental barrier, is still limited, raising concerns about possible negative effects on both the mother and the health of the fetus. Contrast agents that are unable to cross the placenta in a way that is safe for the fetus are desirable. In recent years, some preclinical studies, carried out in rodent models, have evaluated the role of long circulating liposomal nanoparticle-based blood-pool gadolinium contrast agents that do not penetrate the placental barrier due to their size and therefore do not expose the fetus to the contrast agent during pregnancy, preserving it from any hypothetical risks. Hence, we performed a literature review focusing on contrast and non-contrast MRI use during pregnancy.

The Implications of EU Regulation 2016/429 on Neglected Diseases of Small Ruminants including Contagious Agalactia with Particular Reference to Italy.

After almost 40 years, the 27 member states (MS) of the European Union (EU) will comply with the European Law 429/2016 in 2021 by completing a process of unification and harmonization of all regulations related to animal health between MS. These new provisions are based on modern scientific principles on animal health, on long-term epidemiological data, and, above all, on the most current risk assessment and analysis. The paper describes all changes and updates, which will impact the Italian current National regulation. A total of 58 animal diseases have been included in the Annex II ("Listing") and Annex IV ("Categorization") of the new Delegated Act (DA 2018/1629). Five diseases comprising the great viral epizooties were automatically included on the list because of their primary importance. These diseases include foot and mouth disease (FMD), African swine fever (ASF), classical swine fever (CSF), highly pathogenic avian influenza (HPAI), and African horse sickness (AHS). Another 53 diseases have been identified by the ad hoc assessment on listing and categorization of animal diseases developed by the European Food Safety Association. Seventeen communicable diseases of the Order Artiodactlya (sheep, goats, deer, etc.) have been listed including foot and mouth disease, sheep and goat pox, and pestes de petits ruminants. In addition, other endemic diseases affecting more than one species include blue tongue, tuberculosis, brucellosis, and anthrax. There are five categories (A-E) based on the degree of action to be undertaken throughout the EU for each disease. These vary from complete eradication for diseases not normally found in the EU like FMD (category A) for establishing surveillance for diseases like West Nile that present high risk but lack control tools (category E).

The Role of Bacterial Colonization of the Suture Thread in Early Identification and Targeted Antibiotic Treatment of Surgical Site Infections: A Prospective Cohort Study.

Background: The aim of the present study is to investigate the role of the colonization of suture thread to identify patients at risk of developing a surgical site infection (SSI) after clean surgical procedures. Methods: Patients who underwent elective clean surgery procedures at the Surgery Unit of the AOU-University of Campania Luigi Vanvitelli in a 21-month period were prospectively enrolled. For each patient, a synthetic absorbable thread in Lactomer 9-1 was inserted into the surgical site at the end of surgery and microbiologically evaluated after 48 h. Antibiotic prophylaxis was chosen according to international guidelines. Results: A total of 238 patients were enrolled; 208 (87.4%) of them were subjected to clean procedures without the placement of prosthesis, and 30 (12.6%) with prosthesis. Of the 238 patients, 117 (49.2%) underwent an antimicrobial prophylaxis. Overall, 79 (33.2%) patients showed a bacterial colonization of the thread: among the 208 without the implantation of prosthesis, 19 (21.8%) of the 87 with antibiotic prophylaxis and in 58 (47.9%) of the 121 without it; among the 30 patients with the implantation of prosthesis, only two patients showed a colonized thread. The patients with antibiotic prophylaxis developed a colonization of the thread less frequently than those without it (17.9% vs. 47.9%, p < 0.001). SSI was observed in six (2.5%) patients, all of them showing a colonized thread (7.6% vs. 0%, p < 0.001). The bacteria identified in colonized threads were the same as those found in SSIs. Conclusions: Our study presents a new method that is able to precociously assess patients who have undergone clean procedures who may develop SSI, and identify the microorganism involved.

A Preliminary Study for Quantitative Assessment with HFUS (High- Frequency Ultrasound) of Nodular Skin Melanoma Breslow Thickness in Adults Before Surgery: Interdisciplinary Team Experience.

BACKGROUND: Cutaneous melanoma is one of the most severe skin diseases. Nodular melanoma is the second melanoma subtype in order of frequency. The prognosis of skin melanoma depends on the vertical growth of the tumor (Breslow index). For this measurement, excisional biopsy is strongly recommended. This is, however, an invasive procedure and may cause damage to the lymphatic drainage system. The HFUS system, , can be extremely useful for determining tumor thickness in the preoperative phase, given its high resolution capacity. The aim of this preliminary study is to define the role of HFUS for the nodular skin melanoma Breslow thickness in adults before surgery by making a comparison with histological features. METHODS: In this study, 14 melanocytic lesions (8 male and 6 female) were evaluated with dermatoscopic clinical features strongly indicative of nodular melanoma. Out of these, excisional biopsy of 7 lesions was requested. The ultrasounds were performed preoperatively. The images were acquired through the first ultrasound scanner with ultra-high frequency probes (range from 50MHz to 70 MHz) available on the market under the EEC mark (Vevo "MD, FUJIFILM Visual Sonics, Amsterdam, the Netherlands) equipped with a linear probe of 50-70 MHz. RESULTS: From the ultrasonographic analysis of 14 nodular melanoma thickness was determined for the presence of two hyperechogenic laminae, separated by a hypo / anechoic space. The twelve lesions were in situ while the other two lesions showed ultrasonography for example; the satellite lesions (less than two centimeters from the primary lesion) and in transit (localizable to more than two centimeters from the primary lesion). Four of these lesions were ulcerated. A comparsion was made the 7 lesions on between the thickness calculated with this method, and that obtained on the bioptic piece. The presence of a positive concordance has been evident in all of the cases. CONCLUSION: If further studies are needed to support its widespread clinical use, its is believed that, in expert hands and with an interdisciplinary team, HFUS is already capable to reliably calculate a Breslow index in a large majority of patients with cutaneous melanoma.

Comparative Study of NGS Platform Ion Torrent Personal Genome Machine and Therascreen Rotor-Gene Q for the Detection of Somatic Variants in Cancer.

Molecular profiling of a tumor allows the opportunity to design specific therapies which are able to interact only with cancer cells characterized by the accumulation of several genomic aberrations. This study investigates the usefulness of next-generation sequencing (NGS) and mutation-specific analysis methods for the detection of target genes for current therapies in non-small-cell lung cancer (NSCLC), metastatic colorectal cancer (mCRC), and melanoma patients. We focused our attention on EGFR, BRAF, KRAS, and BRAF genes for NSCLC, melanoma, and mCRC samples, respectively. Our study demonstrated that in about 2% of analyzed cases, the two techniques did not show the same or overlapping results. Two patients affected by mCRC resulted in wild-type (WT) for BRAF and two cases with NSCLC were WT for EGFR according to PGM analysis. In contrast, these samples were mutated for the evaluated genes using the therascreen test on Rotor-Gene Q. In conclusion, our experience suggests that it would be appropriate to confirm the WT status of the genes of interest with a more sensitive analysis method to avoid the presence of a small neoplastic clone and drive the clinician to correct patient monitoring.

Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer.

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.