Circulating microRNAs can predict chemotherapy-induced toxicities in patients being treated for primary breast cancer.

PURPOSE: Prescribing NAC for breast cancer is a pragmatic treatment strategy for several reasons; however, certain patients suffer chemotherapy-induced toxicities. Unfortunately, identifying patients at risk of toxicity often proves challenging. MiRNAs are small non-coding RNA molecules which modulate genetic expression. The aim of this study was to determine whether circulating miRNAs are sensitive biomarkers that can identify the patients likely to suffer treatment-related toxicities to neoadjuvant chemotherapy (NAC) for primary breast cancer. METHODS: This secondary exploratory from the prospective, multicentre translational research trial (CTRIAL ICORG10/11-NCT01722851) recruited 101 patients treated with NAC for breast cancer, from eight treatment sites across Ireland. A predetermined five miRNAs panel was quantified using RQ-PCR from patient bloods at diagnosis. MiRNA expression was correlated with chemotherapy-induced toxicities. Regression analyses was performed using SPSS v26.0. RESULTS: One hundred and one patients with median age of 55 years were recruited (range: 25-76). The mean tumour size was 36 mm and 60.4% had nodal involvement (n = 61) Overall, 33.7% of patients developed peripheral neuropathies (n = 34), 28.7% developed neutropenia (n = 29), and 5.9% developed anaemia (n = 6). Reduced miR-195 predicted patients likely to develop neutropenia (P = 0.048), while increased miR-10b predicted those likely to develop anaemia (P = 0.049). Increased miR-145 predicted those experiencing nausea and vomiting (P = 0.019), while decreased miR-21 predicted the development of mucositis (P = 0.008). CONCLUSION: This is the first study which illustrates the value of measuring circulatory miRNA to predict patient-specific toxicities to NAC. These results support the ideology that circulatory miRNAs are biomarkers with utility in predicting chemotherapy toxicity as well as treatment response.

Evaluating the Role of Circulating MicroRNAs in Predicting Long-Term Survival Outcomes in Breast Cancer: A Prospective, Multicenter Clinical Trial.

BACKGROUND: While long-term outcomes have improved for patients with breast cancer, 20% to 30% will still develop recurrence, and identifying these patients remains a challenge. MicroRNAs (miRNAs) are small, noncoding molecules that modulate genetic expression and affect oncogenesis. STUDY DESIGN: This prospective, multicenter trial (ICORG10/11-NCT01722851) recruited patients undergoing neoadjuvant chemotherapy across 8 Irish centers. Predetermined miRNAs were quantified from patient whole blood using quantitative reverse transcriptase polymerase chain reaction. Venous sampling was performed at diagnosis (timepoint 1) and midway during neoadjuvant chemotherapy (timepoint 2 [T2]). miRNA expression profiles were correlated with recurrence-free survival (RFS), disease-free survival (DFS), and overall survival. Data analysis was performed using R v3.2.3. RESULTS: A total of 124 patients were recruited with a median age of 55.0 years. The median follow-up was 103.1 months. Increased miR-145 expression at T2 was associated with improved RFS (hazard ratio 0.00; 95% confidence interval [CI] 0.00 to 0.99; p = 0.050). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved RFS (p = 0.041). Increased miR-145 expression at T2 trended towards significance in predicting improved DFS (hazard ratio 0.00; 95% CI 0.00 to 1.42; p = 0.067). Using survival regression tree analysis, a relative cutoff of increased miR-145 expression greater than 0.222 was associated with improved DFS (p = 0.012). No miRNAs correlated with overall survival. CONCLUSIONS: ICORG10/11 is the first Irish multicenter, translational research trial evaluating circulatory miRNAs as biomarkers predictive of long-term survival and correlated increased miR-145 expression with enhanced outcomes in early-stage breast cancer. Validation of these findings is required in the next generation of translational research trials.

The surgical burden of sebaceous naevus excision in childhood.

Prophylactic excision of sebaceous naevi during childhood has been common practice due to the risk of malignant transformation into basal cell carcinoma (BCC). With incidence of BCC now recognised as 0.8%, a more conservative approach to management is being advocated. The aim of this study was to evaluate the surgical burden produced by the traditional approach of prophylactic excision in childhood. METHODS: A retrospective analysis of all sebaceous naevi excised in a tertiary-referral paediatric hospital between January 2007 and December 2017 was conducted. RESULTS: No malignancy was identified in this consecutive series of 189 patients. General anaesthetic was required in 99% of cases with 23% (n = 43) requiring more than one general anaesthetic. Staged-excision was performed in 17% (n = 33), with tissue expanders used in 2% (n = 3) and rotation flap in 1.6% (n = 3). Post-operative sequelae requiring re-operative intervention occurred in 7% (n = 13). CONCLUSIONS: Routine excision of sebaceous naevi during childhood carries a high burden of care and is not necessary for cancer prevention. Excision can be safely delayed until patients are old enough to participate in decision-making about their surgery.

Evaluating the Role of Circulating MicroRNAs to Aid Therapeutic Decision Making for Neoadjuvant Chemotherapy in Breast Cancer: A Prospective, Multicenter Clinical Trial.

OBJECTIVE: To evaluate whether circulating micro ribonucleic acids (miRNAs) predict response to neoadjuvant chemotherapy (NAC) and inform decision-making in breast cancer patients. INTRODUCTION: Deciphering response to NAC remains a challenge. Those unlikely to respond may benefit from NAC de-escalation before completion, while "responders" should complete treatment. Establishing biomarkers which identify response to NAC is imperative to personalize treatment strategies. miRNAs are small noncoding RNA molecules which modulate genetic expression. miRNAs are believed to inform response to NAC. METHODS: This prospective, multicenter trial (NCT01722851) recruited 120 patients treated with NAC across 8 Irish treatment sites. Predetermined miRNAs were quantified from patient whole bloods using relative quantification polymerase chain reactiond. Venous sampling was performed at diagnosis and midway during NAC. Trends in miRNA expression between timepoints were correlated with treatment response. Data analysis was performed using R 3.2.3. RESULTS: A total of 120 patients were included (median age: 55 years). Overall, 49.2% had luminal breast cancers (59/120), 17.5% luminal B (L/HER2) (21/120), 12.5% human epidermal growth factor receptor-2 positive (HER2+) (15/120), and 20.8% triple negative disease (25/120). In total, 46.7% of patients responded to NAC (56/125) and 26.7% achieved a pathological complete response (pCR) (32/120). For patients with L/HER2, increased Let-7a predicted response to NAC ( P =0.049), while decreased miR-145 predicted response to NAC in HER2+ ( P =0.033). For patients with luminal breast cancers, reduced Let-7a predicted achieving a pCR ( P =0.037) and reduced miR-145 predicted achieving a pCR to NAC in HER2+ ( P =0.027). CONCLUSIONS: This study illustrates the potential value of circulatory miRNA measurement in predicting response to NAC. Further interrogation of these findings may see miRNAs personalize therapeutic decision-making for patients undergoing NAC for early breast cancer.

Use of a synthetic biodegradable temporising matrix after necrotising fasciitis infection of the thigh.

Biodegradable temporising matrix (BTM NovoSorb; PolyNovo, Melbourne, Australia) is a novel synthetic polyurethane dermal substitute. Licensed in Europe in 2020, it was developed primarily for reconstruction of infected wounds. We present a case of a healthy man in his 60s with necrotising fasciitis of his left thigh. His medical history was significant for recurrent left thigh liposarcoma that was treated years earlier with surgical excision and adjuvant radiotherapy. The affected area was within the previously irradiated tissue, debrided down to fascia and dressed with a vacuum-assisted closure to help regenerate the wound bed. Reconstruction options were limited by having a circumferential thigh defect that was infected. Following the use of NovoSorb BTM, the area was dressed with Acticoat Flex 7 antimicrobial barrier dressing for 5 weeks. Patient mobilisation was permitted. The material integrated very well and formed a soft, pliable healthy dermal layer that was autografted with split thickness skin grafts. This resulted in durable cover of the thigh with good aesthetic contour and minimal contracture.

Malignant epithelioid hemangioendothelioma of the ear.

Skin cancer is the most common cancer in Ireland. Our patient presented for removal of a cutaneous lesion on his ear. The histopathological diagnosis was malignant epithelioid hemangioendothelioma. It is very rare for this to present primarily as a cutaneous lesion. Here, we discuss the management of this patient and the surveillance he required. It is important to consider alternative histological diagnoses in patients presenting with cutaneous lesions and how this affects management and prognosis.

Metastatic and locally aggressive BCC: Current treatment options.

The treatment of locally advanced and metastatic BCC presents a significant clinical challenge. Treatment options have evolved recently to include the use of hedgehog inhibitors Vismodigib and Sonidigib and immunotherapy with Cemiplimab.

Skin deep: Cutaneous manifestation of PIP implant rupture.

PIP (Poly Implant Prothèse, France) implants were readily employed for breast reconstruction until withdrawn from the market in 2010. These implants have an early and increased risk of rupture compared to non-PIP implants. This report outlines a significant cutaneous manifestation of PIP-implant rupture not previously described in the literature. This patient developed significant cutaneous xanthomatous inflammation with sinus tract formation that has yet to resolve despite explantation. Further investigation is warranted to elucidate the aetiology of this clinical sign and the optimal management of the cutaneous manifestation.

Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer.

Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308-0.943, p < 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy.

The long-term outcomes following internal fixation for intracapsular hip fractures in an Irish tertiary referral centre.

BACKGROUND: The burden associated with hip fractures is increasing worldwide. Arthroplasty procedures are more commonly performed for intracapsular fractures due to increased risk of compromise to the femoral head blood supply. However, we know from the Irish Hip Fracture Database that a significant proportion of these fractures undergo internal fixation. AIMS: We sought to investigate the long-term outcomes for these patients including revision rates, functional outcome and mortality rates. METHODS: All intracapsular fractures treated by internal fixation (IF) from 2005 to 2009 were identified. Pre-operative anatomical fracture location and level of fracture displacement was established. Hospital records were used to record mortality and revision rates. The modified Harris hip score was our primary functional outcome measure. RESULT: One hundred twelve intracapsular fractures underwent IF over a 5-year period. The mean age was 68.6 (range 14-95 years). A mean follow-up time of 8.15 years (range 6.7-10.1 years) was achieved. There was a 5-year mortality rate of 36.6%. There was a significantly higher revision rate in displaced fractures (24.4%) than in undisplaced fractures (11.1%) (p = 0.01). We found no difference in functional outcome between displaced fractures [85.9 (± 16.9)] and undisplaced fractures [86.01 (± 18.8)]. Those aged younger than 65 at the time of surgery had a significantly better MHHS (p = 0.02) at long-term follow-up; however, there was a revision rate of 43.8% in this group. CONCLUSION: Whilst a good functional outcome can be achieved with internal fixation, particularly in younger patients, the risk of requiring revision surgery approaches 50% for these patients.

Patent nasopalatine ducts: Evidence to support persistence of the vomeronasal system?

The vomeronasal system is comprised of the nasopalatine duct and the vomeronasal organ. While this system functions in chemodetection in mammals, its presence and function in adult humans remains to be clearly elucidated. Here, a case of asymptomatic, bilateral, patent nasopalatine ducts is presented. We postulate that the presence of these patent structures represents persistence of the embryological nasopalatine duct component of the vomeronasal organ into adult life

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Exploring circulating micro-RNA in the neoadjuvant treatment of breast cancer.

Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in vivo tumour response to chemotherapeutics. Currently, there is no effective means of identifying chemotherapeutic responders from non-responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy. Micro-RNAs (miRNAs) are small non-coding RNA molecules. With their tissue-specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood-borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed.

Evolution of a research field-a micro (RNA) example.

Background. Every new scientific field can be traced back to a single, seminal publication. Therefore, a bibliometric analysis can yield significant insights into the history and potential future of a research field. This year marks 21 years since that first ground-breaking microRNA (miRNA) publication. Here, we make the case that the miRNA field is mature, utilising bibliometrics. Methods. Utilising the Web of Science™ (WoS) database publication and citation information, we charted the history of miRNA-related publications, describing and dissecting contributions by publication type (plus category, pay-per-view or open access), journal (highlighting dominant journals), by country, citations and languages. Results. We found that the United States of America (USA) publishes the most miRNA papers, followed by China and Germany. Significantly, publications attributed to the USA also receive the most citations per publication, followed by a close grouping of England, Germany and France. We also describe the relevance and acceptance of the miRNA field to different research areas, through its uptake in areas from oncology to plant sciences. Exploring the recent momentous change in publishing, we find that although pay-per view articles vastly out-number open-access articles, the citation rate of pay-per-view articles is currently less than double that of open-access. Conclusions. We believe the trends described here represent the typical evolution of a research field. By analysing publications, citations and distribution patterns, key moments in the evolution of this research area are recognised, indicating the maturation of the miRNA field and providing guidance for future research endeavours.