Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer.

BACKGROUND: Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy. METHODS: We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed. RESULTS: A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups. CONCLUSIONS: Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.).

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation.

BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1-treated human dermal LECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSIONS: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.

Mild exercise expedites joint clearance and slows joint degradation in a joint instability model of osteoarthritis in male rats.

OBJECTIVE: Exercise remains a hallmark treatment for post-traumatic osteoarthritis (PTOA) and may maintain joint homeostasis in part by clearing inflammatory cytokines, cells, and particles. It remains largely unknown whether exercise-induced joint clearance can provide therapeutic relief of PTOA. In this study, we hypothesized that exercise could slow the progression of preclinical PTOA in part by enhancing knee joint clearance. DESIGN: Surgical medial meniscal transection was used to induce PTOA in 3-month-old male Lewis rats. A sham surgery was used as a control. Mild treadmill walking was introduced 3 weeks post-surgery and maintained to 6 weeks post-surgery. Gait and isometric muscle torque were measured at the study endpoint. Near-infrared imaging tracked how exercise altered lymphatic and venous knee joint clearance during discrete time points of PTOA progression. RESULTS: Exercise mitigated joint degradation associated with PTOA by preserving glycosaminoglycan content and reducing osteophyte volume (effect size (95% Confidence Interval (CI)); 1.74 (0.71-2.26)). PTOA increased hind step widths (0.57 (0.18-0.95) cm), but exercise corrected this gait dysfunction (0.54 (0.16-0.93) cm), potentially indicating pain relief. Venous, but not lymphatic, clearance was quicker 1-, 3-, and 6-weeks post-surgery compared to baseline. The mild treadmill walking protocol expedited lymphatic clearance rate in moderate PTOA (3.39 (0.20-6.59) hrs), suggesting exercise may play a critical role in restoring joint homeostasis. CONCLUSIONS: We conclude that mild exercise has the potential to slow disease progression in part by expediting joint clearance in moderate PTOA.

Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases.

Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.

Mechanotransduction activates canonical Wnt/ß-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves.

Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/ß-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of ß-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/ß-catenin signaling in LECs. In turn, Wnt/ß-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking ß-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/ß-catenin signaling and, in turn, FOXC2.

Lentiviral overexpression of VEGFC in transplanted MSCs leads to resolution of swelling in a mouse tail lymphedema model.

BACKGROUND: Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Despite the various physical therapy and surgical options available, most treatments are palliative and fail to address the underlying lymphatic vascular insufficiency driving lymphedema progression. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases with a wide range of therapeutic effects that reduce inflammation, fibrosis, and oxidative stress, while promoting lymphatic vessel (LV) regeneration. Specifically, stem cell transplantation is suggested to promote LV restoration, rebuild lymphatic circulation, and thus potentially be utilized towards an effective lymphedema treatment. In addition to stem cells, studies have proposed the administration of vascular endothelial growth factor C (VEGFC) to promote lymphangiogenesis and decrease swelling in lymphedema. AIMS: Here, we seek to combine the benefits of stem cell therapy, which provides a cellular therapeutic approach that can respond to the tissue environment, and VEGFC administration to restore lymphatic drainage. MATERIALS & METHODS: Specifically, we engineered mesenchymal stem cells (MSCs) to overexpress VEGFC using a lentiviral vector (hVEGFC MSC) and investigated their therapeutic efficacy in improving LV function and tissue swelling using near infrared (NIR) imaging, and lymphatic regeneration in a single LV ligation mouse tail lymphedema model. RESULTS: First, we showed that overexpression of VEGFC using lentiviral transduction led to an increase in VEGFC protein synthesis in vitro. Then, we demonstrated hVEGFC MSC administration post-injury significantly increased the lymphatic contraction frequency 14-, 21-, and 28-days post-surgery compared to the control animals (MSC administration) in vivo, while also reducing tail swelling 28-days post-surgery compared to controls. CONCLUSION: Our results suggest a therapeutic potential of hVEGFC MSC in alleviating the lymphatic dysfunction observed during lymphedema progression after secondary injury and could provide a promising approach to enhancing autologous cell therapy for treating lymphedema.

Effect of Human Synovial Fluid From Osteoarthritis Patients and Healthy Individuals on Lymphatic Contractile Activity.

The lymphatic system has been proposed to play a crucial role in preventing the development and progression of osteoarthritis (OA). As OA develops and progresses, inflammatory cytokines and degradation by-products of joint tissues build up in the synovial fluid (SF) providing a feedback system to exacerbate disease. The lymphatic system plays a critical role in resolving inflammation and maintaining overall joint homeostasis; however, there is some evidence that the lymphatics can become dysfunctional during OA. We hypothesized that the functional mechanics of lymphatic vessels (LVs) draining the joint could be directly compromised due to factors within SF derived from osteoarthritis patients (OASF). Here, we utilized OASF and SF derived from healthy (non-OA) individuals (healthy SF (HSF)) to investigate potential effects of SF entering the draining lymph on migration of lymphatic endothelial cells (LECs) in vitro, and lymphatic contractile activity of rat femoral LVs (RFLVs) ex vivo. Dilutions of both OASF and HSF containing serum resulted in a similar LEC migratory response to the physiologically endothelial basal medium-treated LECs (endothelial basal medium containing serum) in vitro. Ex vivo, OASF and HSF treatments were administered within the lumen of isolated LVs under controlled pressures. OASF treatment transiently enhanced the RFLVs tonic contractions while phasic contractions were significantly reduced after 1 h of treatment and complete ceased after overnight treatment. HSF treatment on the other hand displayed a gradual decrease in lymphatic contractile activity (both tonic and phasic contractions). The observed variations after SF treatments suggest that the pump function of lymphatic vessel draining the joint could be directly compromised in OA and thus might present a new therapeutic target.

Lymphatic injury alters the contractility and mechanosensitivity of collecting lymphatics to intermittent pneumatic compression.

KEY POINTS: We present the first in vivo evidence that lymphatic contraction can entrain with an external oscillatory mechanical stimulus. Lymphatic injury can alter collecting lymphatic contractility, but not much is known about how its mechanosensitivity to external pressure is affected, which is crucial given the current pressure application methods for treating lymphoedema. We show that oscillatory pressure waves (OPW), akin to intermittent pneumatic compression (IPC) therapy, optimally entrain lymphatic contractility and modulate function depending on the frequency and propagation speed of the OPW. We show that the OPW-induced entrainment and contractile function in the intact collecting lymphatics are enhanced 28 days after a contralateral lymphatic ligation surgery. The results show that IPC efficacy can be improved through proper selection of OPW parameters, and that collecting lymphatics adapt their function and mechanosensitivity after a contralateral injury, switching their behaviour to a pump-like configuration that may be more suited to the altered microenvironment. ABSTRACT: Intermittent pneumatic compression (IPC) is commonly used to control the swelling due to lymphoedema, possibly modulating the collecting lymphatic function. Lymphoedema causes lymphatic contractile dysfunction, but the consequent alterations in the mechanosensitivity of lymphatics to IPC is not known. In the present work, the spatiotemporally varying oscillatory pressure waves (OPW) generated during IPC were simulated to study the modulation of lymphatic function by OPW under physiological and pathological conditions. OPW with three temporal frequencies and three propagation speeds were applied to rat tail collecting lymphatics. The entrainment of the lymphatics to OPW was significantly higher at a frequency of 0.05 Hz compared with 0.1 Hz and 0.2 Hz (P = 0.0054 and P = 0.014, respectively), but did not depend on the OPW propagation speed. Lymphatic function was significantly higher at a frequency of 0.05 Hz and propagation speed of 2.55 mm/s (P = 0.015). Exogenous nitric oxide was not found to alter OPW-induced entrainment. A contralateral lymphatic ligation surgery was performed to simulate partial lymphatic injury in rat tails. The intact vessels showed a significant increase in entrainment to OPW, 28 days after ligation (compared with sham) (P = 0.016), with a similar increase in lymphatic transport function (P = 0.0029). The results suggest an enhanced mechanosensitivity of the lymphatics, along with a transition to a pump-like behaviour, in response to a lymphatic injury. These results enhance our fundamental understanding of how lymphatic mechanosensitivity assists the coordination of lymphatic contractility and how this might be leveraged in IPC therapy.

Current trends in the treatment of HR+/HER2+ breast cancer.

Treatment for HR+/HER2+ patients has been debated, as some tumors within this luminal HER2+ subtype behave like luminal A cancers, whereas others behave like non-luminal HER2+ breast cancers. Recent research and clinical trials have revealed that a combination of hormone and targeted anti-HER2 approaches without chemotherapy provides long-term disease control for at least some HR+/HER2+ patients. Novel anti-HER2 therapies, including neratinib and trastuzumab emtansine, and new agents that are effective in HR+ cancers, including the next generation of oral selective estrogen receptor downregulators/degraders and CDK4/6 inhibitors such as palbociclib, are now being evaluated in combination. This review discusses current trials and results from previous studies that will provide the basis for current recommendations on how to treat newly diagnosed patients with HR+/HER2+ disease.

No evidence of benefit for laminar flow in theatre for sling-assisted, implant-based breast reconstruction.

INTRODUCTION: Recent years have seen a large increase in the proportion and number of sling-assisted, implant-based breast reconstructions. These are associated with significant rates of loss of the reconstruction. Various methods have been suggested to reduce this loss rate. One such method is the use of operating theatres with laminar flow. The majority of cases of sling-assisted, implant-based breast reconstruction in south-east Scotland are performed in two adjacent theatres, one with laminar flow and one without. This provided the opportunity to assess whether there was any difference in outcome potentially attributable to laminar flow. METHODS: Patients undergoing sling-assisted, implant-based breast reconstruction between August 2013 and December 2018 were studied with follow up for at least 6 months. RESULTS: 307 patients underwent a total of 470 procedures. 247 procedures were performed with laminar flow and 223 without. There was no difference in the indications for mastectomy, incision used or rates of smoking or radiotherapy between the two groups. Implant loss occurred in 15.8% of procedures with laminar flow and 14.3% of those without (p = 0.66). Wound problems occurred in 27.5% of procedures with laminar flow and 27.8% of those without (p = 0.97). There was no significant difference in loss rates between surgeons, mastectomy indication, sling materials or with chemotherapy use. Increased loss rates were observed in smokers, with radiotherapy, with incisions other than transverse, with larger breasts and with increasing patient weight. CONCLUSION: This study finds no evidence of benefit for laminar flow in theatre for sling-assisted, implant-based breast reconstruction.

The Kinetics of Lymphatic Dysfunction and Leukocyte Expansion in the Draining Lymph Node during LTB4 Antagonism in a Mouse Model of Lymphedema.

The mechanisms of lymphedema development are not well understood, but emerging evidence highlights the crucial role the immune system plays in driving its progression. It is well known that lymphatic function deteriorates as lymphedema progresses; however, the connection between this progressive loss of function and the immune-driven changes that characterize the disease has not been well established. In this study, we assess changes in leukocyte populations in lymph nodes within the lymphatic drainage basin of the tissue injury site (draining lymph nodes, dLNs) using a mouse tail model of lymphedema in which a pair of draining collecting vessels are left intact. We additionally quantify lymphatic pump function using established near infrared (NIR) lymphatic imaging methods and lymph-draining nanoparticles (NPs) synthesized and employed by our team for lymphatic tissue drug delivery applications to measure lymphatic transport to and resulting NP accumulation within dLNs associated with swelling following surgery. When applied to assess the effects of the anti-inflammatory drug bestatin, which has been previously shown to be a possible treatment for lymphedema, we find lymph-draining NP accumulation within dLNs and lymphatic function to increase as lymphedema progresses, but no significant effect on leukocyte populations in dLNs or tail swelling. These results suggest that ameliorating this loss of lymphatic function is not sufficient to reverse swelling in this surgically induced disease model that better recapitulates the extent of lymphatic injury seen in human lymphedema. It also suggests that loss of lymphatic function during lymphedema may be driven by immune-mediated mechanisms coordinated in dLNs. Our work indicates that addressing both lymphatic vessel dysfunction and immune cell expansion within dLNs may be required to prevent or reverse lymphedema when partial lymphatic function is sustained.

Evidence-based orthopaedic trauma care in the United Kingdom: Guidelines, registries, carrots and sticks.

In the United Kingdom (UK), orthopaedic trauma surgeons utilise evidence-based practice through distillation of high-quality primary research, interrogation of registries and implementation of evidence-based guidelines. Concurrent with this ambition of providing exemplar care based on robust patient centred research, there has evolved a culture of remuneration 'by results'. Therefore, there is a drive for excellence combined with a system of collation and validation of data input as well as remuneration where care excels. There are several organisations involved in each stage of this process, the output of which has much that is pertinent to the globally similar consequences of physical injury. However, their relevance and impact within the UK is magnified as they are written against the backdrop of a unified healthcare system. In this article, we will describe the roles of the different organisations guiding and regulating trauma practice across the UK and discuss how the interplay of these impacts on clinical care.

Unlocking the transcriptomic potential of formalin-fixed paraffin embedded clinical tissues: comparison of gene expression profiling approaches.

BACKGROUND: High-throughput transcriptomics has matured into a very well established and widely utilised research tool over the last two decades. Clinical datasets generated on a range of different platforms continue to be deposited in public repositories provide an ever-growing, valuable resource for reanalysis. Cost and tissue availability normally preclude processing samples across multiple technologies, making it challenging to directly evaluate performance and whether data from different platforms can be reliably compared or integrated. METHODS: This study describes our experiences of nine new and established mRNA profiling techniques including Lexogen QuantSeq, Qiagen QiaSeq, BioSpyder TempO-Seq, Ion AmpliSeq, Nanostring, Affymetrix Clariom S or U133A, Illumina BeadChip and RNA-seq of formalin-fixed paraffin embedded (FFPE) and fresh frozen (FF) sequential patient-matched breast tumour samples. RESULTS: The number of genes represented and reliability varied between the platforms, but overall all methods provided data which were largely comparable. Crucially we found that it is possible to integrate data for combined analyses across FFPE/FF and platforms using established batch correction methods as required to increase cohort sizes. However, some platforms appear to be better suited to FFPE samples, particularly archival material. CONCLUSIONS: Overall, we illustrate that technology selection is a balance between required resolution, sample quality, availability and cost.

Factors affecting the number of sentinel lymph nodes removed in patients having surgery for breast cancer.

PURPOSE: The goal of sentinel lymph node biopsy is to establish the presence or absence of cancer cells in regional axillary nodes. The number of sentinel nodes harvested from each patient varies. The aim of this study was to determine what factors influence the number of sentinel nodes excised at sentinel node biopsy. METHODS: Data from 426 patients with breast cancer who underwent sentinel lymph node biopsy at the Edinburgh Breast Unit by 10 different experienced breast surgeons were included in this analysis. Univariate and multivariable statistical analysis was performed. RESULTS: In the multivariate analysis the number of sentinel nodes biopsied varied significantly between operating surgeon (p < 0.0001) and was also statistically associated with the use of neoadjuvant chemotherapy (p < 0.0001) and with the number of involved lymph nodes (p < 0.0001). More nodes were removed in patients who received neoadjuvant chemotherapy and had metastases in sentinel lymph nodes. CONCLUSIONS: This study shows that the surgeon plays a pivotal and significant role in determining the numbers of sentinel nodes removed by sentinel lymph node biopsy. Surgeons should monitor their own data on the average numbers of sentinel nodes they remove. Some surgeons may not be removing sufficient numbers of sentinel nodes to maintain a low false negative rate for this procedure.

Visual conditions affecting eye growth alter diurnal levels of vitreous DOPAC.

In chicks, the diurnal patterns of retinal dopamine synthesis and release are associated with refractive development. To assess the within-day patterns of dopamine release, we assayed vitreal levels of DOPAC (3,4-dihydroxyphenylacetic acid) using high performance liquid chromatography with electrochemical detection, at 4-h intervals over 24 h in eyes with experimental manipulations that change ocular growth rates. Chicks were reared under a 12 h light/12 h dark cycle; experiments began at 12 days of age. Output was assessed by modelling using the robust variance structure of Generalized Estimating Equations. Continuous spectacle lensdefocus or form deprivation: One group experienced non-restricted visual input to both eyes and served as untreated "normal" controls. Three experimental cohorts underwent monocular visual alterations known to alter eye growth and refraction: wearing a diffuser, a negative lens or a positive lens. After one full day of device-wear, chicks were euthanized at 4-h intervals over 24 h (8 birds per time/condition). Brief hyperopic defocus: Chicks wore negative lenses for only 2 daily hours either in the morning (starting at ZT 0; n = 16) or mid-day (starting at ZT 4; n = 8) for 3 days. Vitreal DOPAC was assayed. In chicks with bilateral non-restricted vision, or with continuous defocus or form-deprivation, there was a diurnal variation in vitreal DOPAC levels for all eyes (p < 0.001 for each). In normal controls, DOPAC was highest during the daytime, lowest at night, and equivalent for both eyes. In experimental groups, regardless of whether experiencing a growth stimulatory input (diffuser; negative lens) or growth inhibitory input (positive lens), DOPAC levels were reduced compared both to fellow eyes and to those of normal controls (p < 0.001 for each). These diurnal variations in vitreous DOPAC levels under different visual conditions indicate a complexity for dopaminergic mechanisms in refractive development that requires further study.

Effects of different metabolic states and surgical models on glucose metabolism and secretion of ileal L-cell peptides: results from the HIPER-1 study.

AIM: To compare the impact of four surgical procedures (mini-gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition) vs medical management on gut peptide secretion, ß-cell function and resolution of hyperglycaemia in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A mixed-meal tolerance test was administered 6-24 months after each surgical procedure (mini-gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition; n=30 in each group) and the results were compared with those obtained in matched lean (n=30) and obese (n=30) people with type 2 diabetes undergoing medical management. RESULTS: Participants in the mini-gastric bypass and ileal transposition groups had a greater increase in plasma glucose concentration after the mixed-meal tolerance test than those in the sleeve gastrectomy and transit bipartition groups. Participants in the mini-gastric bypass group exhibited the greatest increase in the incremental area under the curve of plasma glucose concentration above baseline (P<0.0001). Insulin sensitivity was similar across surgical groups, and statistically greater in participants in the surgical groups than in obese participants in the non-surgical group (P<0.0001). ß-cell responsiveness to glucose was greater in participants in the sleeve gastrectomy and transit bipartition groups than in the mini-gastric bypass and ileal transposition groups (P<0.001) despite a smaller incremental increase above baseline in the area under the plasma glucagon-like peptide-1 concentration curve relative to ileal transposition. Postoperative ß-cell function was the strongest predictor of hyperglycaemia resolution. CONCLUSIONS: The present study showed that the level of ß-cell function after bariatric surgery is the strongest predictor of hyperglycaemia resolution. The study also demonstrates a disconnect between postprandial GLP-1 levels and ß-cell function among the studied surgical procedures.

Twenty-five years of change in the management of the axilla in breast cancer.

Sentinel lymph node (SLN) biopsy is now used worldwide. It has led to many changes in how we manage the axilla in patients with breast cancer. This review covers four areas of management of the axilla in breast cancer: assessing the clinically node-negative axilla, managing the clinically negative axilla found to be involved at SLN biopsy, management of the clinically positive axilla in the context of neo-adjuvant chemotherapy, and treatment of the diseased axilla when radical therapy is required. We suggest that the evidence supports an optimum number of 3 nodes to be removed for accurate SLN biopsy. Breast cancer departments that have not adopted Z0011 patient management cannot continue to avoid change. The evidence is clear: Not all patients with limited axillary nodal disease on sentinel node biopsy need axillary lymph node dissection. For patients who do need axillary treatment, axillary radiotherapy continues to be under-used. Patients undergoing neo-adjuvant chemotherapy can be safely assessed by post-therapy SLN biopsy, with retrieval of any previously biopsied involved nodes by targeted axillary dissection. There is much to support the trend to doing less in the axilla. We are obliged to act based on the available robust clinical trial data in a way that limits morbidity while at the same time does not increase the risk of disease recurrence.

Merkel cell carcinoma update: the case for two tumours.

Merkel cell carcinoma (MCC) is an aggressive tumour with neuroendocrine differentiation. Clinically significant differences within the entity we know as MCC are apparent. This review aims to evaluate the evidence for differences in tumours within Merkel cell carcinoma and to stratify these. A literature search of research pertaining to various characteristics MCC was undertaken from 1972, when Merkel cell carcinoma was first described, to 2018, using PubMed and similar search engines. A total of 41 papers were analysed, including clinical trials, laboratory-based research and reviews. A proportion of MCC has Merkel cell polyomavirus genome integrated (MCPyV+) while others do not (MCPyV-). Both types have a different mutation burden. MCPyV+ tumours are likely true neuroendocrine carcinomas, with a dermal origin, probably from fibroblasts which have been transformed by integration of the viral genome. MCPyV-tumours are likely derived from either keratinocytes or epidermal stem cells, are probably squamous cell carcinomas with neuroendocrine differentiation, and are related to sun damage. Prognostic factors (apart from tumour stage) include the MCPyV status, with MCPyV+ tumours having a better prognosis. P63 expression confers a worse prognosis in most studies. CD8+ lymphocytes play an important role, providing a possible target for PD1/PD-L1 blockade treatment. The incidence of MCC varies from country to country. Countries such as Australia have a high rate and a far greater proportion of MCPyV- tumours than places such as the United Kingdom. MCC doubtlessly encompasses two tumours. The two tumours have demonstrated differences in prognosis and management. One is a neuroendocrine carcinoma related to MCPyV integration likely derived from fibroblasts, and the other is a UV-related squamous cell carcinoma with neuroendocrine differentiation, presumptively derived from either keratinocytes or epidermal stem cells. We propose naming the former Merkel type sarcoma and the latter squamous cell carcinoma, Merkel type.

An infrared 3D scanning device as a novel limb volume measurement tool in breast cancer patients.

BACKGROUND: Lymphedema is a common complication of breast cancer treatment that affects one in five breast cancer survivors, yet there is no reliable method to detect lymphedema in the subclinical range. The objective of this study was to determine the feasibility and reliability of using an infrared 3D scanning device (ISD) as a peri-operative limb volume measurement tool. METHODS: Fifteen patients were analyzed based on inclusion criteria. Peri-operative measurements were obtained using tape measure and an ISD. Volumes were calculated using a standard algorithm for tape measure and a custom algorithm for ISD measurements. Linear regression models were used to assess ISD and tape measurement volume and circumference correlation. One-way ANOVA was used to compare change in percent difference at set time points post-operatively (2-3 weeks, 4-6 weeks, and 7-12 weeks) for both ISD and tape measure. t tests for unequal variances with the Bonferroni correction were performed among these groups. RESULTS: There is a positive linear correlation (R2 = 0.8518) between absolute volume measurements by the ISD and tape measure. Analyses over 2-10 weeks post-operatively showed that the ISD was able to detect volume changes in both the unaffected and the affected arm. Furthermore, the affected arm tended to have a greater increase in volume in the majority of patients, indicating these patients could be at risk for lymphedema. CONCLUSIONS: Technology utilizing infrared 3D scanners can reliably measure limb volume pre- and post-treatment similarly to tape measure in a small sample of patients. Further research using 3D scanning technology with a longer follow up is warranted.

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours.

BACKGROUND: The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model. METHODS: Consecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13-120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as "dormant", and the remaining 20 patients as "acquired resistant". RESULTS: Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment. CONCLUSIONS: This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.