Oncoplastic surgery in the USA: a review of where we started, where we are today and where we are headed.

The surgical management of breast cancer has evolved tremendously over the last century and now includes oncoplastic techniques that improve both cosmetic and oncologic outcomes for patients. The purpose of this review is to provide the reader with a broad overview of the history of oncoplastic breast surgery in the United States (USA), and to summarize important patient factors and technical innovations for optimal operative planning in the era of multimodal treatment of breast cancer. The indications for oncoplastic surgery (OPS) have broadened significantly as more women pursue breast conservation with preservation of their native breast tissue. The operative philosophy of OPS is based on fundamental reconstructive principles, with technique selection based largely on tumor size and location. Reduction mammoplasty and mastopexy techniques have become some of the most utilized procedures in OPS due to their versatility to address tumors in almost all areas of the breast. Volume replacement techniques with locoregional perforator flaps continue to gain popularity as a single-stage reconstructive option for women with large tumor to breast ratios, especially with specialized plastic surgeons at high volume, academic centers. The oncologic advantages of OPS have allowed women to avoid mastectomy with improved margin control, re-excision rates, and equivalent overall survival all while preserving the aesthetic outcomes for these patients. Despite the proven benefits of OPS, numerous healthcare systems barriers including insurance status, geographic location, referral patterns, and racial disparities all continue to play a role in access to surgical sub-specialized breast oncology care demonstrating the need for ongoing research and education about oncoplastic principles.

CD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema.

T cell-mediated responses have been implicated in the development of fibrosis, impaired lymphangiogenesis, and lymphatic dysfunction in secondary lymphedema. Here we show that CD4+ T cells are necessary for lymphedema pathogenesis by utilizing adoptive transfer techniques in CD4 knockout mice that have undergone tail skin and lymphatic excision or popliteal lymph node dissection. We also demonstrate that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells such as dendritic cells. CD4+ T cell activation is associated with differentiation into a mixed T helper type 1 and 2 phenotype, as well as upregulation of adhesion molecules and chemokines that promote migration to the skin. Most importantly, we find that blocking T cell release from lymph nodes using a sphingosine-1-phosphate receptor modulator prevents lymphedema, suggesting that this approach may have clinical utility.

Regulatory T Cells Mediate Local Immunosuppression in Lymphedema.

Patients who suffer from lymphedema have impaired immunity and, as a result, are at an increased risk for infections. Furthermore, previous studies have shown that lymphadenectomy impairs acquisition of adaptive immune responses and antibody production in response to foreign antigens. Although it is clear that antigen presentation in lymph nodes plays a key role in adaptive immunity, the cellular mechanisms that regulate impaired immune responses in patients with lymphedema or following lymphatic injury remain unknown. We have previously found that axillary lymph node dissection, both clinically and in a mouse model, results in a marked increase in the number of regulatory T cells in the ipsilateral limb. In this study, we focus on the role of regulatory T cells in immunosuppression and show that regulatory T-cell proliferation in tissues distal to site of lymphatic injury contributes to impaired innate and adaptive immune responses. More importantly, using Foxp3-DTR transgenic mice, we show that depletion of regulatory T cells in the setting of lymphatic injury restores these critical immune-mediated responses. These findings provide additional evidence that immune responses following lymphatic injury play a key role in mediating the pathology of lymphedema.

Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema.

INTRODUCTION: Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. METHODS: We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later. RESULTS: LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses. CONCLUSIONS: LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

Obesity-induced lymphatic dysfunction is reversible with weight loss.

KEY POINTS: Obesity induces lymphatic leakiness, decreases initial lymphatic vessel density, impairs collecting vessel pumping and decreases transport of macromolecules. Obesity results in perilymphatic inducible nitric oxide synthase (iNOS) expression and accumulation of T cells and macrophages. Deleterious effects of obesity on the lymphatic system correlate with weight gain. Weight loss restores lymphatic function in obese animals and decreases perilymphatic iNOS and inflammatory cell accumulation. ABSTRACT: Although clinical and experimental studies have shown that obesity results in lymphatic dysfunction, it remains unknown whether these changes are permanent or reversible with weight loss. In the current study, we used a mouse model of diet-induced obesity to identify putative cellular mechanisms of obesity-induced lymphatic dysfunction, determine whether there is a correlation between these deleterious effects and increasing weight gain, and finally examine whether lymphatic dysfunction is reversible with diet-induced weight loss. We report that obesity is negatively correlated with cutaneous lymphatic collecting vessel pumping rate (r = -0.9812, P < 0.0005) and initial lymphatic vessel density (r = -0.9449, P < 0.005). In addition, we show a significant positive correlation between weight gain and accumulation of perilymphatic inflammatory cells (r = 0.9872, P < 0.0005) and expression of inducible nitric oxide synthase (iNOS; r = 0.9986, P < 0.0001). Weight loss resulting from conversion to a normal chow diet for 8 weeks resulted in more than a 25% decrease in body weight and normalized cutaneous lymphatic collecting vessel pumping rate, lymphatic vessel density, lymphatic leakiness, and lymphatic macromolecule clearance (all P < 0.05). In addition, weight loss markedly decreased perilymphatic inflammation and iNOS expression. Taken together, our findings show that obesity is linearly correlated with lymphatic dysfunction, perilymphatic inflammation and iNOS expression, and that weight loss via dietary modification effectively reverses these deleterious effects.

Exercise training improves obesity-related lymphatic dysfunction.

KEY POINTS: Obesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells. ABSTRACT: Although previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, including VEGFR-3 and Prox1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity-induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications.

Inhibition of Inflammation and iNOS Improves Lymphatic Function in Obesity.

Although recent studies have shown that obesity decreases lymphatic function, the cellular mechanisms regulating this response remain unknown. In the current study, we show that obesity results in perilymphatic accumulation of inflammatory cells and that local inhibition of this response with topical tacrolimus, an inhibitor of T cell differentiation, increases lymphatic vessel density, decreases perilymphatic iNOS expression, increases lymphatic vessel pumping frequency, and restores lymphatic clearance of interstitial fluid to normal levels. Although treatment of obese mice with 1400W, a selective inhibitor of iNOS, also improved lymphatic collecting vessel contractile function, it did not completely reverse lymphatic defects. Mice deficient in CD4(+) cells fed a high fat diet also gained weight relative to controls but were protected from lymphatic dysfunction. Taken together, our findings suggest that obesity-mediated lymphatic dysfunction is regulated by perilymphatic accumulation of inflammatory cells and that T cell inflammatory responses are necessary to initiate this effect.

Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity.

Obesity is a major risk factor for inflammatory dermatologic diseases, including atopic dermatitis and psoriasis. In addition, recent studies have shown that obesity impairs lymphatic function. As the lymphatic system is a critical regulator of inflammatory reactions, we tested the hypothesis that obesity-induced lymphatic dysfunction is a key regulator of cutaneous hypersensitivity reactions in obese mice. We found that obese mice have impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity. In addition, obese mice displayed heightened dermatitis responses to inflammatory skin stimuli, resulting in both higher peak inflammation and a delayed clearance of inflammatory responses. Injection of recombinant vascular endothelial growth factor-C remarkably increased lymphangiogenesis, lymphatic function, and lymphatic endothelial cell expression of chemokine (C-C motif) ligand 21, while decreasing inflammation and expression of inducible nitrous oxide synthase. These changes resulted in considerably decreased dermatitis responses in both lean and obese mice. Taken together, our findings suggest that obesity-induced changes in the lymphatic system result in an amplified and a prolonged inflammatory response.

Th2 cytokines inhibit lymphangiogenesis.

Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4) and interleukin-13 (IL-13) have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

Saturación sensorial y lactancia materna como métodos analgésicos no farmacológicos: estudio randomizado controlado / Sensory overload and breastfeeding as analgesic method no pharmacologic: control randomized study

OBJETIVO: Verificar el efecto analgésico de la saturación sensorial (Sat) y compararlo con la lactancia materna (LM) y un grupo control. MATERIAL Y MÉTODOS: Ensayo clínico, randomizado con 167 recién nacidos a término sanos, en quiénes se cuantificó la intensidad de dolor agudo al recibir una vacuna (hepatitis B) a las 48 horas de vida. Se formaron tres grupos de manera aleatoria: grupo 1 (control, sin método analgésico), grupo 2 (analgesia con LM) y grupo 3 (analgesia con Sat); los estímulos sensoriales fueron: táctil (caricias de la madre sobre el rostro y espalda), olfatorio (colonia sin alcohol), auditivo (voz de la madre), gustativo (lactancia materna), visual (rostro de la madre frente a su bebé). Se utilizó la Escala para Dolor Agudo Neonatal (DAN: Douleur Aiguë du Nouveau-né), con un score de dolor del 1 al 10 y 7 categorías de dolor. RESULTADOS: El grupo con saturación sensorial tuvo menos dolor (3.02 en la escala de DAN); el grupo dos (lactancia materna): 4.15, y control: 9.02. Hubo diferencia significativa entre grupos. Dolor extremo, se presentó en 60% del grupo control, 3,8% en el grupo lactancia materna y 0% en el grupo con saturación sensorial. La categoría NO DOLOR fue más frecuente en el grupo tres (Sat): 33,3% versus 16,9% del grupo con LM y 0% grupo control, p<0.0001. CONCLUSIONES: La saturación sensorial tuvo mayor efecto analgésico que la lactancia materna. Ambas demostraron buen efecto analgésico, comparadas con el grupo control.

OBJECTIVES: To verify the analgesic effect of sensory overload (SO) and compared with breastfeeding (BF) and a control group. MATERIAL AND METHODS: We conducted a randomized clinical trial in 167 healthy term infants, in which the intensity acute pain was quantified to receive hepatitis B vaccine within 48 hours of life. Three groups were formed at random: one group (control, no method of analgesia), group two (analgesia with BF) and group three (analgesia with SO), sensory stimuli were: touch (petting of the mother on baby face and back), olfactory (colony nonalcoholic), auditory (motherÆs voice), gustatory (breastfeeding), visual (mother and baby - face to face). We used the Neonatal Acute Pain Scale (DAN: Douleur Aigue du Nouveau-né), which gives a pain score of 1 to 10, giving 7 categories of pain. RESULTS: In group three (sensory overload) expressed less pain with an average score of 3.02 on the scale of DAN, the group two (breastfeeding): 4.15, and one group (control): 9.02, with significant difference between groups. The category of extreme pain occurred in 60% of the control group, 3.8% of the breastfed group and there was not extreme pain in the sensory overload group. NO PAIN category was more frequent in all three group (Sat): 33.3% versus 16.9% (group LM) and 0% (control group), p <0.0001. CONCLUSIONS: The sensory overload has greater analgesic effect of breastfeeding. Both demonstrate good analgesic effect compared with the control group.

Dolor agudo neonatal con estímulos dolorosos repetitivos, estudio randomizado comparando tres métodos analgésicos no farmacológicos / Neonatal acute pain with repetitive painful stimuli, randomized trial comparing three analgesic non pharmacological methods

Introducción: La analgesia no farmacología es raramente utilizada en las unidades de neonatología. Los estímulos dolorosos repetitivos tienen efectos negativos a largo plazo. Objetivos: Verificar que los métodos analgésicos no farmacológicos son afectivos en estímulos dolorosos repetitivos; determinar cuál método es más efectivo. Material y método; Se realice un ensayo clínica, randomizado, con tres grupos formados de manera aleatoria, con recién nacidos sanos a termino por grupo. Fueron sometidos a tres estímulos dolorosos durante los tres primero días de vida (vacuna contra hepatitis B, BCG y muestra para grupo sanguíneo). El primer grupo (A) recibió lactancia materna y contacto piel como método analgésico no farmacológico durante el estímulo doloroso, el grupo (B) recibió dextrosa al 10 por ciento y el grupo (C) una tetina sin nada. Se utilizó la escala para el Dolor Agudo Neonatal (DAN, Carbajal y col.) y la Escala ABC (Bellieni y col.) para la cuantificación del dolor. Fueron comparados los 3 grupos en cada uno de los tres estímulos repetitivos. Resultados: Para ambas escalas el grupo B expresó menor dolor en los tres estímulos, con 97,5 por ciento de NO DOLOR vs 87,5 por ciento (A) y 85 por ciento (C) (p<0.036) en la escala ABC, y 95 por ciento vs 85 por ciento (A) y 70 por ciento (C) para la categoría NO DOLOR con a categoría DAN (p<0.022). Esta diferencia se mantuvo en las otras categorías de dolor. Se observó que el efecto analgésico es mayor con el estimulo repetitivos. Siendo la categoría NO DOLOR en el grupo B para el primer estimulo 70 por ciento, 85 por ciento en el segundo y 95 por ciento en el tercero (p<0.020). Este efecto se observó también en los grupos A y C. Conclusiones: la dextrosa al 10 por ciento tuvo mayor efecto analgésico comparada con los otros grupos. Los métodos analgésicos no farmacológicos estudiados aumentan su efectividad con estimulo dolorosos repetitivos.

Introduction: Non pharmacological methods are rarely used in neonatal units. repeated painful stimuli have long noxious effects. Objective: To verify the effectiveness of non pharmacological methods in repeated painful procedures; to determine which method is more effective. Material and methods: We conducted a randomized controlled trial. Newborns were randomly assigned into 3 groups (n=40 per group). All of them underwent painful procedures during the first 3 days of life (hepatitis B, BCG and blood sample for determine group and factor). Group A received breast feeding and skin to skin contact as non pharmacological method during the painful stimuli, group B receive dextrose 10 por ciento and group C only suction. Douleur Aigue Nouveauûne scores (DAN, Carvajal et al.) and ABC scale (Bellieni et al.) were used to assess neonatal pain. The 3 groups were compared in each stimulus to determine the most effective method, and the effectiveness in repeated painful stimuli. Results: Group B showed the most analgesic effect in the stimuli, with 97, 5 percent for NO PAIN vs. 87, 5 percent (A) and 85 percent (C) (p<0,036) with ABC scale, and 95 percent vs. 85 (A) and 70 percent (C) for NO PAIN with DAN scale (p<0,022). This difference was constant with all categories of pain. We observed that analgesic effect is greater in repeated painful stimuli. NO PAIN category was 70 percent in group B in the first stimuli, 85 percent in the second and 95 percent in third (9<0,020). This effect was also observed in groups A and C. Conclusions: Dextrose 10 percent seems to offer the best analgesic effect compared with breast feeding and suction. Non pharmacological methods studied increase their effectiveness in repeated painful stimuli.

Variación y distribución genética de los SNP's 19, 43 y 63 del gen de susceptibilidad de diabetes tipo 2 Calpaina 10 (Capn10) en la población peruana / Variation and genetic distribution of SNP's 19, 43 y 63 of the susceptibility gene calpain 10 (Capn10) for the type 2 diabetes in the peruvian population

La diabetes tipo 2 es una enfermedad compleja que tiene un componente genético. Calpaina 10 (CAPN10) es un gen de susceptibilidad para este gen y está localizado en 2q37.3. Pacientes de algunas poblaciones de origen amerindio presentan las frecuencias alélicas de los SNP19, 43 y 63 del gen CAPN10, que sugiere una relación causal entre este gen y la biabetes tipo 2. El origen filogenético común, nos permite suponer que CAPN10 también sería un gen de susceptibilidad en la población peruana nativa y mestiza, lo cual nos motivó a investigar esta relación en nuestra población. Se obtuvieron resultados de la frecuencia alélica de los SNP19, 43 y 63 de CAPN10 en 129 controles normales de Lima, la mayoría de origen mestizo. Además de la prueba del equilibrio de Hardy-Weinberg (H-W) para determinar si la población tiene una distribución genéticamente homogénea en dichos marcadores. Se puede concluir que la prueba de H-W sugiere fuertemente que nuestra población control es adecuada para un estudio de asociación y desequilibrio de ligamiento en pruebas caso-control. Esto a su vez es la base para futuros estudios de asociación y desequilibrio de ligamiento, postulando a CAPN10 como gen de susceptibilidad de diabetes tipo 2 en la población peruana.

Type 2 diabetes is a complex genetic disorder, where the gene calpain 10 (CAPN10) located in 2q37.3, plays an important role. Allele frequencies of SNP19, 43 and 63 are present in affected Amerindian populations and might suggest a possible relationship between CAPN10 and type 2 diabetes. The fact that Amerindian populations has a common phyllogenetic origin was our main motivation for studying this possible relation, because it would suggest' that CAPN10 is a susceptibility gene for native and admixed Peruvian populations. Allelic frequencies of SNP19, 43 and 63 of calpain 10 was obtained of 129 normal controls from Lima, most of them admixed population. Hardy-Weinberg test (H-W) was used in order to determine if the population had a genetically homogenous distribution for the employed molecular markers. It can be concluded that the H-W test strongly suggests that the control population is adequate for an association and linkage disequilibrium in case-control studies. Furthermore, this would mean be thstart of future association and linkage disequilibrium studies where CAPN10 would be considered as a susceptibility gene for type 2 diabetes in Peruvian population.