Radioactive seed localization is a safe and effective tool for breast cancer surgery: an evaluation of over 25,000 cases.

Radioactive seed localization (RSL) provides a precise and efficient method for removing non-palpable breast lesions. It has proven to be a valuable addition to breast surgery, improving perioperative logistics and patient satisfaction. This retrospective review examines the lessons learned from a high-volume cancer center's RSL program after 10 years of practice and over 25 000 cases. We provide an updated model for assessing the patient's radiation dose from RSL seed implantation and demonstrate the safety of RSL to staff members. Additionally, we emphasize the importance of various aspects of presurgical evaluation, surgical techniques, post-surgical management, and regulatory compliance for a successful RSL program. Notably, the program has reduced radiation exposure for patients and medical staff.

Use of bilateral prophylactic nipple-sparing mastectomy in patients with high risk of breast cancer.

BACKGROUND: Nipple-sparing mastectomy (NSM) is being performed increasingly for risk reduction in high-risk groups. There are limited data regarding complications and oncological outcomes in women undergoing bilateral prophylactic NSM. This study reviewed institutional experience with prophylactic NSM, and examined the indications, rates of postoperative complications, incidence of occult malignant disease and subsequent breast cancer diagnosis. METHODS: Women who had bilateral prophylactic NSM between 2000 and 2016 were identified from a prospectively maintained database. Rates of postoperative complications, incidental breast cancer, recurrence and overall survival were evaluated. RESULTS: A total of 192 women underwent 384 prophylactic NSMs. Indications included BRCA1 or BRCA2 mutations in 117 patients (60·9 per cent), family history of breast cancer in 35 (18·2 per cent), lobular carcinoma in situ in 29 (15·1 per cent) and other reasons in 11 (5·7 per cent). Immediate breast reconstruction was performed in 191 patients. Of 384 NSMs, 116 breasts (30·2 per cent) had some evidence of skin necrosis at follow-up, which resolved spontaneously in most; only 24 breasts (6·3 per cent) required debridement. Overall, there was at least one complication in 129 breasts (33·6 per cent); 3·6 and 1·6 per cent had incidental findings of ductal carcinoma in situ and invasive breast cancer respectively. The nipple-areola complex was preserved entirely in 378 mastectomies. After a median follow-up of 36·8 months, there had been no deaths and no new breast cancer diagnoses. CONCLUSION: These findings support the use of prophylactic NSM in high-risk patients. The nipples could be preserved in the majority of patients, postoperative complication rates were low, and, with limited follow-up, there were no new breast cancers.

ANTECEDENTES: La mastectomía con preservación del pezón (nipple-sparing mastectomy, NSM) se realiza cada vez más para reducir riesgos en los grupos de pacientes de alto riesgo. Se dispone de pocos datos sobre complicaciones y resultados oncológicos en mujeres sometidas a NSM bilateral profiláctica. Este estudio revisó la experiencia institucional de la NSM profiláctica, y analizó las indicaciones, tasas de complicaciones postoperatorias, incidencia de enfermedad maligna oculta y diagnóstico de subsiguiente cáncer de mama. MÉTODOS: Se identificaron mujeres sometidas a NSM bilateral profiláctica durante el periodo 2000-2016 a partir de una base de datos prospectiva. Se evaluaron tasas de complicaciones postoperatorias, cáncer de mama incidental, recidiva y supervivencia global. RESULTADOS: Un total de 192 mujeres fueron sometidas a 384 NSMs profilácticas. Las indicaciones incluyeron mutaciones BRCA1 o BRCA2 en 117 (61%) pacientes, historia familiar de cáncer de mama en 35 (18%), carcinoma lobulillar in situ en 29 (15%) y otros motivos en 11 (5,7%). La reconstrucción mamaria inmediata se realizó en 191 pacientes. De las 384 NSMs, 116 (30%) presentaron alguna evidencia de necrosis de la piel durante el seguimiento y la mayoría se resolvieron de forma espontánea, con solo 24 (6,2%) mamas que requirieron desbridamiento. Globalmente hubo al menos una complicación en 129 (34%) mamas; 3,6% y 1,6% tuvieron hallazgos incidentales de carcinoma ductal in situ o cáncer de mama invasivo, respectivamente. El complejo areola-pezón se preservó completamente en 378 mastectomías. Tras una mediana de seguimiento de 36,8 meses, no hubo fallecimientos ni ningún diagnóstico nuevo de cáncer de mama. CONCLUSIÓN: Estos hallazgos apoyan la utilización de la NSM profiláctica en pacientes de alto riesgo. En la mayoría pacientes fue posible la preservación del pezón, las tasas de complicaciones postoperatorias fueron bajas y, con un seguimiento limitado, no hubo nuevos casos de cáncer de mama.

Breast cancer in young black women.

BACKGROUND: Young age at breast cancer diagnosis is associated with negative prognostic outcomes, and breast cancer in black women often manifests at a young age. This study evaluated the effect of age on breast cancer management and outcomes in black women. METHODS: This was a retrospective cohort study of all black women treated for invasive breast cancer between 2005 and 2010 at a specialized tertiary-care cancer centre. Clinical and treatment characteristics were compared by age. Kaplan-Meier methodology was used to estimate overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 666 black women were identified. Median BMI was 30 (range 17-56) kg/m2 and median tumour size was 16 (1-155) mm. Most tumours were oestrogen receptor-positive (66·4 per cent). Women were stratified by age: less than 40 years (74, 11·1 per cent) versus 40 years or more (592, 88·9 per cent). Younger women were significantly more likely to have a mastectomy, axillary lymph node dissection and to receive chemotherapy, and were more likely to have lymphovascular invasion and positive lymph nodes, than older women. The 5-year OS rate was 88·0 (95 per cent c.i. 86·0 to 91·0) per cent and the 5-year DFS rate was 82·0 (79·0 to 85·0) per cent. There was no statistically significant difference in OS by age (P = 0·236). Although DFS was inferior in younger women on univariable analysis (71 versus 88 per cent; P < 0·001), no association was found with age on multivariable analysis. CONCLUSION: Young black women with breast cancer had more adverse pathological factors, received more aggressive treatment, and had worse DFS on univariable analysis. Young age at diagnosis was, however, not an independent predictor of outcome.

ANTECEDENTES: El diagnóstico de cáncer de mama a una edad joven se asocia con un pronóstico de resultados negativo, y en mujeres de raza negra, el cáncer de mama con frecuencia se manifiesta a edades tempranas. Este estudio analiza el efecto de la edad en el tratamiento y resultados del cáncer de mama en mujeres de raza negra. MÉTODOS: Estudio de cohortes retrospectivo de todas las mujeres de raza negra tratadas por cáncer de mama invasivo entre 2005-2010 en un centro oncológico terciario de alta especialización. Se compararon las características clínicas y del tratamiento en función de la edad. Se estimó la supervivencia global (overall survival, OS) y la supervivencia libre de enfermedad (disease-free survival, DFS) con el método de Kaplan-Meier y se utilizó la prueba de log-rank para las comparaciones entre grupos. RESULTADOS: Se identificaron un total de 666 mujeres de raza negra. La mediana del tamaño del tumor fue de 16 mm (rango 1-155 mm). La mayoría de los tumores fueron positivos para el receptor de estrógenos (66,4%); la mediana del índice de masa corporal (IMC) fue 30 kg/m2 (rango 17,2-56,5). Se estratificaron a las mujeres por su edad: < 40 años (n = 74; 11,1%) frente a ≥ 40 años (n = 592; 88,9%). La probabilidad de recibir una mastectomía, un vaciamiento ganglionar axilar y quimioterapia fue significativamente superior en las pacientes jóvenes y además fueron más propensas a presentar invasión linfovascular y ganglios linfáticos positivos en comparación con las mujeres mayores. Las OS y DFS a los 5 años fueron del 88,0% (i.c. del 95% 86-91%) y del 82% (i.c. del 95% 79-85%), respectivamente. No se observaron diferencias estadísticamente significativas en la OS (P = 0,236) en función de la edad. Aunque en el análisis univariado la DFS fue peor en las mujeres jóvenes (71% versus 88%, log-rank P < 0,001), en el análisis multivariable no se confirmó la asociación con la edad. CONCLUSIÓN: Las mujeres jóvenes de raza negra con cáncer de mama tuvieron más factores patológicos adversos, recibieron un tratamiento más agresivo y tuvieron una DFS peor en el análisis univariado. Sin embargo, la edad temprana en el momento del diagnóstico no fue un factor predictivo independiente del resultado.

Will surgery be a part of breast cancer treatment in the future?

The combination of smaller, screen-detected cancers, improved efficacy of systemic therapy, and increasing use of neoadjuvant therapy with rising rates of pathologic complete response has prompted interest in studying elimination of surgery for some women with breast cancer. In order to determine whether this is a high priority area for research, knowledge of the proportion of cancers cured by surgery, the morbidity of current surgical approaches to breast cancer, and patient treatment preferences must be considered. This article reviews these topics and addresses some of the concerns about elimination of surgery in the settings of patients with small amounts of non-high-grade DCIS and in those who appear to have a pathologic complete response to neoadjuvant chemotherapy.

Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity-breast cancer link.

BACKGROUND/OBJECTIVES: Obesity (body mass index (BMI)⩾30 kg m-2) is associated with an increased risk of estrogen-dependent breast cancer after menopause. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are elevated in breast tissue of obese women. Recently, the regulation of aromatase by the p53-hypoxia-inducible factor-1α (HIF1α)/pyruvate kinase M2 (PKM2) axis was characterized in adipose stromal cells (ASCs) of women with Li-Fraumeni Syndrome, a hereditary cancer syndrome that predisposes to estrogen-dependent breast cancer. The current study aimed to determine whether stimulation of aromatase by obesity-associated adipokine leptin involves the regulation of the p53-HIF1α/PKM2 axis. SUBJECTS/METHODS: Human breast ASCs were used to characterize the p53-HIF1α/PKM2-aromatase axis in response to leptin. The effect of pharmacological or genetic modulation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), p53, Aha1, Hsp90, HIF1α and PKM2 on aromatase promoter activity, expression and enzyme activity was examined. Semiquantitative immunofluorescence and confocal imaging were used to assess ASC-specific protein expression in formalin-fixed paraffin-embedded tissue sections of breast of women and mammary tissue of mice following a low-fat (LF) or high-fat (HF) diet for 17 weeks. RESULTS: Leptin-mediated induction of aromatase was dependent on PKC/MAPK signaling and the suppression of p53. This, in turn, was associated with an increase in Aha1 protein expression, activation of Hsp90 and the stabilization of HIF1α and PKM2, known stimulators of aromatase expression. Consistent with these findings, ASC-specific immunoreactivity for p53 was inversely associated with BMI in breast tissue, while HIF1α, PKM2 and aromatase were positively correlated with BMI. In mice, HF feeding was associated with significantly lower p53 ASC-specific immunoreactivity compared with LF feeding, while immunoreactivity for HIF1α, PKM2 and aromatase were significantly higher. CONCLUSIONS: Overall, findings demonstrate a novel mechanism for the obesity-associated increase in aromatase in ASCs of the breast and support the study of lifestyle interventions, including weight management, which may reduce breast cancer risk via effects on this pathway.

Applying the Care Group model to tuberculosis control: findings from a community-based project in Mozambique.

BACKGROUND: We describe the effectiveness of an innovative community-based social mobilization approach called Care Groups to improve the effectiveness of the national tuberculosis (TB) program by increasing TB testing and improving treatment outcomes in six districts of rural Mozambique. METHODS: The Care Group approach, which was implemented in a population of 218 191, enabled a facilitator to meet every 6 months with 10-12 community health volunteers (forming a Care Group) to share key TB messages and then for them to convey these messages over the subsequent 6 months to 10-12 households. Three household surveys were performed over 5 years to measure population-level changes in knowledge and behaviors. Data from village TB, laboratory, and district registers were also used to monitor activities and outcomes. RESULTS: There were substantial improvements in TB-related knowledge and behaviors in the number of patients initiating treatment, in the percentage of patients receiving directly observed treatment, in treatment success, and in TB-related mortality. CONCLUSION: Care Groups are uniquely suited to address some of the challenges of TB control. This project sheds light on a new strategy for engaging communities to address not only TB, but other health priorities as well.

De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017.

The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.

Nipple-sparing mastectomy in patients with BRCA1/2 mutations and variants of uncertain significance.

BACKGROUND: Nipple-sparing mastectomy (NSM) is associated with improved cosmesis and is being performed increasingly. Its role in BRCA mutation carriers has not been well described. This was a study of the indications for, and outcomes of, NSM in BRCA mutation carriers. METHODS: BRCA mutation carriers who underwent NSM were identified. Details of patient demographics, surgical procedures, complications, and relevant disease stage and follow-up were recorded. RESULTS: A total of 177 NSMs were performed in 89 BRCA mutation carriers between September 2005 and December 2013. Twenty-six patients of median age 41 years had NSM for early-stage breast cancer and a contralateral prophylactic mastectomy. Mean tumour size was 1·4 (range 0·1-3·5) cm. Sixty-three patients of median age 39 years had prophylactic NSM, eight of whom had an incidental diagnosis of ductal carcinoma in situ. There were no local or regional recurrences in the 26 patients with breast cancer at a median follow-up of 28 (i.q.r. 15-43) months. There were no newly diagnosed breast cancers in the 63 patients undergoing prophylactic NSM at a median follow-up of 26 (11-42) months. All patients had immediate breast reconstruction. Five patients (6 per cent) required subsequent excision of the nipple-areola complex for oncological or other reasons. Skin desquamation occurred in 68 (38·4 per cent) of the 177 breasts, and most resolved without intervention. Debridement was required in 13 (7·3 per cent) of the 177 breasts, and tissue-expander or implant removal was necessary in six instances (3·4 per cent). CONCLUSION: NSM is an acceptable choice for patients with BRCA mutations, with no evidence of compromise to oncological safety at short-term follow-up. Complication rates were acceptable, and subsequent excision of the nipple-areola complex was rarely required.

DNA vaccine cocktail expressing genotype A and C HBV surface and consensus core antigens generates robust cytotoxic and antibody responses in mice and Rhesus macaques.

There are well over a quarter of a billion chronic hepatitis B virus (HBV) carriers across the globe. Most carriers are at high risk for development of liver cirrhosis and subsequent progression to hepatocellular carcinoma. It is therefore imperative to develop new approaches for immunotherapy against this infection. Antibodies and cytotoxic T cells to different HBV antigens are believed to be important for reducing viral load and clearing HBV-infected cells from the liver. Some of the major challenges facing current vaccine candidates have been their inability to induce both humoral and cellular immunity to multiple antigenic targets and the induction of potent immune responses against the major genotypes of HBV. In this study, highly optimized synthetic DNA plasmids against the HBV consensus core (HBc) and surface (HBs) antigens genotypes A and C were developed and evaluated for their immune potential. These plasmids, which encode the most prevalent genotypes of the virus, were observed to individually induce binding antibodies to HBs antigens and drove robust cell-mediated immunity in animal models. Similar responses to both HBc and HBs antigens were observed when mice and non-human primates were inoculated with the HBc-HBs cocktails. In addition to the cytotoxic T lymphocyte activities exhibited by the immunized mice, the vaccine-induced responses were broadly distributed across multiple antigenic epitopes. These elements are believed to be important to develop an effective therapeutic vaccine. These data support further evaluation of multivalent synthetic plasmids as therapeutic HBV vaccines.

Inducing humoral and cellular responses to multiple sporozoite and liver-stage malaria antigens using exogenous plasmid DNA.

A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum malaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four P. falciparum antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4(+) and CD8(+) T cell compartments. Furthermore, hepatic CD8(+) lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8(+) granzyme B(+) T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.

Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53.

MicroRNAs (miRNAs) regulate the expression of multiple proteins in a dose-dependent manner. We hypothesized that increased expression of miRNAs encoded on chromosome 21 (chr 21) contribute to the leukemogenic function of trisomy 21. The levels of chr 21 miRNAs were quantified by qRT-PCR in four types of childhood acute lymphoblastic leukemia (ALL) characterized by either numerical (trisomy or tetrasomy) or structural abnormalities of chr 21. Suprisingly, high expression of the hsa-mir-125b-2 cluster, consisting of three miRNAs, was identified in leukemias with the structural ETV6/RUNX1 abnormality and not in ALLs with trisomy 21. Manipulation of ETV6/RUNX1 expression and chromatin immunoprecipitation studies showed that the high expression of the miRNA cluster is an event independent of the ETV6/RUNX1 fusion protein. Overexpression of hsa-mir-125b-2 conferred a survival advantage to Ba/F3 cells after IL-3 withdrawal or a broad spectrum of apoptotic stimuli through inhibition of caspase 3 activation. Conversely, knockdown of the endogenous miR-125b in the ETV6/RUNX1 leukemia cell line REH increased apoptosis after Doxorubicin and Staurosporine treatments. P53 protein levels were not altered by miR-125b. Together, these results suggest that the expression of hsa-mir-125b-2 in ETV6/RUNX1 ALL provides survival advantage to growth inhibitory signals in a p53-independent manner.

Breast conservation and negative margins: how much is enough?

There is no standard definition of what constitutes an adequate negative margin of resection in invasive cancer or ductal carcinoma in situ (DCIS). The definition of a negative margin used in randomized trials was tumor not touching ink. Tumor touching ink, whether invasive or DCIS, increases the risk of local recurrence (LR). In invasive cancer, convincing evidence that more widely negative margins decrease the risk of LR is lacking, and multiple other biologic and treatment factors influence the risk of LR. In DCIS treated with radiotherapy, evidence that margins wider than 2mm are beneficial is also lacking. Techniques of pathologic processing are a source of variation in margin assessment. The need for margins larger than tumor not touching ink (invasive cancer) and 2mm (DCIS) should be considered in the context of the multiple other factors known to impact upon LR.

FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning.

The objective of this study is to determine if immune reconstitution of FOXP3+ T regulatory cells correlates with clinical improvement of IPEX syndrome following allogeneic hematopoietic stem cell transplant. An 8-months-old male infant with a mutation in the polyadenylation site of FOXP3 gene, absence of FOXP3 protein expression and clinical manifestations of IPEX syndrome, including eczema, colitis, failure to thrive, TPN requirement, and elevated serum IgE, underwent matched unrelated hematopoietic stem cell transplant. After reduced-intensity conditioning with alemtuzumab followed by fludarabine and melphalan the patient's neutrophils engrafted day +15 and platelets day +29. Patient was a full donor chimera day +28 and +60. Intracellular FOXP3 protein expression in CD4+ T cells was absent pre-HSCT. After transplantation, percentage CD4+ T cells expressing FOXP3+CD25 bright phenotype quickly increased from 4.5 (day +29) to 23% (day +90) and continued in this trend. Foxp3 mRNA expression confirmed flow cytometry data. Serum IgE levels decreased from 5,000 IU/ml pre-transplant to 6 IU/ml on day +90, eczema resolved, and secretory diarrhea and feeding intolerance improved. T regulatory cell reconstitution is evident soon after HSCT following reduced-intensity conditioning correlating with development of full donor chimerism. Increased FOXP3 expression correlates with correction of clinical and laboratory manifestations of IPEX syndrome providing direct evidence that HSCT is a curative procedure for this disorder.

Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors.

BACKGROUND: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose. PATIENTS AND METHODS: The doses of cilengitide were 600 or 1200 mg/m(2) as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate. RESULTS: Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity. CONCLUSIONS: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.