Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.

Diabetes induces several malfunctions in male germ cells. The aim of this study was to analyze the levels and localization of the glucose transporter GLUT8 and insulin in the testes of rats induced to a diabetic status by a single dose of streptozotocin. One month after inducing diabetes, the GLUT8 immunoreactivity in diabetic rats was mainly located associated to the acrosomic system of spermatids, and at low levels in Leydig cells. Neither the immunohistochemical localization of this transporter nor its levels showed any difference when compared to control rats. Furthermore, it was observed that control rat testes expressed insulin, which was diffusely located in the cytoplasm of both Leydig cells and early elongated spermatids and concentrated in a cytoplasmic compartment in the more mature spermatids. Testicular insulin levels measured by western blot were reduced by more than half in diabetic rats, although the distribution of the hormone was unchanged. These results indicate that i) insulin is produced by testicular cells, ii) insulin is depleted by streptozotocin-induced diabetes, and iii) that insulin depletion and hyperglycemia do not regulate the expression of GLUT8 in testes. These results also suggest that testicular production of insulin could play a role in regulating spermatogenesis and/or glucose metabolism in these organs.

Abstract Background: Accurate assessment of the extent of breast cancer with breast MRI (BMRI) yields additional findings (AF) that must be characterized in order to guide treatment. The aim of our study was to analyze the work-up of AF seen in pre-therapeutic BMRI and their impact on therapeutic approach and re-excision rates.Methods: From 07/2002 to 04/2007 we studied prospectively 465 consecutive patients with a diagnosis of breast cancer that underwent a pre-treatment BMRI to evaluate disease extent. BMRI studies were performed with a 1,0 and a 1,5 T magnet and coronal T2-weighted fast spin-echo and contrast-enchanced T1-weighted 3D gradient-echo sequences were evaluated. Post-processing included parametric, multiplanar reconstructions and maximum intensity projections. Fischer's scale was used to characterize additional lesions (AL). AL >5 mm were classified as: increase in tumor size, multifocal, multicentric and contralateral disease. AF that would potentially change therapeutic approach were re-evaluated with 2nd-look ultrasound (US), biopsied if found and/or marked with clips or with a radioisotope (ROLL). BI-RADS 3 lesions were followed up with BMRI. Gold standards were pathology reports and follow-up >2 years for benign lesions. Therapeutic change based on MRI findings was deemed correct in malignant AF and incorrect if pathology was benign. Re-excision rates and disease-free intervals were calculated.Results. A total of 280 AF were found in 222 (47,7%) patients. US studies were performed in 111 patients, in 99 of which the AL (89,1%) was found. 63 patients underwent biopsies and 48 of them (76,1%) were malignant. ROLL procedures were performed in 32 patients and malignancy rate was 65,6%. Follow-up BMRI studies for BI-RADS 3 lesions were performed in 42 patients (9%). BMRI found index lesions seen by mammography or US in 98,9% of the patients and did not find additional multifocal or multicentric disease in 10 patients, yielding a total negative predictive value of 96,7% for BMRI (6 invasive and 9 intraductal cancers). Therapeutic approach was changed in 107 patients (23%) and considered correct in 92 (86%) representing 19,7% of all patients and incorrect in 15 (14%) corresponding to 3,2% of the total. Re-excision due to positive margins during the first 6 months was performed in 39/323 patients treated with conservative surgery (re-excision rate of 12%). Mean follow-up was 48,4 months (m) (6,7-81,4 m) and mean disease-free interval was 45 m (6,7-81,4 m).Conclusion: Work-up of AF diagnosed in BMRI allows accurate treatment adjusted to disease extent in 96,8% of the patients. Additional work-up using US and close correlation with the rest of conventional modalities is the mandatory behaviour to ensure an integrated evaluation of AF. This policy allows a correct treatment in 86% of the patients with potential therapeutic change. Overtreatment was induced in 14% of these patients. Regarding the overall series of 465 patients submitted to BMRI, the 15 patients who were overtreated represent 3,2% of the total. The precision level of preoperative MRI in this scenario is clearly superior to conventional modalities when combined in an integrated multimodality approach. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4023.

El estudio histológico del ganglio centinela axilar (GC) está estableciéndose como un procedimiento habitual en la cirugía del carcinoma infiltrante de mama. Los falsos negativos descritos son imputables tanto a la identificación del verdadero ganglio centinela como al protocolo aplicado para el estudio de dicho ganglio. Estudiamos 62 enfermas de carcinoma infiltrante de mama, clínicamente N0 (TNM), subsidiarias de exéresis tumoral y vaciamiento axilar. En todas se practicó linfogammagrafía y detección intraoperatoria tras la administración peritumoral de 99mTc-nanocoloide de albúmina. El estudio histológico del GC se efectuó realizando pares de cortes de 4µ y tinción mediante hematoxilina-eosina (H/E) y técnica rápida de citoqueratinas (CK) por congelación. Del total de 62 enfermas, en dos no fue posible detectar el GC. De las 60 restantes, 18 presentaban metástasis en el GC, sin observarse afectación de otros ganglios en 6 de ellas. Diez de estas enfermas mostraron la presencia de micrometástasis exclusivamente (depósito tumoral ≤ 2 mm). En dos de estos diez últimos casos, el diagnóstico de las micrometástasis sólo fue posible a partir de los cortes teñidos con CK. No se obtuvo ningún resultado falso negativo. La linfogammagrafía, previa inyección peritumoral de volúmenes pequeños y dosis bajas del radiotrazador, permite obtener excelentes resultados en la localización intraoperatoria del GC en el cáncer de mama. Su posterior estudio mediante CK rápida permite disminuir el número de falsos negativos de la técnica. Histopathological examination of the axillary sentinel node (SN) is becoming a routine procedure in the surgical phase of infiltrating ductal carcinoma of the breast (IDC). The SN exam may yield false negative cases mainly due to identification failure of the SN but some of the false negative cases may be the result of the pathological examination procedure applied. Sixty two (62) cases of clinically staged N0 IDC of the breast by TNM nomenclature were assigned to breast surgery along with conventional axillary node dissection. The identification technique included lymphoscintigraphy and intraoperative gamma-detecting probe after peritumoral injection of 99mTc-labeled colloids. The histological study of SN was performed with paired 4 µm slices and staining with hematoxylin-eosin and with a fast method of cytokeratins for freezing. In only two of the 62 patients, it was not possible to identify the SN. Eighteen of the remaining 60 had SN involvement by metastasis, having no metastases in the other nodes of the axillary dissection in 6 of them. Ten of those were micrometastasis (size of metastasis = or < 0.2 cm). In two out of these last 10 cases, diagnosis of the micrometastasis was only possible using slices stained with CK. There were no false negative results. The lymphoscintigraphy, after peritumoral injection of small volumes and low dose of the tracer, makes it possible to obtain excellent results in the intraoperative detection of the SN in breast cancer. The study of this SN with a fast method for CK decreases the number of false negative results of the technique.

INTRODUCTION:Histopathological examination of the axillary sentinel node (SN) is becoming a routine procedure in the surgical phase of infiltrating ductal carcinoma of the breast (IDC). The SN exam may yield false negative cases mainly due to identification failure of the SN but some of the false negative cases may be the result of the pathological examination procedure applied.MATERIAL AND METHODS:Sixty two (62) cases of clinically staged N0 IDC of the breast by TNM nomenclature were assigned to breast surgery along with conventional axillary node dissection. The identification technique included lymphoscintigraphy and intraoperative gamma-detecting probe after peritumoral injection of 99mTc-labeled colloids.The histological study of SN was performed with paired 4 microm slices and staining with hematoxylin-eosin and with a fast method of cytokeratins for freezing.RESULTS:In only two of the 62 patients, it was not possible to identify the SN. Eighteen of the remaining 60 had SN involvement by metastasis, having no metastases in the other nodes of the axillary dissection in 6 of them. Ten of those were micrometastasis (size of metastasis= or <0.2 cm). In two out of these last 10 cases, diagnosis of the micrometastasis was only possible using slices stained with CK. There were no false negative results.CONCLUSIONS:The lymphoscintigraphy, after peritumoral injection of small volumes and low dose of the tracer, makes it possible to obtain excellent results in the intraoperative detection of the SN in breast cancer. The study of this SN with a fast method for CK decreases the number of false negative results of the technique.

Alteration in diversity and composition of gut microbiota is related to many diseases, including obesity. Microbes responsible for obesity change the energy harvesting, fat deposition, and insulin resistance in the host organism. Gut microbes control all the processes like metabolism, adiposity, intake and expenditure of energy, appetite, which are crucial for obesity. Therefore gut microbes might be considered as a suitable target to control obesity. Promising metabolic therapies are required to maintain weight for a healthy life. At present, we are in a new era where microbial metabolites are being used to treat diseases. Lipstatin, a secondary metabolite produced by Streptomyces toxytricini, possess inhibitory activity against pancreatic lipase. Many other bacteria and fungus produce secondary metabolites, which are beneficial in the regulation of obesity. Without any doubt, microbes have proved beneficial for human beings. We have hardly studied the surface of the microbe’s potential.

Cardiovascular disease is the leading cause of death worldwide. High cholesterol level is a risk factor for coronary artery disease. Cholesterol production is regulated by the enzyme 3‑hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins, HMG-CoA reductase inhibitors, are often used as lipid-lowering drugs to prevent cardiovascular disease. Therefore, this study aimed to evaluate the inhibitory activity of several atorvastatin derivatives and assess their inhibitory activity against the HMG-CoA reductase enzyme. Atorvastatin derivatives S1, S2, and S3 were synthesized by acylation of the benzene ring of atorvastatin. Moreover, the amine group of atorvastatin was treated with ethanol and sulfuric acid, to provide atorvastatin-anthranilic acid derivatives (S4 and S5). An in silico docking study was performed on the HMG-CoA reductase (PDB ID: 1HWK), and it was observed that compound S3 with a propargyl functional group had the highest binding affinity (∆G= -6.8 kcal/mol). The obtained results showed that S3 compound could significantly inhibit HMG-CoA reductase activity compared to controls pravastatin and atorvastatin (P<0.05). The in vivo antihyperlipidemic activity results discovered that compound S3 increased HDL, and decreased cholesterol, LDL and triglyceride compared to the atorvastatin during 60 days of treatment (P < 0.05). Liver enzyme levels and rabbit liver histology study showed no toxicity for the S3 compound. Additionally, the S3 might be considered as an effective medicine in preventing atherosclerosis.

A total of 153,245 patients are living with a solid organ transplant in the US. In addition, patients are experiencing high 5-year survival rates after transplantation. Thus, primary care physicians will be caring for transplanted patients. The aim of this review is to update primary care physicians on chronic diseases, screening for malignancy, immunizations, and contraception in the transplant patient. Several studies on the treatment of hypertension and hyperlipidemia demonstrate that most agents used to treat the general population also can be used to treat transplant recipients. Little information exists on the medical management of diabetes in the transplant population, but experts in the area believe that the treatment of diabetes should be similar. Transplant recipients are at increased risk for all malignancies. Aggressive screening should be employed for all cancers with a proven screening benefit. Killed immunizations are safe for the transplant population, but live virus vaccines should be avoided. Women of childbearing age should be counseled about the impact of immunosuppressants on the efficacy and side effects of contraception.