Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study.

INTRODUCTION: The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMP-activated protein kinase (AMPK) and an inhibition of mammalian target of rapamycin mTOR signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced insulin receptor (IR)-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in patients remain unknown. METHODS: We conducted a neoadjuvant, single-arm, "window of opportunity" trial to examine the clinical and biological effects of metformin on patients with breast cancer. Women with untreated breast cancer who did not have diabetes were given 500 mg of metformin three times daily for ≥2 weeks after diagnostic biopsy until surgery. Fasting blood and tumor samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of tumors was used to characterize cellular markers before and after treatment. RESULTS: Levels of IR expression decreased significantly in tumors (P = 0.04), as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase 1/2 (ERK1/2, T202/Y204), AMPK (T172) and acetyl coenzyme A carboxylase (S79) (P = 0.0001, P < 0.0001, P < 0.005 and P = 0.02, respectively). All tumors expressed organic cation transporter 1, with 90% (35 of 39) exhibiting an Allred score of 5 or higher. CONCLUSIONS: Reduced PKB/Akt and ERK1/2 phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. These results are consistent with beneficial anticancer effects of metformin and highlight key factors involved in sensitivity, which could be used to identify patients with breast cancer who may be responsive to metformin-based therapies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.

Comparing the DN4 tool with the IASP grading system for chronic neuropathic pain screening after breast tumor resection with and without paravertebral blocks: a prospective 6-month validation study.

Investigating protective strategies against chronic neuropathic pain (CNP) after breast cancer surgery entails using valid screening tools. The DN4 (Douleur Neuropathique en 4 questions) is 1 tool that offers important research advantages. This prospective 6-month follow-up study seeks to validate the DN4 and assess its responsiveness in screening for CNP that satisfies the International Association for the Study of Pain (IASP) definition and fulfills its grading system criteria after breast tumor resection with and without paravertebral blocks (PVBs). We randomized 66 females to standardized general anesthesia and sham subcutaneous injections, or PVB and total intravenous anesthesia. The 6-month CNP risk was assessed using the IASP grading system and the DN4 screening tools. We evaluated the DN4 sensitivity, specificity, and responsiveness in capturing the impact of PVB on the CNP risk relative to the IASP grading system. Data from 64 patients showed similar demographic characteristics in both groups. Twenty patients in both groups met the grading system CNP criteria; among these, 18 patients also met the DN4 CNP criteria. Furthermore, 15 patients in both groups did not meet the grading system CNP criteria; among these, 9 patients also did not meet the DN4 CNP criteria. Therefore, the sensitivity and specificity of the DN4 were estimated at 90% and 60%, respectively. Both screening tools suggested that PVB reduced the 6-month CNP risk. Our results suggest that the DN4 can reliably identify CNP at 6 months after breast tumor resection and detect the preincisional PVB effect on the risk of developing such pain.

Ultrasound-guided multilevel paravertebral blocks and total intravenous anesthesia improve the quality of recovery after ambulatory breast tumor resection.

BACKGROUND: Regional anesthesia improves postoperative analgesia and enhances quality of recovery (QoR) after ambulatory surgery. This randomized, double-blinded, parallel-group, placebo-controlled trial examines the effects of multilevel ultrasound-guided paravertebral blocks (PVBs) and total intravenous anesthesia on QoR after ambulatory breast tumor resection. METHODS: Sixty-six women were randomized to standardized general anesthesia (control group) or PVBs and propofol-based total intravenous anesthesia (PVB group). The PVB group received T1-T5 PVBs with 5 ml of 0.5% ropivacaine per level, whereas the control group received sham subcutaneous injections. Postoperative QoR was designated as the primary outcome. The 29-item ambulatory QoR tool was administered in the preadmission clinic, before discharge, and on postoperative days 2, 4, and 7. Secondary outcomes included block success, pain scores, intra- and postoperative morphine consumption, time to rescue analgesia, incidence of nausea and vomiting, and hospital discharge time. RESULTS: Data from sixty-four patients were analyzed. The PVB group had higher QoR scores than control group upon discharge (146 vs. 131; P < 0.0001) and on postoperative day 2 (145 vs. 135; P = 0.013); improvements beyond postoperative day 2 lacked statistical significance. None of the PVB group patients required conversion to inhalation gas-based general anesthesia or experienced block-related complications. PVB group patients had improved pain scores on postanesthesia care unit admission and discharge, hospital discharge, and postoperative day 2; their intraoperative morphine consumption, incidence of nausea and vomiting, and discharge time were also reduced. CONCLUSION: Combining multilevel PVBs with total intravenous anesthesia provides reliable anesthesia, improves postoperative analgesia, enhances QoR, and expedites discharge compared with inhalational gas- and opioid-based general anesthesia for ambulatory breast tumor resection.

Prognostic significance of a positive axillary lymph node fine-needle aspirate in patients with invasive breast carcinoma.

BACKGROUND: Image-guided axillary lymph node fine-needle aspirates (FNAs) correlate well with pathologic lymph node staging in cases of invasive breast carcinoma. The objective of this study was to determine the prognostic significance of a positive lymph node. METHODS: Consecutive cases of nonmetastatic (M0) invasive breast carcinoma evaluated by image-guided FNA were identified (4-year period, median follow-up of 51 months). "Positive" and "nonpositive" groups were compared using Kaplan-Meier survival analysis. Multivariate Cox regression was used to correct for clinicopathologic and treatment factors. A total of 142 cases was included, 70 with positive axillary FNA and 72 with a nonpositive result. RESULTS: FNA-positive and nonpositive cases did not differ in patient age, tumor subtype, or hormone receptor status. Positive FNA was significantly associated with advanced T and N pathologic stage, and with HER2 (human epidermal growth factor receptor 2) positivity. FNA-positive patients were more likely to undergo mastectomy and to receive chemotherapy. Kaplan-Meier analysis showed that positive FNA is associated with poor prognosis, both with respect to disease-free survival (89% nonpositive versus 73% positive at 5 years, P < .001) and overall survival (94% versus 81%, respectively, at 5 years, P = .01). Multivariate analysis showed that when correcting for other variables, FNA positivity was not independently significant. CONCLUSIONS: Positive axillary lymph node FNA is associated with poor prognosis on univariate analysis. By contrast, overall nodal staging is independently significant on multivariate analysis. The prognostic significance of axillary FNA likely results from its ability to predict for nodal status. Axillary FNA has utility as a preoperative staging procedure.

Sentinel nodes in breast cancer: relevance of axillary level II nodes and optimal number of nodes that need to be removed.

BACKGROUND: In some patients, the radiocolloid used to perform sentinel lymph node biopsy (SLNB) for breast cancer appears in a number of lymph nodes and in different levels of the axilla. Most positive sentinel lymph node specimens (SLNSs) removed during SLNB are identified in level I of the axilla and within the first 4 SLNSs. Our objective was to verify the staging accuracy of harvesting only the first 4 SLNSs and to determine the relevance of SLNSs that reside in level II of the axilla. METHODS: A prospective database documenting the method of identification, radioisotope count, order of retrieval, and axillary level of SLNSs from 893 SLNBs was analyzed. RESULTS: A median of 2 SLNSs (range 1-9) were removed per patient. More than 4 SLNSs were found in 8.0%. All SLNSs harboring the largest nodal metastases were identified within the first 4 harvested. Twenty-one percent (184 of 870) of patients had level II SLNSs; 4.9% (9 of 184) were positive. When SLNSs were positive in both levels I and II, the nodal metastases were always of greater or equal size in the level I nodes. Only one patient (0.5%) had a positive level II SLNS macrometastasis (> 2 mm, pN1), with a negative level I SLNS, but it was the hottest node and was removed first. CONCLUSIONS: Removal of more than the first 4 hottest SLNSs does not improve staging accuracy. Level II nodes can be ignored if a hotter level I SLNS is first identified.