Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

PURPOSE: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Retromer disruption promotes amyloidogenic APP processing.

Retromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aß is found in late endosomal compartments, we speculated that retromer malfunction might enhance amyloidogenic APP processing by promoting interactions between APP and secretase enzymes in late endosomes. We have evaluated changes in amyloid precursor protein (APP) processing and trafficking as a result of disrupted retromer activity by knockdown of Vps35, a vacuolar sorting protein that is an essential component of the retromer complex. Knocking down retromer activity produced no change in the quantity or cellular distribution of total cellular APP and had no affect on internalization of cell-surface APP. Retromer deficiency did, however, increase the ratio of secreted Aß42:Aß40 in HEK-293 cells over-expressing APP695, due primarily to a decrease in Aß40 secretion. Recent studies suggest that the retromer-trafficked protein, Wntless, is secreted at the synapse in exosome vesicles and that these same vesicles contain Aß. We therefore hypothesized that retromer deficiency may be associated with altered exosomal secretion of APP and/or secretase fragments. Holo-APP, Presenilin and APP C-terminal fragments were detected in exosomal vesicles secreted from HEK-293 cells. Levels of total APP C-terminal fragments were significantly increased in exosomes secreted by retromer deficient cells. These data suggest that reduced retromer activity can mimic the effects of familial AD Presenilin mutations on APP processing and promote export of amyloidogenic APP derivatives.

Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers.

Sustained treatment of estrogen receptor (ER)-positive breast cancer with ER-targeting drugs results in ER mutations and refractory unresponsive cancers. Androgen receptor (AR), which is expressed in 80%-95% of ER-positive breast cancers, could serve as an alternate therapeutic target. Although AR agonists were used in the past to treat breast cancer, their use is currently infrequent due to virilizing side effects. Discovery of tissue-selective AR modulators (SARMs) has renewed interest in using AR agonists to treat breast cancer. Using translational models, we show that AR agonist and SARM, but not antagonist, inhibit the proliferation and growth of ER-positive breast cancer cells, patient-derived tissues, and patient-derived xenografts (PDX). Ligand-activated AR inhibits wild-type and mutant ER activity by reprogramming the ER and FOXA1 cistrome and rendering tumor growth inhibition. These findings suggest that ligand-activated AR may function as a non-canonical inhibitor of ER and that AR agonists may offer a safe and effective treatment for ER-positive breast cancer.

Percutaneous radiofrequency-assisted excision of fibroadenomas.

INTRODUCTION: Fibroadenomas are a frequently encountered benign tumor that will occur in approximately 10% of women during their lifetime. Although the natural history would suggest fibroadenomas diagnosed with minimally invasive needle core biopsy can be safely observed, the majority are still surgically removed in the operating room. In an effort to limit the more than 500,000 surgical fibroadenoma removals performed each year, percutaneous excision has become a viable alternative. Percutaneous excision of intact fibroadenomas versus removal with a multiple core sampling technique has the dual potential advantage of causing minimal intervention combined with provision of adequate sample for thorough histopathology and margin analysis for confirmation of complete removal. An 18-month retrospective analysis was undertaken to evaluate the utilization of a new radiofrequency-assisted biopsy device in the successful removal and continued absence of histologically confirmed fibroadenomas on 4- to 6-month follow-up imaging. METHODS: Between April 2004 and November 2005, 100 patients underwent ultrasound- or stereotactic-guided, radiofrequency-assisted intact percutaneous excision of 106 diagnosed fibroadenomas of the breast. Patients were comprised of 100 women whose ages ranged from 18-70 years (median age, 45 years). RESULTS: Indications for the procedure included palpable mass, 77; abnormal mammogram, 13; and abnormal ultrasound, 10, as the patient's initial presentation. Ultrasound was used to guide the procedure in 82 patients, and stereotactic was used in 18 patients. One early study procedure was performed under general anesthesia; the remaining studies were performed under local anesthesia (1% lidocaine) using from 10 to 45 mL. On pathologic examination, the tumors ranged in size from 6 to 27 mm (mean diameter, 14 mm) and weighed from 0.6 to 2.0 g (mean weight, 1.0 g). Patients reported minimum discomfort related to the procedure; pain scores ranged from 0 to 10 (mean pain score, <1). Complications were minimal, with only 2 patients having bleeding, which was controlled by conservative measures. At the 4- to 6-month follow-up, 79 of 85 (93%) evaluable patients showed no physical or imaging evidence of residual fibroadenoma, an additional 5 patients have reported no physical findings or further complaints and have required no further need for medical evaluation, 8 have been lost to follow-up, and 2 have yet to be reevaluated. CONCLUSIONS: Percutaneous ultrasound- or stereotactic-guided, radiofrequency-assisted excision of fibroadenomas of the breast may be performed in an ambulatory setting under local anesthesia. The procedure provides intact specimens that in most cases appear to be completely removed after follow-up of 4 to 6 months. The procedure is well tolerated by patients and is associated with minimal complications.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology.

Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder with no clear etiology. Pathological hallmarks of the disease include the loss of dopaminergic neurons from the substantia nigra (SN) and the presence of Lewy bodies (LBs) (alpha-synuclein and ubiquitin-positive, eosinophilic, cytoplasmic inclusions) in many of the surviving neurons. Experimental modeling of PD neurodegeneration using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-pyridinium (MPP(+)) has identified changes in gene expression of different endoplasmic reticulum (ER) stress proteins associated with MPTP- and PD-related neurodegeneration. We show that the protein disulfide isomerase (PDI) family member pancreatic protein disulfide isomerase (PDIp), previously considered exclusively expressed in pancreatic tissue, is uniquely upregulated among PDI family members within 24 h following exposure of retinoic acid (RA)-differentiated SH-SY5Y human neuroblastoma cells to either 1 mM MPP(+) or 10 microM of the highly specific proteasome inhibitor lactacystin. RT-PCR confirms PDIp expression in brain of post-mortem human PD subjects and immunohistochemical studies demonstrate PDIp immunoreactivity in LBs. Collectively, these findings suggest that increased PDIp expression in dopaminergic (DA) neurons might contribute to LB formation and neurodegeneration, and that this increased PDIp expression may be the result of proteasome impairment.

Insulin degrading enzyme is expressed in the human cerebrovascular endothelium and in cultured human cerebrovascular endothelial cells.

Insulin degrading enzyme (IDE) is found in the cytosol, peroxisomes and plasma membrane of many cells. Although it preferentially cleaves insulin it can also cleave many other small proteins with diverse sequences including the monomeric form of the amyloid beta peptide (A beta). In the brain, IDE has been reported to be expressed predominantly in neurons. In this study, IDE expression was detected in cultured human cerebrovascular endothelial cells. Using laser capture microdissection followed by PCR analysis, it was found that IDE mRNA is expressed in human brain blood vessels. Using immunofluorescence and multiphoton microscopy IDE was localized to the endothelium of the cerebrovascular blood vessels in human.

The evolution of breast surgery: where technology and compassion meet.

The origins and development of The American Society of Breast Surgeons are closely tied to technology. Innovative technical progress means less-invasive procedures, more precise diagnoses, more outpatient services, and--with all of this--less pain and stress for our patients. It means more compassionate breast care for women. The Society's mission revolves around improving all aspects of patient care, and this is where technology and compassion meet.

Low-risk palpable breast masses removed using a vacuum-assisted hand-held device.

BACKGROUND: This study evaluates the safety, efficacy, and patient acceptance of a vacuum-assisted, hand-held biopsy device (Mammatome) in the percutaneous removal of breast masses using ultrasound guidance. METHODS: A multicenter, nonrandomized study evaluated 216 women with low-risk palpable lesions. Lesions 1.5 to 3.0 cm in size were removed using an 8-gauge probe. Those lesions <1.5 cm were removed with the 11-gauge probe. Follow-up evaluation was performed at 10 days and 6 months after biopsy. RESULTS: A total of 127 patients had biopsies using the 8-gauge probe, and 89 patients had biopsies using the 11-gauge probe. At 6-month follow-up, 98% of the lesions remained nonpalpable, 73% with no ultrasonographically visible evidence of the original lesion. Most complications were mild and anticipated. Most patients (98%) were satisfied with incision appearance, and 92% of patients would recommend the procedure to others. CONCLUSIONS: Percutaneous removal of palpable benign breast masses using the Mammotome system is feasible and safe, and yields high patient satisfaction. The results at 6 months after biopsy demonstrated the effectiveness of benign lesion removal, with correlative clinical data demonstrating lack of palpability and no need for additional procedures. Continuing evaluation of long-term efficacy is ongoing.

Percutaneous removal of benign breast masses using a vacuum-assisted hand-held device with ultrasound guidance.

BACKGROUND: This study evaluates the safety, efficacy, and patient acceptance of a vacuum-assisted, hand-held biopsy device (Mammotome) in percutaneous removal of breast masses using ultrasound guidance. METHODS: A multicenter, nonrandomized study evaluated 124 women with low-risk palpable lesions. Lesions 1.5 cm but

Updates in breast ultrasound.

Ultrasound is becoming an indispensable tool for the surgeon in the diagnosis and treatment of a variety of breast problems. Hands-on ultrasound education for surgeons and the ongoing improvements in imaging technology have made surgeon-performed breast ultrasound an effective method of identifying and diagnosing breast lesions and have increased the surgeon's ability to perform ultrasound-guided interventional procedures. This article reviews the current state of surgeon-performed breast ultrasound.

Traditional electrosurgery and a low thermal injury dissection device yield different outcomes following bilateral skin-sparing mastectomy: a case report.

INTRODUCTION: Although a skin- and nipple-sparing mastectomy technique offers distinct cosmetic and reconstructive advantages over traditional methods, partial skin flap and nipple necrosis remain a significant source of post-operative morbidity. Prior work has suggested that collateral thermal damage resulting from electrocautery use during skin flap development is a potential source of this complication. This report describes the case of a smoker with recurrent ductal carcinoma in situ (DCIS) who experienced significant unilateral skin necrosis following bilateral skin-sparing mastectomy while participating in a clinical trial examining mastectomy outcomes with two different surgical devices. This unexpected complication has implications for the choice of dissection devices in procedures requiring skin flap preservation. CASE PRESENTATION: The patient was a 61-year-old Caucasian woman who was a smoker with recurrent DCIS of her right breast. As part of the clinical trial, each breast was randomized to either the standard of care treatment group (a scalpel and a traditional electrosurgical device) or treatment with a novel, low thermal injury dissection device, allowing for a direct, internally controlled comparison of surgical outcomes. Post-operative follow-up at six days was unremarkable for both operative sites. At 16 days post-surgery, the patient presented with a significant wound necrosis in the mastectomy site randomized to the control study group. Following debridement and closure, this site progressively healed over 10 weeks. The contralateral mastectomy, randomized to the alternative device, healed normally. CONCLUSION: We hypothesize that thermal damage to the subcutaneous microvasculature during flap dissection may have contributed to this complication and that the use of a low thermal injury dissection device may be advantageous in select patients undergoing skin- and nipple-sparing mastectomy.

Pyroglutamate-Aß 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Aß 11 forming the central core.

N-terminal truncated amyloid beta (Aß) derivatives, especially the forms having pyroglutamate at the 3 position (AßpE3) or at the 11 position (AßpE11) have become the topic of considerable study. AßpE3 is known to make up a substantial portion of the Aß species in senile plaques while AßpE11 has received less attention. We have generated very specific polyclonal antibodies against both species. Each antibody recognizes only the antigen against which it was generated on Western blots and neither recognizes full length Aß. Both anti-AßpE3 and anti-AßpE11 stain senile plaques specifically in Alzheimer's disease cerebral cortex and colocalize with Aß, as shown by confocal microscopy. In a majority of plaques examined, AßpE11 was observed to be the dominant form in the innermost core. These data suggest that AßpE11 may serve as a generating site for senile plaque formation.

A novel ultrasound-guided electrosurgical loop device for intra-operative excision of breast lesions; an improvement in surgical technique.

BACKGROUND: The rate of involved margins after the excision of breast lesions using standard surgical techniques has historically ranged from approximately 20% to 45%. The localization and excision of breast lesions using intraoperative ultrasound has provided significant improvement. The authors report their collective experience with a novel technique utilizing the Phantom flexible loop electrosurgical device under ultrasound guidance for the intraoperative excision of breast lesions. METHODS: Seventy-nine breast lesions were excised using the Phantom device with intraoperative ultrasound. Rate of reexcision, excised specimen size, and size of the lumpectomy incision were reviewed. RESULTS: Fifty-nine of 79 lesions were malignant. Fifty-one (86.4%) had noninvolved final margins; 8 (13.6%) involved margins. The average specimen size was 21.3 cm3, compared with a range of 60 to 100 cm3 in the literature. CONCLUSIONS: These results demonstrate improved efficiency, a decrease in the volume of excision, smaller incision size, and very low need for reoperation secondary to involved margins using the Phantom device for real-time, ultrasound-guided lumpectomy.

Four-year clinical update from the American Society of Breast Surgeons MammoSite brachytherapy trial.

BACKGROUND: We present a 4-year update on the efficacy, cosmetic results, and complications of MammoSite breast brachytherapy in patients enrolled in the American Society of Breast Surgeons registry trial. METHODS: A total of 1,449 breasts in 1,440 patients with early stage breast cancer undergoing breast-conserving therapy were treated with adjuvant, accelerated partial breast irradiation (APBI) (34 Gy in 3.4-Gy fractions) delivered with the MammoSite device. The median follow-up period for the entire group was 36.1 months. RESULTS: The 3-year actuarial rate of ipsilateral breast tumor recurrence was 2.15%. The 3-year actuarial rate of axillary recurrence was .36%. Complication rates were as follows: infection, 9.5%; seroma, 26.8% (symptomatic seroma, 12.7%); and fat necrosis, 2.0%. The percentages of breasts with good or excellent cosmetic results were as follows: 12 months, 95%; 24 months, 94%; 36 months, 94%; and 48 months, 91%. CONCLUSIONS: Locoregional control, complications, and cosmetic outcomes from MammoSite APBI at the 4-year update are acceptable and similar to results seen with other forms of APBI.

Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures.

Insulin degrading enzyme (IDE) is expressed in the brain and may play an important role there in the degradation of the amyloid beta peptide (Abeta). Our results show that cultured human cerebrovascular endothelial cells (HCECs), a primary component of the blood-brain barrier, express IDE and may respond to exposure to low levels of Abeta by upregulating its expression. When radiolabeled Abeta is introduced to the medium of cultured HCECs, it is rapidly degraded to smaller fragments. We believe that this degradation is largely the result of the action of IDE, as it can be substantially blocked by the presence of insulin in the medium, a competitive substrate of IDE. No inhibition is seen when an inhibitor of neprilysin, another protease that may degrade Abeta, is present in the medium. Our evidence suggests that the action of IDE occurs outside the cell, as inhibitors of internalization fail to affect the rate of the observed degradation. Further, our evidence suggests that degradation by IDE occurs on the plasma membrane, as much of the IDE present in HCECs was biotin-labeled by a plasma membrane impermeable reagent. This activity seems to be polarity dependent, as measurement of Abeta degradation by each surface of differentiated HCECs shows greater degradation on the basolateral (brain-facing) surface. Thus, IDE could be an important therapeutic target to decrease the amount of Abeta in the cerebrovasculature.