Re-emphasizing the concept of adequacy of intraoperative assessment of the axillary sentinel lymph nodes for identifying nodal positivity during breast cancer surgery

BACKGROUND: Although sentinel lymph node (SLN) biopsy is a standard of care for the evaluation of the axillary lymph nodes during breast cancer surgery, a substantial degree of variation exists among individual surgeons as to what represents an adequate assessment. The aim of the current study was to assess when metastatic disease was first identified within consecutively harvested SLN candidates for invasive breast cancers demonstrating a positive SLN. METHODS: We retrospectively analyzed a series of 400 breast cancers from a recently published prospective randomized clinical trial. A combined radiocolloid and blue dye technique was used. All potential SLN candidates, containing counts of at least 10% of the hottest SLN and/or containing blue dye, were harvested and were consecutively numbered in the order of the decreasing level of counts (with the hottest SLN representing SLN #1). RESULTS: Among 371 invasive breast cancers, a SLN was identified within 353 cases (95%). Mean number of SLNs identified was 2.5 (range, 1 to 9), with a single SLN identified in 104 (29%) cases, two identified in 110 (31%), three identified in 73 (21%), four identified in 35 (10%), five identified in 16 (5%), and six or more identified in 15 (4%). A positive SLN was found in 104 (29%) cases. SLN #1 was the first positive SLN in 86 (83%). SLN #2 was the first positive SLN in 15 (14%). SLN #3, SLN #4, and SLN #5 were the first positive SLN in one case (1%) each. A positive SLN was found in 18% (19/104) of cases when a single SLN was identified, as compared to in 34% (85/249) when two or more SLNs were identified (P = 0.003). CONCLUSION: The accurate and optimal assessment of the axilla during breast cancer surgery requires persistence and diligence for attempting to identify all potential SLN candidates in order to avoid failing to recognize a positive SLN. The scenario in which only a single negative SLN candidate is intraoperatively identified is one that should raise some concern to the operating surgeon

Accurate path integration in continuous attractor network models of grid cells

Grid cells in the rat entorhinal cortex display strikingly regular firing responses to the animal's position in 2-D space and have been hypothesized to form the neural substrate for dead-reckoning. However, errors accumulate rapidly when velocity inputs are integrated in existing models of grid cell activity. To produce grid-cell-like responses, these models would require frequent resets triggered by external sensory cues. Such inadequacies, shared by various models, cast doubt on the dead-reckoning potential of the grid cell system. Here we focus on the question of accurate path integration, specifically in continuous attractor models of grid cell activity. We show, in contrast to previous models, that continuous attractor models can generate regular triangular grid responses, based on inputs that encode only the rat's velocity and heading direction. We consider the role of the network boundary in the integration performance of the network and show that both periodic and aperiodic networks are capable of accurate path integration, despite important differences in their attractor manifolds. We quantify the rate at which errors in the velocity integration accumulate as a function of network size and intrinsic noise within the network. With a plausible range of parameters and the inclusion of spike variability, our model networks can accurately integrate velocity inputs over a maximum of ~10–100 meters and ~1–10 minutes. These findings form a proof-of-concept that continuous attractor dynamics may underlie velocity integration in the dorsolateral medial entorhinal cortex. The simulations also generate pertinent upper bounds on the accuracy of integration that may be achieved by continuous attractor dynamics in the grid cell network. We suggest experiments to test the continuous attractor model and differentiate it from models in which single cells establish their responses independently of each other

GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER⁺) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER⁺breast cancer cells</p> <p>Methods</p> <p>We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.</p> <p>Results</p> <p>GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.</p> <p>Conclusion</p> <p>Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER⁺breast cancer.</p

Combined approach of perioperative 18F-FDG PET/CT imaging and intraoperative 18F-FDG handheld gamma probe detection for tumor localization and verification of complete tumor resection in breast cancer

<p>Abstract</p> <p>Background</p> <p>¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) has become an established method for detecting hypermetabolic sites of known and occult disease and is widely used in oncology surgical planning. Intraoperatively, it is often difficult to localize tumors and verify complete resection of tumors that have been previously detected on diagnostic PET/CT at the time of the original evaluation of the cancer patient. Therefore, we propose an innovative approach for intraoperative tumor localization and verification of complete tumor resection utilizing ¹⁸F-FDG for perioperative PET/CT imaging and intraoperative gamma probe detection.</p> <p>Methods</p> <p>Two breast cancer patients were evaluated. ¹⁸F-FDG was administered and PET/CT was acquired immediately prior to surgery. Intraoperatively, tumors were localized and resected with the assistance of a handheld gamma probe. Resected tumors were scanned with specimen PET/CT prior to pathologic processing. Shortly after the surgical procedure, patients were re-imaged with PET/CT utilizing the same preoperatively administered ¹⁸F-FDG dose.</p> <p>Results</p> <p>One patient had primary carcinoma of breast and a metastatic axillary lymph node. The second patient had a solitary metastatic liver lesion. In both cases, preoperative PET/CT verified these findings and demonstrated no additional suspicious hypermetabolic lesions. Furthermore, intraoperative gamma probe detection, specimen PET/CT, and postoperative PET/CT verified complete resection of the hypermetabolic lesions.</p> <p>Conclusion</p> <p>Immediate preoperative and postoperative PET/CT imaging, utilizing the same ¹⁸F-FDG injection dose, is feasible and image quality is acceptable. Such perioperative PET/CT imaging, along with intraoperative gamma probe detection and specimen PET/CT, can be used to verify complete tumor resection. This innovative approach demonstrates promise for assisting the oncologic surgeon in localizing and verifying resection of ¹⁸F-FDG positive tumors and may ultimately positively impact upon long-term patient outcomes.</p

Ductal carcinoma in situ and sentinel lymph node metastasis in breast cancer

<p>Abstract</p> <p>Background</p> <p>The impact of sentinel lymph node biopsy on breast cancer mimicking ductal carcinoma in situ (DCIS) is a matter of debate.</p> <p>Methods</p> <p>We studied the rate of occurrence of sentinel lymph node metastasis in 255 breast cancer patients with pure DCIS showing no invasive components on routine pathological examination. We compared this to the rate of occurrence in 177 patients with predominant intraductal-component (IDC) breast cancers containing invasive foci equal to or less than 0.5 cm in size.</p> <p>Results</p> <p>Most of the clinical and pathological baseline characteristics were the same between the two groups. However, peritumoral lymphatic permeation occurred less often in the pure DCIS group than in the IDC-predominant invasive-lesion group (1.2% vs. 6.8%, p = 0.002). One patient (0.39%) with pure DCIS had two sentinel lymph nodes positive for metastasis. This rate was significantly lower than that in patients with IDC-predominant invasive lesions (6.2%; p < 0.001).</p> <p>Conclusions</p> <p>Because the rate of sentinel lymph node metastasis in pure DCIS is very low, sentinel lymph node biopsy can safely be omitted.</p

Gamma probes and their use in tumor detection in colorectal cancer

The purpose of this article is to summarize the role of gamma probes in intraoperative tumor detection in patients with colorectal cancer (CRC), as well as provide basic information about the physical and practical characteristics of the gamma probes, and the radiopharmaceuticals used in gamma probe tumor detection. In a significant portion of these studies, radiolabeled monoclonal antibodies (Mabs), particularly 125I labeled B72.3 Mab that binds to the TAG-72 antigen, have been used to target tumor. Studies have reported that intraoperative gamma probe radioimmunodetection helps surgeons to localize primary tumor, clearly delineate its resection margins and provide immediate intraoperative staging. Studies also have emphasized the value of intraoperative gamma probe radioimmunodetection in defining the extent of tumor recurrence and finding sub-clinical occult tumors which would assure the surgeons that they have completely removed the tumor burden. However, intraoperative gamma probe radioimmunodetection has not been widely adapted among surgeons because of some constraints associated with this technique. The main difficulty with this technique is the long period of waiting time between Mab injection and surgery. The technique is also laborious and costly. In recent years, Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) use in gamma probe tumor detection surgery has renewed interest among surgeons. Preliminary studies during surgery have demonstrated that use of FDG in gamma probe tumor detection during surgery is feasible and useful

DAX-1 expression in human breast cancer: comparison with estrogen receptors ER-α, ER-β and androgen receptor status

BACKGROUND: So far there have been no reports on the expression pattern of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) in human breast cells and its relationship to the estrogen receptors, ER-α and ER-β, and the androgen receptor (AR). METHODS: In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas. RESULTS: In BBD and breast carcinomas, DAX-1 was present in both the nuclei and the cytoplasm of epithelial cells, although in infiltrative carcinomas the percentage of nuclear immunoreaction was higher than in CIS. An important relation was observed between DAX-1 and AR expression and between this orphan receptor and nodal status. CONCLUSION: DAX-1 might modify the AR and ER-β intracellular location, and because a direct positive relation between the expression of these three receptors was found it could be assumed that the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies

A Longitudinal Comparison of Arm Morbidity in Stage I–II Breast Cancer Patients Treated with Sentinel Lymph Node Biopsy, Sentinel Lymph Node Biopsy Followed by Completion Lymph Node Dissection, or Axillary Lymph Node Dissection

Background:\ud Long-term shoulder and arm function following sentinel lymph node biopsy (SLNB) may surpass that following complete axillary lymph node dissection (CLND) or axillary lymph node dissection (ALND). We objectively examined the morbidity and compared outcomes after SLNB, SLNB + CLND, and ALND in stage I/II breast cancer patients.\ud \ud Materials and Methods:\ud Breast cancer patients who had SLNB (n = 51), SLNB + CLND (n = 55), and ALND (n = 65) were physically examined 1 day before surgery (T0), and after 6 (T1), 26 (T2), 52 (T3), and 104 (T4) weeks. Differences in 8 parameters between the affected and unaffected arms were calculated. General linear models were computed to examine time, group, and interaction effects.\ud \ud Results:\ud All outcomes changed significantly, mostly nonlinearly, over time (T0–T4). Between T1 and T4, limitations decreased in abduction (all groups); anteflexion, abduction-exorotation, abduction strength (SLNB + CLND, ALND); flexion strength (SLNB + CLND); and arm volume (SLNB, SLNB + CLND). At T4, limitations in anteflexion (SLNB, ALND), abduction (SLNB + CLND, ALND), exorotation (ALND), abduction-exorotation (all groups), and volume (SLNB + CLND, ALND) increased significantly compared with T0. The SLNB group showed an advantage in anteflexion, abduction, abduction-exorotation, and volume. Groups changed significantly but differently over time in anteflexion, abduction, abduction/exorotation, abduction strength, flexion strength, and volume. Effect sizes varied from 0.19 to 0.00.\ud \ud Conclusion:\ud Initial declines in range of motion and strength were followed by recovery, although not always to presurgery levels. Range of motion and volume outcomes were better for SLNB than ALND, but not strength. SLNB surpassed SLNB + CLND in 2 of the range of motion variables. The clinical relevance of these results is negligible

Empirical studies on informal patient payments for health care services: a systematic and critical review of research methods and instruments

<p>Abstract</p> <p>Background</p> <p>Empirical evidence demonstrates that informal patient payments are an important feature of many health care systems. However, the study of these payments is a challenging task because of their potentially illegal and sensitive nature. The aim of this paper is to provide a systematic review and analysis of key methodological difficulties in measuring informal patient payments.</p> <p>Methods</p> <p>The systematic review was based on the following eligibility criteria: English language publications that reported on empirical studies measuring informal patient payments. There were no limitations with regard to the year of publication. The content of the publications was analysed qualitatively and the results were organised in the form of tables. Data sources were Econlit, Econpapers, Medline, PubMed, ScienceDirect, SocINDEX.</p> <p>Results</p> <p>Informal payments for health care services are most often investigated in studies involving patients or the general public, but providers and officials are also sample units in some studies. The majority of the studies apply a single mode of data collection that involves either face-to-face interviews or group discussions.</p> <p>One of the main methodological difficulties reported in the publication concerns the inability of some respondents to distinguish between official and unofficial payments. Another complication is associated with the refusal of some respondents to answer questions on informal patient payments.</p> <p>We do not exclude the possibility that we have missed studies that reported in non-English language journals as well as very recent studies that are not yet published.</p> <p>Conclusions</p> <p>Given the recent evidence from research on survey methods, a self-administrated questionnaire during a face-to-face interview could be a suitable mode of collecting sensitive data, such as data on informal patient payments.</p

Axillary lymph node dissection for breast cancer utilizing Harmonic Focus®

<p>Abstract</p> <p>Background</p> <p>For patients with axillary lymph node metastases from breast cancer, performance of a complete axillary lymph node dissection (ALND) is the standard approach. Due to the rich lymphatic network in the axilla, it is necessary to carefully dissect and identify all lymphatic channels. Traditionally, these lymphatics are sealed with titanium clips or individually sutured. Recently, the Harmonic Focus^®, a hand-held ultrasonic dissector, allows lymphatics to be sealed without the utilization of clips or ties. We hypothesize that ALND performed with the Harmonic Focus^®will decrease operative time and reduce post-operative complications.</p> <p>Methods</p> <p>Retrospective review identified all patients who underwent ALND at a teaching hospital between January of 2005 and December of 2009. Patient demographics, presenting pathology, treatment course, operative time, days to drain removal, and surgical complications were recorded. Comparisons were made to a selected control group of patients who underwent similar surgical procedures along with an ALND performed utilizing hemostatic clips and electrocautery. A total of 41 patients were included in this study.</p> <p>Results</p> <p>Operative time was not improved with the use of ultrasonic dissection, however, there was a decrease in the total number of days that closed suction drainage was required, although this was not statistically significant. Complication rates were similar between the two groups.</p> <p>Conclusion</p> <p>In this case-matched retrospective review, there were fewer required days of closed suction drainage when ALND was performed with ultrasonic dissection versus clips and electrocautery.</p