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Negative surgical margins at the time of lumpectomy are essential to achieving optimal patient outcomes. Numerous techniques have been investigated to enhance the accuracy of intraoperative margin analysis. Achieving clear margins at the time of lumpectomy is important because it can facilitate time to treatment of the breast cancer patient and reduce the need for subsequent reoperative procedures to achieve negative margins.

Although conservative breast surgery is favored for the treatment of early stage breast cancer, mastectomy still has a place in the armamentarium of the surgeon. In the case of T3, multicentric, and inflammatory breast cancer, it is the treatment of choice. From the patient’s point of view, it is a good choice if they don’t want to or cannot have radiation therapy. It can be accompanied by skin sparing and nipple skin sparing techniques and reconstruction to improve the aesthetic outcome.

This chapter provides the reader with an overview of the key milestones in the development of the current understanding and management of breast cancer. Although the milestones listed here are important ones, the list is by no means comprehensive. The historical evolution of breast cancer treatment begins with the ancient civilizations, moves through the Middle Ages, and the 18th and 19th centuries and broadly covers the advent of breast reconstruction, radiotherapy, chemotherapy, and advances in cancer biology during the 20th century through current therapies.

This chapter describes the evolution of breast cancer ideology, detection, and treatment, which resulted in advancement from the radical mastectomy to modern day breast conservation therapy. Radical mastectomy is necessary for the patient with locally advanced disease involving the pectoralis muscles, and the technique is thoroughly described.

The aberrations of normal development and involution (ANDI) classification of benign breast disorder (BBD) provides an overall framework for benign conditions of the breast that encompasses both pathogenesis and the degree of abnormality. It is a bidirectional framework based on the fact that most BBDs arise from normal physiologic processes: one component defines BBD along a spectrum from normal to mild abnormality (“disorder”) to severe abnormality (“disease”); the other component defines the pathogenesis of the condition. Together these two components provide a comprehensive framework into which most BBDs can be fit. This scheme is based on the recommendations of the international multidisciplinary working group held in 1992.

Introduction: The surgical techniques used in mastectomy are in constant evolution because of advancement in knowledge and the needs of patients. Methodology: Literature review of different types of mastectomy. Results: Halsted radical mastectomy (RM), the first effective surgery in treating breast cancer, was later modified by Patey, Madden, and others to preserve the pectoralis major muscle. Studies showed comparable survival outcomes between the two types of mastectomy. The modified radical mastectomy (MRM) became the standard treatment for women with stage I and II breast cancer in the 1970s. However, the axillary lymph node dissection (ALND), a part of modified radical mastectomy, was associated with significant side effects. Hence, the simple mastectomy (SM) was developed to spare the ALND and focus on treating the local disease only. Studies showed that survival after SM with or without radiation was comparable to those with RM. Recently, adjuvant systemic treatment has been shown to significantly improve disease-free and overall survival in patients with node-positive breast cancer, which requires nodal staging to guide therapy. Sentinel lymph node biopsy (SLNB) was invented to provide adequate pathologic nodal status in clinically negative axilla. Today, SM coupled with SLNB has largely replaced the MRM. Additional modifications to mastectomy by sparing the skin and the nipple areolar complex further increased its popularity. Discussion: The evolution of surgical treatment of breast cancer is governed by the principles of controlling the local disease and providing adequate pathology with minimal adverse effects. The validity of any new procedure requires confirmation.

As the number of breast cancer survivors increases, more women are at risk for locoregional recurrence of their initial tumor or the growth of a new primary breast cancer. Clinicians managing these patients should follow published breast cancer–specific and general cancer survivorship guidelines. Recent reports suggest that reducing the rate of locoregional failure improves overall survival. Gene expression studies have indentified several breast cancer subtypes that correlate with prognosis, response to therapy, and recurrence. Patients experiencing a locoregional recurrence require comprehensive multidisciplinary planning and treatment. Prior staging procedures, local treatments, and systemic treatments significantly influence the multimodal managment of these patients. Complete excision with negative margins and radiation therapy, if possible, is the preferred local therapy. Rarely, radical surgery and reconstruction may be required to achieve tumor-free margins. The type, dose, duration, and response to any initial systemic therapy must be carefully reviewed in the treatment planning of these patients. Ideally, all these patients should be presented at a multidisciplinary breast cancer conference for comprehensive multimodal treatment planning.

This chapter outlines the anatomy, blood, and nerve supply of the mammary gland and its embryologic development and hormonal influences through the various stages of life as well as the axilla, chest wall, and related metastatic sites.

Background The Intrabeam (Carl Zeiss) brachytherapy device (IB) is an electronic brachytherapy device that can be used to deliver low energy x-rays (50 kV) to a lumpectomy cavity at the time of lumpectomy for breast cancer. Reported experience with IB for breast cancer in the United States has been extremely limited. Here we describe our experience and analyze the impact of IB on our multidisciplinary breast cancer program. Study Design This is a retrospective review of a prospectively collected breast cancer database. Patient characteristics, treatment characteristics, recurrence, and cosmesis were analyzed. Cost data were also analyzed to determine the impact of IB on the breast cancer program. Results Seventy-eight patients underwent 80 IB treatments in this series between November 2010 and October 2012. Most patients had invasive ductal carcinoma. Mean total operative time for patients receiving lumpectomy, sentinel node biopsy, and IB was 132 minutes (range 79 to 243 minutes). Intrabeam brachytherapy was the only adjuvant radiation required in 81% of patients, and only 15% of patients required additional operation after the index lumpectomy procedure. At 12 months of follow-up, cosmesis was good to excellent in 92% of patients. There have been no local recurrences in patients treated in this series. Intrabeam brachytherapy is associated with considerably lower costs ($1,857) than conventional whole breast radiation therapy ($9,653). Conclusions Implementation of IB impacts treatment planning and operating room use in a multidisciplinary breast cancer program. The safety profile, ease of administration, and reduced costs of IB favor its more widespread use in selected patients with early-stage breast cancer.

The early development of total parenteral nutrition and its evolution as an adjunct to the nutritional, metabolic, and antineoplastic therapy of cancer patients is described. Examples related to the sine wave of responses to new data and discovery are placed in context to understand better past, present, and how and where to proceed in the future to achieve optimal results from multimodal comprehensive management of patients with malignancies. Practical and philosophic thoughts are proffered to justify continued, intensified, logical, controlled clinical studies directed toward establishing the most rational, safe, and effective use of total parenteral nutrition in treating patients with cancer.

Background Percutaneous needle biopsy, also known as minimally invasive breast biopsy (MIBB), has become the gold standard for the initial assessment of suspicious breast lesions. The purpose of this study is to determine modern rates of MIBB and open breast biopsy. Methods The Florida Agency for Health Care Administration outpatient surgery and procedure database was queried for patients undergoing open surgical biopsy and MIBB between 2003 and 2008. Results Although there was an increase in the use of MIBB, the overall rate of open surgical biopsy remained high (∼30%). A reduction in the open biopsy rate from 30% to 10% could be associated with a charge reduction of >$37.2 million per year. Conclusions The current rate of open surgical breast biopsy remains high. Interventions and quality initiatives are warranted, which could lead to a reduction in unnecessary operations for women, improved patient care, and a reduction in breast health care costs.

Background Local recurrence remains the major cause of death in patients with retroperitoneal sarcoma (RPS). There is no consensus regarding management of patients with recurrent RPS. Study Design We performed a retrospective review of patients with recurrent RPS managed at 2 tertiary care centers between 1983 and 2008. Presentation, treatments, and outcomes were analyzed. Results Seventy-eight patients were identified and analyzed. Sixteen patients (22%) presented with concurrent metastatic disease; survival in this subset of patients was poor (median 12 months). Forty-eight patients underwent resection of the first local recurrence of RPS. Palliation of tumor-related symptoms was achieved in 79% with operation. Survival was significantly better in patients having complete (p = 0.001) and incomplete resection (p = 0.02) compared with patients having biopsy only. Among patients with first local recurrence, high grade tumor (p = 0.0001) and no resection (p = 0.007) were significantly associated with reduced survival. On multivariate analysis, radiation therapy, multifocality, histologic subtype, and time to local recurrence did not significantly correlate with survival. Second and third local recurrences occurred at shorter intervals compared with first local recurrence and were less likely to be completely resectable. Patients undergoing resection of second and third local recurrences had survival similar to that in patients undergoing resection of first local recurrence. Conclusions Tumor biology (high grade) is a significant prognostic factor for patients with recurrent RPS. Resection should be considered in patients with first and subsequent local recurrences (even if multifocal) of RPS because it is associated with improved survival. Operation should also be considered for palliation of symptoms in patients in whom resection is not possible.

The role of operation in patients with Multiple Endocrine Neoplasia Type 1 (MEN-1) and Zollinger-Ellison Syndrome (ZES) is controversial. Our institutional bias for this disease has, in general, been towards aggressive imaging and operative removal of localized gastrinomas. Few studies have reported long-term outcomes in patients with MEN-1 and ZES. A single institution retrospective review of all patients with MEN-1 and ZES from 1970 to present was performed. Twelve patients were identified (median age = 37 years at diagnosis). The median follow-up was 18 years from diagnosis of ZES. Common symptoms associated with gastrinoma in these patients were diarrhea (n = 6), abdominal pain (n = 4), and nausea/vomiting (n = 4). Most commonly identified sites of gastrinoma were: pancreas (n = 10), duodenum (n = 4), lymph nodes (n = 3), and liver (n = 1). Fifteen celiotomies were performed in total (median = 1; range 0-3). Operative procedures performed included: distal pancreatectomy (n = 4), acid reducing procedure (n = 4), enucleation of pancreatic gastrinoma (n = 3), duodenal resection (n = 3), pancreaticoduodenectomy (n = 1), and other (n = 7). One patient had a transient biochemical cure after operation lasting 3 years. Only one patient in this series had documented liver metastases of gastrinoma and no patients expired of metastatic gastrinoma. There was one postoperative patient death, secondary to respiratory arrest thought to be a result of aspiration or pulmonary embolus. Three patients died of nondisease related causes, and seven patients were alive at the time of last follow-up. Operations rarely result in biochemical cures in patients with MEN-1 and ZES. In our experience, resection of localized gastrinomas often did not require extended surgical resection and were associated with excellent long-term outcomes.

Purpose To characterize the magnitude of volume change in the postoperative tumor bed before and during radiotherapy, and to identify any factors associated with large volumetric change. Methods and Materials Thirty-six consecutive patients with early-stage or preinvasive breast cancer underwent breast-conserving therapy at our institution between June 2006 and October 2007. Computed tomography (CT) scans of the breast were obtained shortly after surgery, before the start of radiotherapy (RT) for treatment planning, and, if applicable, before the tumor bed boost. Postoperative changes, seroma, and surgical clips were used to define the tumor bed through consensus agreement of 3 observers (B.P., D.I., and J.L.). Multiple variables were examined for correlation with volumetric change. Results Between the first and last scan obtained (median time, 7.2 weeks), the tumor bed volume decreased at least 20% in 86% of patients ( n = 31) and at least 50% in 64% of patients ( n = 23). From the postoperative scan to the planning scan (median time, 3 weeks), the tumor bed volume decreased by an average of 49.9%, or approximately 2.1% per postoperative day. From planning scan to boost scan (median interval, 7 weeks), the median tumor bed volume decreased by 44.6%, at an average rate of 0.95% per postoperative day. No single factor was significantly associated with a change in tumor bed volume greater than 20%. Conclusions The average postlumpectomy cavity undergoes dramatic volumetric change after surgery and continues this change during RT. The rate of change is inversely proportional to the duration from surgery. In this study no factors studied predicted large volumetric change.

Nodular fasciitis (NF) typically presents as an enlarging soft tissue mass with imaging characteristics that may be suggestive of soft tissue sarcoma or desmoid tumor. This presentation can make a correct diagnosis and management of patients with NF a challenge. We report our recent experience with two cases of NF that were both referred with a diagnoses of “soft tissue sarcoma.” Patient 1 was a 46-year-old woman who had undergone breast augmentation and was referred with a rapidly growing firm mass on the left chest wall beneath the breast implant. Computed tomography of the chest noted the mass to be 8 cm X 11 cm in size displacing the implant laterally with no radiological involvement of the bony structures of the chest. Core biopsy was suggestive of inflammation only. Given the clinical suspicion of malignancy, the patient underwent resection of the mass with implant removal. Final pathology showed NF. Patient 2 was a 65-year-old woman referred with an enlarging tender 3-cm infraclavicular mass and a clinical diagnosis of “soft tissue sarcoma.” Preoperative biopsy suggested NF. The patient underwent complete excision, which confirmed the diagnosis. These cases highlight the clinical issues associated with management of patients with NF. Current approaches to evaluation, diagnosis, and treatment of NF are discussed.

Background Most patients with Zollinger-Ellison Syndrome (ZES), even those in whom gastrinoma is found and resected at initial operation, will suffer from persistent or recurrent disease in longterm followup. There is currently no consensus about managing patients with recurrent or persistent ZES. Our unit has historically maintained an aggressive approach toward monitoring and reoperation for patients with sporadic ZES. Study Design We performed a review of a consecutive series of patients evaluated and managed at our institution between 1970 and 2007 for ZES. "Biochemical cure" was defined as normal serum gastrin assays and negative imaging studies. Reoperations were performed for elevations in serum gastrin assays and positive findings on imaging studies. Results Fifty-two patients with sporadic ZES were analyzed. Median followup was 14 years. Among patients with sporadic ZES, 37 patients underwent operative management. The most common operations were resection of duodenal gastrinoma (n=8) and total gastrectomy (n=7). Nine patients underwent 15 reoperations for recurrent or persistent disease. "Biochemical cure" was obtained in four patients (44%) undergoing reoperation for ZES. Three of these patients remained without evidence of recurrence at 4, 9, and 12 years after their curative re-resection. Only one of nine patients who underwent reoperation died of metastatic gastrinoma. Conclusions Primary and reoperative surgery in patients with sporadic ZES results in a significant rate of "biochemical cure." In selected patients with recurrent or persistent disease, reoperation for resection of gastrinoma is associated with excellent longterm survival and is warranted.

Pathologic nipple discharge often presents a diagnostic and therapeutic dilemma for clinicians. We present two patients with pathologic nipple discharge in whom breast MR facilitated preoperative identification of and management of otherwise occult index lesions. Breast MR should be considered in the toolbox for evaluation of occult nipple discharge when other available strategies have failed to demonstrate an underlying etiology for the pathologic discharge. The use of breast MR in this setting may permit directed evaluation and management of potentially malignant lesions.

Idiopathic granulomatous mastitis, also known as idiopathic granulomatous lobular mastitis, is a benign breast lesion that represents both a diagnostic and therapeutic dilemma. We report two cases of granulomatous mastitis recently evaluated and managed at our institution. To better understand this rare disease, we analyzed treatment outcomes in reported cases of granulomatous mastitis. One hundred sixteen cases were subsequently analyzed. Primary management strategies included observation (n = 9), steroids (n = 29), partial mastectomy (n = 75), and mastectomy (n = 3). Success rates with each treatment were observation, 56 per cent; steroids, 42 per cent; partial mastectomy, 79 per cent; and mastectomy, 100 per cent. Based on this analysis, we propose a clinically useful algorithm for both workup and management of these challenging cases.

Purpose: Delayed breast cellulitis (DBC) is characterized by the late onset of breast erythema, edema, tenderness, and warmth. This retrospective study analyzes the risk factors and clinical course of DBC. Methods and Materials: From 1985 through 2004, 580 sequential women with 601 stage T0–2N0–1 breast cancers underwent breast conserving therapy. Cases of DBC were identified according to accepted clinical criteria: diffuse breast erythema, edema, tenderness, and warmth occurring >3 months after definitive surgery and >3 weeks after radiotherapy. Potential risk factors analyzed included patient comorbidity, operative technique, acute complications, and details of adjunctive therapy. Response to treatment and long-term outcome were analyzed to characterize the natural course of this syndrome. Results: Of the 601 cases, 16%, 52%, and 32% were Stage 0, I, and II, respectively. The overall incidence of DBC was 8% (50/601). Obesity, ecchymoses, T stage, the presence and aspiration of a breast hematoma/seroma, removal of >5 axillary lymph nodes, and arm lymphedema were significantly associated with DBC. The median time to onset of DBC from the date of definitive surgery was 226 days. Ninety-two percent of DBC patients were empirically treated with antibiotics. Fourteen percent required more invasive intervention. Twenty-two percent had recurrent episodes of DBC. Ultimately, 2 patients (4%) underwent mastectomy for intractable breast pain related to DBC. Conclusion: Although multifactorial, we believe DBC is primarily related to a bacterial infection in the setting of impaired lymphatic drainage and may appear months after completion of radiotherapy. Invasive testing before a trial of antibiotics is generally not recommended.

Fifty-eight patients with Dukes' C classification of carcinoma of the large bowel were placed on adjuvant immuno- or chemoimmunotherapy with Bacillus calmette guerin (BCG) or combination of 5-fluorouracil (5-FU) plus BCG following primary and definitive surgery, and were followed for up to 21 months. Of twenty-six patients receiving BCG alone by scarification, five have relapsed with 75% of freedom from disease estimated at 15.1 months compared with 10.1 months in a group of carefully selected historical controls who had surgery alone (p = 0.12). The survival of all patients receiving BCG alone has not reached the 75 percentile yet, and the difference from controls is currently estimated at the 18% level. The combination of 5-FU plus BCG (studied in 32 patients) may be superior to BCG alone at this time, in that it appears to more effectively protect against tumor recurrence (75 percentile not yet reached compared to control, (p = 0.08). The survival of patients on 5-FU plus BCG also appears to be improved (p = 0.09). No patients have expired compared to a 75 percentile survival of 16.6 months in the control. Serial determination of plasma CEA was crucial in the clinical follow-up of these patients. Frequent CEA detetminations have led to early detection of clinical relapse. In the elevation of CEA suggests tumor recurrence with a high degree of probability in patients with past history of cancer of the large bowel.

While sentinel lymph node biopsy (SLNB) has virtually replaced axillary dissection as the initial diagnostic procedure for invasive breast cancer, the role of SLNB in ductal carcinoma in situ (DCIS) remains controversial. The purpose of this study was to review our experience with SLNB in DCIS. All patients with DCIS or DCIS with microinvasion (DCISM) who underwent SLNB from June 1997 to April 2002 at the University of Florida were included for analysis. The indications for SLNB were at the discretion of the treating surgeon. Lymphatic mapping involved a sequential dermal-peritumoral radiocolloid injection and dynamic lymphoscintigraphy followed by an intraoperative assessment of radioactivity with a handheld gamma probe. All sentinel lymph nodes (SLNs) with radioactive counts>or=10% of the ex vivo counts of the most radioactive SLN were removed. Pathologic analysis consisted of slicing the SLN at 2 mm intervals for permanent section. All paraffin blocks of the SLNs were step sectioned in 4 microm sections (92 microm spacing) through the entire lymph node. Slides were then stained with an immunohistochemical stain for cytokeratin (AE1/AE3) and evaluated by microscopy. Nodal metastases were classified using the 6th edition of the American Joint Committee on Cancer (AJCC) staging manual. From April 1998 to April 2002, 43 patients with DCIS underwent SLNB at the University of Florida. Seven patients (16%) with multifocal or extensive DCIS (five patients) or DCISM (two patients) who underwent SLNB had a positive sentinel node. Two of the three patients considered positive by immunohistochemistry alone had either DCISM or invasive disease. Four (80%) of the five patients with extensive DCIS and a positive sentinel node were ultimately determined to have invasive or microinvasive disease. While SLNB remains controversial in DCIS, our data suggest that patients with extensive DCIS should undergo SLNB at the initial procedure to avoid the need for a second operation. Data from clinical trials are needed to determine the impact of SLNB results on overall survival in patients with DCIS.

My colleagues and I have been using intraoperative frozen-section analysis (FSA) to evaluate lumpectomy margins in an attempt to reduce the number of additional operations that patients with ductal carcinoma in situ or stage I and II breast cancer would have to endure. We review our experience in breast-conservation therapy (BCT) at the University of Florida (Gainesville) to determine the effectiveness of this approach.Operative reports, operative logs, and pathology reports were retrospectively reviewed for patients who had BCT from January 2001 to January 2004. Ninety-seven patients (116 operations) were reviewed.Nineteen patients required an additional operation (19.6%). Forty-three patients had positive margins on paraffin-embedded histologic analysis (44.3%). Accuracy of FSA was 84% when evaluated on a per-case basis, and 96% on a per-slide basis. False negatives were identified in 22 patients, affecting the operative pathway of 19 patients (19.6%) and were identified more frequently in cases of ductal carcinoma in situ (p0.001). There were no false positives. Additional operative time required for FSA was approximately 13 minutes per case. Eighty-four (86.6%) patients had successful BCT and 13 patients (13.4%) required mastectomy.Intraoperative analysis of margins using FSA is effective at minimizing the number of additional operations, with 19 patients benefiting from immediate intervention in this study. The authors believe that the number of second operations prevented and the high BCT rates justify performing FSA. Ductal carcinoma in situ is more difficult to identify in FSA. Preoperative discussions with the patient should reflect these findings.

Carcinoma of the esophagus and gastroesophageal junction (GEJ) is an aggressive disease with a poor prognosis.1–3 Because of poor outcomes with surgery alone, an increasing number of patients with locoregionally advanced esophageal cancer are treated with preoperative chemoradiation (CRT) and surgery.4,5 The impact of this treatment paradigm shift on the pathologic stage (pTNM) esophageal cancer staging system has not been clearly defined. When surgery alone is the primary therapy, the best predictor of survival and long-term survival is the surgical pathologic stage according to the American Joint Committee on Cancer (AJCC) staging criteria.6,7 Because of pathologic down-staging, the possibility exists that CRT-treated patients may have different survivals than patients treated with surgery alone. Additionally, it is well known that a complete pathologic response (pP) (path CR, 0% residual cancer) following CRT is associated with improved long-term survival.8–10 We have recently demonstrated that a partial pP is also prognostic following CRT, with improved outcomes in patients who have partial pPs (1%–50% residual cancer) compared with no pP (>50% residual cancer).11 This manuscript extends these initial observations and evaluates the impact of complete and partial pPs on the pTNM esophageal cancer staging system. Our study shows that pP is an independent predictor for long-term survival in patients treated with CRT. In this manuscript, we propose a modified pTNM esophageal cancer staging system to incorporate this prognostic factor (pP: P0, 0% residual; P1, 1%–50% residual; P2, >50% residual) into the pTNM staging system to better predict long-term outcome for esophageal cancer patients treated with CRT.

Background VEGF is best known for its angiogenic properties. We have found that VEGF expression is increased in neuroblastoma cells cocultured with hepatocytes. In addition, we have previously shown that neuroblastoma cells cultured with exogenous VEGF have an increase in the expression of VEGF receptors. Therefore, we hypothesized that the expression of VEGF receptors would be up-regulated in neuroblastoma cells grown in the coculture environment. Materials and methods Two neuroblastoma cell lines (IMR-32 or SK-N-DZ) are used. These cells are cultured alone and in a coculture system with hepatocytes. Message for VEGF and the VEGF receptors KDR, flt-1, flt-4, neuropilin 1 (NRP-1), and neuropilin 2 (NRP-2) are measured with RT-PCR. Flt-4, NRP-1, and NRP-2 protein expression is measured with Western blot. Results The receptors KDR and flt-1 are not detected in either cell line in either control or coculture conditions. Message for VEGF and flt-4 is significantly increased in the cocultured IMR-32 cells, while that for NRP-1 and NRP-2 is unchanged in these cells. VEGF and its receptors are unchanged in cocultured SK-N-DZ cells. Conclusions Neuroblastoma cells express specific VEGF receptors that are differentially regulated in the different cell lines. These findings suggest that the heterogeneity of neuroblastomas may limit the utility of targeting VEGF and its receptors as sole treatments for the tumor, and that successful therapies will be dependent upon the specific biology of the tumor.

To evaluate the efficacy of preoperative radiotherapy alone or combine with chemotherapy. Between 1975 to 1997, 318 patients with locally advanced rectal adenocarcinomas were treated with preoperative radiation therapy. Between 1991 and 1997, approximately 60% of patients received fluorouracil (5-FU)-based adjuvant chemotherapy. Patients treated since 1991 had improved downstaging compared with those treated prior to 1991. Patients treated between 1991 and 1997 were also more likely to undergo a sphincter preserving surgical procedure. Preoperative chemoradiation probably results in improved downstaging and survival compared with preoperative irradiation alone.

Background/Purpose: Vascular endothelial growth factor (VEGF) is best known for its angiogenic properties, but its mitogenic capacity may be more important for tumorigenesis. The ability of VEGF to induce specific biologic activities may be dependent on the amount and type of VEGF receptors present. The authors hypothesize that neuroblastoma cells express specific VEGF receptors and that their expression may be altered when the cells are exposed to differing cytokines and culture environments. Methods: Four groups of human neuroblastoma cells (IMR-32) are studied. (1) Control cells: cultured in standard media. (2) VEGF cells: VEGF added to the media. (3) Tumor necrosis factor alpha (TNF-α) cells: TNF-α added to the media. (4) Serum starved cells: cultured in serum-depleted media. Reverse transcriptase polymerase chain reaction (RT-PCR) is utilized to measure the VEGF receptors flt-1, KDR/flk-1, flt-4, neuropilin 1 (NRP-1), and neuropilin 2 (NRP-2). Results: Flt-1 and KDR are not detected in any groups. Flt-4, NRP-1, and NRP-2 are present in the IMR-32 cells, and their expression is significantly increased by the administration of VEGF. Neuroblastoma cells cultured with TNF-α or in serum-depleted media have a significant decrease in the expression of these receptors. Conclusions: The authors show that neuroblastoma cells express specific VEGF receptors that may be altered by mitogenic or apoptotic stimuli. Specifically targeting VEGF and its receptors may be another therapeutic strategy for the treatment of neuroblastoma. J Pediatr Surg 38:514-521. Copyright 2003, Elsevier Science (USA). All rights reserved.

Several patient and tumor factors go into the decision process to determine whether a breast cancer patient is a good candidate for breast-conserving therapy. The patient must be seen by all disciplines before any therapeutic intervention. When used appropriately, breast-conserving therapy produces maximal disease control and improves quality of life in patients with early-stage breast cancer.

Upregulation of nuclear factor (NF)-κB is found in many forms of cancer. Activation of NF-κB in cancer cells by chemotherapy or radiation can blunt the ability of this therapy to induce cell death. Proteasome inhibitors stimulate apoptosis in part via prevention of NF-κB activation. We sought to determine whether constitutive NF-κB activity is present in human colon cancer. In addition we studied whether alterations of NF-κB activity with a proteasome inhibitor would prevent colon cancer cell growth and induce apoptosis. We demonstrated constitutive transcriptional activation of NF-κB in SW48 and SW116 colon cancer cells by luciferase and electromobility shift assays. This was confirmed by p65 immunostaining. This activity was further induced in the presence of chemotherapy. In colon cancer specimens constitutive activation of NF-κB was observed in the majority of tumors. Treatment with the proteasome inhibitor (MG-132) inhibited growth and also stimulated apoptosis of colon cancer cells. We conclude that inhibition of NF-κB activation may be a logical therapy for certain cancers. This can be done via specific approaches on molecules necessary for keeping NF-κB inactivated in the cytoplasm. Other potentially useful ways to promote apoptosis in cancer cells include the utilization of proteasome inhibitors. Such inhibitors are currently being evaluated in clinical trials.

Isosulfan blue is a commonly used agent in the detection of sentinel lymph nodes during cancer surgery. Similar to any drug, it is possible to have an allergic reaction to this increasingly popular chemical during breast cancer operations. We present one case of anaphylactic shock in response to injection of isosulfan blue for the purpose of localizing the sentinel node and review the medical literature. A thorough knowledge of possible isosulfan blue side effects, including their presentation and subsequent therapy, is essential for the modern breast surgeon.

Although sentinel lymph node (SLN) biopsy is rapidly becoming the standard of care for small breast cancers the optimal radiocolloid injection technique remains controversial. We report our experience with sequential dermal-peritumoral radiocolloid injection that takes advantage of both techniques. One hundred eighteen patients with clinical stage Ti8, T1, T2 and N0 breast cancer underwent SLN biopsy at the University of Florida. Twelve to 18 hours before surgery patients received either an injection of 0.5 to 1.0 mCi 50:50 filtered:unfiltered technetium sulfur colloid into the dermis overlying the tumor and/or a peritumoral injection of a 3 to 4-mCi of radiocolloid 30 minutes later. Dynamic lymphoscintigraphy was performed and the topographical location of all imaged lymph nodes was marked on the skin. The next morning the surgeon utilized a hand-held gamma probe to remove all SLN(s) defined as any lymph node with radioactive counts 10 per cent or more of the ex vivo counts of the most radioactive SLN [internal mammary (IM) nodes were not removed]. The SLN identification rate was 98.5 per cent (3 IM nodes) for dermal injection (D), 83.3 per cent (1 IM node) for peritumoral injection (P), and 100 per cent (14 IM nodes) for sequential dermal-peritumoral injection (DP) ( p < 0.05 DP versus D). Sequential DP 50:50 filtered:unfiltered technetium sulfur colloid injection results in a rapid, high SLN identification rate that persists until surgery the next morning. Delineation of nonaxillary SLNs may lead to more accurate breast cancer staging and may also influence the delivery of IM node radiation.

BACKGROUND: Our institution has previously demonstrated a survival advantage conferred by preoperative neoadjuvant therapy for locally advanced rectal cancers. We now report our results using transanal excision as definitive surgical therapy in a selected group of patients who experienced significant downstaging of T3 rectal cancers after neoadjuvant therapy. STUDY DESIGN: Seventy-four patients diagnosed with locally advanced (T3) rectal cancers were treated with neoadjuvant chemoradiotherapy. After neoadjuvant therapy, 11 (14.9%) patients who had significant downstaging of their tumors were selected to undergo transanal excision of their residual rectal cancers. Intraoperative cryostat evaluation was used to confirm negative margin status, and all patients were subsequently followed with routine endoscopy, transrectal ultrasonography, and digital rectal examinations. RESULTS: Tumors were located between 1 cm and 7 cm from the anal verge (mean 4.3 ± 0.6 cm), and were located in lateral, anterior, and posterior positions. Mean followup was 55.2 ± 8.9 months (median 47.9 months). Imaging studies using CT, MRI, transrectal ultrasonography, or combination demonstrated suspicious lymph nodes in three patients. After neoadjuvant therapy, these lymph nodes were no longer demonstrated in two patients. There were no local recurrences, nodal metastases, or operative mortalities. One patient (9%) developed distant metastases (pulmonary nodules), and remains alive 30 months after transanal excision. One patient (9%) experienced sphincter laxity, which was successfully repaired, and is now asymptomatic. One patient (9%) developed postoperative urgency that resolved spontaneously. CONCLUSIONS: In patients who have initial bulky (T3) lesions, and experience significant downstaging after neoadjuvant chemoradiotherapy, transanal excision appears to be a safe and effective treatment, preserving sphincter function and avoiding laparotomy.

Several groups have developed clinical guidelines for the management of breast cancer, yet little data exist regarding their validation. Therefore, we examined the effect of published National Comprehensive Cancer Network (NCCN) guidelines for invasive breast cancer on survival, quality of life (QOL), and hospital cost. From 260 consecutive breast cancer patients, 129 patients were identified for analysis: 93 patients (72%) were treated according to the guidelines (NCCN+), while the treatment of 36 patients (28%), with a similar stage distribution, deviated from the guidelines (NCCN-). Patients were excluded from analysis with a diagnosis of carcinoma in situ, inflammatory cancer, stage IV disease, and comorbid conditions that affected treatment. The 5-year survival was 87.6% for the NCCN+ patients versus 83.3% for NCCN- patients (P = 0.319 by Kaplan-Meier). Twelve QOL parameters were evaluated using a Likert-type scale (1 = severe and 5 = none). NCCN+ patients had a cumulative QOL score of 4.18 +/- 0.08 versus 4.24 +/- 0.14 for NCCN- patients (P = 0.745). Treatment-related costs were $20,300 +/- 1800 for NCCN+ patients versus $59,700 +/- 25,200 for NCCN- patients (P = 0.016 by t test). Although deviation from NCCN breast cancer guidelines had no effect on perceived quality of life or survival, there was a significant decrease in cost in the NCCN+ group. These findings suggest that adherence to NCCN guidelines can significantly reduce the cost of breast cancer care without adversely affecting either survival or quality of life.

Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.

IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.

The effect of black tea polyphenols on 1,2-dimethylhydrazine (DMH)-induced oxidative DNA damage in rat colon mucosa has been investigated. Fischer 344 rats were treated orally with thearubigin (TR) or theafulvin (TFu) for 10 days (40 mg/kg), injected ip with DMH (20 mg/kg) or saline and sacrificed 24 hr after DMH administration. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured in colonic mucosa DNA and expressed as a ratio relative to 2'-deoxyguanosine (2dG). Control rat mucosa had 8-OHdG values of 1.12 +/- 0.14/10(5) dG (mean +/- SEM, n=11), whereas DMH-treated rats significantly higher values (1.52 +/- 0.14/10(5) dG, n=26, P0.05). Pretreatment of rats with TR had significantly inhibited DMH-induced oxidative DNA damage 0.99 +/- 0.09/10(5) dG, n=10, P0.05) and a similar, although less marked, effect was observed with TFu (1.15 +/- 0.19/10(5), n=9, P=0.06). These findings confirm that DMH causes oxidative DNA damage in the colon mucosa of rats and demonstrate that this effect is prevented by the consumption of complex polyphenols from black tea.

Tumor necrosis factor (TNF)-α and Fas ligand (FasL) are trimeric proteins that induce apoptosis through similar caspase-dependent pathways. Hepatocytes are particularly sensitive to inflammation-induced programmed cell death, although the contribution of TNF-α and/or FasL to this injury response is still unclear. Here, we report that d-galactosamine and lipopolysaccharide-induced liver injury in C57BL/6 mice is associated with increased hepatic expression of both TNF-α and FasL mRNA. Pretreatment of mice with a TNF-binding protein improved survival, reduced plasma aspartate aminotransferase concentrations, and attenuated the apoptotic liver injury, as determined histologically and by in situ 3′ OH end labeling of fragmented nuclear DNA. In contrast, pretreatment of mice with a murine-soluble Fas fusion protein (Fasfp) had only minimal effect on survival, and apoptotic liver injury was either unaffected or exacerbated depending on the dose of Fasfp employed. Similarly, mice with a spontaneous mutation in FasL (B6Smn.C3H- Faslgldderived from C57BL/6) were equally sensitive tod-galactosamine/lipopolysaccharide-induced shock. We conclude that the shock and apoptotic liver injury afterd-galactosamine/lipopolysaccharide treatment are due primarily to TNF-α release, whereas increased FasL expression appears to contribute little to the mortality and hepatic injury.

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-α and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. β-Galactosidase expression in mice receiving intratracheal instillation of Adv/β-gal (adenovirus construct expressing β-galactosidase) was transient (less than 14 days), but a significant early increase of β-galactosidase expression was seen in mice lacking either or both TNF-α receptors. Absence of TNF-α or the p55 receptor significantly attenuated the Ab response to both adenovirus and β-galactosidase. Human IL-10 expression in the lung suppressed local TNF-α production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with β-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-α signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with β-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with β-galactosidase, and is nonimmunogenic in the lung.

Background The management of small pancreatic cystic lesions presents a clinical challenge. Methods We reviewed our experience with 78 patients who presented with a cystic pancreatic lesion who underwent operative management between 1995 and 2005. Data on cyst characteristics were analyzed in the context of pathologic findings following resection. Results Among 78 patients, there were 55 (71%) females; median age 63 years. Patients presented with: an incidental finding (48%), pain (40%), acute pancreatitis (4%), other (8%). Operations were distal pancreatectomy (n = 47), pancreaticoduodenectomy (n = 16), and other (n = 15). Most patients had a non-malignant lesion (n = 65, 83%) (mucinous cystadenoma (n = 29), serous cystadenoma (n = 15), IPMN without invasion (n = 8), pseudocyst (n = 8), other benign (n = 5)). Malignant lesions (adenocarcinoma, neuroendocrine tumor, and other) were found in 13 patients (17%). The risk of malignancy increased with size: 5 cm (n = 30), 30%. Pre-operative cyst fluid cytology was performed in 41 patients. The negative predictive value (NPV) of cytology for malignancy was 88% and the positive predictive value (PPV) was 80%. The NPV of CA 19-9 for malignancy was 90%; the PPV was 50%. Conclusions Initial conservative management of small cystic pancreatic lesions may be indicated in selected patients. J. Surg. Oncol. 2009;100:372–374. © 2009 Wiley-Liss, Inc.

Background. Tumor necrosis factor-α (TNF-α) is a member of a large family of predominantly homotrimeric type II membrane-associated proteins with both proinflammatory and apoptosis-inducing properties. Although TNF-α expression has been studied extensively, little is known about the expression of other members of the TNF-α superfamily during acute inflammatory processes. Methods. TNF-α, Fas ligand (FasL), and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) messenger RNA (mRNA) expression were examined in liver, lung, spleen, and kidney after either a cecal ligation and puncture or endotoxemic shock with use of semiquantitative reverse transcriptase-polymerase chain reaction. Results. Cecal ligation and puncture increased TNF-α mRNA in lung and liver (both P

The application of gene therapy to acute inflammation has not received as much research attention as has the treatment of genetically-based diseases, cancer, and viral infections. However, gene therapy as a drug delivery system offers several theoretical and practical advantages over current protein delivery systems. These include the ability to target therapies to individual tissues or cell types, to locally produce proteins that can act intracellularly or in an autocrine, juxtacrine, or paracrine fashion, and to sustain new protein synthesis for periods up to several weeks after a single administration. Although retrovirus, herpes simplex, and adeno-associated virus have been proposed for gene therapy in cancer and in genetic diseases, nonviral and adenovirus approaches appear most applicable as drug delivery systems due to their rapid onset and short duration of transgene expression. The relative modest transduction efficiencies obtained at present with nonviral approaches, and the inherent inflammatory properties of first-generation adenovirus constructs, however, have limited their usefulness to date. The present review discusses the theoretical and practical benefits of specific gene therapy approaches for the treatment of acute inflammatory diseases, as well as our experiences with liposome:plasmid DNA and adenovirus-based approaches. Although a number of technical and theoretical hurdles remain before it can be evaluated in humans with acute inflammation, gene therapy offers a novel approach for the treatment of acute inflammation, and will likely enter the armamentarium of critical care physicians in the near future.

Breast cancer affects 1 in 8 women today.1 The treatment of breast diseases comprises 14–25% of general surgeons’ practice volume.2,3 Yet, approximately half of all general surgeons perform only two or fewer breast cases per month. Unquestionably, long-term survival after surgery for breast cancer depends upon stage.4 More recently, survival has been linked to performance measures. For instance, survival is greater at hospitals performing greater than 125–150 breast cancer surgeries per year.5–8 Additionally, survival is greater if surgeons perform greater than 15 breast cancer operations per year.8 Finally, completion of a surgical oncology fellowship resulted in a 36% reduction in the risk of death at 5 years when controlled for hospital volume, surgeon volume, age, stage, and race.8–10 Can one infer from these studies that “breast-focused” surgeons are more competent? The criticisms of these studies have been that they often emanate from authors who may be prejudiced toward the results. In fact, there is an observation that, if a surgeon works in a hospital with a cancer center designation, the results from the treatment of breast cancer are not based on any specific surgical or breast disease training other than the general surgical residence.8 The implication would be that the multimodality approach to the treatment of the disease is the reason for any increased survival rather than the judgmental or technical expertise of the surgeon.