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Bilateral risk-reducing mastectomy (BRRM) is the surgical removal of both breasts to reduce the risk of cancer. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, outcomes, and risks of BRRM to update the society's 2017 statement. We held a virtual meeting to outline key topics and conducted a literature search using PubMed to identify relevant articles. After literature review, recommendations were made according to group consensus. Individuals with a high lifetime risk of breast cancer due to pathogenic variants in high penetrance breast cancer-predisposition genes, early chest or breast radiation exposure, or a compelling family history should be counseled on the option of BRRM. However, BRRM is not recommended for most patients with high-risk lesions and may be contraindicated in patients who have other competing cancers and/or a high risk of surgical complications. BRRM effectively reduces the risk of breast cancer development, although the survival benefit is unclear. For patients with low-to-moderate breast cancer risk, alternative management strategies should be encouraged, including lifestyle modifications, high-risk screening, and risk-reducing medications. Discussions of BRRM should cover: (1) breast-cancer risk estimates; (2) the procedure's degree of risk reduction and impact on survival; (3) surgical techniques, potential surgical complications and long-term sequelae; and (4) alternatives to surgery. Surgeons should encourage shared and informed decision making with patients who have an elevated lifetime risk of developing breast cancer., Competing Interests: Disclosure Oluwadamilola M. Fayanju has received research support from Gilead Sciences, Inc. that is outside the scope of this work. Chantal Reyna has received an honoraria from Elucent Medical that is outside the scope of this work and the relationship has been terminated. Anna Weiss reports the following disclosures: advisory board/consulting fees from Merck and Myriad Laboratories, Inc.; honoraria from the Society of Breast Imaging, MJH Lifesciences, and Breast Cancer Foundation New Zealand; food and beverage from Endomag. Judy C. Boughey receives funding, paid to her institution, from Eli Lilly and SymBioSis, and sits on the Data Safety Monitoring Committee of Cairns Surgical. She has received honoraria from PER, PeerView, OncLive, EndoMag, and Up-To-Date. Andrea V. Barrio has received a speaking honorarium from Novartis. Jennifer K. Plichta serves on a committee for the National Comprehensive Cancer Network. She has received grant funding from Earlier.org that is outside the scope of this work, and has received honoraria from the National Consortium of Breast Centers. Marie Catherine Lee is a paid consultant for Elucent Medical and Provepharm. Puneet Singh, Doreen M. Agnese, Miral Amin, Astrid Botty van den Bruele, Erin E. Burke, David N. Danforth Jr, Frederick M. Dirbas, Firas Eladoumikdachi, Olga Kantor, Shicha Kumar, Cindy Matsen, Toan T. Nguyen, Tolga Ozmen, Ko Un Park, Shayna L. Showalter, Toncred Styblo, Nicholas Tranakas, Ashley Woodfin, and Christine Laronga have no conflicts of interest to declare that may be relevant to the contents of this work., (© 2024. Society of Surgical Oncology.)

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences., (© 2024. Society of Surgical Oncology.)

Infective endocarditis (IE), a disease of the endocardial surface of the heart, is usually of bacterial origin and disproportionally affects individuals with underlying structural heart disease. Although IE is typically associated with Gram-positive bacteria, a minority of cases are caused by a group of Gram-negative species referred to as the HACEK group. These species, classically associated with the oral cavity, consist of bacteria from the genera Haemophilus (excluding Haemophilus influenzae ), Aggregatibacter , Cardiobacterium , Eikenella , and Kingella . Aggregatibacter actinomycetemcomitans , a bacterium of the Pasteurellaceae family, is classically associated with Aggressive Periodontitis and is also concomitant with the chronic form of the disease. Bacterial colonization of the oral cavity serves as a reservoir for infection at distal body sites via hematological spreading. A. actinomycetemcomitans adheres to and causes disease at multiple physiologic niches using a diverse array of bacterial cell surface structures, which include both fimbrial and nonfimbrial adhesins. The nonfimbrial adhesin EmaA (extracellular matrix binding protein adhesin A), which displays sequence heterogeneity dependent on the serotype of the bacterium, has been identified as a virulence determinant in the initiation of IE. In this chapter, we will discuss the known biochemical, molecular, and structural aspects of this protein, including its interactions with extracellular matrix components and how this multifunctional adhesin may contribute to the pathogenicity of A. actinomycetemcomitans.

Protein glycosylation is critical to the quaternary structure and collagen-binding activity of the extracellular matrix protein adhesin A (EmaA) associated with Aggregatibacter actinomycetemcomitans. The glycosylation of this large, trimeric autotransporter adhesin is postulated to be mediated by WaaL, an enzyme with the canonical function to ligate the O-polysaccharide (O-PS) antigen with a terminal sugar of the lipid A-core oligosaccharide of lipopolysaccharide (LPS). In this study, we have determined that the Escherichia coli waaL ortholog (rflA) does not restore collagen binding of a waaL mutant strain of A. actinomycetemcomitans but does restore O-PS ligase activity following transformation of a plasmid expressing waaL. Therefore, a heterologous E. coli expression system was developed constituted of two independently replicating plasmids expressing either waaL or emaA of A. actinomycetemcomitans to directly demonstrate the necessity of ligase activity for EmaA collagen binding. Proper expression of the protein encoded by each plasmid was characterized, and the individually transformed strains did not promote collagen binding. However, coexpression of the two plasmids resulted in a strain with a significant increase in collagen binding activity and a change in the biochemical properties of the protein. These results provide additional data supporting the novel hypothesis that the WaaL ligase of A. actinomycetemcomitans shares a dual role as a ligase in LPS biosynthesis and is required for collagen binding activity of EmaA., (© 2023 The Authors. Molecular Oral Microbiology published by John Wiley & Sons Ltd.)

Aggregatibacter actinomycetemcomitans is a gram-negative bacterium associated with periodontal disease and a variety of disseminated extra-oral infections. Tissue colonization is mediated by fimbriae and non-fimbriae adhesins resulting in the formation of a sessile bacterial community or biofilm, which confers enhanced resistance to antibiotics and mechanical removal. The environmental changes experienced by A. actinomycetemcomitans during infection are detected and processed by undefined signaling pathways that alter gene expression. In this study, we have characterized the promoter region of the extracellular matrix protein adhesin A (EmaA), which is an important surface adhesin in biofilm biogenesis and disease initiation using a series of deletion constructs consisting of the emaA intergenic region and a promotor-less lacZ sequence. Two regions of the promoter sequence were found to regulate gene transcription and in silico analysis indicated the presence of multiple transcriptional regulatory binding sequences. Analysis of four regulatory elements, CpxR, ArcA, OxyR, and DeoR, was undertaken in this study. Inactivation of arcA, the regulator moiety of the ArcAB two-component signaling pathway involved in redox homeostasis, resulted in a decrease in EmaA synthesis and biofilm formation. Analysis of the promoter sequences of other adhesins identified binding sequences for the same regulatory proteins, which suggests that these proteins are involved in the coordinate regulation of adhesins required for colonization and pathogenesis., (© 2023 The Authors. Molecular Oral Microbiology published by John Wiley & Sons Ltd.)

Aggregatibacter actinomycetemcomitans , a causative agent of periodontitis and non-oral diseases, synthesizes a trimeric extracellular matrix protein adhesin A (EmaA) that mediates collagen binding and biofilm formation. EmaA is found as two molecular forms, which correlate with the serotype of the bacterium. The canonical protein (b-EmaA), associated with serotypes b and c, has a monomeric molecular mass of 202 kDa. The collagen binding activity of b-EmaA is dependent on the presence of O-polysaccharide (O-PS), whereas biofilm activity is independent of O-PS synthesis. The EmaA associated with serotype a strains (a-EmaA) has a monomeric molecular mass of 173 kDa and differs in the amino acid sequence of the functional domain of the protein. In this study, a- emaA was confirmed to encode a protein that forms antenna-like appendages on the surface of the bacterium, which were found to be important for both collagen binding and biofilm formation. In an O-PS-deficient talose biosynthetic ( tld ) mutant strain, the electrophoretic mobility of the a-EmaA monomers was altered and the amount of membrane-associated EmaA was decreased when compared to the parent strain. The mass of biofilm formed remained unchanged. Interestingly, the collagen binding activity of the mutant strain was similar to the activity associated with the parent strain, which differs from that observed with the canonical b-EmaA isoform. These data suggest that the properties of the a-EmaA isoform are like those of b-EmaA, with the exception that collagen binding activity is independent of the presence or absence of the O-PS.

Purpose: Adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can mediate durable responses in patients with metastatic melanoma. This retrospective analysis provides long-term follow-up and describes the effect of prior therapy on outcomes after ACT-TIL., Patients and Methods: Patients with metastatic melanoma underwent surgical resection of a tumor for generation of TILs and were treated with a lymphodepleting preparative regimen followed by adoptive transfer of TILs and intravenous IL2. Clinical characteristics of enrolled patients and treatment characteristics of TIL infusion products over two decades of ACT were analyzed to identify predictors of objective response., Results: Adoptive transfer of TILs mediated an objective response rate of 56% (108/192) and median melanoma-specific survival of 28.5 months in patients naïve to anti-programmed cell death-1 (PD-1) therapy compared with 24% (8/34) and 11.6 months in patients refractory to anti-PD-1 (aPD-1). Among patients with BRAF V600E/K-mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs. 60%) and decreased survival (9.3 vs. 50.7 months) when compared with those patients naïve to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the aPD-1-naïve cohort have ongoing responses after a single treatment and 10-year melanoma-specific survival of 96%., Conclusions: Patients previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma. See related commentary by Sznol, p. 5156., (©2021 American Association for Cancer Research.)

Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis.

Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with periodontal disease and multiple disseminated extra-oral infections. Colonization of these distinct physiological niches is contingent on the expression of specific surface proteins during the initiation of developing biofilms. In this investigation, we studied fimbriae and three well-characterized nonfimbrial surface proteins (EmaA, Aae, and ApiA/Omp100) for their contribution to biofilm formation. Mutations of these proteins in multiple strains covering four different serotypes demonstrated variance in biofilm development that was strain dependent but independent of serotype. In a fimbriated background, only inactivation of emaA impacted biofilm mass. In contrast, inactivation of emaA and/or aae affected biofilm formation in nonfimbriated A. actinomycetemcomitans strains, whereas inactivation of apiA/omp100 had little effect on biofilm formation. When these genes were expressed individually in Escherichia coli, all transformed strains demonstrated an increase in biofilm mass compared to the parent strain. The strain expressing emaA generated the greatest mass of biofilm, whereas the strains expressing either aae or apiA/omp100 were greatly reduced and similar in mass. These data suggest a redundancy in function of these nonfimbrial adhesins, which is dependent on the genetic background of the strain investigated., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immune cells are present in normal breast tissue and in breast carcinoma. The nature and distribution of the immune cell subtypes in these tissues are reviewed to promote a better understanding of their important role in breast cancer prevention and treatment. We conducted a review of the literature to define the type, location, distribution, and role of immune cells in normal breast tissue and in in situ and invasive breast cancer. Immune cells in normal breast tissue are located predominantly within the epithelial component in breast ductal lobules. Immune cell subtypes representing innate immunity (NK, CD68 + , and CD11c + cells) and adaptive immunity (most commonly CD8 + , but CD4 + and CD20 + as well) are present; CD8 + cells are the most common subtype and are primarily effector memory cells. Immune cells may recognize neoantigens and endogenous and exogenous ligands and may serve in chronic inflammation and immunosurveillance. Progression to breast cancer is characterized by increased immune cell infiltrates in tumor parenchyma and stroma, including CD4 + and CD8 + granzyme B + cytotoxic T cells, B cells, macrophages and dendritic cells. Tumor-infiltrating lymphocytes in breast cancer may serve as prognostic indicators for response to chemotherapy and for survival. Experimental strategies of adoptive transfer of breast tumor-infiltrating lymphocyte may allow regression of metastatic breast cancer and encourage development of innovative T-cell strategies for the immunotherapy of breast cancer. In conclusion, immune cells in breast tissues play an important role throughout breast carcinogenesis. An understanding of these roles has important implications for the prevention and the treatment of breast cancer., (Published by Elsevier Inc.)

Breast ductal cytologic atypia is an important risk factor for sporadic breast cancer. Characterization of the associated normal breast tissue is needed to develop additional methods of risk assessment and new targets for breast cancer prevention. We conducted a prospective clinical trial evaluating women at normal-risk or at high-risk for sporadic breast cancer. Breast ductal cells were collected and studied cytologically and by gene expression profiling, and breast ductal architectural changes were studied by breast ductal endoscopy (BDE) and breast MRI. One hundred and forty subjects were studied, 70 at high risk (RR, 2.0-4.6) and 70 at normal risk. Cytologic atypia was present in 22.9% of high-risk and 25.7% of normal-risk subjects. Ductal endoscopy was performed in 89 subjects and revealed benign intraductal abnormalities, primarily intraductal fibrous webbing suggesting chronic inflammation, in 40.4% of high-risk and 5.4% of normal-risk subjects, respectively ( P 2 = 0.0002). Two high-risk subjects with atypia and no normal-risk subjects with atypia developed invasive breast cancer. Gene expression profiling of ductal cells showed comparable gene expression profiles without enriched expression of previously defined oncogenic signatures in subjects with cellular atypia compared with those without atypia, and in high-risk subjects compared with normal-risk subjects (FDR > 0.5). Cytologic ductal atypia in normal-risk subjects does not appear to be of clinical significance. Atypia in women at high risk may be associated with benign and malignant breast ductal abnormalities; these characteristics of high-risk ductal cells may not be reflected in gene expression profiles., (©2020 American Association for Cancer Research.)

Background: Preoperative chemotherapy is important in the management of women with breast cancer, with the ability to downstage the breast primary tumor and axillary lymph nodes. Long-term studies are needed to identify late toxicities, recurrence patterns, and equivalency with postoperative chemotherapy for recurrence-free survival (RFS) and overall survival (OS)., Patients and Methods: We conducted a single-institution prospective randomized control trial comparing preoperative or postoperative fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor chemotherapy for women with untreated clinical stage II (T1N1, T2N0, and T2N1) breast cancer. Long-term follow-up was conducted to define toxicities, recurrence patterns and RFS and OS., Results: Fifty-three women with clinical stage II breast cancer were randomized, 26 patients to receive preoperative chemotherapy and 27 to receive postoperative chemotherapy. Long-term follow-up, with a median of 25.3 years, was obtained. Local or systemic recurrence occurred in 8 women in the preoperative group and in 10 women in the postoperative group, and recurrences were predominantly within 10 years of treatment. Late toxicities included local upper extremity paresthesia's, upper extremity edema and congestive heart failure in 1 patient each. Analysis revealed no difference in RFS (20-year RFS probabilities; preoperative: 61.3%, postoperative: 54.7%, P=0.42), or in OS between the 2 treatment groups (20-year probabilities, preoperative: 64.6%, postoperative: 62.2%, P=0.44). Twenty-five of 53 patients (47%) were alive and without disease at this follow-up., Conclusion: Twenty-five-year follow-up for this prospective randomized trial confirms the equivalency of preoperative versus postoperative chemotherapy with fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor for stage II breast cancer for both RFS and OS.

Periodontitis is an inflammatory disease caused by polymicrobial biofilms. The periodontal pathogen Aggregatibacter actinomycetemcomitans displays two proteinaceous surface structures, the fimbriae and the nonfimbrial extracellular matrix binding protein A (EmaA), as observed by electron microscopy. Fimbriae participate in biofilm biogenesis and the EmaA adhesins mediate collagen binding. However, in the absence of fimbriae, A. actinomycetemcomitans still retains the potential to form robust biofilms, suggesting that other surface macromolecules participate in biofilm development. Here, isogenic mutant strains lacking EmaA structures, but still expressing fimbriae, were observed to have reduced biofilm potential. In strains lacking both EmaA and fimbriae, biofilm mass was reduced by 80%. EmaA enhanced biofilm formation in different strains, independent of the fimbriation state or serotype. Confocal microscopy revealed differences in cell density within microcolonies between the EmaA positive and mutant strains. EmaA-mediated biofilm formation was found to be independent of the glycosylation state and the precise three-dimensional conformation of the protein, and thus this function is uncorrelated with collagen binding activity. The data suggest that EmaA is a multifunctional adhesin that utilizes different mechanisms to enhance bacterial binding to collagen and to enhance biofilm formation, both of which are important for A. actinomycetemcomitans colonization and subsequent infection., (Copyright © 2018 American Society for Microbiology.)

Purpose: This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Patients and Methods: Tumor-infiltrating lymphocytes (TIL) were expanded from resected ovarian cancer metastases, which were analyzed by whole-exome and transcriptome sequencing to identify autologous somatic mutations. All mutated neoepitopes, independent of prediction algorithms, were expressed in autologous antigen-presenting cells and then cocultured with TIL fragment cultures. Secretion of IFNγ or upregulation of 41BB indicated a T-cell response. Results: Seven women with metastatic ovarian cancer were evaluated, and 5 patients had clear, dominant T-cell responses to mutated neoantigens, which were corroborated by comparison with the wild-type sequence, identification of the minimal epitope, human leukocyte antigen (HLA) restriction element(s), and neoantigen-specific T-cell receptor(s). Mutated neoantigens were restricted by HLA-B, -C, -DP, -DQ, and/or -DR alleles and appeared to principally arise from random, somatic mutations unique to each patient. We established that TP53 "hotspot" mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S) expressed by two different patients' tumors were both immunogenic in the context of HLA-DRB3*02:02. Conclusions: Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. In addition, transfer of TP53 "hotspot" mutation-reactive T-cell receptors into peripheral blood T cells could be evaluated as a gene therapy for a diverse range of tumor histologies. Clin Cancer Res; 24(22); 5562-73. ©2018 AACR See related commentary by McNeish, p. 5493 ., (©2018 American Association for Cancer Research.)

Purpose: Atypical ductal and atypical lobular hyperplasia (AH) of the breast are important proliferative lesions which are associated with a significantly increased risk for breast cancer. The breast cancer which develops in association with AH may occur synchronously, representing local progression, or metachronously at a later date in either the ipsilateral or contralateral breast. These high-risk characteristics of AH suggest they contain significant genomic changes., Methods: To define the genomic changes in AH, a comprehensive review of the literature was conducted to identify the numerical chromosomal and structural chromosomal changes, DNA methylation, and gene expression abnormalities in atypical ductal and atypical lobular hyperplasia., Results: AHs are characterized by advanced genomic changes including aneuploidy, loss of heterozygosity, gross chromosomal rearrangements such as amplifications and large-scale deletions, DNA methylation of tumor suppressor and other genes, and gene expression differences between AH and surrounding normal breast tissue including significant estrogen receptor expression. Many of these changes are shared by an associated synchronous breast cancer, consistent with an important precursor role for AH. At the same time, many of the genomic changes of AHs are also shared by common sporadic breast cancer, consistent with a high risk for future development of metachronous breast cancer., Conclusions: This molecular profile should help clarify the genomic characteristics and malignant predisposition of AH, and aid in the identification of new targets for the prevention of breast cancer.

Background: Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma., Methods: In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m 2 ] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov, number NCT01814046., Findings: From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure., Interpretation: To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality., Funding: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women.

Purpose: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion., Patients and Methods: A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response., Results: CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred., Conclusion: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI., (© 2016 by American Society of Clinical Oncology.)

Background: There is a strong need to define the molecular changes in normal at-risk breast epithelium to identify biomarkers and new targets for breast cancer prevention and to develop a molecular signature for risk assessment. Improved methods of breast epithelial sampling are needed to promote whole-genome molecular profiling, increase ductal epithelial cell yield, and reduce sample cell heterogeneity., Methods: We developed an improved method of breast ductal sampling with ductal lavage through a 22-gauge catheter and collection of ductal samples with a microaspirator. Women at normal risk or increased risk for breast cancer were studied. Ductal epithelial samples were analyzed for cytopathologic changes, cellular yield, epithelial cell purity, quality and quantity of DNA and RNA, and use in multiple downstream molecular applications., Results: We studied 50 subjects, including 40 subjects at normal risk for breast cancer and 37 subjects with non-nipple aspirate fluid-yielding ducts. This method provided multiple 1.0 mL samples of high ductal epithelial cell content (median ≥8 samples per subject of ≥5,000 cells per sample) with 80%-100% epithelial cell purity. Extraction of a single intact ductal sample (fluid and cells) or the separate frozen cellular component provided DNA and RNA for multiple downstream studies, including quantitative reverse transcription- polymerase chain reaction (PCR) for microRNA, quantitative PCR for the human telomerase reverse transcriptase gene, whole-genome DNA amplification, and array comparative genomic hybridization analysis., Conclusion: An improved breast epithelial sampling method has been developed, which should significantly expand the acquisition and biomarker analysis of breast ductal epithelium in women at risk for breast cancer.

In the setting of the 25-year follow-up of the Canadian National Breast Screening Study, the Society of Surgical Oncology continues to endorse mammographic screening for women beginning at 40 years of age, while acknowledging that mammography has both risks and benefits. Further investigation is warranted to develop better screening methods and to determine optimal screening schedules for women based on their risk of future breast cancer and their imaging characteristics.

Importance: Malignant melanoma has an unusual propensity to metastasize to the small bowel; however, malignant melanoma with metastatic spread to the appendix presenting as acute appendicitis has rarely been reported. We describe cases of melanoma of the appendix presenting with appendicitis and review our institutional experience with this entity., Observations: Medical records were reviewed in patients with melanoma at the National Cancer Institute between January 1, 1953, and December 31, 2010, who underwent appendectomy. Of 5822 cases of melanoma treated at the National Institutes of Health, appendectomies were performed on 31 patients, 2 of whom had acute appendicitis secondary to malignant obstruction and presented with symptoms of vague abdominal pain. Both patients had been heavily pretreated for metastatic melanoma and had multiple sites of intraperitoneal and extraperitoneal disease. On exploratory laparotomy, both patients showed clinical evidence of acute appendicitis, and an appendectomy was performed. Both patients recovered fully from the operation and proceeded to further systemic therapy., Conclusions and Relevance: Although rare, the diagnosis of appendicitis should be considered in patients with melanoma and acute abdominal pain. Timely surgical intervention may allow palliation and the ability to pursue subsequent systemic treatment.

Breast cancer is the most common malignancy in women in the United States but significant disparities exist for African American women compared to Caucasian women. African American women present with breast cancer at a younger age and with a greater incidence under the age of 50 years, develop histologically more aggressive tumors that are at a more advanced stage at presentation, and have a worse disease-free and overall survival than Caucasian women. The biological characteristics of the primary tumor play an important role in determining the outcome of the disparity, and significant differences have been identified between African American and Caucasian breast cancer in steroid receptor and growth factor receptor content, mutations in cell cycle components, chromosomal abnormalities, and tumor suppressor and other cancer genes. The consequences of the biological factors are influenced by a variety of nonbiological factors, including socioeconomic, health care access, reproductive, and confounding factors. The nonbiological factors may act directly to enhance (or inhibit) the consequences of the biological changes, indirectly to facilitate outcome of the disparity, or as a cofounding factor, driving the association between the biological factors and the disparity. The prevention and management of the disparities will require an understanding of the relationship of biological and nonbiological factors. The present review was undertaken to promote this understanding by describing the biological basis of the four major disparities - early age of onset, more advanced stage of disease, more aggressive histologic changes, and worse survival - and the important relationship to the nonbiological factors. A model is proposed to provide a comprehensive view of this relationship, with the goal of facilitating an understanding of each disparity and the issues that need to be addressed to eliminate the disparity.

Breast conservation therapy (BCT) consisting of lumpectomy and postoperative radiation has become an accepted alternative to mastectomy (MRM) for the treatment of early stage breast cancer. We currently report the 25 year outcomes of a single institution, prospective, randomized clinical trial at the National Cancer Institute. 237 women with pathologically confirmed invasive breast tumors 5 cm or less were accrued between 1979 and 1987 and randomized to receive either BCT or MRM. Overall survival was the primary endpoint. Patients with node positive disease were included and treated with doxorubicin and cyclophosphamide. Both arms received axillary dissection. BCT patients had radiation to the whole breast followed by a boost. At a median follow-up of 25.7 years, overall survival was 43.8% for the MRM group and 37.9% for BCT (P = 0.38). Although the cumulative incidence of a disease-free survival event was higher in BCT patients (29.0% MRM vs. 56.4% BCT, P = 0.0017), the additional treatment failures were primarily isolated ipsilateral breast tumor recurrences (IBTR's) requiring salvage mastectomy. 22.3% of BCT patients experienced an IBTR. Distant disease and second cancers were similar in both arms. After 25 years, long term survival between BCT and MRM continues to be similar in patients treated for early stage breast cancer. Patients receiving BCT may be at risk for additional treatment-related morbidity, which may occur as a late event. Further studies are required to delineate patients at higher risk for these events, and prolonged follow up should be encouraged after treatment for all women.

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease.

Inflammatory breast cancer (IBC) is a rare clinicopathologic entity with a poor prognosis, lagging far behind any other form of nonmetastatic breast cancer. Since the advent of systemic chemotherapy over 35 years ago, only minimal progress has been made in long-term outcome. Although multiple randomized trials of high-dose chemotherapy and autologous progenitor cell transplantation (ASCT) for the treatment of breast cancer have yielded disappointing results, these data are not necessarily relevant to IBC, a distinct clinical and pathologic entity. Therefore, the optimal multimodality therapy for IBC is not well established, and remains unsatisfactory. We treated 21 women with nonmetastatic IBC with a multimodality strategy including high-dose melphalan (Mel)/etoposide and ASCT. The treatment was overall tolerated with acceptable morbidity, and no post-ASCT 100-day mortality. With a median potential follow-up of approximately 8 years, the estimated progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) at 6 years from on-study date are: 67%, 55%, and 69%, respectively. These results from a small phase II study are among the most promising of mature outcome data for IBC. They strongly suggest, along with results of several already published phase II trials, that ASCT could play a significant role in the first line treatment of IBC.

Purpose: Ductal lavage has been used for risk stratification and biomarker development and to identify intermediate endpoints for risk-reducing intervention trials. Little is known about patient characteristics associated with obtaining nipple aspirate fluid (NAF) and adequate cell counts (> or =10 cells) in ductal lavage specimens from BRCA mutation carriers., Methods: We evaluated patient characteristics associated with obtaining NAF and adequate cell counts in ductal lavage specimens from the largest cohort of women from BRCA families yet studied (BRCA1/2 = 146, mutation-negative = 23, untested = 2). Fisher's exact test was used to evaluate categorical variables; Wilcoxon nonparametric test was used to evaluate continuous variables associated with NAF or ductal lavage cell count adequacy. Logistic regression was used to identify independent correlates of NAF and ductal lavage cell count adequacy., Results: From 171 women, 45 (26%) women had NAF and 70 (41%) women had ductal lavage samples with > or =10 cells. Postmenopausal women with intact ovaries compared with premenopausal women [odds ratio (OR), 4.8; P = 0.03] and women without a prior breast cancer history (OR, 5.2; P = 0.04) had an increased likelihood of yielding NAF. Having breast-fed (OR, 3.4; P = 0.001), the presence of NAF before ductal lavage (OR, 3.2; P = 0.003), and being premenopausal (OR, 3.0; P = 0.003) increased the likelihood of ductal lavage cell count adequacy. In known BRCA1/2 mutation carriers, only breast-feeding (OR, 2.5; P = 0.01) and the presence of NAF (OR, 3.0; P = 0.01) were independent correlates of ductal lavage cell count adequacy., Conclusions: Ductal lavage is unlikely to be useful in breast cancer screening among BRCA1/2 mutation carriers because the procedure fails to yield adequate specimens sufficient for reliable cytologic diagnosis or to support translational research activities.

Background and Objectives: Evaluation of the ductal epithelium of the breast at increased risk for breast cancer is needed to define the carcinogenic pathway, for risk assessment, and to improve selection of women for chemoprevention therapy. We studied the feasibility of combining breast ductal endoscopy with ductal lavage in the high-risk contralateral breast of women with ipsilateral breast cancer for the evaluation of high-risk ducts and acquisition of ductal epithelial cells for analysis., Methods: Breast ducts were studied by ductal lavage and ductal endoscopy, and epithelial cell content studied cytologically and quantitatively., Results: Twenty-five subjects and 44 ducts, including 22 (50.0%) which did not produce nipple aspirate fluid (NAF), were studied. Cellular atypia was present in five subjects. Ductal endoscopy was performed on 1 or more ducts in 24 subjects. Structural changes were noted in 63.6% of the ducts, most commonly fibrous stranding or bridging. Ductal sampling with endoscopic brush and coil sampling devices provided additional cellular samples of relatively pure ductal epithelial content (> or = 91% purity) in 8/11 subjects., Conclusions: Breast ductal endoscopy combined with ductal lavage represents a feasible approach for characterizing the ducts and ductal epithelium of the high-risk breast, especially in a research setting., ((c) 2006 Wiley-Liss, Inc.)

Purpose: Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis., Patients and Methods: Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m(2)) and docetaxel (75 mg/m(2)) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7., Results: A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone., Conclusion: Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.

The membrane receptor Fas (Apo-1/CD95) is an important initiator of programmed cell death induced by anti-Fas antibody or Fas ligand. MCF-7 human breast cancer cells have low levels of Fas receptor (FasR) and are resistant to anti-FasR antibody mediated apoptosis, however two naturally occurring substances, interferon and all-trans retinoic acid (AT), act synergistically to enhance antiproliferative processes in these cells, suggesting this combination may also be an effective means for enhancing FasR expression. When this was studied, it was found that IFN-gamma and AT in combination acted synergistically to induce expression of FasR mRNA and FasR protein in a time-dependent and dose-dependent manner. This induction required continuous protein synthesis, and STAT1 protein, but not PKR or TR1 protein, was induced in a manner quantitatively and temporally related to FasR protein induction, and consistent with STAT1 mediation of the synergistic effect of IFN-gamma and AT on FasR expression. FasR-induced cells were resistant to stimulation of apoptosis by anti-FasR antibody, however treatment with cycloheximide rendered these cells sensitive to antibody-induced apoptosis, suggesting endogenous blockade to signaling. These cells did not express caspase 3, or FLIP(L), but strongly expressed the endogenous inhibitor of apoptosis Bcl-2, indicating a type II Fas signaling pathway. Expression of these proteins was not modulated by IFN/AT, however treatment of Fas-induced cells with Bcl-2 specific small interfering RNA (SiRNA) downregulated Bcl-2 protein expression and rendered these cells sensitive to the cytotoxic effects of anti-Fas antibody. These findings indicate that IFN-gamma+AT in combination modulate Fas signaling and provide a novel mechanism for the promotion of cell death in breast cancer cells.

Purpose: To evaluate the effect of an ipsilateral breast tumor recurrence (IBTR) after breast-conservation therapy (BCT) on survival., Methods and Materials: One hundred twenty-one women were randomized to BCT. Patients with an IBTR were analyzed to determine survival. Analysis was performed with Kaplan-Meier estimates, log-rank tests, and time-dependent covariate Cox models., Results: At a median follow-up of 18.4 years, 27 patients had an IBTR. The median survival time after IBTR was 13.1 years. The 5-year survival rate was 91.8% (95% confidence interval [CI], 81.5-100%). The 10-year survival rate was 54.3% (95% CI, 35.8-82.6%). According to a Cox model with time-dependent covariates, the hazard ratio or relative risk of dying for those with an IBTR at <5.3 years after BCT relative to patients without an IBTR after BCT is 1.47 (95% CI, 1.02-2.12%; p = 0.04). The hazard ratio for those who relapse after 5.3 years is 0.59 (95% CI, 0.22-1.61%; p = 0.31). Age at randomization, original tumor size, and the presence of positive regional nodes at initial presentation were not found to be associated with decreased survival., Conclusions: There seems to be a significant association of early IBTR after BCT with decreased survival. Local control should be maximized.

Purpose: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer., Experimental Design: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m(2) i.v. day 1) and capecitabine (1000 mg/m(2) orally twice daily days 2-15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m(2) i.v. day 1) and capecitabine (937.5 mg/m(2) orally twice daily days 2-15)., Results: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m(2) at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m(2)/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine., Conclusions: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m(2) docetaxel and 1600 mg/m(2)/day days 2-15 is recommended.

Purpose: To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy., Patients and Methods: Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy., Results: OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients., Conclusion: Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.

We conducted a pilot study of dose dense doxorubicin and cyclophosphamide (AC) combination chemotherapy followed by infusional paclitaxel (T) in primary breast cancer to determine its safety and feasibility. Twenty-two subjects (10 with stage II and > or = 4 positive lymph nodes, and 12 with stage III disease) were treated with AC (A 60 mg/m2 and C 2000 mg/m2) with filgrastim every 14 days for three cycles followed by infusional paclitaxel (140 mg/m2 over 96 h) every 14 days for three cycles. Mean overall cycle length was 15.3 days and mean duration of therapy was 92 days. Dose reductions of C or T were required in 7/132 (5.3%) cycles for mucositis, diarrhea, or failure to recover platelets by day 15. Ninety-five percent of subjects had grade 4 neutropenia and 1 subject had a platelet nadir of < 20,000. Actual delivered dose intensity (DI) over six cycles was: A 27 mg/m2 per week; C 892 mg/m2 per week; T 64 mg/m2 per week (90.6, 89.2, and 91.4% of planned DI, respectively). Average total dose administered was: A 180 mg/m2; C 5880 mg/m2; T 403 mg/m2 (100, 98, and 96% of planned total doses, respectively). Clinical response rate in 10 subjects receiving neoadjuvant therapy was 100% (4 complete response, 6 partial response). Four subjects had a pathologic complete response (three subjects without evidence of malignancy and one subject with ductal carcinoma in situ.) Administration of dose dense AC followed by infusional paclitaxel in 14-day cycles is feasible and this regimen is active in breast cancer.

Background: Between 1979-1987, the National Cancer Institute conducted a randomized, prospective study of mastectomy (MT) versus breast conservation therapy (BCT) in the treatment of patients with early-stage breast carcinoma. After a median potential follow-up of 18.4 years, the authors present the updated results., Methods: After informed consent was obtained from each patient, 237 evaluable women with clinical AJCC Stage I and Stage II breast carcinoma were enrolled on an institutionally reviewed protocol and randomly assigned to undergo modified radical MT (116 patients) or BCT (121 patients), which was comprised of lumpectomy, axillary lymph node dissection, and radiation therapy. Negative surgical margins in the lumpectomy arm were not required. The 237 randomized patients were followed for a median potential follow-up of 18.4 years. The primary endpoints were overall survival and disease-free survival., Results: At a median follow-up of 18.4 years, there was no detectable difference with regard to overall survival between patients treated with MT and those treated with BCT (58% vs. 54%; P = 0.67 overall). Twenty-seven women in the BCT arm (22%) experienced an in-breast event. After censoring in-breast events in the BCT arm that were salvaged successfully by MT, disease-free survival also was found to be statistically similar (67% in the MT arm vs. 63% in the BCT arm; P = 0.64 overall). There was no statistically significant difference with regard to contralateral breast carcinoma between the two treatment arms (P = 0.70)., Conclusions: After nearly 20 years of follow-up, there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with MT compared with those treated with BCT. For BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up. There was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups.

Background: Preoperative chemotherapy for stage II breast cancer may reduce locoregional tumors and provides initial treatment for systemic micrometastases. We conducted a prospective, randomized trial to evaluate the ability of intensive preoperative chemotherapy to enhance the outcome of this approach., Methods: Patients with clinical stage II breast cancer (T2N0, T1N1, and T2N1) were prospectively randomized to receive either preoperative or postoperative chemotherapy with five 21-day cycles of fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor. Local therapy consisted of modified radical mastectomy or segmentectomy/axillary dissection/breast radiotherapy, according to patient preference., Results: Fifty-three women were randomized (26 preoperative chemotherapy and 27 postoperative chemotherapy). The objective clinical response rate of the primary tumor to preoperative chemotherapy was 80%, and the pathologic complete response rate was 20%. Preoperative chemotherapy reduced the overall incidence and number of axillary lymph node metastases. There was no difference in the use of breast-conserving local therapy between the two treatment arms. There were 20 local/regional or distant recurrences (9 preoperative and 11 postoperative). There was no difference in the overall or disease-free survival between the preoperative and postoperative chemotherapy arms., Conclusions: Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy.

Purpose: In women with breast cancer, knowledge of the local/regional extent of the tumor is essential for staging, treatment planning, monitoring response to therapy, and follow-up. Positron emission tomography (PET) is an important imaging test which can detect tumor at multiple sites in women with breast cancer. We compared the ability of PET to provide a comprehensive view of the local/regional extent of tumor in women with stage I, II and stage III, IV breast cancer., Materials and Methods: Forty-six women with breast cancer underwent PET using 18F-FDG. 18FDG uptake in the breast primary tumor, associated skin, axillary and internal mammary lymph nodes, and the contralateral breast was determined qualitatively, and correlated with histologic, clinical and radiographic findings., Results: Twenty-four patients were premenopausal and 22 were postmenopausal, with the following distribution according to clinical stage: stage I--2 patients, stage II--16, stage III--16, stage IV--12 patients. Among stage I, II patients, the sensitivity for detection of the primary tumor was 83.3%, and for detection of axillary lymph node metastases was 42.9%. 18FDG-PET was negative for the breast skin, contralateral breast, and internal mammary lymph nodes in all stage I, II patients, in agreement with clinical and radiographic findings. Among 28 stage III, IV patients, the sensitivity of 18FDG-PET for detection of the primary tumor was 90.5%, and for detection of axillary lymph node metastases 83.3%. Fourteen patients had clinically advanced changes in the skin, and the sensitivity of PET for detection of skin changes was 76.9%. 18FDG-PET was positive in the internal mammary lymph nodes in 25.0%, and negative in the contralateral breast in all patients with stage III, IV breast cancer. 18FDG-PET was studied in 10 patients following neoadjuvant chemotherapy, and showed a strong correlation with clinical response, and with clinical and pathological findings post-treatment at multiple local/regional sites., Conclusion: 18FDG-PET can provide a comprehensive image of local/regional tumor in women with breast cancer. 18FDG-PET may play a greater role in women with stage III, IV breast cancer because of increased sensitivity and the increased involvement of multiple local/regional sites with tumor.

Objective: To evaluate the clinical presentation, diagnostic procedures, and surgical management of hepatic abscesses in patients with chronic granulomatous disease (CGD)., Summary Background Data: Chronic granulomatous disease is a rare inherited primary immunodeficiency in which phagocytes cannot destroy catalase-positive bacteria and fungi. Defects in the phagocytic cells' respiratory burst lead to life-threatening infections, including hepatic abscess. These abscesses are recurrent and often multiple and are treated differently from bacterial abscesses in patients without CGD., Methods: Between 1980 and 2000, 61 cases of hepatic abscess in 22 patients with CGD were treated at the National Institutes of Health. Clinicopathologic features were investigated by retrospective review of the medical records, radiographs, and histopathology., Results: Twelve of the 61 cases were primary hepatic abscesses. Twenty-nine of the cases were recurrent hepatic abscesses, and 20 cases were persistent hepatic abscesses. The median age at the time of initial hepatic abscess presentation was 14 years. Subjective fever was the most frequent presenting symptom, and the erythrocyte sedimentation rate was elevated in 98% of cases. Fifty-two cases were managed surgically and eight cases were managed with percutaneous drainage. One patient refused surgery. The surgical complication rate was 56%; however, there were no deaths directly related to the hepatic abscesses. Staphylococcus aureus was the most frequent organism identified in culture (88% of positive cultures). Aggressive surgery and antibiotics ultimately resulted in successful treatment of all patients., Conclusions: Hepatic abscesses occurring in patients with CGD represent a difficult diagnostic and treatment challenge. Early excision and treatment with antibiotics directed against S. aureus is necessary. General surgeons should be aware of this rare immunodeficiency and should aggressively manage hepatic abscesses in these patients.