Preoperative Risk Factors for Lymphedema in Inflammatory Breast Cancer.

BACKGROUND: Prophylactic lymphatic bypass or LYMPHA (LYmphatic Microsurgical Preventive Healing Approach) is increasingly offered to prevent lymphedema following breast cancer treatment, which develops in up to 47% of patients. Previous studies focused on intraoperative and postoperative lymphedema risk factors, which are often unknown preoperatively when the decision to perform LYMPHA is made. This study aims to identify preoperative lymphedema risk factors in the high-risk inflammatory breast cancer (IBC) population. METHODS: Retrospective review of our institution's IBC program database was conducted. The primary outcome was self-reported lymphedema development. Multivariable logistic regression analysis was performed to identify preoperative lymphedema risk factors, while controlling for number of lymph nodes removed during axillary lymph node dissection (ALND), number of positive lymph nodes, residual disease on pathology, and need for adjuvant chemotherapy. RESULTS: Of 356 patients with IBC, 134 (mean age: 51 years, range: 22-89 years) had complete data. All 134 patients underwent surgery and radiation. Forty-seven percent of all 356 patients (167/356) developed lymphedema. Obesity (body mass index > 30) (odds ratio [OR]: 2.7, confidence interval [CI]: 1.2-6.4, p = 0.02) and non-white race (OR: 4.5, CI: 1.2-23, p = 0.04) were preoperative lymphedema risk factors. CONCLUSION: Patients with IBC are high risk for developing lymphedema due to the need for ALND, radiation, and neoadjuvant chemotherapy. This study also identified non-white race and obesity as risk factors. Larger prospective studies should evaluate potential racial disparities in lymphedema development. Due to the high prevalence of lymphedema, LYMPHA should be considered for all patients with IBC.

Bladder metastasis from inflammatory breast cancer presenting with hematuria and hydronephrosis.

We report a rare case of a 56-year-old Ukrainian female with inflammatory breast cancer (IBC) who underwent neoadjuvant chemoradiation and left radical mastectomy with her clinical course complicated by disease recurrence with bone and bladder metastases 2.5 years after her initial diagnosis. We highlight the presentation and diagnosis of genitourinary involvement of metastatic IBC, which has not previously been described in the literature.

[A Case Report of Luminal A Male Inflammatory Breast Cancer that Was Difficult to Treat Because of Trousseau Syndrome].

This report describes the case of a 67-year-old male with inflammatory breast cancer. He had noticed a left breast mass about seven years previously, but he had ignored it. He then visited our hospital 4 months previously when multiple small masses occurred in the left front chest wall. The tumor was diagnosed as skin metastasis of breast cancer by skin biopsy and he was referred to our department. The tumor cells were positive for estrogen receptor and progesterone receptor, and negative for HER2/neu, and the Ki67 expression was 10-15%. The subtype of his breast cancer was luminal A type. It had secondary inflammatory breast cancer and preceded chemotherapy. Also, as the veins in the lower extremity were filled with thrombus, we gave him an anticoagulant (Edoxaban), but due to the malignant hyper coagulable state (Trousseau syndrome) a CV port could not be implanted. 3 courses of docetaxel every 3 weeks failed to control the disease. Since an obstruction of the right iliac artery was newly observed, the anticoagulant was changed to cilostazol and rivaroxaban, but left second finger and fourth finger necrosis occurred due to peripheral circulatory failure. The condition of the disease was stabilized by FEC (5-FU, epirubicin, cyclophosphamide) therapy, but it became difficult to secure the blood vessel. Without constructing a CV port because of the thrombus, chemotherapy was changed to S-1 oral administration, and strength to the chest wall Modulated radiotherapy intensity modulated radiation therapy (IMRT) was performed. Although the tumor was reduced, the condition of the whole body gradually weakened and the patient died a year and a half after the start of the treatment. This case of inflammatory luminal in male breast cancer that caused thrombus was difficult to treat. Thrombosis in advanced cancer patients is often pointed out, but since male breast cancer patients tend to take a long time to visit the hospital after becoming aware of the mass and arrive at an advanced state, it is necessary to notify the public of the existence of male breast cancer.

Prediction of Bone Metastasis in Inflammatory Breast Cancer Using a Markov Chain Model.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare yet aggressive variant of breast cancer with a high recurrence rate. We hypothesized that patterns of metastasis differ between IBC and non-IBC. We focused on the patterns of bone metastasis throughout disease progression to determine statistical differences that can lead to clinically relevant outcomes. Our primary outcome of this study is to quantify and describe this difference with a view to applying the findings to clinically relevant outcomes for patients. SUBJECTS, MATERIALS, AND METHODS: We retrospectively collected data of patients with nonmetastatic IBC (n = 299) and non-IBC (n = 3,436). Probabilities of future site-specific metastases were calculated. Spread patterns were visualized to quantify the most probable metastatic pathways of progression and to categorize spread pattern based on their propensity to subsequent dissemination of cancer. RESULTS: In patients with IBC, the probabilities of developing bone metastasis after chest wall, lung, or liver metastasis as the first site of progression were high: 28%, 21%, and 21%, respectively. For patients with non-IBC, the probability of developing bone metastasis was fairly consistent regardless of initial metastasis site. CONCLUSION: Metastatic patterns of spread differ between patients with IBC and non-IBC. Selection of patients with IBC with known liver, chest wall, and/or lung metastasis would create a population in whom to investigate effective methods for preventing future bone metastasis. IMPLICATIONS FOR PRACTICE: This study demonstrated that the patterns of metastasis leading to and following bone metastasis differ significantly between patients with inflammatory breast cancer (IBC) and those with non-IBC. Patients with IBC had a progression pattern that tended toward the development of bone metastasis if they had previously developed metastases in the liver, chest wall, and lung, rather than in other sites. Selection of patients with IBC with known liver, chest wall, and/or lung metastasis would create a population in whom to investigate effective methods for preventing future bone metastasis.

Inflammatory breast cancer and chest wall disease: The oncologist perspective.

Chest wall inflammatory and lymphangitic breast cancer represents a clinical spectrum and a model disease. Inflammation and the immune response have a role in the natural history of this special clinical presentation. Preclinical models and biomarker studies suggest that inflammatory breast cancer comprises a more important role for the tumour microenvironment, including immune cell infiltration and vasculogenesis, especially lympho-angiogenesis. Across this clinical continuum of the chest wall disease there is an important role of the inflammation cascade. The activation of mature dendritic cells (DCs) through toll like receptors (TLRs) or by inflammatory cytokines converts immature DCs into mature DCs that present specific antigen to T cells, thereby activating them. Maturation of DCs is accompanied by co-stimulatory molecules and secretion of inflammatory cytokines polarizing lymphocytic, macrophages and fibroblast infiltration. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. Immune and microenvirnment factors can induce phenotypic, morphological, and functional changes in breast cancer cells. We can hypothesize that similar inflammatory conditions in vivo may support both the rapid metastasis and tight tumor emboli that are characteristic of chest wall disease and that targeted anti-inflammatory therapy may play a role in this patient population. The current review will review biological and clinical data of this special condition.

Locoregional recurrence of breast cancer presenting as upper limb venous thromboembolism.

Locoregional recurrence of breast cancer is a major concern for both patient and oncologist. Presentation as venous thromboembolism (VTE) carries risk of delayed diagnosis and has a poor prognosis. Here we describe, for the first time in the literature, a delayed diagnosis of local recurrence of infiltrative inflammatory breast cancer presenting as extensive deep venous thrombosis of the upper arm veins. This case demonstrates the need for a high level of vigilance for recurrence of malignancy in patients with no concurrent risk factors for VTE and atypical clinical progression in order to reach a timely diagnosis.

Thrombocytosis as a prognostic factor in inflammatory breast cancer.

PURPOSE: Platelets are essential components of hemostasis and also play an important role in the tumor microenvironment. The purposes of our research were to examine the role of thrombocytosis in inflammatory breast cancer (IBC) and to know which cytokine drives thrombocytosis. METHODS: We reviewed the medical records of 3654 patients with stage I-III breast cancer treated between 1998 and 2013, including 230 patients (6%) with IBC. We used Chi-squared test or Fisher's exact test to compare the variables between patients with and without thrombocytosis. Multivariate Cox regression models were used to determine the association of thrombocytosis with overall survival. We also examined baseline serum cytokine levels in 81 patients with primary IBC to determine the association of inflammatory cytokines with thrombocytosis. RESULTS: We found that thrombocytosis was the only variable that predicted prognosis. Fifty-five patients (1.5%) had thrombocytosis. Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC (3.4% vs. 1.4%, p = 0.015). In patients with IBC, thrombocytosis was associated with worse overall survival [hazard ratio 2.38, 95% confidence interval (CI) 1.05-5.4, p = 0.0378]. Circulating levels of growth-regulated oncogene (GRO) (odds ratio 1.003, 95% CI 1.001-1.005, p = 0.0019) and transforming growth factor ß (TGF-ß) (odds ratio 1.3, 95% CI 1.128-1.499, p = 0.0003) were associated with thrombocytosis. CONCLUSIONS: Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC and it was associated with poor prognosis. GRO and TGF-ß were associated with thrombocytosis in IBC.

MicroRNA 301A Promotes Intestinal Inflammation and Colitis-Associated Cancer Development by Inhibiting BTG1.

BACKGROUND & AIMS: Intestinal tissues from patients with inflammatory bowel disease (IBD) and colorectal cancer have increased expression of microRNA-301a (MIR301A) compared with tissues from patients without IBD. We studied the mechanisms of MIR301A in the progression of IBD in human tissues and mice. METHODS: We isolated intestinal epithelial cells (IECs) from biopsy samples of the colon from 153 patients with different stages of IBD activity, 6 patients with colitis-associated cancer (CAC), and 35 healthy individuals (controls), enrolled in the study in Shanghai, China. We measured expression of MIR301A and BTG anti-proliferation factor 1 (BTG1) by IECs using quantitative reverse-transcription polymerase chain reaction. Human colon cancer cell lines (HCT-116 and SW480) were transfected with a lentivirus that expresses MIR301A; expression of cytokines and tight junction proteins were measured by quantitative reverse transcription polymerase chain reaction, flow cytometry, and immunofluorescence staining. We generated mice with disruption of the microRNA-301A gene (MIR301A-knockout mice), and also studied mice that express a transgene-encoding BTG1. Colitis was induced in knockout, transgenic, and control (C57BL/B6) mice by administration of dextran sulfate sodium (DSS), and mice were given azoxymethane to induce colorectal carcinogenesis. Colons were collected and analyzed histologically and by immunohistochemistry; tumor nodules were counted and tumor size was measured. SW480 cells expressing the MIR301A transgene were grown as xenograft tumors in nude mice. RESULTS: Expression of MIR301A increased in IECs from patients with IBD and CAC compared with controls. MIR301A-knockout mice were resistant to the development of colitis following administration of DSS; their colon tissues expressed lower levels of interleukin 1ß (IL1ß), IL6, IL8, and tumor necrosis factor than colons of control mice. Colon tissues from MIR301A-knockout mice had increased epithelial barrier integrity and formed fewer tumors following administration of azoxymethane than control mice. Human IECs expressing transgenic MIR301A down-regulated expression of cadherin 1 (also called E-cadherin or CDH1). We identified BTG1 mRNA as a target of MIR301A; levels of BTG1 mRNA were reduced in inflamed mucosa from patients with active IBD compared with controls. There was an inverse correlation between levels of BTG1 mRNA and levels of MIR301A in inflamed mucosal tissues from patients with active IBD. Human colon cancer cell lines that expressed a MIR301A transgene increased proliferation; they had increased permeability and decreased expression of CDH1 compared with cells transfected with a control vector, indicating reduced intestinal barrier function. BTG1 transgenic mice developed less severe colitis than control mice following administration of DSS. SW480 cells expressing anti-MIR301A formed fewer xenograft tumors in nude mice than cells expressing a control vector. CONCLUSIONS: Levels of MIR301A are increased in IECs from patients with active IBD. MIR301A reduces expression of BTG1 to reduce epithelial integrity and promote inflammation in mouse colon and promotes tumorigenesis. Strategies to decrease levels of MIR301A in colon tissues might be developed to treat patients with IBD and CAC.

Human cytomegalovirus infection enhances NF-κB/p65 signaling in inflammatory breast cancer patients.

Human Cytomegalovirus (HCMV) is an endemic herpes virus that re-emerges in cancer patients enhancing oncogenic potential. Recent studies have shown that HCMV infection is associated with certain types of cancer morbidity such as glioblastoma. Although HCMV has been detected in breast cancer tissues, its role, if any, in the etiology of specific forms of breast cancer has not been investigated. In the present study we investigated the presence of HCMV infection in inflammatory breast cancer (IBC), a rapidly progressing form of breast cancer characterized by specific molecular signature. We screened for anti-CMV IgG antibodies in peripheral blood of 49 non-IBC invasive ductal carcinoma (IDC) and 28 IBC patients. In addition, we screened for HCMV-DNA in postsurgical cancer and non-cancer breast tissues of non-IBC and IBC patients. We also tested whether HCMV infection can modulate the expression and activation of transcriptional factor NF-κB/p65, a hallmark of IBC. Our results reveal that IBC patients are characterized by a statistically significant increase in HCMV IgG antibody titers compared to non-IBC patients. HCMV-DNA was significantly detected in cancer tissues than in the adjacent non-carcinoma tissues of IBC and IDC, and IBC cancer tissues were significantly more infected with HCMV-DNA compared to IDC. Further, HCMV sequence analysis detected different HCMV strains in IBC patients tissues, but not in the IDC specimens. Moreover, HCMV-infected IBC cancer tissues were found to be enhanced in NF-κB/p65 signaling compared to non-IBC patients. The present results demonstrated a correlation between HCMV infection and IBC. Etiology and causality of HCMV infection with IBC now needs to be rigorously examined.

The genesis and unique properties of the lymphovascular tumor embolus are because of calpain-regulated proteolysis of E-cadherin.

The genesis and unique properties of the lymphovascular tumor embolus are poorly understood largely because of the absence of an experimental model that specifically reflects this important step of tumor progression. The lymphovascular tumor embolus is a blastocyst-like structure resistant to chemotherapy, efficient at metastasis and overexpressing E-cadherin (E-cad). Conventional dogma has regarded E-cad as a metastasis-suppressor gene involved in epithelial-mesenchymal transition. However, within the lymphovascular embolus, E-cad and its proteolytic processing by calpain and other proteases have a dominant oncogenic rather than suppressive role in metastasis formation and tumor cell survival. Studies using a human xenograft model of inflammatory breast cancer, MARY-X, demonstrated the equivalence of xenograft-generated spheroids with lymphovascular emboli in vivo with both structures demonstrating E-cad overexpression and specific proteolytic processing. Western blot revealed full-length (FL) E-cad (120 kDa) and four fragments: E-cad/NTF1 (100 kDa), E-cad/NTF2 (95 kDa), E-cad/NTF3 (85 kDa) and E-cad/NTF4 (80 kDa). Compared with MARY-X, only E-cad/NTF1 was present in the spheroids. E-cad/NTF1 was produced by calpain, E-cad/NTF2 by γ-secretase and E-cad/NTF3 by a matrix metalloproteinase (MMP). Spheroidgenesis and lymphovascular emboli formation are the direct result of calpain-mediated cleavage of E-cad and the generation of E-cad/NTF1 from membrane-associated E-cad rather than the de novo presence of either E-cad/NTF1 or E-cad/CTF1. E-cad/NTF1 retained the p120ctn-binding site but lost both the ß-catenin and α-binding sites, facilitating its disassembly from traditional cadherin-based adherens junctions and its 360° distribution around the embolus. This calpain-mediated proteolysis of E-cad generates the formation of the lymphovascular embolus and is responsible for its unique properties of increased homotypic adhesion, apoptosis resistance and budding.

Lymphoma of the breast: a mimic of inflammatory breast cancer.

BACKGROUND: Unusual presentation of breast lymphoma with signs and symptoms suggestive of inflammatory breast cancer. DISCUSSION: Lymphoma of the breast is uncommon whether it is primary or secondary. Most breast lymphomas are of B cell origin. The most frequent mode of presentation is a painless breast mass. The clinical presentation of localized left breast erythema and edema with an associated left breast mass is common for an inflammatory breast cancer but highly unusual for lymphoma of the breast. CONCLUSION: In patients with a left breast mass associated with erythema and edema, the differential diagnosis should include breast lymphoma in addition.

Reflections on lymphoedema, fungating wounds and the power of touch in the last weeks of life.

Terminal care is a significant chapter of life in which each individual has the right to expect dignity, compassion, holistic care, and quality of life. The case of 'Sally', a 57-year-old woman with a diagnosis of inflammatory breast cancer, left arm lymphoedema, and a fungating chest wound, gave palliative care nurses a multitude of distressing and complex challenges to manage. Management of lymphoedema is often put into the 'too hard basket', especially in the palliative care setting. Similarly, fungating wounds are hard to confront, and the power of touch is often underestimated. The aim of this case study is to explore and reflect on how these issues entwine, and how vital it is for nurses to feel comfortable in providing the most appropriate care. As a result of reflection on Sally's care management many issues were highlighted, including the crucial need to relieve her symptoms with timely, appropriate, dignified, and respectful care, optimizing her sense of worth and quality of life.