Christopher R. Conley

A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells

IntroductionCyclo-oxygenase (COX)-2 expression correlates directly with highly aggressive and metastatic breast cancer, but the mechanism underlying this correlation remains obscure. We hypothesized that invasive human breast cancer cells that over-express COX-2 have the unique ability to differentiate into extracellular-matrix-rich vascular channels, also known as vasculogenic mimicry. Vascular channels have been associated with angiogenesis without involvement of endothelial cells, and may serve as another mechanism by which tumor cells obtain nutrients to survive, especially in less vascularized regions of the tumor.MethodsTo determine whether COX-2 regulates vascular channel formation, we assessed whether treatment with celecoxib (a selective COX-2 inhibitor) or silencing COX-2 synthesis by siRNA inhibits vascular channel formation by breast cancer cell lines. Cell lines were selected based on their invasive potential and COX-2 expression. Additionally, gene expression analysis was performed to identify candidate genes involved in COX-2-induced vascular channel formation. Finally, vascular channels were analyzed in surgically resected human breast cancer specimens that expressed varying levels of COX-2.ResultsWe found that invasive human breast cancer cells that over-express COX-2 develop vascular channels when plated on three-dimensional matigel cultures, whereas non-invasive cell lines that express low levels of COX-2 did not develop such channels. Similarly, we identified vascular channels in high-grade invasive ductal carcinoma of the breast over-expressing COX-2, but not in low-grade breast tumors. Vascular channel formation was significantly suppressed when cells were treated with celecoxib or COX-2 siRNA. Inhibition of channel formation was abrogated by addition of exogenous prostaglandin E2. In vitro results were corroborated in vivo in tumor-bearing mice treated with celecoxib. Using gene expression profiling, we identified several genes in the angiogenic and survival pathways that are engaged in vascular channel formation.ConclusionAntivascular therapies targeting tumor cell vasculogenic mimicry may be an effective approach to the treatment of patients with highly metastatic breast cancer.

[14C]urea breath test for diagnosis of Helicobacter pylori

H. pylori is a potent urease producer, a characteristic that has been exploited in the development of the[14C]- and [13C]urea breath tests. The prevalence of H. pylori infection also is known to increase with advancing age; however, the individual patients age has not routinely been considered when interpreting urea breath test results. The aim of this study was to validate a short, age-adjusted [14C] urea breath test for use in diagnosing H. pylori infections. Forty-one subjects (28 volunteers, 13 patients) underwent esophagogastroduodenoscopy with biopsies. Subjects were defined as being H. pylori positive if histology or culture was positive. In addition, all subjects completed a 120-min [14C]urea breath test. A logistic regression analysis adjusting for age was used to estimate the probability of H. pylori positivity as a function of the14C values generated. Sixteen subjects were H. pylori-positive, and 25 were H. pylori negative. The14C values generated between 15 and 80 min were found to be equally predictive in identifying H. pylori-positive subjects. Advancing age was associated with a higher probability of H. pylori positivity. By taking advantage of the statistical probabilities, older patients could be accurately diagnosed with H. pylori at lower14C values. We found that [14C]urea breath test to be both a sensitive and specific test that can be abbreviated to a 30-min examination (total test time). Moreover, our mathematical model indicates that a patients age should be considered in order to optimize interpretation of the [14C]urea breath test, although further observations are needed to confirm this model.

Prevalence ofHelicobacter pylori in specific forms of gastritis

Helicobacter pylori colonization of the gastric mucosa is strongly associated with chronic nonspecific gastritis; moreover, there is evidence to suggest thatH. pylori may cause this form of gastritis. However, there is little or no information on the prevalence ofH. pylori in specific forms of gastritis. Our hypothesis was that ifH. pylori was pathogenic in chronic nonspecific gastritis, organisms would be found frequently in this type of gastritis but infrequently in specific forms of gastritis. Prevalence rates ofH. pylori were determined independently in patients with eosinophilic and Crohns gastritis, Menetriers disease, and chronic nonspecific gastritis. The prevalence ofH. pylori in patients with chronic nonspecific gastritis was 71%, whereas the organism was not identified in patients with any form of specific gastritis. This finding further supports the accumulating evidence thatH. pylori is a primary pathogenic factor in chronic nonspecific gastritis.

Sentinel lymph node metastases detected by immunohistochemistry only do not mandate complete axillary lymph node dissection in breast cancer

AbstractBackground: The significance of breast cancer sentinel lymph node (SLN) metastases detected only by immunohistochemistry staining (IHC) remains poorly understood. This study attempted to quantify the risk of non-SLN metastases. Methods: A prospectively collected database of 750 consecutive SLN biopsy procedures in breast cancer patients was reviewed. Medical records were reviewed to supplement the database. Results: SLNs were identified in 738 (98.4%) of these procedures in 723 patients. Of these, 151 patients (20.5%) had metastases detected by hematoxylin and eosin staining (H&E), and 33 (4.6%) of the 718 with known IHC staining results had metastases detected by IHC only. Twenty-eight (84.8%) of 33 patients with IHC-detected metastases underwent complete axillary lymph node dissection (CALND). The median primary tumor size was 2.0 cm among those undergoing CALND and 0.9 cm among the five patients treated without CALND (P = .10). Two of the 28 patients (7.1%) had additional metastases detected with CALND. These patients had a T3 or T4 invasive lobular primary tumor. Of 24 patients with T1 or T2 primary tumors and IHC-detected metastases who underwent CALND, none had additional metastases detected. Median follow-up was 14.5 months. All patients with IHC-detected SLN metastases were treated with adjuvant systemic therapy. None of the five patients with IHC-detected metastases not undergoing CALND has subsequently manifested clinical axillary disease. Conclusions: CALND could have been or was safely omitted in 29 of 29 patients with T1 or T2 primary tumors and metastases detected by IHC. Such patients should be counseled about this low risk before CALND is recommended.

Update on intravenous leiomyomatosis: report of five patients and literature review

The objective of this study was to review management and results of surgical therapy of intravenous leiomyomatosis (IVL). A retrospective review of five patients treated at the Mayo Clinic between 2002 and 2012 and a literature review from 1970 to the present were performed. IVL is a rare condition, often overlooked, misdiagnosed or inadequately treated. Despite its benign histological features, invasion of large vessels and cardiac extension can occur and be fatal. Appropriate diagnosis and a radical surgical approach to IVL provide optimal outcomes. Incomplete resection and/or microscopic foci of IVL can lead to recurrence. Surgery should always aim for complete tumor excision and include hysterectomy and bilateral salpingoophorectomy. Radical parametrectomy and intravenous tumor resection may be necessary.

Sclerotic bone metastases from sarcomatoid renal cell carcinoma

Abstract We present a case of sarcomatoid renal cell carcinoma with multiple sclerotic skeletal metastatic lesions. Renal cell carcinoma is frequently metastatic at presentation, with a high incidence of skeletal involvement, classically described as osteolytic. However, sclerotic or osteoblastic metastatic skeletal lesions from renal cell carcinoma are rare, with only two previous reports identified in the literature, neither of which involved the sarcomatoid variant of renal cell carcinoma. In our case the sclerotic metastases were characterized by bone scan, computed tomography (CT), magnetic resonance imaging (MRI), and histologic analysis.

A phase 2 study of lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) for untreated low-grade non-Hodgkin lymphoma requiring therapy

Patients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m2 day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m2 days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenströms macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.

CD5+ Persistent Polyclonal B-Cell Lymphocytosis in a Male

Persistent polyclonal B-cell lymphocytosis with binucleate lymphocytes is a rare lymphoproliferative syndrome of uncertain cause that is strongly associated with HLA-DR7 positivity, cigarette smoking, and female sex. As yet, there is no explanation for the strong sex predilection. We report the third case of persistent polyclonal B-cell lymphocytosis in a male. Other notable findings in this case are lack of HLA-DR7 and strong positive CD5 markers in the polyclonal B-cell population. To our knowledge, CD5 expression has not been mentioned or reported in association with this syndrome.

An Organization Model to Assist Individual Physicians, Scientists, and Senior Health Care Administrators With Personal and Professional Needs

Abstract Working as a physician, scientist, or senior health care administrator is a demanding career. Studies have demonstrated that burnout and other forms of distress are common among individuals in these professions, with potentially substantive personal and professional consequences. In addition to system‐level interventions to promote well‐being globally, health care organizations must provide robust support systems to assist individuals in distress. Here, we describe the 15‐year experience of the Mayo Clinic Office of Staff Services (OSS) providing peer support to physicians, scientists, and senior administrators at one center. Resources for financial planning (retirement, tax services, college savings for children) and peer support to assist those experiencing distress are intentionally combined in the OSS to normalize the use of the Office and reduce the stigma associated with accessing peer support. The Office is heavily used, with approximately 75% of physicians, scientists, and senior administrators accessing the financial counseling and 5% to 7% accessing the peer support resources annually. Several critical structural characteristics of the OSS are specifically designed to minimize potential stigma and reduce barriers to seeking help. These aspects are described here with the hope that they may be informative to other medical practices considering how to create low‐barrier access to help individuals deal with personal and professional challenges. We also detail the results of a recent pilot study designed to extend the activity of the OSS beyond the reactive provision of peer support to those seeking help by including regular, proactive check‐ups for staff covering a range of topics intended to promote personal and professional well‐being.

Secondary Philadelphia chromosome and erythrophagocytosis in a relapsed acute myeloid leukemia after hematopoietic cell transplantation

The acquisition of the Philadelphia chromosome (Ph) as a secondary change during the course of hematopoietic malignancies is rare and is associated with poor prognosis. Few cases of secondary Ph have been reported after hematopoietic cell transplantation (HCT). A secondary Ph at relapse is of clinical importance because it provides a therapeutic target for tyrosine kinase inhibitors along with or in replacement of chemotherapy. We describe a case of relapsed acute myeloid leukemia (AML) after HCT that developed a BCR-ABL1 translocation along with erythrophagocytosis by blasts as a secondary change at the time of relapse. The progression of this patients myeloid neoplasm from myelodysplastic syndrome to AML to relapsed AML after HCT was accompanied by a stepwise cytogenetic evolution: A deletion 20q abnormality subsequently acquired a deletion 7q and, finally, at relapse after HCT, a secondary Ph was gained. The relationship between the secondary Ph and the erythrophagocytosis by blasts is not clear. We review the possible pathogenesis and cytogenetic associations of erythrophagocytosis by blasts, a rare feature in acute leukemias.