Current approaches and challenges in early detection of breast cancer recurrence.

Early detection of breast cancer recurrence is a key element of follow-up care and surveillance after completion of primary treatment. The goal is to improve survival by detecting and treating recurrent disease while potentially still curable assuming a more effective salvage surgery and treatment. In this review, we present the current guidelines for early detection of recurrent breast cancer in the adjuvant setting. Emphasis is placed on the multidisciplinary approach from surgery, medical oncology, and radiology with a discussion of the challenges faced within each setting.

Future directions for the early detection of recurrent breast cancer.

The main goal of follow-up care after breast cancer treatment is the early detection of disease recurrence. In this review, we emphasize the multidisciplinary approach to this continuity of care from surgery, medical oncology, and radiology. Challenges within each setting are briefly addressed as a means of discussion for the future directions of an effective and efficient surveillance plan of post-treatment breast cancer care.

Future directions for monitoring treatment responses in breast cancer.

In the prior review, we outlined the current standard of care for monitoring treatment responses in breast cancer and discussed the many challenges associated with these strategies. We described the challenges faced in common clinical settings such as the adjuvant setting, neoadjuvant setting, and the metastatic setting. In this review, we will expand upon future directions meant to overcome several of these current challenges. We will also explore several new and promising methods under investigation to enhance how we monitor treatment responses in breast cancer. Furthermore, we will highlight several new technologies and techniques for monitoring breast cancer treatment in the adjuvant, neoadjuvant and metastatic setting.

Current approaches and challenges in monitoring treatment responses in breast cancer.

Monitoring response to treatment is a key element in the management of breast cancer that involves several different viewpoints from surgery, radiology, and medical oncology. In the adjuvant setting, appropriate surgical and pathological evaluation guides adjuvant treatment and follow up care focuses on detecting recurrent disease with the intention of improving long term survival. In the neoadjuvant setting, assessing response to chemotherapy prior to surgery to include evaluation for pathologic response can provide prognostic information to help guide follow up care. In the metastatic setting, for those undergoing treatment, it is crucial to determine responders versus non-responders in order to help guide treatment decisions. In this review, we present the current guidelines for monitoring treatment response in the adjuvant, neoadjuvant, and metastatic setting. In addition, we also discuss challenges that are faced in each setting.

Cytogenetic abnormalities precede morphological abnormalities in developing malignant conditions: report of 2 cases.

We previously hypothesized that cytogenetic abnormalities precede morphological abnormalities in developing malignant conditions. In this context we evaluated additional cases to further confirm that hypothesis. We report on 2 additional cases in which clonal cytogenetic abnormalities were observed in otherwise morphologically normal samples. Case 1 is a bone marrow from a 73 year old male with transformed follicular lymphoma (FL), while case 2 is a lymph node from a 53-year-old with lymphadenopathy, both referred to the cytogenetics laboratory for evaluation. A 73-year-old male presented with an enlarging left inguinal mass surrounding and obliterating the left iliac vein. A tissue core biopsy of the mass revealed recurrent high grade FL with diffuse large B-cell lymphoma (DLBCL). Examination of a random bone marrow biopsy of the adjacent left posterior iliac crest showed only mild hypercellularity (50%) and no evidence of malignancy, and the results were confirmed by flow cytometry. Cytogenetic evaluation revealed an interstitial deletion, del (9)(q13q32). In case 2, morphologically the lymph node showed extensive paracortical hyperplasia with numerous eosinophils and no clear indication of a neoplastic process with no abnormal lymphoid population observed by flow. PCR studies for TCR gamma and IgH gene rearrangements were negative for clonality. Chromosome analysis demonstrated 47,XY,+add(1)(p22),t(3;14)(q27;q11.2)[13]/46,XY[7]. FISH studies showed a BCL6 gene rearrangement but no TCRAD rearrangement. A subsequent inguinal lymph node biopsy showed DLBCL. These cases along with the other cases in the literature provide further evidence of genetic abnormalities preceding morphological abnormalities in developing malignant conditions.

Dedifferentiated Liposarcoma of the Retroperitoneum with Extensive Leiomyosarcomatous Differentiation and beta-Human Chorionic Gonadotropin Production.

Dedifferentiated liposarcomas may display a variety of "heterologous" lines of differentiation, including osseous, vascular, skeletal, and/or smooth muscular. There have been six previously reported examples of leiomyosarcomas associated with high levels of serum human chorionic gonadotropin (hCG) production, comprised of cases originating from the retroperitoneum, spermatic cord, small intestine, and uterus. This report describes the first example of a dedifferentiated liposarcoma that combined both of the aforementioned features: extensive heterologous (leiomyosarcomatous) differentiation and beta-hCG production (maximum serum levels 1046 mIU/ml, reference <5 mIU/ml). The tumor, which originated in the retroperitoneum in the region of the right kidney, was rapidly progressive and ultimately fatal within three months of its diagnosis. In addition to characteristic morphologic features, lipogenic and smooth muscle differentiation were confirmed with immunohistochemical stains for MDM2 and smooth muscle actin, respectively. The tumor also displayed diffuse immunoreactivity for beta-hCG in both primary and metastatic sites. This case further expands the clinicopathologic spectrum of lipogenic tumors.

MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma.

The MHC class II transactivator (CIITA) acts in the cell nucleus as the master regulator of MHC class II (MHC II) gene expression. It is important to study CIITA regulation in multiple myeloma since MHC expression is central to ability of myeloma cells to present antigen and to the ability of the immune system to recognize and destroy this malignancy. Regulation of CIITA by IFN-gamma in B lymphocytes occurs through the CIITA type IV promoter (pIV), one of the four potential promoters (pI-pIV) of this gene. To investigate regulation of CIITA by IFN-gamma in multiple myeloma cells, first the ability of these cells to respond to IFN-gamma was examined. RT-PCR analyses show that IFN-gammaR1, the IFN-gamma-binding chain of the IFN-gamma receptor, is expressed in myeloma cells and IRF-1 expression increases in response to IFN-gamma treatment. Western blotting demonstrates that STAT1 is activated by phosphorylation in response to IFN-gamma. RT-PCR and functional promoter analyses show that IFN-gamma upregulates the activity of CIITA pIV, as does ectopic expression of IRF-1 or IRF-2. In vivo protein/DNA binding studies demonstrate protein binding at the GAS, E box and IRF-E sites. In vitro studies confirm the binding of IRF-1 and IRF-2 to CIITA pIV. Although multiple myeloma cells express PRDI-BF1/Blimp-1, a factor that represses both the CIITA type III and IV promoters, they retain the capability to upregulate CIITA pIV and MHC II expression in response to IFN-gamma treatment. These findings are the first to demonstrate that although PRDI-BF1/Blimp-1 diminishes the constitutive ability of these cells to present antigen by limiting CIITA and MHC II expression, it is possible to enhance this expression through the use of cytokines, like IFN-gamma.

Clonogenic analysis reveals reserve stem cells in postnatal mammals. II. Pluripotent epiblastic-like stem cells.

Undifferentiated cells have been identified in the prenatal blastocyst, inner cell mass, and gonadal ridges of rodents and primates, including humans. After isolation these cells express molecular and immunological markers for embryonic cells, capabilities for extended self-renewal, and telomerase activity. When allowed to differentiate, embryonic stem cells express phenotypic markers for tissues of ectodermal, mesodermal, and endodermal origin. When implanted in vivo, undifferentiated noninduced embryonic stem cells formed teratomas. In this report we describe a cell clone isolated from postnatal rat skeletal muscle and derived by repetitive single-cell clonogenic analysis. In the undifferentiated state it consists of very small cells having a high ratio of nucleus to cytoplasm. The clone expresses molecular and immunological markers for embryonic stem cells. It exhibits telomerase activity, which is consistent with its extended capability for self-renewal. When induced to differentiate, it expressed phenotypic markers for tissues of ectodermal, mesodermal, and endodermal origin. The clone was designated as a postnatal pluripotent epiblastic-like stem cell (PPELSC). The undifferentiated clone was transfected with a genomic marker and assayed for alterations in stem cell characteristics. No alterations were noted. The labeled clone, when implanted into heart after injury, incorporated into myocardial tissues undergoing repair. The labeled clone was subjected to directed lineage induction in vitro, resulting in the formation of islet-like structures (ILSs) that secreted insulin in response to a glucose challenge. This study suggests that embryonic-like stem cells are retained within postnatal mammals and have the potential for use in gene therapy and tissue engineering.