Axillary sentinel lymph node biopsy after mastectomy: a case report

<p>Abstract</p> <p>Background</p> <p>Sentinel lymph node biopsy has been established as the preferred method for staging early breast cancer. A prior history of mastectomy is felt to be a contraindication.</p> <p>Case presentation</p> <p>A patient with recurrent breast cancer in her skin flap was discovered to have positive axillary sentinel nodes by sentinel lymph node biopsy five years after mastectomy for ductal carcinoma in situ.</p> <p>Conclusion</p> <p>A prior history of mastectomy may not be an absolute contraindication to sentinel lymph node biopsy.</p

Workshop Report for Cancer Research: Defining the Shades of Gy: Utilizing the Biological Consequences of Radiotherapy in the Development of New Treatment Approaches—Meeting Viewpoint

The ability to physically target radiotherapy using image-guidance is continually improving with photons and particle therapy that include protons and heavier ions such as carbon. The unit of dose deposited is the gray (Gy); however, particle therapies produce different patterns of ionizations, and there is evidence that the biological effects of radiation depend on dose size, schedule, and type of radiation. This National Cancer Institute (NCI)–sponsored workshop addressed the potential of using radiation-induced biological perturbations in addition to physical dose, Gy, as a transformational approach to quantifying radiation

Abstract 1682: Radiation-induced autophagy is dependent on Sirtuin 3.

Abstract Sirtuin family members (Sirtuin 1 to 7) are highly conserved proteins, both structurally and functionally, and have either NAD+ dependent enzymatic activity (Sirtuin 1,2, 3, 5 and 7) for deacetylation of proteins or ADP ribosyl transferase activity (Sirtuin 4 and 6). Their functions in metabolic processes and chromatin remodeling have been conserved throughout evolution. Sirtuin 1 and Sirtuin 2 have been shown to be linked with several neurological disorders. The role of other Sirtuins in neurodegenerative disorders is not known. Radiation therapy (RT), one of the preferred and widely accepted treatments for intracranial primary and secondary metastatic tumors, may lead to long-term irreversible neurotoxicity in susceptible individuals with cognitive dysfunction similar to that observed in other neurodegenerative disorders. There are ample data which demonstrate that aberrant autophagic process and dysfunctional mitochondria are important factors leading to several neurological diseases, such as Huntington's disease and Parkinson's dementia. Among the Sirtuins, Sirtuin 3, 4 and 5 are localized within mitochondria, however, their role in radiation-induced neurotoxicity has not been evaluated. Using Sirtuin 3 knockout (KO) mice generated through genomic deletion allowed us the opportunity to study its role in autophagy and mitochondrial function during exposure to radiation. Preliminary reports show Sirtuin 3 in the adult mouse brain to be localized primarily within hippocampus and subcortical plate. Through flow cytometry and immunofluorescence stainin of mouse embryonic fibroblasts (MEFs) derived from Sirtuin 3 KO mice, we demonstrate that loss of Sirtuin 3 alters rates of basal autophagy. Furthermore, immunoblot analysis of autophagic marker LC3B I &amp;II in the presence and absence of hydrolase inhibitors (E64d &amp; Pepstatin A) exhibits that loss of Sirtuin 3 stimulates autophagy. Radiation treatment of Sirtuin 3 wild-type and knockout MEFs exhibited dose dependent induction of autophagy. Staining with mitotracker red and JC1 illustrates that MEFs lacking Sirtuin 3 retain mitochondria with abnormal morphology and disturbed membrane potential which can further enhanced by radiation treatment and exposure to the ionophore Carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Enrichment of lower form of LC3B in Sirtuin 3 KO cells upon treatment with CCCP and radiation suggests that loss of Sirtuin 3 sensitizes cells towards enhanced autophagy via mitophagy. Taken together, this study indicates that Sirtuin 3 is an important player in deciding cell fate via mitophagy during radiation treatment and has important implications in further studies of radiation-induced neurotoxicity. Citation Format: Sadhanshu Shukla, DeeDee Smart. Radiation-induced autophagy is dependent on Sirtuin 3. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1682. doi:10.1158/1538-7445.AM2013-1682</jats:p

Abstract 4354: Proteomic analysis of acute radiation response following whole brain irradiation: Is Sirt2 a key player of radiation-induced neurotoxicity

Abstract Radiation therapy (RT) is one of the most effective and widely used treatments of both primary and metastatic intracranial tumors. Recent technical advances in RT and multimodality approach to treatment have increased the life span of patients. However, a major concern remains as to radiation's effect on long term neurotoxicity and cognitive impairment. Acute and sub acute effects of RT following whole brain RT appear to be reversible, but we hypothesize that these acute changes provide a platform for alteration of the central nervous system (CNS) microenvironment that is responsible for delayed irreversible neurotoxicity. To improve the quality of life of patients and to improve efficacy of whole brain RT, we require effective and targeted approaches to minimize cognitive dysfunction. In order to understand the acute molecular events involved after RT and to identify potential markers that lead to long-term neurotoxicity and dementia, we performed quantitative mass spectroscopy using the iTRAQ (isobaric tag of relative and absolute quantitation) technique on C57 Bl/6 mouse brain tissue extract 72 hours following whole brain RT versus sham-irradiated controls. We found significant changes up- and down-regulation of critical proteins in multiple canonical pathways to be affected, but interestingly some of the most significant changes were in proteins vital to Huntington and Parkinson's signaling pathways. Additionally, we explored the role of Sirtuin 2 (Sirt2), a Class III histone deacetylase which is abundant in CNS and has been shown to mediate oxidative stress response in animal models of neurodegeneration which produce dementia, within the context of whole brain RT. Our aim was to investigate if Sirt2 might be a potential target to mitigate neurotoxic effects induced by RT. Our proteomic analysis of the brain tissue extracts of Sirt2 genomic knockout mice shows that the absence of Sirt2 affects several metabolic and signaling pathways including Huntington, Parkinson's, as well as mitochondrial-mediated signaling. Several factors were found to be uniquely and differentially expressed in Sirt2 knockout tissues under radiation condition. This study indicates that Sirt2 might be a key player in radio sensitization of the CNS and a potential clinical target for minimizing radiation-induced neurocognitive dysfunction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4354. doi:1538-7445.AM2012-4354</jats:p

Radiosensitizers in the temozolomide era for newly diagnosed glioblastoma

Abstract Glioblastoma (GBM) is a challenging diagnosis with almost universally poor prognosis. Though the survival advantage of postoperative radiation (RT) is well established, around 90% of patients will fail in the RT field. The high likelihood of local failure suggests the efficacy of RT needs to be improved to improve clinical outcomes. Radiosensitizers are an established method of enhancing RT cell killing through the addition of a pharmaceutical agent. Though the majority of trials using radiosensitizers have historically been unsuccessful, there continues to be interest with a variety of approaches having been employed. Epidermal growth factor receptor inhibitors, histone deacetylase inhibitors, antiangiogenic agents, and a number of other molecularly targeted agents have all been investigated as potential methods of radiosensitization in the temozolomide era. Outcomes have varied both in terms of toxicity and survival, but some agents such as valproic acid and bortezomib have demonstrated promising results. However, reporting of results in phase 2 trials in newly diagnosed GBM have been inconsistent, with no standard in reporting progression-free survival and toxicity. There is a pressing need for investigation of new agents; however, nearly all phase 3 trials of GBM patients of the past 25 years have demonstrated no improvement in outcomes. One proposed explanation for this is the selection of agents lacking sufficient preclinical data and/or based on poorly designed phase 2 trials. Radiosensitization may represent a viable strategy for improving GBM outcomes in newly diagnosed patients, and further investigation using agents with promising phase 2 data is warranted.</jats:p

SIRT2 Interacts with β-Catenin to Inhibit Wnt Signaling Output in Response to Radiation-Induced Stress

Abstract Wnt signaling is critical to maintaining cellular homeostasis via regulation of cell division, mitigation of cell stress, and degradation. Aberrations in Wnt signaling contribute to carcinogenesis and metastasis, whereas sirtuins have purported roles in carcinogenesis, aging, and neurodegeneration. Therefore, the hypothesis that sirtuin 2 (SIRT2) directly interacts with β-catenin and whether this interaction alters the expression of Wnt target genes to produce an altered cellular phenotype was tested. Coimmunoprecipitation studies, using mouse embryonic fibroblasts (MEF) from Sirt2 wild-type and genomic knockout mice, demonstrate that β-catenin directly binds SIRT2. Moreover, this interaction increases in response to oxidative stress induced by ionizing radiation. In addition, this association inhibits the expression of important Wnt target genes such as survivin (BIRC5), cyclin D1 (CCND1), and c-myc (MYC). In Sirt2 null MEFs, an upregulation of matrix metalloproteinase 9 (MMP9) and decreased E-cadherin (CDH1) expression is observed that produces increased cellular migration and invasion. Together, these data demonstrate that SIRT2, a tumor suppressor lost in multiple cancers, inhibits the Wnt signaling pathway in nonmalignant cells by binding to β-catenin and that SIRT2 plays a critical role in the response to oxidative stress from radiation. Implications: Disruption of the SIRT2–β-catenin interaction represents an endogenous therapeutic target to prevent transformation and preserve the integrity of aging cells against exogenous stressors such as reactive oxygen species. Mol Cancer Res; 12(9); 1244–53. ©2014 AACR.</jats:p