Cardiac tamponade as an unusual presentation of advanced breast cancer in pregnancy

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in pregnancy. Though the prognosis by stage is not different from that in nonpregnant women, it is more likely to present at an advanced stage in pregnancy. CASE: A 28-year-old primigravida presented with dyspnea and pleuritic chest pain. The workup revealed cardiac tamponade. Pericardiocentesis and subsequent pericardial window were performed. Cytology of the pericardial fluid revealed poorly differentiated adenocarcinoma. Ultrasonography displayed a right breast mass, and biopsy identified it as the primary source of the cancer. CONCLUSION: Cardiac tamponade is an unusual presentation of advanced breast cancer. To the best of our knowledge, it has not previously been described as occurring in pregnancy.     

The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells

High grade epithelial ovarian cancers are relatively sensitive to DNA damaging platinum-based chemotherapy, suggesting that the dependencies of ovarian tumors on DNA damage response pathways can be harnessed for therapeutic purposes. Our goal was to determine if the DNA damage mark gamma-H2AX phosphorylation (pH2AX) could be used to identify suitable cytotoxic histone deacetylase inhibitors (HDACi) for ovarian cancer treatment. Nineteen chemically diverse HDACi compounds were tested in 7 ovarian cancer cell lines. Fluorescent, biochemical and cell-based assays were performed to assess DNA damage by induction of pH2AX and to measure cell viability and apoptosis. The relationships between pH2AX and the cellular effects of cell viability and apoptosis were calculated. Selected HDACi were tested in combination with cisplatin and other DNA damaging agents to determine if the HDACi improved upon the effects of the DNA damaging agents. The HDACi compounds induced differing levels of pH2AX expression. High levels of pH2AX in HDACi-treated ovarian cancer cells were tightly associated with decreased cell viability and increased apoptosis. Consequently, a ketone-based HDACi was chosen and found to enhance the effects of cisplatin, even in ovarian cancer cells with extreme resistance to DNA damaging drugs. In conclusion, a fluorescent-based assay for pH2AX can be used to determine cellular responses to HDACi in vitro and may be a useful tool to identify potentially more effective HDACi for the treatment of ovarian cancer. In addition, these results lend support to the inclusion of ketone-derived HDACi compounds for future development.     

Early Detection of Treatment-Induced Mitotic Arrest Using Temporal Diffusion Magnetic Resonance Spectroscopy

PURPOSE: A novel quantitative magnetic resonance imaging (MRI) method, namely, temporal diffusion spectroscopy (TDS), was used to detect the response of tumor cells (notably, mitotic arrest) to a specific antimitotic treatment (Nab-paclitaxel) in culture and human ovarian xenografts and evaluated as an early imaging biomarker of tumor responsiveness. METHODS: TDS measures a series of apparent diffusion coefficients (ADCs) of tissue water over a range of effective diffusion times, which may correspond to diffusion distances ranging from subcellular to cellular levels (~ 3-20 μm). By fitting the measured ADC data to a tissue model, parameters reflecting structural properties such as restriction size in solid tumors can be extracted. Two types of human ovarian cell lines (OVCAR-8 as a responder to Nab-paclitaxel and NCI/ADR-RES as a resistant type) were treated with either vehicle (PBS) or Nab-paclitaxel, and treatment responses of both in vitro and in vivo cases were investigated using TDS. RESULTS: Acute cell size increases induced by Nab-paclitaxel in responding tumors were confirmed by flow cytometry and light microscopy in cell culture. Nab-paclitaxel–induced mitotic arrest in treated tumors/cells was quantified histologically by measuring the mitotic index in vivo using a mitosis-specific marker (anti-phosphohistone H3). Changes in the fitted restriction size, one of the parameters obtained from TDS, were able to detect and quantify increases in tumor cell sizes. All the MR results had a high degree of consistency with other flow, microscopy, and histological data. Moreover, with an appropriate analysis, the Nab-paclitaxel–responsive tumors in vivo could be easily distinguished from all the other vehicle-treated and Nab-paclitaxel–resistant tumors. CONCLUSION: TDS detects increases in cell sizes associated with antimitotic-therapy–induced mitotic arrest in solid tumors in vivo which occur before changes in tissue cellularity or conventional diffusion MRI metrics. By quantifying changes in cell size, TDS has the potential to improve the specificity of MRI methods in the evaluation of therapeutic response and enable a mechanistic understanding of therapy-induced changes in tumors.     

Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy

Background

New treatment strategies are emerging to target DNA damage response pathways in ovarian cancer. Our group has previously shown that the class I biased HDAC inhibitor romidepsin (FK228) induces DNA damage response and has potent cytotoxic effects in ovarian cancer cells. Here, we investigated newly discovered HDAC inhibitors, thailandepsin A (TDP-A) and thailandepsin B (TDP-B), to determine the effects on cell viability, apoptosis and DNA damage response in ovarian cancer cells.

Methods

FK228, TDP-A and TDP-B were tested in five ovarian cancer cell lines. Cellular viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Immunofluorescence assays were used to assess activated caspase 3. Western blots were performed to detect protein expression of PARP cleavage, pH2AX, P-glycoprotein and tubulin acetylation.

Results

Treatment with TDPs decreased cell viability at nanonomolar concentrations in four of the five ovarian cancer cell lines studied. Similar to FK228, both TDP compounds exerted minimal effects on NCI/ADR-RES ovarian cancer cells. Across the four cell lines sensitive to the TDPs, TDP-B consistently had a greater inhibitory effect than TDP-A on cell viability. TDP-B also had relatively greater effects on promoting cell apoptosis and induction of pH2AX (a mark of DNA damage response), than TDP-A. These antitumor effects of TDP-B were of similar magnitude to those induced by an equal concentration of FK228. Similar to FK228, the nanomolar concentrations of the TDPs had little effect on tubulin acetylation (a mark of class II HDAC6 inhibition).

Conclusions

The new small molecule HDAC inhibitors TDP-A and TDP-B are FK228 analogues that suppress cell viability and induce apoptosis at nanomolar drug concentrations. TDP-B showed the most similarity to the biological activity of FK228 with greater cytotoxic effects than TDP-A in vitro. Our results indicate that FK228-like small molecule class I HDAC-biased HDAC inhibitors have therapeutic potential for ovarian cancer.     

Genetic counseling,testing, and screening for breast and ovarian cancer: practical and social considerations

Breast and ovarian cancer are complex diseases that develop from multiple genetic alterations. In an era of genomics and advancing technologies, scientific knowledge regarding specific mechanisms of cancer development is evolving rapidly. In this context, identifying women with hereditary breast or ovarian cancer syndrome is becoming more complicated. Cancer genetic counselors must convey new scientific information, accurately assess cancer risk, and offer available options for genetic testing and medical interventions when there are still more questions than definitive answers.     

Gynecologic cancer disparities: A report from the Health Disparities Taskforce of the Society of Gynecologic Oncology

Objectives

To review the extent of health disparities in gynecologic cancer care and outcomes and to propose recommendations to help counteract the disparities.

Methods

We searched the electronic databases PubMed and the Cochrane Library. We included studies demonstrating quantifiable differences by race and ethnicity in the incidence, treatment, and survival of gynecologic cancers in the United States (US). Most studies relied on retrospective data. We focused on differences between Black and White women, because of the limited number of studies on non-Black women.

Results

White women have a higher incidence of ovarian cancer compared to Black women. However, the all-cause ovarian cancer mortality in Black women is 1.3 times higher than that of White women. Endometrial and cervical cancer mortality in Black women is twice that of White women. The etiology of these disparities is multifaceted. However, much of the evidence suggests that equal care leads to equal outcomes for Black women diagnosed with gynecologic cancers. Underlying molecular factors may play an additional role in aggressive tumor biology and endometrial cancer disparities.

Conclusion

Gynecologic cancer disparities exist between Black and White women. The literature is limited by the lack of large prospective trials and adequate numbers of non-Black racial and ethnic groups. We conclude with recommendations for continued research and a multifaceted approach to eliminate gynecologic cancer disparities.     

Hdac3 is essential for the maintenance of chromatin structure and genome stability

Hdac3 is essential for efficient DNA replication and DNA damage control. Deletion of Hdac3 impaired DNA repair and greatly reduced chromatin compaction and heterochromatin content. These defects corresponded to increases in histone H3K9,K14ac; H4K5ac; and H4K12ac in late S phase of the cell cycle, and histone deposition marks were retained in quiescent Hdac3-null cells. Liver-specific deletion of Hdac3 culminated in hepatocellular carcinoma. Whereas HDAC3 expression was downregulated in only a small number of human liver cancers, the mRNA levels of the HDAC3 cofactor NCOR1 were reduced in one-third of these cases. siRNA targeting of NCOR1 and SMRT (NCOR2) increased H4K5ac and caused DNA damage, indicating that the HDAC3/NCOR/SMRT axis is critical for maintaining chromatin structure and genomic stability.