Trastuzumab and lapatinib provide clinical benefit to women with human epidermal growth factor receptor 2 (HER)-positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. Consequently, there is an urgent need to identify new predictive factors for these agents. The aim of this study was to investigate the role of receptor tyrosine kinase signaling and phosphoinositide 3-kinase (PI3K)/AKT pathway activation in conferring resistance to trastuzumab and lapatinib. To address this question, we evaluated response to trastuzumab and lapatinib in a panel of 18 HER2-amplified cell lines, using both two-and three-dimensional culture. The SUM-225,

Primary vulvar and vaginal cancers are rare female genital tract malignancies which are staged using the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging. These cancers account for approximately 2,700 deaths annually in the USA. The most common histologic subtype of both vulvar and vaginal cancers is squamous cell carcinoma, with an increasing role of the human papillomavirus (HPV) in a significant number of these tumors. Lymph node involvement is the hallmark of FIGO stage 3 vulvar cancer while pelvic sidewall involvement is the hallmark of FIGO stage 3 vaginal cancer. Imaging techniques include computed tomography (CT), positron emission tomography (PET)-CT, magnetic resonance imaging (MRI), and PET-MRI. MRI is the imaging modality of choice for preoperative clinical staging of nodal and metastatic involvement while PET-CT is helpful with assessing response to neoadjuvant treatment and for guiding patient management. Determining the pretreatment extent of disease has become more important due to modern tailored operative approaches and use of neoadjuvant chemoradiation therapy to reduce surgical morbidity. Moreover, imaging is used to determine the full extent of disease for radiation planning and for evaluating treatment response. Understanding the relevant anatomy of the vulva and vaginal regions and the associated lymphatic pathways is helpful to recognize the potential routes of spread and to correctly identify the appropriate FIGO stage. The purpose of this article is to review the clinical features, pathology, and current treatment strategies for vulvar and vaginal malignancies and to identify multimodality diagnostic imaging features of these gynecologic cancers, in conjunction with its respective 2009 FIGO staging system guidelines.

Aldose reductase (AR) is implicated to play a critical role in diabetes and cardiovascular complications because of the reaction it catalyzes. Our data reveal that peroxisome proliferator WY 14,643, follows a pure non-competitive inhibition pattern in the aldehyde reduction activity as well as in the alcohol oxidation activity of AR. This finding communicates for the first time a novel feature of WY 14,643 in regulating AR activity. In addition, this observation indicates that AR, AR-like proteins and aldo-keto reductase (AKR) members may be involved in the WY 14,643 mechanism of action when it is administered as PPAR agonist.

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This catheter with conductive elements inhibits bacterial colonization in vitro when very small electric current (4-8 µA) is applied across the tip for 8-24 hours. In vivo validation is requisite to future translation to the clinical setting.

#2013 Background: Trastuzumab and lapatinib therapy provide proven clinical benefits to women with HER-2 positive breast tumors. However, not all patients that have high HER-2 levels respond. Here we describe the development and characterization of models of both clinical forms of trastuzumab resistance, i.e., de novo and acquired resistance.
 Materials and Methods: Models of acquired resistance were established by culturing BT-474 and SKBR3 cells in high dose trastuzumab (105 μg/ml) for nine months. De novo resistance was examined in a panel of 17 HER-2 amplified cell lines. Response to the dual EGFR-HER2 inhibitor, lapatinib, was also measured. For each agent, response was measured by two independent assays; cell count and colony formation assay. Levels of HER-2, p-HER-2, EGFR, p-EGFR, IGF-1R, p-IGF-1R, p95, PTEN, and p27, and the presence of PIK3CA activating mutations were assessed in each cell line.
 Results: Both BT-474 and SKBR3 conditioned cell lines have a reduced response to trastuzumab but remain sensitive to lapatinib. Analysis of the panel of HER-2 amplified cell lines revealed that SUM-225, HCC-1419, HCC-1954, HCC-1569 and JIMT-1 are models of de novo resistance to trastuzumab. The SUM-225 and HCC-1419 cell lines, despite being trastuzumab resistant, were exquisitely sensitive to lapatinib. The UACC-893, UACC-732, HCC-1569, MDA-MB-361 and JIMT-1 cell lines were identified as being resistant to lapatinib (IC50 > 1 μM), whereas the HCC-1569 and JIMT-1 were resistant to both trastuzumab and lapatinib. Resistance to trastuzumab correlated significantly with active PI3K signaling (p = 0.003), as assessed by combined analysis of PTEN status and PIK3CA mutation status. Response to lapatinib correlated significantly with levels of HER-2 (p = 0.013), pHER-2 (p = 0.086), p95 (p = 0.033), p-EGFR (p = 0.019) and p-IGFR (p = 0.046).
 Conclusion: We have identified reliable, HER-2 overexpressing, cell line models of response and resistance to trastuzumab and lapatinib. Our analysis of these models indicates that activated PI3K signaling plays a crucial role in de novo resistance to trastuzumab while high levels of RTK signaling appears to sensitize HER-2 positive cells to lapatinib treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2013.

Introduction The imaging features of unresectable hepatic malignancies that underwent radiofrequency ablation (RFA) in combination with lyso-thermosensitive liposomal doxorubicin (LTLD) were determined. Materials and Methods A phase I dose escalation study combining RFA with LTLD was performed with peri- and post- procedural CT and MRI. Imaging features were analyzed and measured in terms of ablative zone size and surrounding penumbra size. The dynamic imaging appearance was described qualitatively immediately following the procedure and at one month follow-up. The control group receiving liver RFA without LTLD was compared to the study group in terms of imaging features and post ablative zone size dynamics at follow-up. Results Post treatment scans of hepatic lesions treated with RFA and LTLD have distinctive imaging characteristics when compared to those treated with RFA alone. The addition of LTLD resulted in a regular or smooth enhancing rim on T1W MRI which often correlated with increased attenuation on CT. The LTLD treated ablation zones were stable or enlarged in the four weeks following ablation in 69% of study subjects as opposed to conventional RFA where the ablation zone underwent involution compared to immediate-post procedure. Conclusion The imaging features following RFA with LTLD were different from those after standard RFA and can mimic residual or recurrent tumor. Knowledge of the subtle findings between the two groups can help avoid misinterpretation and proper identification of treatment failure in this setting. Increased size of the LTLD treated ablation zone after RFA suggests ongoing drug-induced biological effects.

Breast cancer incidence among transgender and nonbinary (TGNB) individuals is not well characterized owing to the absence of robust data collection among this patient population. Consequently, breast cancer risks are largely unknown, and screening guidelines are not based on robust evidence. Additionally, TGNB patients experience barriers to access health care. A first step in improving data collection, research, and ultimately care of TGNB individuals is the identification of group members and demonstration to patients that our breast imaging centers are champions of LGBTQ+ health. At our institution, patients who present for breast imaging complete an iPad-administered breast imaging history and breast cancer risk assessment survey. Using the modified Tyrer-Cuzick model, the lifetime risk of developing breast cancer is estimated, and additional key history that may impact breast care and future breast imaging is collected. Under the previous clinic workflow, patients are identified as either “male” or “female” and complete a corresponding gender-specific survey. To improve care, we revised the survey using gender-inclusive language and developed four versions to allow patients to separately self-report their sex assigned at birth and gender identity. Relevant queries relating to hormone use and gender-affirming chest/breast surgery that are concordant with six gender-identity groups were added. Long-term collection of these inclusive data by imaging centers has the potential to enhance the data set available to improve breast care and better understand breast cancer risk and outcomes among TGNB populations.