Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix.

OBJECTIVES: Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease. METHODS: Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40-100 moderate, and ≥100 high. RESULTS: Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%). CONCLUSIONS: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

The Kids Are Alright: a New Generation of Educators.

Generational theory states that as a result of experiencing the same life-altering, world-wide events at key developmental ages, individuals of a given generation share unique perspectives, values, and traits compared to other generations as reported by Johnson and Romanello (Nurse Educ. 30(5):212-216, 2005) and Howe and Strauss 2000. Thus, while individual variation still exists, generational theory can be used as a tool to predict individual behavior and capitalize on shared traits in the workplace or educational setting. The millennial generation, born between 1981 and 1996, has previously been negatively perceived; however, application of generational theory can allow for a reshaping of public perception. For example, there now exists ample research, both within and outside of medical education, on how to take advantage of typical traits of the millennial student to maximize their learning, such as Twenge (Med Educ. 43(5):398-405, 2009), Eckleberry-Hunt and Tucciarone (J Grad Med Educ. 3(4):458-461, 2011), and Nicholas (Int J Learn Annu Rev. 15(6):27-34, 2008). As the cohort ages, the focus has shifted to helping millennials reach their full potential as employees. However, due to intensive and lengthy training required, medicine is only now seeing the first cohort of millennials entering the workforce as faculty physicians. As such, academic medicine is seeing millennials move from the learner role into that of the teacher. Thus far, the influence of the shared generational characteristics on their success and challenges as clinician educators and educational leaders is novel and has not been explored in the literature. By overlaying generational theory on Srinivasan et al.'s (Acad Med. 86(10):1211-1220, 2011) proposed six competencies for medical educators, we predict the strengths and challenges of millennial medical educators and hypothesize on the impact this generation may have on academic medicine.