Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma.

BACKGROUND: Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. METHODS: Next-generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium-term follow-up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. RESULTS: Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN, PIK3CA, and FGFR2, genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. CONCLUSIONS: Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC.

Pathway to the Papanicolaou smear: The development of cervical cytology in twentieth-century America and implications in the present day.

George Papanicolaou, a Greek immigrant and cytopathologist, was responsible for what is now colloquially known as the "Pap smear"-undoubtedly one of the greatest advances in medicine and public health of the last century. However, his landmark research on the development of cervical cytology for the detection of precancerous lesions of the cervix ("New Cancer Diagnosis," 1928) made a rather inauspicious debut in an unlikely venue: John Harvey Kellogg's Third Race Betterment Conference-a meeting devoted to the furtherance of the concept and implementation of eugenics. Herein, we discuss the stark juxtaposition of Papanicolaou's landmark discovery amid the pseudoscience of the third Race Betterment Conference. We discuss the latency of Papnicolaou's discovery-its potential implications unrealized-until co-publication with Herbert Traut, which catapulted Papanicolaou's research to the scientific foreground. This gave rise to public health initiatives aimed at establishing the Pap smear as a screening tool. We further delineate the progress made in recent decades with the identification of HPV as the etiological agent for cervical cancer, and the subsequent development of the HPV vaccine, and discuss ongoing research in the present day. In this way, we hope to provide a background and historical context for the development of the Pap smear.

Clonal evolution in paired endometrial intraepithelial neoplasia/atypical hyperplasia and endometrioid adenocarcinoma.

Endometrial intraepithelial neoplasia (EIN) and atypical endometrial hyperplasia (AH) are histomorphologically defined precursors to endometrioid adenocarcinoma, which are unified as EIN/AH by the World Health Organization. EIN/AH harbors a constellation of molecular alterations similar to those found in endometrioid adenocarcinoma. However, the process of clonal evolution from EIN/AH to carcinoma is poorly characterized. To investigate, we performed next-generation sequencing, copy number alteration (CNA) analysis, and immunohistochemistry for mismatch repair protein expression on EIN/AH and endometrioid adenocarcinoma samples from 6 hysterectomy cases with spatially distinct EIN/AH and carcinoma. In evaluating all samples, EIN/AH and carcinoma did not differ in mutational burden, CNA burden, or specific genes mutated (all P>.1). All paired EIN/AH and carcinoma samples shared at least one identical somatic mutation, frequently in PI(3)K pathway members. Large CNAs (>10 genes in length) were identified in 83% of cases; paired EIN/AH and carcinoma samples shared at least one identical CNA in these cases. Mismatch repair protein expression matched in all paired EIN/AH and carcinoma samples. All paired EIN/AH and carcinoma samples had identical The Cancer Genome Atlas subtype, with 3 classified as "copy number low endometrioid" and 3 classified as "microsatellite instability hypermutated." Although paired EIN/AH and carcinoma samples were clonal, private mutations (ie, present in only one sample) were identified in EIN/AH and carcinoma in all cases, frequently in established cancer-driving genes. These findings indicate that EIN/AH gives rise to endometrioid adenocarcinoma by a complex process of subclone evolution, not a linear accumulation of molecular events.

Expression of the opioid growth factor-opioid growth factor receptor axis in human ovarian cancer.

OBJECTIVE: The opioid growth factor (OGF) and its receptor (OGFr), serve as inhibitory axis regulating cell proliferation in normal cells and cancer. We investigated the presence and relative expression of OGF and OGFr in normal human ovarian surface epithelial (HOSE) cells, benign ovarian cysts, and ovarian cancers. METHODS: Surgical samples of 16 patients with ovarian cancer and 27 patients with ovarian benign cysts were obtained intraoperatively. HOSE were collected by scraping the surface of normal ovaries of 10 post menopausal women undergoing hysterectomy and oophorectomy. Semiquantitative immunohistochemistry was used to assess the presence, distribution, and levels of OGF and OGFr. Receptor binding assays measured binding capacity and affinity of OGFr for radiolabeled OGF. RESULTS: OGF and OGFr were present in HOSE cells, ovarian cysts, and ovarian cancers. Compared to HOSE cells, OGF and OGFr protein levels were reduced 29% and 34% (p<0.001), respectively, in ovarian cysts, and decreased 58% and 48% (p<0.001), respectively, in ovarian cancers. Binding assays revealed 5.4 fold fewer OGFr binding sites in cancers than cysts (p<0.05). Levels of OGF and OGFr were comparable in primary, metastatic, or recurrent ovarian cancers. CONCLUSION: We have shown that a native opioid pathway, the OGF-OGFr axis, is present in human ovarian cancer. Importantly, the expression of OGF and OGFr is diminished in human ovarian cancer. As OGF and OGFr normally function in maintaining cell proliferation, therapy to harness OGF/OGFr function could provide a useful biologic-based treatment for human ovarian cancer.

Advance care planning for patients with ALS: feasibility of an interactive computer program.

This pilot study examined whether an interactive, computer based decision aid can help patients with amyotrophic lateral sclerosis (ALS) engage in effective advance care planning. Individuals being treated for ALS (>18 years old, English speaking, and without dementia) were recruited to use a decision aid and complete pre-/post-intervention measures. Seventeen individuals completed the pre-intervention questionnaires and decision aid; 16/17 (94%) completed the post-intervention measures, and none reported any burden from the intervention. 'Overall satisfaction' with the decision aid was very high (mean = 8.5 ± 0.27: 1 = not at all satisfied, 10 = extremely satisfied), as was 'perceived accuracy' of the computer generated advance directive in reflecting patients' wishes (mean = 8.6 ± 0.27: 1 = not at all accurate, 10 = extremely accurate). Participants judged the 'amount of information' provided by the intervention appropriate (mean = 6.8 ± 0.38: 1 = too little, 5 = about right, 10 = too much), and on a detailed, 12-item assessment judged the decision aid very positively (mean = 4.16 ± 0.16: 1 = very dissatisfied, 5 = very satisfied). The intervention prompted many participants to discuss advance care planning with loved ones and to share their computer generated advance directive with their physician. This study demonstrates that individuals with ALS can successfully complete a computer based decision aid for advance care planning, and suggests that this intervention can help promote effective advance care planning.

Laparoscopic conversion rate for uterine cancer surgical staging.

OBJECTIVE: To estimate the conversion rate of attempted laparoscopic staging for primary endometrial adenocarcinoma. METHODS: Two hundred thirty-five consecutive patients with primary endometrial adenocarcinoma underwent attempted laparoscopic staging regardless of age, body mass index (BMI, calculated as weight (kg)/[height (m)]²), uterine size, and prior surgery. No patients were excluded. RESULTS: Mean BMI was 39 (range, 22-77), and 85 patients (36%) had a BMI higher than 40 kg/m². Mean blood loss was 162 mL (range, 25-1850 mL), mean operating room time was 2 hours (range, 1-4 hours 20 minutes), and mean hospital stay was 1 day (range, 1-4 days). There were six conversions (3%) to laparotomy or vaginal hysterectomy, all occurring in patients with a BMI higher than 40; mean BMI of conversions was 66 (range, 55-77). CONCLUSION: Of 235 consecutive cases of attempted laparoscopic staging for primary endometrial adenocarcinoma, conversion to laparotomy or vaginal hysterectomy occurred in 3% of the total patients and 7% in patients with a BMI of 40 or higher.

Gastric emptying and intestinal absorption of ingested water and saline by hypovolemic rats.

Recent experiments showed that in a one-bottle test conducted 16h after sc injection of polyethylene glycol (PEG) solution, hypovolemic rats consumed water or 0.30 M NaCl in an initial drinking episode but did not empty the ingested fluid from the stomach or absorb it from the small intestine very rapidly, certainly not as rapidly as when 0.15M NaCl was consumed (Smith et al., Am J Physiol 292: R2089-R2099, 2007). The present experiments examined the patterns of water and 0.30 M NaCl ingestion and the movement of consumed fluid through the gastrointestinal tract when PEG-treated rats were given a two-bottle delayed-access test. We found that both fluids always were consumed in the first drinking episode, that the fluid mixture ingested was equivalent to 0.10-0.15M NaCl, and that gastric emptying rate and net fluid absorption from the small intestine usually were much faster than when PEG-treated rats drank either water or hypertonic saline alone. Thus, ingestion of water and 0.30 M NaCl by hypovolemic rats in the same episode adaptively facilitated the movement into the circulation of a near-isotonic fluid that is ideal for restoring plasma volume deficits.