Eva Chalas

ΔNp73, A Dominant-Negative Inhibitor of Wild-type p53 and TAp73, Is Up-regulated in Human Tumors

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH2 terminally truncated isoform. ΔNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. ΔNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. ΔNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. ΔNp73 efficiently counteracts transactivation function, apoptosis, and growth suppression mediated by wild-type p53 and TAp73, and confers drug resistance to wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous ΔNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. ΔNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, ΔNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of ΔNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73. This trait might be selected for in human cancers.

The management of pseudomyxoma peritonei

The management of nine patients with pseudomyxoma peritonei was reviewed. Aggressive surgical resection of tumor is the standard of treatment, with many patients requiring multiple laparotomies. Chemotherapy, including the use of cisplatin is not effective. Long‐term nutritional support provides a better quality of survival for select patients.

Uterine papillary serous carcinoma evolves via a p53-driven pathway

Uterine papillary serous carcinoma (UPSC) is a highly aggressive type of endometrial cancer that occurs in the absence of hyperestrogenism and endometrial hyperplasia. Biologically, UPSC belongs to a distinct group of aggressive neoplasms of the extended Müllerian epithelium that are characterized by hypoestrogenism, advanced disease at diagnosis, a serous papillary histotype, and a dismal prognosis. There is mounting evidence that loss of p53 function is critical for the molecular genetic cause of all tumors in this group. To further assess the role of p53 alterations in UPSC, we studied 40 patients using immunohistochemical expression analysis. Thirty-four tumors (85%) showed intense nuclear overexpression of p53, whereas six tumors (15%) were p53 negative. Thirteen p53-positive tumors had multiple samplings from distinct anatomic sites, and all showed complete concordance in p53 staining, suggesting that p53 alterations occur early in UPSC carcinogenesis. p53 positivity was associated with loss of hormone receptors. Thirty-nine cases were concomitantly analyzed for estrogen or progesterone receptor expression. Among those, 31 tumors were p53 positive but hormone receptor negative throughout, in contrast to only two tumors that were diffusely p53 positive and focally hormone receptor positive. Patients whose tumors overexpressed p53 had a statistically significant shorter survival than those whose tumors did not at 24 and 48 months (P = .03). This study represents one of the two largest analyses published to date that confirm the strong association between UPSC and p53 overexpression. Furthermore, we suggest that the concept of UPSC be broadened: UPSC is a p53-driven neoplasm that biologically is a kin to other serous papillary malignancies of the ovaries and peritoneum. This group of tumors bypasses the slow hormone-dependent pathway of tumorigenesis but instead undergoes early p53 alterations that lead to rapid tumor development.

Correlation of histology and detection of human papillomavirus DNA in vulvar cancers

The purpose of this study was to correlate the histological findings and clinical information for vulvar precancers and cancers with the detection of human papillomavirus (HPV). Forty-five squamous cell lesions (twenty-two high-grade squamous intraepithelial lesions (SILs) and twenty-three invasive cancers) were analyzed for HPV DNA after amplification by the polymerase chain reaction. HPV DNA was noted in 13/22 (59%) high-grade SILs and 7/23 (30%) invasive cancers. For the invasive cancers, HPV DNA was detected in 0/13 that had substantial keratinization compared to 7/10 with minimal keratinization. Adjacent SIL was noted in 6/7 (86%) HPV-positive cancers compared to 1/16 (6%) in the HPV negative group. The mean age of the two groups was equivalent. The rate of metastases (3/7, 43%) for the HPV-positive group was higher than that for the HPV-negative (4/16, 25%) group. We conclude that vulvar cancers, unlike squamous cell carcinoma of the cervix, which is associated with HPV DNA in most cases, can be differentiated into two groups on the basis of histological findings and presence of HPV DNA.

Transcutaneous electrical nerve stimulation as an adjunct for controlling chemotherapy-induced nausea and vomiting in gynecologic oncology patients.

BACKGROUND To evaluate the efficacy of a miniaturized portable transcutaneous electrical nerve stimulation (TENS) unit (ReliefBand) as an adjunct to standard antiemetic therapy for controlling nausea and vomiting induced by cisplatin-based chemotherapy in gynecologic oncology patients. METHODS Forty-two patients were enrolled in a randomized, double-blind, placebo-controlled parallel-subjects trial with a follow-up crossover trial. All patients received a standardized antiemetic protocol, then wore the ReliefBand continuously for 7 days. RESULTS Thirty-two patients were evaluable for the parallel-subjects component, 16 in each group. The percentage of patients with absent or minimal nausea was 59% overall, which was similar to that for both the active (56%) and placebo (62%) groups. The incidence and severity of nausea and vomiting was similar for each group. Eighteen patients completed two consecutive cycles and were evaluable for the crossover component. The average age of the crossover patients and their dose intensity were comparable with those of the overall study population (56.3 versus 58.6 years and 22.7 versus 22.7 mg/m2/week, respectively). The percentage of cycles with absent or minimal nausea was 47% overall, which was similar to that of the active (50%) and placebo (44%) cycles. However, the severity of nausea was significantly lower in the active cycles during days 2 to 4. Patients averaged less than one episode of vomiting daily in each cycle. CONCLUSIONS The ReliefBand is an effective adjunct to standard antiemetic agents for controlling nausea induced by cisplatin-based chemotherapy in gynecologic oncology patients.

Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer.

Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases. We reviewed studies pertaining to prophylactic bilateral salpingo-oophorectomy in women at average risk of ovarian cancer who are undergoing hysterectomy for benign disease. We also reviewed the role of prophylactic bilateral salpingo-oophorectomy in preventing ovarian cancer based on the level of risk of the patient. For women at average risk of ovarian cancer who are undergoing a hysterectomy for benign conditions, the decision to perform prophylactic bilateral salpingo-oophorectomy should be individualized after appropriate informed consent, including a careful analysis of personal risk factors. Several studies suggest an overall negative health effect when prophylactic bilateral salpingo-oophorectomy is performed before the age of menopause. Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.

Loss of p53 function in uterine papillary serous carcinoma

In contrast to endometrioid carcinoma, uterine papillary serous carcinoma (UPSC) is an aggressive type of endometrial cancer. Loss of p53 function is critical for the molecular pathogenesis of UPSC. Both UPSC and its putative precursor, endometrial intraepithelial carcinoma (EIC), show abnormal p53 overexpression in most tumors. To further assess the nature of p53 alterations in UPSC, we systematically reevaluated a subset of our previous cohort of UPSC patients. In the current study, we correlate mutations of the p53 gene as detected by direct sequencing of exons 5 through 8 with p53 accumulation and expression of Waf-1 in 32 UPSC tumors. Waf-1 is a downstream effector of p53-mediated G1 arrest after DNA damage and, thus, an indicator of p53 functionality. Although 78% of tumors exhibited strong nuclear p53 immunoreactivity in 100% of tumor cells, we were able to detect p53 mutations in 53%. As expected, all p53 mutant tumors (17 cases) exhibited p53 overexpression. Seventy percent of those (12 tumors) showed concomitant lack of Waf-1 expression consistent with transcriptionally inactive p53, whereas the other five tumors showed Waf-1 staining in only a minor fraction of tumor cells consistent with p53-independent Waf-1 expression. In contrast, 47% (15 cases) of tumors failed to exhibit p53 mutations; interestingly, more than half of those (eight cases) showed strong nuclear p53 accumulation in all tumor cells but lacked concomitant Waf-1 expression. These findings are consistent with a mutation-dependent and -independent type of p53 inactivation in UPSC that are both associated with nuclear overexpression. Our findings suggest that the combined immunocytochemical analysis of p53 and Waf-1 is a valuable means of assessing the functional status of p53. In summary, p53 alterations are common in UPSC and probably responsible for its aggressive biological behavior.

A randomized controlled trial of postoperative nasogastric tube decompression in gynecologic oncology patients undergoing intra-abdominal surgery

Objective To evaluate the effect of nasogastric decompression after extensive intra-abdominal surgery in gynecologic oncology patients. Methods Over a 1-year period, 110 gynecologic oncology patients undergoing extensive intra-abdominal surgery were enrolled in a randomized controlled trial of postoperative nasogastric tube versus intra-operative orogastric tube decompression. Results The nasogastric and orogastric groups were similar in age, case distribution, surgery length, and blood loss. The nasogastric group had significantly longer times to first passage of flatus and tolerance of a clear liquid diet than did the orogastric group. However, both groups were similar in time to tolerance of a regular diet and hospital stay. On average, the nasogastric tube was maintained for 3.2 ± 2.1 days (range 1–8) after surgery. The average daily nasogastric output was 440 ± 283 mL (range 68–1565). No patient in the orogastric group required a nasogastric tube postoperatively, but one patient in the nasogastric group had a nasogastric tube reinserted for recurrent nausea and vomiting. Use of a nasogastric tube led to significantly more subjective complaints, eg, ear pain, painful swallowing, and nasal soreness, but did not significantly reduce the incidence of abdominal distention or nausea and vomiting. Major complications, eg, pneumonia, atelectasis, gastrointestinal bleeding, and wound breakdown or infection, occurred equally in both groups. However, the incidence of febrile morbidity was significantly greater in the nasogastric group. There were no known anastamotic complications or aspirations in either group. Postoperative changes in hematological indices and electrolytes were comparable in both groups. Conclusion Postoperative nasogastric tube decompression in gynecologic oncology patients undergoing extensive intra-abdominal surgery does not appear to provide any substantial benefit but significantly increases patient discomfort. As a result of this study, we have eliminated postoperative nasogastric decompression except in highly selected circumstances, such as extensive bowel surgery in patients with prior irradiation or substantial edema from bowel obstruction.

A randomized controlled trial of a regular diet as the first meal in gynecologic oncology patients undergoing intraabdominal surgery

OBJECTIVE To prospectively evaluate the safety and efficacy of a regular diet as the first meal after intraabdominal surgery in gynecologic oncology patients. METHODS During a 20‐month period, 254 gynecologic oncology patients undergoing intraabdominal surgery were enrolled in a randomized controlled trial of a clear liquid diet compared with a regular diet as the first postoperative meal. All patients received their first meal on the first postoperative day in the absence of nausea, vomiting, or symptomatic abdominal distension. Standard criteria for discharge were used for all study patients. RESULTS The clear liquid and the regular diet groups were similar in age, disease, surgical procedure distribution, surgery length, and estimated blood loss. The incidence of nausea, vomiting, abdominal distention, frequency and duration of nasogastric tube use, passage of flatus before discharge, and percentage of patients who tolerated their diets on the first attempt were comparable for both groups. For those patients who were intolerant of the first attempt at either a clear liquid or regular diet, the time to tolerance was comparable for both groups. The time to development of bowel sounds, passage of flatus, and hospital stay were comparable for both groups. Febrile morbidity, pneumonia, wound complications, and atelectasis occurred equally in both groups. There were no known anastamotic complications or aspirations in either group. Postoperative changes in hematologic indices and electrolytes were comparable in both groups. CONCLUSION A regular diet as the first meal after intraabdominal surgery in gynecologic oncology patients is safe and efficacious.

U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women?

The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDAs methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.