Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000-2013.

BACKGROUND: We sought to evaluate the impact of adjuvant chemotherapy on overall survival (OS) in patients with stage I endometrioid epithelial ovarian cancer (EEOC) or ovarian clear cell cancer (OCCC) using a national database. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I EEOC or OCCC from 2000 to 2013. We sought to identify predictors of chemotherapy use and to assess the impact of chemotherapy on OS in these patients. OS was compared using the log-rank test and the Cox proportional hazards model. RESULTS: In all, 3552 patients with FIGO stage I EEOC and 1995 patients with stage I OCCC were identified. Of the 1600 patients (45%) with EEOC who underwent adjuvant chemotherapy, the 5-year OS rate was 90%, compared with 89% for those who did not undergo adjuvant chemotherapy (P = 0.807). Of the 1374 (69%) patients with OCCC who underwent adjuvant chemotherapy, the 5-year OS rate was 85%, compared with 83% (P = 0.439) for those who did not undergo adjuvant chemotherapy. Chemotherapy use was associated with younger age, higher substage, and more recent year of diagnosis for both the EEOC and OCCC groups. Only in the subgroup of patients with FIGO substage IC, grade 3 EEOC (n = 282) was chemotherapy associated with an improved 5-year OS-81% compared with 62% (P = 0.003) in untreated patients (HR: 0.583; 95% CI: 0.359-0.949; P = 0.030). In patients with OCCC, there was no significant effect of adjuvant chemotherapy on OS in any substage. CONCLUSIONS: Adjuvant chemotherapy was associated with improved OS only in patients with substage IC, grade 3 EEOC. In stage I OCCC, adjuvant chemotherapy was not associated with improved OS.

Optimal (≤1 cm) but visible residual disease: is extensive debulking warranted?

OBJECTIVES: To determine if extensive upper abdominal surgery (UAS) affected overall survival (OS) in patients left with ≤ 1 cm but visible residual disease after undergoing primary cytoreductive surgery for ovarian cancer. Our secondary objective was to determine if leaving ≤ 1cm but visible residual throughout the small bowel (SB) conferred a worse prognosis. METHODS: All stage IIIB-IV ovarian cancer patients who had visible but ≤ 1 cm residual disease at time of primary cytoreductive surgery from 2001 to 2010 were identified. Extensive UAS procedures and residual SB involvement were recorded. RESULTS: The 219 patients identified with ≤1 cm but visible residual disease had a median OS of 51 months. In this cohort, 127 had extensive UAS performed, and 87 had residual disease involving the SB. Univariate OS analysis was performed. There was no significant difference in OS between patients who did or did not have extensive UAS (45 vs. 52 months, P=0.56), or between patients with or without residual SB disease (45 vs. 51 months, P=0.84). Factors that were significantly associated with OS were age, ASA score, family history, and stage. CONCLUSIONS: Patients cytoreduced to ≤ 1 cm but visible residual disease who required UAS did not have a worse OS than those who did not require UAS. OS was similar if residual disease involved the SB or not. For ovarian cancer patients with disease not amenable to complete gross resection, extensive surgery should still be considered to achieve ≤ 1 cm but visible residual disease status, including cases where the residual disease involves the SB.

Positive peritoneal cytology is highly predictive of prognosis and relapse patterns in stage III (FIGO 2009) endometrial cancer.

OBJECTIVES: According to the updated FIGO system, positive peritoneal cytology does not affect endometrial cancer stage. This revision may reduce rates of obtaining cytology, with unclear implications in advanced disease. This study evaluates the significance of positive cytology in stage III (FIGO 2009) endometrial cancer. METHODS: Eligible patients received treatment for stage III endometrial cancer at a single institution and had peritoneal cytology performed. RESULTS: Of 196 patients, 58% were ≥ 60 years old, 48% had deep myometrial invasion, 71% lymphovascular invasion, 25% cervical invasion, 37% adnexal involvement, 79% nodal involvement, and 46% aggressive histology. Positive cytology was present in 23% (45/196) and significantly associated with cervical stromal invasion, adnexal involvement, and aggressive histology (P ≤ 0.03). There was no significant difference in rates of lymphadenectomy, chemotherapy, or radiation between negative and positive cytology groups. At a median follow-up of 47 months, the 5-year freedom from relapse was 39% for positive cytology vs. 69% for negative, disease-specific survival 42% vs. 77%, and overall survival 34% vs. 72% (P < 0.001). Positive cytology correlated with higher recurrence rates in the para-aortic nodes and peritoneum (30% vs. 9%, 23% vs. 4%; P ≤ 0.008). When controlling for adverse features including aggressive histology, positive cytology was associated with an increased hazard for relapse (HR 2.3; P = 0.002) and death (HR 2.9; P < 0.001). CONCLUSIONS: In stage III endometrial cancer, positive cytology independently predicts outcome and is associated with distinct relapse patterns. Obtaining peritoneal cytology in stage III endometrial cancer is critical.

Reproductive outcomes of patients undergoing radical trachelectomy for early-stage cervical cancer.

OBJECTIVE: To report the reproductive outcomes of patients undergoing fertility-preserving radical trachelectomy (RT) for the treatment of early-stage cervical cancer. METHODS: We analyzed data from our institution's first 105 patients who underwent attempted fertility-sparing surgery with radical trachelectomy, pelvic lymphadenectomy, and cerclage from November 2001 to October 2010. RESULTS: Of the 105 patients who underwent attempted RT, 77 (73%) did not require a conversion to radical hysterectomy or postoperative treatment. The median age was 32 (range, 25-38 years). Most patients (75%) had stage IB1 disease. Sixty-six patients (63%) were nulliparous. Thirty-five women were actively attempting conception 6 months after surgery, and 23 (66%) women were successful in conceiving: there were 20 live births, 3 elective terminations, and 4 spontaneous miscarriages. Four patients had 2 pregnancies each; all delivered their second pregnancy between 32 and 36 weeks. Cerclage erosion through the vaginal wall occurred in 6 cases and was treated by transvaginal removal of protruding suture material. One of these patients experienced a second trimester miscarriage. CONCLUSIONS: The majority of women who attempted to conceive after radical trachelectomy were successful, and most of their pregnancies resulted in full-term births. Assisted reproduction played an important role in select women. Cerclage likely contributed to a post-trachelectomy uterine ability to carry a pregnancy to the third trimester. The second post-trachelectomy pregnancy appears to be at higher risk for preterm delivery than the first pregnancy.

Surgical cytoreduction in stage IV endometrioid endometrial carcinoma.

OBJECTIVE: To evaluate the role of surgical cytoreduction and the amount of residual disease in patients with newly diagnosed stage IV endometrioid endometrial carcinoma (EC). METHODS: Patients with stage IV EC of endometrioid histology who underwent surgery at our institution from 1977 to 2003 were identified. Patients with microscopic stage IV disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier method and compared with log-rank test. RESULTS: A total of 58 patients were identified, of which 9 (15.5%) had no gross residual (NGR) after surgery, 11 (19.0%) had residual disease ≤1 cm, 32 (55.1%) had residual disease >1 cm, and 6 (10.3%) had no cytoreduction attempted. The median PFS was 11.1 months (95% CI, 9.8-12.3) and the median OS was 19.2 months (95% CI, 8.5-29.9) for the cohort. The median PFS was 40.3 months (95% CI, 0-93.9) for patients with NGR disease, 11 months (95% CI, 9.9-12.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients who did not have attempted cytoreduction (P<0.001). The median OS was 42.2 months (95% CI, not estimable) for patients with NGR disease, 19 months (95% CI, 13.9-24.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients that did not have attempted cytoreduction (P<0.001). CONCLUSION: Though stage IV endometrioid EC has a poor prognosis, surgical cytoreduction to no gross residual disease in a highly select group of patients is associated with improved survival.

Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma.

The objective of this study was to evaluate the pattern of chemoresistance in invasive micropapillary/low-grade serous ovarian carcinoma (invasive MPSC/LGSC) and high-grade serous ovarian carcinoma (HGSC) according to extreme drug resistance (EDR) assay testing. Surgical specimens of 44 recurrent ovarian cancer patients harvested at the time of cytoreductive surgery between August 1999 and February 2004 were identified retrospectively from the tumor registry database. Thirteen patients (29.5%) had recurrent invasive MPSC/LGSC and 31 (70.5%) patients had recurrent HGSC. Eight drugs were evaluated; EDR assay results were compared between LGSC and HGSC groups using Fisher exact tests and exact logistic regression models. Compared to HGSC, invasive MPSC/LGSC were more likely to manifest EDR to the drugs paclitaxel (69% vs 14%, P < 0.001), carboplatin (50% vs 17%, P= 0.05), cyclophosphamide (40% vs 23%, P= 0.41), gemcitabine (36% vs 19%, P= 0.40), and cisplatin (33% vs 28%, P= 0.72) and less likely to be resistant to etoposide (0% vs 44%, P= 0.007), doxorubicin (8% vs 45%, P= 0.03), and topotecan (8% vs 21%, P= 0.65). Exact logistic regression estimates revealed that invasive MPSC/LGSC patients had significantly increased probabilities of paclitaxel resistance odds ratio (OR) = 12.5 (95% CI: 2.3-100.0), P= 0.001 and carboplatin resistance OR = 4.8 (95% CI: 0.9-25.0), P= 0.07, while the HGSC cases were more likely to be resistant to etoposide OR = 12.1 (95% CI: 1.7-infinity), P=0.009 and doxorubicin OR = 8.6 (95% CI: 1.0-413.7), P= 0.05. In this retrospective analysis, patients with recurrent invasive MPSC/LGSC were more likely to manifest EDR to standard chemotherapy agents (platinum and paclitaxel). These observations may help to guide chemotherapeutic decision making in these patients if confirmed in a large-scale study.

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling.

Endometrial cancer is the third most common gynecologic malignancy and the ninth most common malignancy for females overall in Hong Kong. Approximately 80% or more of these cancers are endometrioid endometrial adenocarcinomas. The aim of this study was to reveal genes contributing to the development of endometrioid endometrial cancer, which may impact diagnosis, prognosis and treatment of the disease. Whole-genome gene expression analysis was completed for a set of 55 microdissected sporadic endometrioid endometrial adenocarcinomas and 29 microdissected normal endometrium specimens using the Affymetrix Human U133 Plus 2.0 oligonucleotide microarray. Selected genes of interest were validated by quantitative real-time-polymerase chain reaction (qRT-PCR). Pathway analysis was performed to reveal gene interactions involved in endometrial tumorigenesis. Unsupervised hierarchical clustering displayed a distinct separation between the endometrioid adenocarcinomas and normal endometrium samples. Supervised analysis identified 117 highly differentially regulated genes (>or=4.0-fold change), which distinguished the endometrial cancer specimens from normal endometrium. Twelve novel genes including DKK4, ZIC1, KIF1A, SAA2, LOC16378, ALPP2, CCL20, CXCL5, BST2, OLFM1, KLRC1 and MBC45780 were deregulated in the endometrial cancer, and further validated in an independent set of 56 cancer and 29 normal samples using qRT-PCR. In addition, 10 genes were differentially regulated in late-stage cancer, as compared to early-stage disease, and may be involved in tumor progression. Pathway analysis of the expression data from this tumor revealed an interconnected network consisting of 21 aberrantly regulated genes involved in angiogenesis, cell proliferation and chromosomal instability. The results of this study highlight the molecular features of endometrioid endometrial cancer and provide insight into the events underlying the development and progression of endometrioid endometrial cancer.

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines.

The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer.

The putative essential nutrient pyrroloquinoline quinone is neuroprotective in a rodent model of hypoxic/ischemic brain injury.

Pyrroloquinoline quinone is a ubiquitous redox cofactor and putative essential nutrient in mammals. Pyrroloquinoline quinone has recently been demonstrated to depress N-methyl-D-asparate induced electrical responses and is neuroprotective in vitro. In addition, pyrroloquinoline quinone has been demonstrated to act as a free radical scavenger in mammalian tissues. In this study, we demonstrate a neuroprotective effect of pyrroloquinoline quinone in an in vivo cerebral hypoxia/ischemia model in the rodent. Significant reduction in infarct size resulted from pyrroloquinoline quinone pretreatment and also when pyrroloquinoline quinone was administered following induction of hypoxia/ischemia. The neuroprotective effect was not dependent on change in core or cranial temperatures, as there was no difference between temperature measurements in pyrroloquinoline quinone-treated and vehicle-treated controls. No changes in electroencephalographic activity were observed at neuroprotective doses. These findings suggest that pyrroloquinoline quinone may represent a novel class of quinoid reagents of potential use in the treatment of neurological disorders that involve excitotoxicity. This study demonstrates a protective effect of the novel essential nutrient pyrroloquinoline quinone on brain injury in a rodent model of cerebral hypoxia/ischemia. Pyrroloquinoline quinone was neuroprotective when administered before and even after the insult, and did not appear to have significant neurobehavioral side effects. Pyrroloquinoline quinone represents a new class of agents with potential use in the therapy of stroke.

Tobacco and alcohol use among Australian secondary school students in 1990.

OBJECTIVE: To obtain up-to-date prevalence estimates of tobacco smoking and alcohol drinking among Australian secondary students, and to compare these estimates with those obtained from similar studies conducted in 1984 and 1987. DESIGN: Data were collected from 24,892 secondary students aged 12 to 17 years from all Australian States and the Northern Territory. A stratified two-stage sample design was used. First, a random sample of schools was selected and second, for each school a sample of 80 students was randomly selected from predetermined year levels. A total of 351 schools participated in the survey. Students completed an anonymous, self-administered questionnaire on their smoking and drinking behaviours. RESULTS: The prevalence of current smoking (defined as having smoked at least one cigarette in the week preceding the survey) was found to increase with age to reach a peak of 25% among 16-year-old boys and 29% among girls aged 15 years. From the age of 13, smoking was more prevalent among girls than boys. Among current smokers, boys were heavier smokers than were girls. Unlike smoking, drinking was slightly more prevalent among boys than girls; boys were heavier drinkers. The proportion consuming at least one alcoholic drink in the week before the survey rose with age to a peak of 51% of boys and 46% of girls aged 17 years. Comparisons with data obtained from a similar survey conducted in 1987 showed that there had been a decrease in the proportion of 12 to 15 year olds smoking. The prevalence of drinking among both 12 to 15 year olds and 16 to 17 year olds was significantly lower in 1990 than 1987. CONCLUSIONS: While the continuing downward trends in smoking and drinking among younger students is encouraging, the results show that there are still large numbers of students smoking and drinking.

The use and abuse of the emergency ambulance service: some of the factors affecting the decision whether to call an emergency ambulance.

Over a 1-month period all patients arriving in the accident and emergency department by ambulance following a '999' call were questioned using a standard proforma. They were assessed as to whether their medical condition warranted ambulance transfer. A number of social and practical points were analyzed to see whether they would identify any group of patients who used the emergency service without medical need. Overall 289 patients were questioned. Of these 178 (62%) were considered to have medically warranted an ambulance call whereas 111 (38%) did not. A number of features which were more likely to result in an unjustified call were identified. These would suggest that basic knowledge of first aid by the public is poor and should be improved.

Tobacco and alcohol use among Australian secondary schoolchildren in 1987.

A survey of 19 166 secondary schoolchildren aged 12-17 years in five Australian states, the Australian Capital Territory and the Northern Territory was undertaken in 1987 to determine the prevalence of tobacco and alcohol use. Current smoking (that is, smoking at least one cigarette in the last week) rose with age to 27% in boys who were aged 16 years and to 30% in girls who were aged 16 years. The prevalence of current drinking (that is, consuming one alcoholic drink in the last week) rose with age to 55% in boys who were aged 16 years and to 50% in girls who were aged 17 years. Compared with an identical survey in 1984, the prevalence of smoking among 12- to 17-year-old schoolchildren had fallen significantly. The prevalence of drinking alcohol among 12- to 15-year-old schoolchildren also had fallen significantly, but not to the same extent as that of smoking; no significant reduction was found in the drinking of alcohol among 16- to 17-year-old schoolchildren. These trends are encouraging, but a need remains for all states to enact tobacco-control legislation, including the prohibition of tobacco advertising.

A study of the knowledge of radiological anatomy of senior house officers in accident and emergency medicine.

Senior house officers working in 10 major accident units were tested on their ability to name normal anatomical features seen on radiographs of commonly X-rayed areas. The results show that, overall, those tested could only identify 77% of the areas correctly. The discussion considers these results and also considers whether it is important to be able to identify the anatomical features presented.

Comparison of urinary N-acetyl-beta-D-glucosaminidase and urinary fibrin degradation products for diagnosis of rejection after renal transplantation.

A comparison was made of two established tests to see which was the better indicator of rejection after renal transplantation. Daily urine samples were assayed for excretion of N-acetyl-beta-D-glucosaminidase (NAG) and fibrin degradation products (FDP). Twenty-five rejection episodes were studied in 19 patients. Both indicators tended to move in parallel. NAG was more often elevated in rejection, namely in 96% of rejection episodes as against 76% for FDP, FDP had the advantage of fewer false positive results and when it correctly indicated rejection its increase above the baseline was relatively greater than for NAG, NAG and FDP can both provide early warning of rejection. NAG is preferred for its ease of assay. Assays are performed daily and are of practical value in clinical management. The results of assays must be interpreted in conjunction with all relevant information.