Cost analysis of the enhanced recovery after surgery protocol applied in advanced ovarian cancer: A secondary outcome of the PROFAST trial.

INTRODUCTION: A randomised trial implementing Enhanced Recovery After Surgery (ERAS) for high complexity advanced ovarian cancer (AOC) surgery (PROFAST) demonstrated a reduction of median length of stay and hospital readmissions when compared to patients managed conventionally. One secondary objective was to determine if an ERAS pathway in the perioperative management of advanced ovarian cancer patients led to cost savings. MATERIAL AND METHODS: Secondary objective of a prospective randomised trial of patients with suspected or diagnosed advanced ovarian cancer allocated to conventional or ERAS perioperative management, carried out at a referral centre from June 2014 to March 2018. Treatment was determined by a computer-generated random allocation system. METHODS: Gross counting was employed to estimate the cost of hospitalisation in wards, intensive care unit (ICU) and surgical care, while micro-costing was used to obtain image and laboratory test costs. Mean costs between trial arms were considered. Sensitivity analyses were performed. RESULTS: Ninety-nine patients (n = 50 ERAS group, n = 49 Conventional group) were included. Mean costs per patient were 10,719€ in the ERAS group and 11,028€ in the conventional group, leading to an average saving of 309€ per patient. These results were based on 96 patients, excluding 3 extreme outliers mainly related with very high ICU costs. Savings, which were significant for hospital ward costs (-33% total; 759€ per patient in first hospitalisation, and 914€ per partient/day of readmission) were found as robust in the sensitivity analysis. CONCLUSIONS: Implementation of an ERAS pathway leads to cost savings when compared to conventional management after AOC surgery.

Expression of Arginine Vasopressin Type 2 Receptor in Canine Mammary Tumours: Preliminary Results.

The aims of this study were to investigate the potential association of arginine vasopressin type 2 receptor (AVPR2) in canine mammary tumours with expression of oestrogen receptors α (ORα) and ß (ORß) and clinicopathological features of the neoplasms. Twenty-six canine mammary tumour samples (11 benign, 15 malignant) were immunolabelled for AVPR2, ORα and ORß antigens. Moderate to intense immunolabelling of AVPR2 antigen, found in all neoplasms, was not significantly associated with expression of ORα or ORß antigens or with clinicopathological features. These findings indicate a potential role for AVPR2 in the development of canine mammary tumours and the use of AVPR2-selective vasopressin analogues as therapeutic options.

Expression of Oxytocin Receptors in Canine Mammary Tumours.

The aims of the present study were: (1) to investigate the presence of oxytocin receptors in benign and malignant canine mammary tumours (CMTs) and to evaluate the possible association between oxytocin receptor (OTR) expression and the expression of oestrogen receptor (OR) α and ORß, and (2) to examine associations between receptor expression and tumour size, clinical stage, histological subtype, tumour grading and lymph node status. Forty-three canine mammary tumour samples (19 benign, 24 malignant) were examined by immunohistochemistry to detect OTR, ORα and ORß expression. Results were expressed as total score for each receptor, calculated as the sum of the percentage of positive cells and the intensity of immunolabelling. In all of the evaluated mammary tumour samples, OTRs were identified and their expression tended to be higher in benign tumours than malignant tumours. Among the malignant tumours, the expression of OTR was significantly higher in grade I and II lesions than in grade III lesions. ORα-positive tumours had a tendency towards a higher OTR total score than ORα-negative tumours. These results report for the first time that CMTs express OTRs and their expression is associated with the presence of ORα. An interaction between oxytocin and the OTR might play a role in the development and progression of this type of neoplasia.

Synchronization of time of ovarian follicular development in llamas (Lama glama) using a protocol based on GnRH and PGF2α.

The aim of this study was to evaluate the effectiveness of a protocol based on GnRH and PGF2α to synchronize the emergence of a new wave of ovarian follicular development in llamas and, therefore, when a new dominant follicle develops. Llamas (n = 18) were assigned to growing, mature or regressing follicle groups according to the phase of the follicular wave at the beginning of treatment. The protocol was initiated with a GnRH analogue (GnRHa) injection on Day 0 followed 7 days later with a d-cloprostenol injection and a second GnRHa injection on Day 10. Ovulation rate after the first GnRHa treatment, day of new follicle emergence, mean plasma progesterone concentration and percentage of animals with a newly developed dominant follicle ≥ 7 mm on Day 10 were evaluated. Ovulation rate after the first GnRHa was less in the regressing than mature and growing follicle groups and new follicular wave emergence occurred earlier in the regressing follicle group than in the other two groups. Mean plasma progesterone concentration in females that had ovulations after the first GnRHa injection was similar. The percentage of animals that had a new follicle ≥ 7 mm on Day 10 was not different among groups and the overall percentage was 66.6%. The total synchronization rate for development of a new wave of follicular development on Day 10 was greater in females having ovulations after the first GnRHa injection than in those that did not have ovulations. In conclusion, the protocol used in the present study was useful for synchronizing ovarian follicular development in 66% of the llamas regardless of the phase of the follicular wave development at the beginning of treatment.

Oestrogen and Progesterone Receptors and COX-2 Expression in Endometrial Biopsy Samples During Maternal Recognition of Pregnancy in Llamas (Lama glama).

Endometrial expression of oestrogen receptor-α (ERα), progesterone receptor (PR) and cyclooxigenase-2 (COX-2) was evaluated in non-pregnant and pregnant llamas during the period when luteolysis/maternal recognition of pregnancy is expected to occur. Females (n = 28) were divided into two groups: non-pregnant llamas were induced to ovulate with a Buserelin injection, and endometrial biopsies were obtained on day 8 (n = 5) or 12 (n = 5) post-induction of ovulation. Animals of the pregnant group (n = 18) were mated with a fertile male. Pregnancy was confirmed by the visualization of the embryo collected by transcervical flushing in 5 of 9 animals on day 8 post-mating and by progesterone profile on day 12 post-mating in 4 of 9 animals, when endometrial biopsies were obtained. An immunohistochemical technique was used to evaluate receptors population and COX-2 expression. Pregnant llamas showed a higher percentage of positive cells and stronger intensity for ERα than for non-pregnant llamas in stroma on day 8 and in the luminal epithelium on day 12 post-induction of ovulation, while a deep decrease in endometrial PR population was reported in pregnant llamas on that day in luminal and glandular epithelia and stroma. In the luminal epithelium, COX-2 expression was lower in pregnant than in non-pregnant animals. Briefly, the increase of ERα in pregnant llamas gives further support to the hypothesis that oestrogens are involved in the mechanism of maternal recognition of pregnancy. Endometrial PR decrease in pregnant llamas might be a necessary event to allow the expression of proteins involved in conceptus attachment, a mechanism widely accepted in other species. Moreover, embryo seems to attenuate maternal PGF(2α) secretion during early pregnancy by decreasing the endometrial expression of COX-2 in the luminal epithelium of pregnant llamas.

Oestrogen, progesterone and oxytocin receptors and COX-2 expression in endometrial biopsy samples from the induction of ovulation to luteolysis in llamas (Lama glama).

Endometrial expression of oestrogen (ERα), progesterone (PR) and oxytocin receptor (OR) and cyclooxygenase-2 (COX-2) was evaluated from the induction of ovulation to luteolysis in llamas. Ovarian activity was daily assessed by ultrasonography in five females. Ovulation was induced immediately after the detection of an ovulatory follicle by a GnRH injection (Day 0). Endometrial samples were obtained by transcervical biopsies from the left and right horns on day 0 and days 4, 8, 10 and 12 post-GnRH. Blood samples were collected daily for progesterone and estradiol-17ß determinations by RIA. An immunohistochemical technique was used to study receptors population and COX-2 expression which were then evaluated by two independent observers. The expression of ERα and PR was highest on day 0 in the luminal epithelium and stroma in association with high plasma estradiol-17ß concentrations. Thereafter, a decrease in ERα population was registered on day 4 and a new increase of its expression was observed between days 8 and 12 in those cell types. Conversely, PR population was gradually down-regulated until its lowest expression was reached on day 10 post-GnRH in the luminal epithelium. Content of OR was similar throughout the study in all cell types. The expression of COX-2 was highest from day 8 to 12 post-GnRH in the luminal epithelium, in relation to the time of maximal PGF2α release. Both steroid receptors populations and COX-2 expression were similar between horns. Meanwhile, OR expression was higher in the right than in the left uterine horn. In summary, this study showed that the loss of endometrium sensitivity to progesterone by days 8-10 post-induction of ovulation and the concomitant increase of COX-2 expression could play a key role in the mechanism of luteolysis and somehow be related to the short corpus luteum lifespan of llamas.

Development of corpus luteum susceptibility to an analog of prostaglandin F2α, throughout the luteal phase in llamas (Lama glama).

The aim of the present study was to evaluate the susceptibility of the corpus luteum to d-cloprostenol (synthetic analog of PGF(2α)) throughout the luteal phase in llamas. Female llamas (n=43) were induced to ovulate by GnRH injection in the presence of an ovulatory follicle and randomly assigned into one of six groups: control and treated with an injection of d-cloprostenol on Day 3, 4, 5, 6 or 8 post GnRH. Blood samples were collected to determine plasma progesterone concentrations. There was no effect of treatment on animals injected on Day 3 or 4 post-GnRH. In animals treated on Day 5, different responses were observed. No effect of treatment was recorded in 27% of the animals whereas 55% of the llamas showed a transitory decrease followed by a recovery in plasma progesterone concentrations after d-cloprostenol injection, indicative of a resurgence of the corpus luteum, extending the luteal phase a day more than in control animals. In the remaining 18% of the animals injected on Day 5, (corresponding to those exhibiting the greatest plasma progesterone concentrations at the day of injection), complete luteolysis was observed. Plasma progesterone concentrations decreased to below 1 ng ml(-1) 24 h after d-cloprostenol in llamas injected on Day 6 or 8 post-GnRH. In conclusion, the corpus luteum of llamas is completely refractory to PGF(2α) until Day 4 after induction of ovulation, being partially sensitive by Day 5 and fully responsive to PGF(2α), by Day 6 after induction of ovulation.

Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels.

BACKGROUND: Our group evaluated the risk of recurrence for optimally treated advanced epithelial ovarian cancer (adEOC) in patients with a low-level rising serum CA-125 concentration within the normal range (0-35 kU/l). In addition, we tested the new proposed early CA-125 signal of progressive disease (EPD) criterion in the same study population. PATIENTS AND METHODS: Patients treated from 1998 to 2006 for adEOC were identified at our institution. Inclusion criteria were as follows: CA-125 at time of diagnosis (>35 kU/l); International Federation of Gynecology and Obstetrics stages III-IV treated with optimal primary treatment; and complete response (CR) to primary treatment with normalization of CA-125. RESULTS: Median progression-free survival and overall survival for the recurrence group (n = 60) were 17.7 and 38.2 months, respectively. The median follow-up time from CR to last contact was 40.2 months for patients in the nonrecurrence group (n = 36). An absolute increase in serum CA-125 levels of >or=5 kU/l compared with baseline CA-125 nadir values was significantly predictive of recurrence (odds ratio for recurrence = 402.98, P < 0.0001). The progression date was predated by the EPD criterion in 77% of patients with known progressive disease (median, 58 days early) with a sensitivity of 90%, a positive predictive value of 96.4%, and a false-positive rate of 5.6%. CONCLUSIONS: Among patients with optimally treated adEOC in complete remission, a low-level increase in serum CA-125 concentration within the normal range is a strong independent predictive factor for disease recurrence. In this patient population, future prospective randomized trials should consider the evaluation of the EPD criterion.

Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer.

BACKGROUND: The amount of residual disease after surgery is considered the most important factor influencing the survival of patients with advanced epithelial ovarian cancer (adEOC). In optimally treated patients with adEOC, there are no well-established prognostic factors [excluding International Federation of Gynecology and Obstetrics (FIGO) stage]. The aim of this retrospective study is to analyze the prognostic value of the CA-125 nadir after the completion of an optimal primary treatment. PATIENTS AND METHODS: Patients treated for adEOC were identified from January 1998 to December 2006. INCLUSION CRITERIA: elevated CA-125 at time of diagnosis (>35 kU/l); FIGO stage III-IV treated with optimal primary treatment (residual tumor <1 cm and carboplatin/taxane-based combination chemotherapy); and complete response to optimal primary treatment with normalization of CA-125. RESULTS: Patients, n = 96: 44 group A (< or =10 kU/l); 52 group B (11-35 kU/l). Median progression-free survival (PFS) was 42 and 20 months for groups A and B, respectively (P = 0.0087). Median overall survival (OS) was 84 and 43 months for groups A and B, respectively (P < 0.0001). The Cox model showed a highly significant impact on PFS and OS in relation to CA-125 nadir levels. CONCLUSIONS: The CA-125 nadir value is a strong independent prognostic factor for optimally treated adEOC after achieving a complete response.

Drugs in prehistory: chemical analysis of ancient human hair.

Concern about drug abuse in modern populations has led to the development of specific methods for identification of cocaine, opiates and cannabis in human hair. Drug use in prehistory can provide indirect evidence of interpopulational contact and social stratification. This paper reports drug evaluation in nineteen ancient hair samples from archaeological sites in northern Chile. Each sample was tested for the presence of traces of cocaine, opiates and cannabis, in order to establish a standard methodology for studies of drug use among prehistoric groups. Although results are negative, this absence of evidence could be due to two main causes: (1) the individuals evaluated did not use any drugs, which does not mean that other members of their cultural group did, or (2) the wide range of known drugs studied did not consider some group specific drugs, derived from local or imported plants, thus meaning that a greater drug range must be tested. In any case, our study confirms that drug testing in prehistoric samples is viable. However, in order to determine what kind of substances were used in prehistoric times new patterns that incorporate all drugs which are not part of the western pharmacopeia must be created. Finally, a methodology for the study of drug use among prehistoric groups using ancient hair samples is described.