Analysis of free cisplatin in microdialysates and plasma ultrafiltrate by liquid chromatography-tandem mass spectrometry.

Cisplatin is a potent cytotoxic agent used in the treatment of various malignancies and exerts its antitumor effect through malignant cell DNA damage and apoptosis induction. Evaluation of systemic delivery of cisplatin is important in optimization of cisplatin treatment. However, accurate quantification of systemic cisplatin is challenging due to its various forms in circulation. This study aimed to develop a sensitive (LOQ < 0.1 µg/mL) and precise Ultra Performance Liquid Chromatography (UPLC) - Tandem Mass Spectrometry (MS/MS) method for quantifying free cisplatin in microdialysates and plasma. Furthermore the aim was to compare free cisplatin concentrations measured in standard plasma samples with those obtained from intravenous microdialysis catheters in a porcine model. The method developed utilizes dichloro(ethylenediamine)platinum(II) as an internal standard that co-elutes with cisplatin, ensuring precise correction for ion suppression/enhancement effects. The method was validated, demonstrating linearity up to 100 µg/mL and good intermediate precision (CV% < 6 %) in the range of 1.0-100 µg/mL, with an LOQ of 0.03 µg/mL. The pharmacokinetic parameters (AUC0-last, Cmax, T1/2, and Tmax) showed no significant differences between the two sampling methods. This validated LC-MS/MS method provides a reliable tool for quantifying systemic free cisplatin concentrations, facilitating future systemic and local pharmacokinetic evaluations for optimization of cisplatin-based cancer treatments.

Low attendance by non-native women to human papillomavirus vaccination and cervical cancer screening - A Danish nationwide register-based cohort study.

BACKGROUND: Cervical cancer is preventable through human papillomavirus vaccination and cervical cancer screening. However, possibly due to systemic, individual (e.g. low socio-economic staus) and socio-cultural barriers, it is likely that non-natives, especially non-westerns, are more prone to attend neither vaccination nor screening (combined non-attendance). This is disturbing as the non-native population in Denmark is predicted to rise to 21% by 2060. We aimed to investigate differences in combined non-attendance by nativity and region of origin, and to analyse the association between country of origin and combined non-attendance adjusted for socio-economic status. SETTING: 1.6.2007-31.12.2016 Denmark. METHODS: Logistic regression was performed to estimate crude and adjusted odds ratios with 95% confidence intervals for combined non-attendance. RESULTS: 170,158 women were included. Overall combined non-attendance was 11.8% [11.7-12.0]; 10.0% [9.8-10.1] for native women and 27.1% [26.4-27.7] for non-native women, with highest degrees among Middle-Eastern and North-Africans (30.1% [29.2-30.9]). Even when adjusted for socio-economics, women from Middle-East and North-Africa had substantially higher odds of combined non-attendance than natives (adj. OR = 7.5 [6.3-8.9] for Somali women). CONCLUSION: Denmark has a relatively low degree of combined non-attendance. However, cervical cancer preventive programmes seem to be better tailored to the needs of native women and do not appear to cater sufficiently to the needs of the fast-growing non-native populations, particularly not to the needs of Middle-Eastern and North African women. In order to secure more just cervical cancer prevention, future studies are recommended to develop tailored intervention sensitive to the need of non-native women.

Validity and reliability of State-Trait Anxiety Inventory in Danish women aged 45 years and older with abnormal cervical screening results.

BACKGROUND: State Trait Anxiety Inventory (STAI) scale was developed in the 1980's and has been widely used both in clinical settings and in research. However the Danish version of STAI has not been validated. The aim of this study was to assess the validity and reliability of STAI - state anxiety scale in Danish women aged 45 years and older with abnormal cervical cancer screening results. METHODS: Women ≥45 years referred with an abnormal cervical cytology and healthy volunteers (n = 12) underwent cognitive interview after completing STAI. Further, STAI was sent out in an electronic questionnaire to women (n = 109) seen at the gynecological department with abnormal cervical cancer screening test during 2018. Validity and reliability of STAI was evaluated according to the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist by examining internal consistency, test-retest reliability, measurement error, floor and ceiling, construct validity and content validity. RESULTS: In the cognitive interviews the content validity was evaluated to be very good. The internal consistency of the scale was excellent with Cronbach's α = 0.93. Test-retest reliability was good with an intra-class correlation coefficient of 0.80 and the systematic difference between test-retest results was negligible. The construct validity was good. CONCLUSION: To our best knowledge, this is the first validation study of the Danish translation of STAI-state anxiety scale. This version of STAI demonstrates an acceptable reliability and validity when used in a gynecological setting.

Can adenocarcinoma in situ of the uterine cervix be treated safely by conisation in combination with endocervical curettage?

OBJECTIVE: To evaluate the prognostic value of endocervical curettage (ECC) after conisation in patients treated for adenocarcinoma in situ (AIS) of the uterine cervix. MATERIALS AND METHODS: Patients with AIS diagnosed between 1990 and 2010 and with a minimum of 1.5 years of follow-up were retrospectively identified using computerised clinical files. RESULTS: The authors identified 195 patients (median age 32 years) with a median follow-up of 6.4 years. ECC was performed in 165 patients. In 144 (87%) the initial ECC was normal. In 129 no recurrence was observed during follow-up (90%). A positive ECC was observed in 21. Thirteen patients had hysterectomies; six hysterectomies were normal. Eight patients treated conservatively developed no recurrent disease. Two patients with a positive ECC did not have a hysterectomy and developed recurrent disease. In patients with affected margins, 17% developed recurrent disease. CONCLUSION: ECC performed during initial conisation is a prognostic tool for the treatment ofAIS. Close follow-up is recommended in patients treated conservatively.

Hoping for the best, preparing for the worst: the lived experiences of women undergoing ovarian cancer surgery.

In this study, the lived experiences of women undergoing ovarian cancer surgery were explored, aiming to provide a patient perspective on being newly diagnosed and starting treatment for ovarian cancer. The study period ran from the first visit in the outpatient clinic, till 8 weeks later, when the women had either begun chemotherapy or completed their recovery. Ten women participated in two qualitative research interviews each, before and after surgery. By applying a phenomenological-hermeneutic text interpretation methodology, the findings were systematically identified, put into meaning-structures, interpreted and discussed. This process constituted the theme: 'Hoping for the best, preparing for the worst'. Final diagnostics and treatment start were extensive life events, where life itself was threatened, although hope and will were present. The women intuitively prepared themselves for the diagnosis and treatment. However, the ability to prepare was influenced by personal lifestyle, social conditions, coping strategies, and experiences of hope. The ability to prepare could be strengthened by providing adjusted information, psychosocial support and physical optimisation during the perioperative period. By offering targeted family counselling and taking good care of the women's general health and well-being, hope could be sustained and early cancer rehabilitation initiated.

Ultrasound and MRI before and after radical hysterectomy: does the operation affect the pelvic floor muscles?

PURPOSE: To evaluate pelvic floor muscles and bladder neck mobility before and after radical hysterectomy for cervical cancer with magnetic resonance imaging (MRI) and ultrasound. METHODS: A prospective follow-up study of 22 patients studied with MRI and ultrasound preoperatively, three and 12 months after radical hysterectomy was carried out. RESULTS: Bladder neck mobility was decreased three months postoperatively, but one year after the operation, it had almost attained the preoperative level. The size of the pelvic floor muscles was reduced three months after the operation, but one year postoperatively, muscle size had almost returned to the preoperative level. Age and number of deliveries affected the starting point in muscle size and the mobility of the bladder neck, but the development was identical in all the women. CONCLUSIONS: We showed that pelvic floor muscle size and mobility of the bladder neck were reduced three months after radical hysterectomy, and that they regenerated to a level only slightly below the preoperative level one year later.

Differences in current clinical features of diploid and triploid hydatidiform mole.

OBJECTIVE: To describe and compare the current clinical features of diploid and triploid molar pregnancy and to evaluate whether the presenting clinical features can predict the ploidy of a molar pregnancy. DESIGN: A retrospective study of the clinical features and ploidy of hydatidiform moles. SETTING: The Departments of Clinical Genetics and Pathology, Aarhus University Hospital and 13 gynaecological wards, Jutland, Denmark. POPULATION: A total of 259 women with molar pregnancy diagnosed between April 1986 and June 2003. METHODS: A review of medical records of consecutively collected, clinically suspected cases of molar pregnancy was performed. The molar ploidy was determined by karyotyping, flow cytometry, and/or analysis of polymorphic DNA markers. MAIN OUTCOME MEASURES: Maternal characteristics, presenting symptoms, initial human chorionic gonadotrophin (hCG), and molar ploidy. RESULTS: In a multiple logistic regression model, initial hCG of > or = 100,000 iu/l (P < 0.001), first-trimester gestational age (P < 0.001), vaginal bleeding (P < 0.001), and maternal age of > or = 40 years (P = 0.03) were independent predictors of diploid mole. Women with excessive uterine size more frequently had a diploid than a triploid mole (P < 0.001). Fifty-four percent of the women with triploid mole and 27% of the women with diploid mole were diagnosed before onset of symptoms (P < 0.001). CONCLUSIONS: The current clinical features of diploid mole are different from those of triploid mole. The presenting clinical profile of a molar pregnancy may be used as an early predictor of the molar ploidy and thus of the prognosis.

Urogynaecological dysfunction after radical hysterectomy.

AIMS: To identify self-reported urogynaecological dysfunctions in women treated by radical hysterectomy, and predict risk factors. METHODS: A survey using questionnaires. Questionnaires were mailed to 396 patients. RESULTS: Symptoms of urinary incontinence and urinary retention were reported by more than one-third, respectively. One-third of the patients reported cystitis and dysuria. However, 78% of the women did not consider their symptoms as a problem. Analyses identified body mass index, at least one delivery, pre-operative urinary incontinence, and pulmonary disease as predictors for development of post-operative urinary incontinence. Predictive variables for urinary retention symptoms were age, cystitis and/or dysuria, previous rupture of the anal sphincter, fetal weight at delivery > or =4000 g, sensation of vaginal dryness, and pre-operative urinary retention symptoms. Considering post-operative cystitis and/or dysuria, fetal weight > or =4000 g, sensation of vaginal dryness, cystitis and/or dysuria before the operation, and physical activity were predictive variables. CONCLUSIONS: Patients can be informed and advised about possible urinary tract symptoms. Special attention in the pre- and post-operative period can be paid to a subgroup of patients at high risk of later urogynaecological problems.

Patients with ovarian cancer have elevated (51)Cr-EDTA plasma clearance early post-operatively.

Plasma clearance of (51)Cr-EDTA (Clp(EDTA)) is widely used to determine glomerular filtration rate prior to carboplatin based chemotherapy. We have observed that many patients with ovarian cancer have elevated Clp in the early post-operative phase compared to later phases. The purpose of this study was to examine whether this observation reflects a systematic difference. We retrospectively analysed data from 53 patients who had undergone surgery for ovarian cancer. Twenty-six patients had Clp(EDTA) measured early after the operation (mean, 8 days (range, 3-16 days)) (early group), and 27 patients had Clp(EDTA) measured late post-operatively (mean, 32 days (range, 19-48 days)) (late group). Clp(EDTA) values was measured before the first, third and fifth course of chemotherapy. Additionally, age, height, weight, cancer stage, ascites and tumour histology were noted. Mean Clp(EDTA) in the early group was significantly higher than in the late group (104+/-4.4 vs 89+/-3.5 ml.min(-1) per 1.73 m(2); P =0.005). Clp(EDTA) declined significantly in the early group from the first measurement after the operation until measurement before the third course of chemotherapy but remained constant in the late group. Clp(EDTA) was not correlated to ascites, cancer stage or tumour histology. It is concluded that patients with ovarian cancer have significantly higher Clp(EDTA) in the early post-operative phase than similar patients with Clp(EDTA) measured late post-operatively.

No effects of human relaxin on the active and passive biomechanical properties of isolated cervical specimens from nonpregnant women.

OBJECTIVE: To evaluate the effect of human relaxin (hRLX-2) on the active and passive biomechanical properties of cervical tissue in vitro. MATERIAL: Cervical samples were obtained from the middle part of the cervix in 22 nonpregnant women undergoing hysterectomy. METHODS: The effect of hRLX-2 (10(-7) M) on the active biomechanical properties was studied on vasopressin (10(-8) M) induced smooth muscle contractions in an organ bath model. The effect on the passive biomechanical properties were studied after incubation of the strips for 48 h with hRLX-2 (10(-8) M and 10(-9) M). Subsequently, the specimens were stretched in a material testing machine until they broke. The load applied and the elongation were simultaneously recorded and the results translated into stress-strain curves. RESULTS: hRLX-2 did not influence the vasopressin-induced contractility of cervical strips from nonpregnant women in this study. No synergistic effect of progesterone could be demonstrated. The passive biomechanical properties (tensile strength, extensibility, stiffness of failure energy) did not change significantly after relaxin incubation. The results obtained in vitro do not suggest an important physiological effect of relaxin on the human nonpregnant cervix.

Cervical collagen in non-pregnant women with previous cervical incompetence.

OBJECTIVE: To study the cervical collagen in non-pregnant women with a history of congenital cervical incompetence. SUBJECTS: Ten non-pregnant women with congenital cervical incompetence, defined as cervical incompetence in the first pregnancy in a woman without previous cervical trauma. Seventy-one normal non-pregnant women (31 nulligravidae, nine nulliparous and 31 parous women) served as controls. METHOD: Cervical biopsies were analysed for the hydroxyproline concentration and extractability to express the concentration and the stability of the collagen. RESULTS: Women with cervical incompetence had markedly lower median cervical hydroxyproline concentration when compared to normal parous women (11.1 (range 6.11-18.5) micrograms/mg wet weight vs. 16.9 (range 7.7-29.8) micrograms/mg wet weight; P = 0.003, Mann Whitney test) and the extractability was almost twice the value found in normal parous women (80.2% vs. 49.5%; P = 0.03, Mann Whitney test). Both pregnancy per ce and parturition caused a significant decrease in the hydroxyproline concentration when compared to values found in nulligravidae (P < 0.0001, Kruskall Wallis test). CONCLUSIONS: Congenital cervical incompetence seems associated with a low collagen concentration in the cervical connective tissue in the non-pregnant state.

Different biomechanical properties of human fetal membranes obtained before and after delivery.

The aim of this study was to elucidate whether the mechanical properties of fetal membranes change during late pregnancy and labour. Membranes delivered by elective caesarean section in week 38 showed different load-strain curves to membranes obtained after spontaneous vaginal delivery at term. A major change in mechanical properties was a decrease in strength of the intact chorioamniotic membrane from 1.39 N to 0.98 N (width of biopsy 4 mm), mainly due to loss of strength of the amniotic component, from 1.27 N to 0.72 N. Moreover, the extensibility of the chorionic component (epsilon Fmax) increased after vaginal delivery from 0.42 to 0.54, resulting in a two-component behaviour of the intact chorioamniotic membrane and further decrease of strength. Based on these observations it is suggested that the amnion is attached to the chorion, act biomechanically in parallel and possess relatively high mechanical strength during pregnancy. After vaginal delivery the two membranes are separated, and pronounced changes are induced in their mechanical properties.

Carcinoma of the cervical stump.

Treatment, prognosis, and complication rate were retrospectively studied in 46 patients with cervical stump cancer. There were no differences in clinical stage distribution and histopathological findings between these patients and patients with cervical cancer of the intact uterus. However, 43 patients were treated by radiation therapy and only 3 patients had a cervical amputation. The 5-year survival rate was 62%, which is comparable to that of cervical cancers. Late complications were found in 22 patients: 3 (7%) had symptoms of severe radiation reactions of the bladder (necrosis or vesicovaginal fistels), 14 (31%) had severe radiation reactions in the rectum and the sigmoid (severe proctitis, stenosis, or rectovaginal fistels) and 7 (18%) had large vault necrosis. It is concluded that the frequency of cervical stump cancer is low, but cancer in the cervical stump is difficult to treat and the rate of severe late complications is so high that it should be considered when one is deciding between supravaginal and total hysterectomy. Moreover, screening for cervical cancer should be performed regularly after supravaginal hysterectomy.

Intra-articular fractures at the base of the fifth metacarpal. A clinical and radiographical study of 64 cases.

The treatment of 64 intra-articular fractures at the base of the fifth metacarpal was studied. 11 fractures with minimal displacement had been immobilised in a plaster cast without reduction. The position was improved in five of 25 fractures treated by closed reduction and a plaster cast, six of nine fractures after percutaneous pinning, and 12 of 19 fractures after open reduction and internal fixation. At follow-up after a median of 4.3 years, 19 of 50 patients answering a questionnaire had intermittent pain, especially on firm grip. 43 patients were re-examined clinically and radiographically: 21 (49%) had decreased grip power, and 28 had radiographical signs of osteoarthrosis.

[Local estrogen premedication reduces the abortion time in prostaglandin E1 analogue-induced abortion in the 2nd trimester]. / Lokal østrogen-fobehandling reducerer aborttiden ven prostaglandin E1 analog-induceret abort i 2. trimester.

Twenty-eight patients (median gestational age 17 weeks) referred for induction of second trimester abortion, were randomized to intracervical preliminary treatment by either 50 mg 17 beta-oestradiol or placebo. Abortion was then induced by 1 mg prostaglandin E1 vagitories. The preliminary treatment caused a significant rise in cervical score and a significant reduction in induction-abortion time especially by reducing the number of patients with prolonged induction-abortion time.

In vitro analysis of muscular contractile ability and passive biomechanical properties of uterine cervical samples from nonpregnant women.

We assessed the maximal muscular contractile ability, the passive biomechanical properties, and the hydroxyproline concentration in uterine cervical tissue samples from 28 nonpregnant women. Circular cervical tissue strips were mounted in organ baths and isometric tension was recorded. The mean (+/- SEM) maximal mechanical responses induced at the length of optimal mechanical performance by K+ (124 mmol/L) equaled 0.16 +/- 0.05 mN/mm2 in the distal cervix and 0.84 +/- 0.47 mN/mm2 in the proximal cervix, as compared with 4.85 +/- 1.0 mN/mm2 in tissues from the isthmus and 6.50 +/- 1.4 mN/mm2 in the fundus. The passive biomechanical properties were analyzed by a materials-testing machine. No significant differences were found between tissues from the distal and proximal cervix or between circular and longitudinal preparations. Tensile strength equaled 1.5-1.7 N/mm2, ie, 10(4)-fold the maximal muscular contractile ability. The extensibility was 0.63-0.76 and the stress-relaxation was 41-48%. The hydroxyproline concentration was 22.5 micrograms/mg wet weight in the distal cervix and 21.6 micrograms/mg in the proximal cervix, as compared with 16.6 micrograms/mg in the isthmus and 12.6 micrograms/mg in the fundus. A method for analysis of the biomechanical properties of the human cervix was designed, and from the measurements obtained it may be concluded that the passive biomechanical strength of the cervix markedly exceeds the active muscular contractile ability. This may be explained by a high collagen concentration and a low content of smooth muscle in the cervical tissue.

Intracervical 17 beta-oestradiol before induction of second-trimester abortion with a prostaglandin E1 analogue.

28 consecutive patients (17.5 weeks pregnant, range 15-21 weeks) referred for therapeutic termination of pregnancy were randomized for pretreatment overnight with either intracervical gel containing 50 mg 17 beta-oestradiol or placebo gel. The induction-abortion time with pessaries containing 16,16-dimethyl-trans-delta 2-prostaglandin E1 methyl ester was significantly reduced in the oestrogen group (median value of 11.5 versus 15 hours). The beneficial effect of oestradiol priming was primarily caused by a reduction of the number of women with high cervical resistance and prolonged induction-abortion time (90 percentiles of 15.5 and 34 hours). Thus, oestrogen pretreatment might reduce the cervical trauma due to the prostaglandins as well as the incidence of cervical incompetence in later pregnancies.

PIP: 28 consecutive patients (17.5 weeks pregnant, range 15-21 weeks), referred for therapeutic termination of pregnancy were randomized for pretreatment overnight with either intracervical gel containing 50 mg 17beta-estradiol or placebo gel. The induction-abortion time with pessaries containing 16,16-dimethyl-trans-delta2-prostaglandin E1 (PGE1) methyl ester was significantly reduced in the estrogen group (median value of 11.5 vs 15 hours). The beneficial effect of estradiol priming was primarily the result of a reduction in the number of women with high cervical resistance and prolonged induction-abortion time (90 percentiles of 15.5 and 34 hours). Thus, estrogen pretreatment might reduce the cervical trauma due to the PGs as well as the incidence of cervical incompetence in later pregnancies.