Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Investigation of Polyphenolic Compounds in Different Varieties of Black Chokeberry Aronia melanocarpa.

The purpose of this work was to study the qualitative and quantitative composition of the main groups of biologically active substances in the fresh fruits of five different varieties of black chokeberry (Aronia melanocarpa (Michx.) Elliot), carried out within the framework of the search for available and cost-effective raw materials for food product fortification. Samples of aronia chokeberry were grown at the Federal Scientific Center named after I.V. Michurin in the Tambov region of Russia. Using a modern chemical-analytical methodology, the contents and profiles of anthocyanin pigments, proanthocyanidins, flavonoids, hydroxycinnamic acids, organic acids (malic, quinic, succinic, and citric), monosaccharides, disaccharides, and sorbitol were determined in detail. Based on the results of the study, the most promising varieties were determined in terms of the content of the main biologically active substances.

Leiomyomatosis peritonealis disseminata associated with ascites and endometriosis: a case report and review of the literature.

We present a case of leiomyomatosis peritonealis disseminata (LPD) and review the literature. LPD is a rare, benign disorder that is characterized by multiple subperitoneal or peritoneal nodules of varying sizes on the omentum and peritoneal surfaces, grossly resembling disseminated carcinoma. It should be differentiated from other peritoneal tumors. It is mostly asymptomatic and diagnosis is often incidental during surgery. One should be aware of the iatrogenic component of this entity. LPD is being documented with increasing frequency. We report the case of a 39-year-old woman with chronic abdominal pain and heavy dysmenorrhea due to endometriosis associated with LPD. She underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy. LPD and endometriosis is a known association. LPD with ascites and endometriosis however has not yet been reported.

Intensity-modulated arc therapy with cisplatin as neo-adjuvant treatment for primary irresectable cervical cancer. Toxicity, tumour response and outcome.

PURPOSE: The goal of this work was to evaluate the feasibility and outcome of intensity-modulated arc therapy ± cisplatin (IMAT ± C) followed by hysterectomy for locally advanced cervical cancer. PATIENTS AND METHODS: A total of 30 patients were included in the study. The primary tumour and PET-positive lymph node(s) received a simultaneous integrated boost. Four weeks after IMAT ± C treatment, response was evaluated. Resection consisted of hysterectomy with or without lymphadenectomy. Tumour response, acute and late radiation toxicity, postoperative morbidity and outcome were evaluated. RESULTS: All hysterectomy specimens were macroscopically tumour-free with negative resection margins; pathological complete response was 40%. In 2 patients, one resected lymph node was positive. There was no excess in postoperative morbidity. Apart from two grade 3 hematologic toxicities, no grade 3 or 4 acute radiation toxicity was observed. No grade 3, 1 grade 4 (4%) intestinal, and 4 grade 3 (14%) urinary late toxicities were observed. The 2-year local and regional control rates were 96% and 100%, respectively. The 2-year distant control rate was 92%. Actuarial 2-year progression free survival rate was 89%. Actuarial 1- and 2-year overall survival rates were 96% and 91%, while 3-year overall survival was 84%. CONCLUSION: Surgery after IMAT ± C is feasible with low postoperative morbidity and radiation toxicity. Local, regional, distant control and survival rates are promising.

Survey: acceptability of opportunistic bilateral salpingectomy in Flanders.

Background: The VVOG (Flemish Society of Obstetrics and Gynaecology) published a consensus statement promoting opportunistic bilateral salpingectomy (OBS). Objectives: The aim of the study was to obtain insight into the current opinion and general practice of Flemish gynaecologists to counsel and perform OBS. Materials and Methods: A questionnaire was distributed to Flemish gynaecologists three months following publication. Main outcome measures: The drawbacks and incentives to counsel and perform OBS were questioned. Results: Complete response rate was obtained from 99 gynaecologists (17%) and 37 trainees (19%). The majority of respondents (77%) always counselled for OBS in patients scheduled for hysterectomy without oophorectomy. Eighteen per cent counselled only above a certain age cut off and/or if patient was already menopausal. The most important incentive to counsel in cases of hysterectomy by the abdominal approach and vaginal hysterectomy (VH) was the opportunity to prevent ovarian cancer. The yet-undetermined risk of premature ovarian failure was mentioned as the most important barrier in counselling women for OBS in those undergoing hysterectomy by the abdominal approach. For VH, the respondents saw the risk of complications and increased surgical time as the most important barriers. Sixty-one percent of gynaecologists preferred to perform bilateral salpingectomy as sterilisation method. Conclusions: Our study suggests that the concept of OBS is already well known in Flanders. There is a positive attitude towards the routine implementation of OBS, although some barriers and doubts about an age cut-off still exist in practice.

The rationale of opportunistic bilateral salpingectomies (OBS) during benign gynaecological and obstetric surgery: a consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG).

Ovarian cancer (OC), is a disease difficult to diagnose in an early stage implicating a poor prognosis. The 5-year overall survival in Belgium has not changed in the last 18 years and remains 44 %. There is no effective screening method (secondary prevention) to detect ovarian cancer at an early stage. Primary prevention of ovarian cancer came in the picture through the paradigm shift that the fallopian tube is often the origin of ovarian cancer and not the ovary itself. Opportunistic bilateral salpingectomy (OBS) during benign gynaecological and obstetric surgery might have the potential to reduce the risk of ovarian cancer by as much as 65 %. Bilateral risk-reducing salpingectomy during a benign procedure is feasible, safe, appears to have no impact on the ovarian function and seems to be cost effective. The key question is whether we should wait for a RCT or implement OBS directly in our daily practice. Guidelines regarding OBS within our societies are therefore urgently needed. Our recommendation is to inform all women without a child wish, undergoing a benign gynaecological or obstetrical surgical procedure about the pro's and the con's of OBS and advise a bilateral salpingectomy. Furthermore, there is an urgent need for a prospective registry of OBS. The present article is the consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG) regarding OBS.

Incorporating PARP-inhibitors into clinical routine: A tailored treatment strategy to tackle ovarian cancer.

DNA repair mechanisms play a key role in oncogenesis and cancer progression in women with BRCA mutation-positive (BRCAm) ovarian cancer (OC). The BRCA1/2 and poly(ADP-ribose) polymerase (PARP) proteins are considered the foremost mediators among the various components of double-strand and single-strand repair, respectively. A series of new therapeutic drugs that target PARP have been developed for BRCAm OC. This class of agents provokes tumour-specific cytotoxicity with minimal side effects by inducing synthetic lethality, of which they are the first clinical example. The European Medicines Agency granted accelerated licensing approval for the first-in-class-drug that inhibits PARP, olaparib (Lynparza™, AstraZeneca). Olaparib can be used as a monotherapeutic maintenance treatment in patients with platinum-sensitive relapsed (germline and/or somatic) BRCAm high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer responsive to platinum-based chemotherapy. Seen in light of these recent events, this review article will focus on (a) how PARP-inhibitors exploit cancer-specific defects in the homologous recombination repair apparatus and (b) how BRCA testing is implemented in routine clinical care.

A cross-sectional, multicentre, epidemiological study on human papillomavirus (HPV) type distribution in adult women diagnosed with invasive cervical cancer in Belgium.

OBJECTIVE: Despite an advanced national cervical cancer screening and vaccination programme cervical cancer is still the third most frequent diagnosed gynaecological tumour in Belgium. The goal of this study is to present the Belgian data of a cross-sectional, multicentre, epidemiological study on human papillomavirus (HPV) type distribution in adult women diagnosed with invasive cervical cancer (ICC) conducted in 12 European countries. MATERIAL AND METHODS: Centres in four major Belgian cities (Antwerp, Brussels, Ghent and Liège) participated in this study. Tissue samples from women with ICC were collected from the period 2001 - 2008. All slides were centrally reviewed and analysed for HPV. The total enrolled cohort included 278 subjects. RESULTS: The histologically eligible cohort comprised of 255 patients (mean age 51.3 ± 15.1 years) and 237 were confirmed HPV positive (mean age 50.6 ± 14.9 years). A single HPV infection was present in 95.8%. The five most frequent HPV types were HPV 16 (68.7%), HPV18 (12.3%), HPV 31 (6.2%), HPV 33 (5.3%) and HPV 45 (1.8%). Multiple HPV types were present in 3.4%, with two HPV types in 2.5% and three HPV types in 0.8%. In the various HPV type combinations observed in multiple infected women, HPV 31 (62.5%) and HPV 33 (50.0%) were the most frequent. The ratio of adenocarcinoma (ADC) versus squamous cell carcinoma (SCC) cases in the histologically eligible cohort was 1:8. Compared to the pooled European data the Belgium HPV 16 is 1.1, HPV 33 is 1.2 and HPV 31 is 1.7 higher and the HPV 18 is 0.8 and HPV 45 is 0.34 lower. CONCLUSION: The 5 most frequent HPV types in Belgium are the same as in the rest of Europe, but the distribution is different. Cervical cancer screening should therefore be HPV type specific and HPV prophylactic vaccination should also focus on other types then HPV 16 and HPV 18. A national registry is needed in order to follow the trends of HPV types in the society and to measure the impact of prevention, for which the data presented in this study can be an important basis.

Hormone therapy in epithelial ovarian cancer.

Although epidemiologic studies, animal experiments and receptor studies have shown that not only normal ovaries but also many malignant ovarian tumors can be considered as endocrine related and hormone dependent, the place of hormonal therapy in the management of patients with ovarian cancer remains unsettled. Most trials of hormonal treatment in ovarian cancer have been retrospective, involved only limited numbers of patients, and lacked important patient-related data and information pertaining to tumor characteristics. In addition, a variety of hormonal preparations with different degrees of potency and in different dosages were included in these studies. A literature review shows that response to hormonal therapy even in a preterminal setting, is modest, with about 8% objective response but almost no side effects. In a similar patient setting, more toxic therapeutic agents do not yield a better response. The place of hormonal therapy in the management of patients with epithelial ovarian cancer needs more thorough evaluation in well-designed randomized trials.

Munchausen syndrome by proxy: father as a perpetrator.

We conclude that fathers, as well as mothers and female caretakers, can be the perpetrators in Munchausen syndrome by proxy. Those same fathers may be even more difficult to detect when they do not fit previously described personalities and traits associated with mothers. We do not know if this case was an isolated incident or if some cases go undetected because fathers are not suspected as perpetrators. We hope that the case described in this article will alert the medical community to the possibility of either parent as a perpetrator in Munchausen syndrome by proxy.

Detection of estrogen DNA-adducts in human breast tumor tissue and healthy tissue by combined nano LC-nano ES tandem mass spectrometry.

For the first time estrogen DNA-adducts were identified in DNA human breast tumor tissue using nano-LC coupled to nano-Electrospray Tandem Mass Spectrometry. Normal breast tissue was analyzed analogously. The data obtained in the five breast tumor and five adjacent normal tissue samples were compared qualitatively, but no straightforward difference was observed. Prior to LC-MS analysis the DNA was enzymatically hydrolyzed to a nucleoside pool. The DNA-hydrolysates were directly injected onto a column switching system developed for on-line sample clean-up and subsequent analysis of the DNA-adducts. In four patients using Premarin, DNA-adducts of 4-hydroxy-equilenin (4OHEN) were detected. All except three samples contained DNA-adducts from 4-hydroxy-estradiol or 4-hydroxy-estrone. Also DNA isolated from eight alcohol fixed and paraffin embedded breast tumor tissue showed the presence of different estrogen DNA-adducts. Worthwhile mentioning is the presence of adducts responding to m/z 570 > m/z 454 transition. This is a well-known SRM-transition indicative for the presence of the 2'-deoxyguanosine (dGuo) adduct of Benzo[a]pyrene.

Methyl alcohol poisoning III. Ocular toxicity.

The ocular toxicity of methyl alcohol has been investigated in six rhesus monkeys. All the animals developed fundus changes within 43 to 171 hours after its ingestion. The only fundus lesion seen was optic disc edema and associated changes, usually of a marked degree. Fluorescein fundus angiography confirmed the findings. The retinal and choroidal circulations, including the retinal capillary bed, were normal. Ophthalmoscopically and angiographically, optic disc edema in methyl alcohol poisoning was indistinguishable from that seen in raised intracranial pressure, except that no increased intracranial pressure was observed. It is postulated that optic disc edema in methyl alcohol poisoning is due to an axoplasmic flow stasis.

Methyl alcohol poisoning. IV. Alterations of the morphological findings of the retina and optic nerve.

The ocular morphological findings of three methyl alcohol-intoxicated rhesus monkeys with optic disc swelling was investigated with light and electron microscopy in conjunction with intravascular horse radish peroxidase. Alterations observed in the optic nerve head were confined to the axons and consisted of swelling and clustering of the mitochondria, disruption of the neurotubules, the formation of vesicles, and enlargement of the axon segments in the prelaminar region. Swelling of the oligodendroglial cytoplasm in contact with the axons and of the astrocytes was seen in the retrolaminar optic nerve and the intraorbital optic nerve. Alterations were not observed in the retina. It is hypothesized that the alterations in the axons are the result of disrupted axoplasmic flow. Possible mechanisms relating methyl alcohol intoxication to disruption of axoplasmic flow are discussed.

Methyl alcohol poisoning. II. Development of a model for ocular toxicity in methyl alcohol poisoning using the rhesus monkey.

Rhesus monkeys were intoxicated with methyl alcohol, using an initial dose of 2 gm/kg and subsequent doses were administered in order to maintain an attenuated and prolonged state of intoxication. Arterial blood samples were drawn for methyl alcohol, formate, PO2, PCO2, and pH, which were monitored periodically throughout the course of the experiment. With the use of these procedures monkeys developed metabolic acidosis with the accumulation of formic acid in the blood and a corresponding decrease in blood bicarbonate. These animals served as models, which allowed for ocular evaluation for early signs related to methyl alcohol poisoning. A mechanism to explain toxicity is proposed and discussed.

Prognostic value of pre- and postoperative serum CA 125 levels in ovarian cancer: new aspects and multivariate analysis.

The prognostic significance of the serum CA 125 level was studied in 687 patients with invasive epithelial ovarian malignancies. The samples were collected preoperatively in 200 and postoperatively in 487 patients. Median follow-up was 27 months (range 3-84). The serum CA 125 level was elevated preoperatively in 90% of cases, with a median value of 429 U/mL. In patients with evidence of disease at the time of sampling, the CA 125 serum level correlated directly to tumor stage, tumor load, and histologic grade. Using Cox multivariate analysis, the preoperative serum CA 125 level had no independent prognostic significance, whereas the postoperative level did. In patients without residual disease after primary surgery, histologic type (P less than .0001), postoperative CA 125 level with 35 U/mL as the cutoff value (P = .0009), and tumor grade (P = .034) were independent prognostic factors for survival. For those with residual tumor after primary surgery, histologic type (P less than .0001), postoperative treatment (P = .0002), size of residual disease (P = .0005), and postoperative serum CA 125 level with 65 U/mL as a cutoff (P = .003) were independent prognostic factors.

Extracellular glutathione peroxidase and ascorbic acid in aqueous humor and serum of patients operated on for cataract.

Patients operated on for cataract (32 men/75 women, aged 50-93 years) were studied with respect to antioxidative agents in aqueous humor and serum. Extracellular glutathione peroxidase (eGSHPx) was demonstrated in aqueous humor for the first time by a radioimmunoassay, the concentration of eGSHPx being 0.66(0.18) mg/l (mean(S.D.)). The concentration of eGSHPx in serum was 3.81(0.84) mg/l, and its level in aqueous humor was 18(7)% of that level. Serum selenium had positive correlations with both serum eGSHPx (r = 0.34, P < 0.001) and aqueous humor eGSHPx (r = 0.25, P = 0.011). However, there was no relation between the concentrations of eGSHPx in aqueous humor and in serum, suggesting that the maintenance of eGSHPx levels in the two fluids is controlled by different mechanisms beside selenium status. There was an inverse correlation between age and serum eGSHPx but not with aqueous humor eGSHPx. The concentration of ascorbic acid in aqueous humor was 2.04(0.58) mmol/l, and it was closely correlated to the level of ascorbic acid in serum (0.052(0.032) mmol/l), r = 0.58 (P < 0.001). The ratio between the level of ascorbic acid in aqueous humor and that in serum was 39(17). There was no significant difference among patients with nuclear (n = 39), cortical (n = 20), posterior-subcapsular (n = 23) or mixed (n = 23) lens opacity with respect to levels of eGSHPx and ascorbic acid in serum and aqueous humor. Since serum ascorbic acid is related to ascorbic acid intake, its association to aqueous humor ascorbic acid indicates that dietary habits are important for maintaining that level which could play an important role in protecting ocular tissue against oxidative damage. The role of eGSHPx secreted into aqueous humor in the oxidant defence system needs further study.

The expression of c-erbB-2 (HER-2/neu) oncogene in invasive ovarian malignancies.

The expression of c-erbB-2 oncogene has been studied in 74 formalin fixed paraffin embedded invasive epithelial ovarian malignancies using a monoclonal c-erbB-2 protein antibody. Only four (5.4%) tumors showed membrane immunostaining. FIGO stage, size of residual disease after primary surgery, histologic type and tumor grade, were identified by the log rank test as prognostic factors for survival. No difference in survival was observed between those with and without membrane staining (24 months probability of survival: 50% and 55.4% respectively). Our results did not show any adverse prognostic effect of c-erbB-2 protein expression in our patients.