Successful treatment of a patient with recurrent metastatic clear cell carcinoma of the uterine cervix.

Clear cell carcinoma (CCC) of the uterine cervix is a rare gynecologic cancer that accounts for 4-9% of adenocarcinoma of the uterine cervix. Two types of uterine cervical CCCs are known: A type that is associated with in utero exposure to diethylstilbestrol (DES) and idiopathic type that is unrelated to DES exposure. Due to its rare incidence, the clinical behavior and pathological characteristics of CCCs are not fully described and treatment recommendations are not standardized. Moreover, only a few cases are reported on the recurrent metastatic CCCs and the results of various treatment trials are inconsistent. We present a case of successfully treated idiopathic metastatic CCC of the uterine cervix that recurred after concurrent chemoradiotherapy.

Treatments for priapism in boys and men with sickle cell disease.

BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review. OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials. MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low. AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

Correcting for misclassification and selection effects in estimating net survival in clinical trials.

BACKGROUND: Net survival, a measure of the survival where the patients would only die from the cancer under study, may be compared between treatment groups using either "cause-specific methods", when the causes of death are known and accurate, or "population-based methods", when the causes are missing or inaccurate. The latter methods rely on the assumption that mortality due to other causes than cancer is the same as the expected mortality in the general population with same demographic characteristics derived from population life tables. This assumption may not hold in clinical trials where patients are likely to be quite different from the general population due to some criteria for patient selection. METHODS: In this work, we propose and assess the performance of a new flexible population-based model to estimate long-term net survival in clinical trials and that allows for cause-of-death misclassification and for effects of selection. Comparisons were made with cause-specific and other population-based methods in a simulation study and in an application to prostate cancer clinical trial data. RESULTS: In estimating net survival, cause-specific methods seemed to introduce important biases associated with the degree of misclassification of cancer deaths. The usual population-based method provides also biased estimates, depending on the strength of the selection effect. Compared to these methods, the new model was able to provide more accurate estimates of net survival in long-term clinical trials. CONCLUSION: Finally, the new model paves the way for new methodological developments in the field of net survival methods in multicenter clinical trials.

Estrogen therapy in patients with prostate cancer: a contemporary systematic review.

PURPOSE: To evaluate the effectiveness and harms of DES in treating prostate cancer compared to other forms of androgen deprivation therapy (orchiectomy, LHRH agonists, and anti-androgens). METHODS: We included clinical trials comparing DES with other forms of ADT (bicalutamide, flutamide, LHRH agonists, or orchiectomy) in PCa treatment. The primary outcomes were overall survival, cancer-specific survival, and progression-free survival, and secondary outcomes were cardiovascular effects. We searched in MEDLINE, EMBASE, Central, and Lilacs from inception to nowadays and saturated information for unpublished data in other sources. We performed a qualitative analysis of all included studies. It was not possible to perform meta-analysis due to low-quality trials and high heterogeneity. RESULTS: Overall, 1700 references were scanned and 14 prospective randomized trials with a total of 3986 patients were included in the final analysis. Although trials showed DES as similarly effective to another forms of ADT, evidences about cardiovascular toxicity in out of date high doses have discouraged its use. In doses of 1 mg, DES has been used as secondary line PCa treatment with safety. CONCLUSIONS: DES might be similarly effective to other forms of ADT on advanced PCa patients, with potential important roles. Intriguingly, the burden of severe cardiovascular toxicity is mainly related to old-fashioned doses of 5.0 and 3.0 mg. Modern PCa hormonal knowledge warrants stout high-quality prospective randomized trials in the low-dose 1 mg DES scenario.

Treatments for priapism in boys and men with sickle cell disease.

BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 15 September 2017.Date of most recent search of trial registries and of Embase: 12 December 2016. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials. MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence but all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome. No significant effect of any of the treatments was seen compared to placebo. Immediate side effects were not found to be significantly different from placebo in the two trials where this information was reported. We considered the quality of evidence to be low to very low as all of the trials were at risk of bias and all had low participant numbers. AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

HIF-1α inhibition by diethylstilbestrol and its polyacetal conjugate in hypoxic prostate tumour cells: insights from NMR metabolomics.

In this study, we have employed 1H NMR metabolomics to assess the metabolic responses of PC3 prostate tumour cells to hypoxia and to pharmacological HIF-1α inhibition by DES or its polyacetal conjugate tert-DES. Oxygen deprivation prompted a number of changes in intracellular composition and metabolic activity, mainly reflecting upregulated glycolysis, amino acid catabolism and other compensatory mechanisms used by hypoxic cells to deal with oxidative imbalance and energy deficit. Cell treatment with a non-cytotoxic concentration of DES, under hypoxia, triggered significant changes in 17 metabolites. Among these, lactate, phosphocreatine and reduced glutathione, whose levels showed opposite variations in hypoxic and drug-treated cells, emerged as possible markers of DES-induced HIF-1α inhibition. Furthermore, the free drug had a much higher impact on the cellular metabolome than tert-DES, particularly concerning polyamine and pyrimidine biosynthetic pathways, known to be tightly involved in cell proliferation and growth. This is likely due to the different cell pharmacokinetics observed between free and conjugated DES. Overall, this study has revealed a number of unanticipated metabolic changes that inform on DES and tert-DES direct cellular effects, providing further insight into their mode of action at the biochemical level.

Urethral Sphincter Mechanism Incompetence in 163 Neutered Female Dogs: Diagnosis, Treatment, and Relationship of Weight and Age at Neuter to Development of Disease.

BACKGROUND: Urethral sphincter mechanism incompetence (USMI) is the most common cause of urinary incontinence in neutered bitches and is most common in dogs weighing >20 kg. OBJECTIVES: To describe a population of neutered bitches with USMI and investigate their initial presentation, the relationship between weight and age at neuter, and treatment. ANIMALS: One hundred and sixty-three female dogs with USMI (UI) diagnosed between January 2009 and December 2012, and 193 continent neutered control (C) bitches. METHODS: Retrospective data were collected from neutered female dogs with USMI and healthy, continent neutered females presented between January 2009 and December 2012. RESULTS: Urinary incontinent dogs weighed more than C dogs (P = .003), and there was no difference in age at neuter. The relationship between weight at diagnosis and age at neuter was found to impact the hazard of USMI. A decrease in the hazard of USMI was found in dogs weighing >25 kg for every month delay of neuter in the first year. The hazard did not change for dogs <15 kg. Median time from neuter to development of incontinence was 3.73 years. Phenylpropanolamine was prescribed in 75.5%, diethylstilbestrol in 21.5%, and both in 3.1% of dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Neutering bitches expected to be >25 kg adult weight later in their first year may decrease the hazard of developing USMI, whereas age at neutering of bitches <25 kg may not impact continence. Heavier dogs have increased risk of USMI, and onset occurs within a few years of neuter.

Diethylstilbestrol: Potential health risks for women exposed in utero and their offspring.

Diethylstilbestrol (DES) is a synthetic estrogen given to pregnant women to prevent miscarriages and preterm labor; the drug was used between 1941 and 1971 in the United States and into the 1980s in other countries. DES exposure is associated with significant long-term health effects, including increased risk for breast cancer, cervical and vaginal clear cell adenocarcinoma, reproductive tract abnormalities, infertility, poor pregnancy outcomes, and early menopause. This article reviews the potential health risks associated with DES exposure, how to assess which patients are at risk, and management recommendations for patients exposed to DES.

Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children.

In utero diethylstilbestrol (DES) exposure has been demonstrated to be associated with somatic abnormalities in adult men and women. Conversely, the data are contradictory regarding the association with psychological or psychiatric disorders during adolescence and adulthood. This work was designed to determine whether prenatal exposure to DES affects brain development and whether it is associated with psychiatric disorders in male and female adolescents and young adults. HHORAGES Association, a national patient support group, has assembled a cohort of 1280 women who took DES during pregnancy. We obtained questionnaire responses from 529 families, corresponding to 1182 children divided into three groups: Group 1 (n = 180): firstborn children without DES treatment, Group 2 (n = 740): exposed children, and Group 3 (n = 262): children born after a previous pregnancy treated by DES. No psychiatric disorders were reported in Group 1. In Group 2, the incidence of disorders was drastically elevated (83.8%), and in Group 3, the incidence was still elevated (6.1%) compared with the general population. This work demonstrates that prenatal exposure to DES is associated with a high risk of psychiatric disorders in adolescence and adulthood.

Diethylstilboestrol (1 mg) in the management of castration-resistant prostate cancer.

OBJECTIVE: To investigate the efficacy of diethylstilboestrol (DES) in patients with advanced prostate cancer refractory to androgen suppression. METHODS: This retrospective study comprises 194 patients with prostate cancer treated with DES (1 mg daily) between 1976 and 2010. Study outcome parameters included demographic data, tumour characteristics, treatment history, prostate-specific antigen (PSA) responses, radiologic studies, adverse events and overall survival. RESULTS: At initiation of oestrogen therapy the mean patient age was 69 years (range: 48-89) and the median PSA was 96 ng/ml (range: 1.9-9,500). The median duration of prior prostate cancer treatment was 29 months (range: 1-365). DES was the second-line treatment in 58 patients and the third/fourth-line therapy in 136 men. A formal (≥50%) PSA response was observed in 95 patients (48.9%) and the median time to progression (TTP) was 250 days (95% CI, 180-360) for this group. An additional 62 patients (31.9%) had a partial PSA response with a median TTP of 150 days (95% CI, 92-180). Thirty-seven patients (19.1%) did not have a PSA response and the median TTP was 90 days (95% CI, 90-97). The median overall survival from the start of oestrogen therapy for the entire cohort was 576 days (95% CI, 482-690). The median overall survival of patients who had a formal (≥50%), partial (<50%) and no PSA response was 756 (95% CI, 670-1,429), 428 (95% CI, 340-630) and 329 (95% CI, 287-510) days, respectively. Thirty-nine patients (20.1%) were still alive at the end of the study. No treatment-related deaths occurred. CONCLUSIONS: In the age of chemotherapy this study highlights the efficacy of oestrogen therapy in castration-refractory prostate cancer. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.

Primary non-clear-cell adenocarcinoma of the vagina in a diethylstilbestrol exposed woman.

A 54-year-old woman with a history of in-utero diethylstilbestrol (DES) exposure, who had a prior hysterectomy for symptomatic leiomyomata and dysmenorrhea, presented for vaginal bleeding. Vaginal biopsies showed a non-clear-cell adenocarcinoma, and the patient was subsequently treated with radiation therapy. We present a case of primary vaginal non-clear-cell adenocarcinoma in a patient with in-utero DES exposure. Continued monitoring of older DES-exposed women for vaginal lesions is warranted because of reported cases of non-clear-cell adenocarcinoma and persistent risk of clear cell adenocarcinoma.

Diethylstilboestrol for the treatment of prostate cancer: past, present and future.

The aim of this review was to discuss the most recent data from current trials of diethylstilboestrol (DES) to identify its present role in advanced prostate cancer treatment as new hormonal therapies emerge. The most relevant clinical studies using DES in castration-refractory prostate cancer (CRPC) were identified from the literature. The safety, efficacy, outcomes and mechanisms of action are summarized. In the age of chemotherapy this review highlights the efficacy of oestrogen therapy in CRPC. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.

Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: retrospective analysis of a single institution experience.

The aim of the present retrospective study was to evaluate the efficacy and safety of diethylstilbestrol (DES) as treatment for patients with castration-resistant prostate cancer (CRPC) and to identify predicting factors of response to DES. Patients treated with DES during the castration-resistant phase following the failure of prior treatment with LH-RH analogs during the castration-sensitive phase were retrieved from a prostate cancer database of our institution. Patients were treated with a daily dose of DES of 1-4 mg (mean, 2.6 mg) and anticoagulants for thromboembolic prophylaxis until disease progression. We analyzed their medical records, biochemical prostate-specific antigen (PSA) response and time to disease progression (TDP). Disease response and progression were identified according to the PCWG2 criteria. Patient data were examined using Kaplan-Meier survival analysis and statistical correlation tests with intra-patient comparison of the LH-RH and DES treatment phases. Forty-three DES-treated CRPC patients were found in our database through July 2011. The median age was 66 years. Sixty-three percent of the patients achieved a ≥50% decline in their serum PSA levels during DES therapy. Median TDP was 20.4 months for LH-RH analog treatment in the castration-sensitive phase, and 7.1 months for DES treatment in the castration-resistant phase. Durable responses (>1 year) were observed in 31% of the patients. Median overall survival was 57 months from the start of the DES therapy. There was no significant correlation between the TDP under LH-RH analogs and under DES therapy among the 38 patients eligible for correlation analysis. However, the magnitudes of serum PSA responses under DES and LH-RH analogs were significantly correlated with each other, and with the TDP under DES therapy. There were no treatment-related deaths. Four patients (9%) developed thromboembolic complications while under treatment, some of which appeared to be related to a discontinuation of thromboprophylaxis. In conclusion, DES confers substantial clinical benefit in the treatment of CRPC, with a relatively good safety profile when administered with thromboprophylaxis. The use of DES may be effective in CRPC, irrespective of the length of the hormone-sensitive period with LH-RH treatment. The magnitude of PSA response to previous treatment with LH-RH analogs, as well as to DES, was predictive of the duration of response to DES.

[Hormonal treatment in prostate cancer]. / Le traitement hormonal du cancer de la prostate.

AIM: To describe drugs used in the hormonal treatment (hormonotherapy) of prostate cancer. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: LHRH analogs and the antiandrogens remain the cornerstone in the treatment of locally advanced and metastatic prostate cancer. New therapeutic classes emerged recently (inhibitor of the synthesis of the androgen, the new antiandrogens) and allowed to grow again the limits of the hormone resistance and define the concept castration-resistant prostate cancer. CONCLUSION: The hormonal treatment of the prostate cancer grew rich of new therapeutic classes which are going to change the medical care of the prostate cancer in the coming years and the urologist must play its full part.

Antitumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer.

BACKGROUND: Abiraterone is a standard treatment for men with castration-resistant prostate cancer (CRPC). We evaluated the antitumour activity of abiraterone following the synthetic oestrogen diethylstilboestrol (DES). METHODS: Castration-resistant prostate cancer patients treated with abiraterone were identified. Demographics, response variables and survival data were recorded. RESULTS: Two-hundred and seventy-four patients received abiraterone, 114 (41.6%) after DES. Pre-chemotherapy abiraterone resulted in ≥50% PSA declines in 35/41 (85.4%) DES-naïve and 20/27 (74.1%) DES-treated patients. Post-docetaxel abiraterone resulted in ≥50% PSA declines in 40/113 (35.4%) DES-naïve and 23/81 (28.4%) DES-treated patients. Time to PSA progression was similar regardless of prior DES. CONCLUSION: Abiraterone has important antitumour activity in men with CRPC even after DES exposure.