Gonadorelins adherence in prostate cancer: A time-series analysis of England's national prescriptions during the COVID-19 pandemic (from Jan 2019 to Oct 2020).

Objective: To examine the effect of the COVID-19 pandemic on gonadorelin analogue prescription for community patients in England. Materials and methods: We included data from all primary-care patients who had relevant prescriptions dispensed in the community in England. Descriptive statistics and interrupted time series analysis over 22 months (15 months before and 7 months after lockdown) was evaluated. Results: A total of 22 months' worth of data were analyzed (or 1 041 638 total items, monthly average 47 347 items). Goserelin; leuprorelin, and triptorelin are the medicines most used by total quantity in the study period. Simple descriptive statistics show that mean values have declined during the pandemic. The Interrupted Time Series (ARIMA Modeling) shows declining trends.After the pandemic's onset, we observe a statistically significant downward trend for goserelin (P = .017) and leuprorelin (P = .014). As these are the major constituents of the model, we interpret this overall data as showing a significant downward category trend. Aside from linearity, a significant step change was noted for leuprorelin (P = .029) showing an increase in prescription items with a similar effect that is close to being statistically significant for goserelin (P = .051).The actual cost of medicines shows minimal variation suggesting that prices of individual medicines have remained stable. The regional data showed variation but this was not statistically significant. In all cases, the Oct-20 figures are lower "year on year." This novel work reports the impact of a global pandemic on prescription volumes of prostate cancer (PCa) medicines. Conclusions: A worrying decrease in prescription medicines raises concerns for the care of PCa patients. We encourage diagnosed patients to discuss their planned care with their doctor.

Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II.

PURPOSE: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer.

BACKGROUND: The treatment of endometrial cancer (EC), the most common gynecological cancer, is currently hampered by the toxicity of current cytotoxic agents, meaning novel therapeutic approaches are urgently required. METHODS: A cohort of 161 patients was evaluated for the expression of the receptor for advanced glycation end products (RAGE) in endometrial tissues. The present study also incorporates a variety of in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy, internalisation and intercellular trafficking. Additionally, we undertook in vivo bio-distribution and toxicity evaluation to determine the suitability of our chosen therapeutic approach, together with efficacy studies in a mouse xenograft model of disease. RESULTS: We have identified an association between over-expression of the receptor for advanced glycation end products (RAGE) and EC (H-score = Healthy: 0.46, SD 0.26; Type I EC: 2.67, SD 1.39; Type II EC: 2.20, SD 1.34; ANOVA, p < 0.0001). Furthermore, increased expression was negatively correlated with patient survival (Spearman's Rank Order Correlation: ρ = - 0.3914, p < 0.05). To exploit this association, we developed novel RAGE-targeting antibody drug conjugates (ADC) and demonstrated the efficacy of this approach. RAGE-targeting ADCs were up to 100-fold more efficacious in EC cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatment alone. Additionally, RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and significantly reduced tumour growth in a xenograft mouse model of disease. CONCLUSIONS: These data, together with important design considerations implied by the present study, suggest RAGE-ADCs could be translated to novel therapeutics for EC patients.

Investigation of the initial steps of the electrochemical reduction of CO2 on Pt electrodes.

The initial steps of the electrochemical reduction of CO2 at Pt electrodes were computationally investigated at the molecular level. Simulations were performed with density functional theory using the B3LYP functional and effective core potential basis sets. The surface was modeled through two clusters comprising 13 and 20 atoms. An implicit solvation model was used to describe solvation effects for two different solvents: water and acetonitrile. It was found that CO2 adsorption is highly favored on negatively charged clusters and takes place passing from a well-defined transition state. The computational evidence suggests that the electrodic CO2 adsorption reaction may be described as a concerted process in which an electron-transfer reaction takes place contextually to CO2 adsorption. Also, the present results suggest that the formation of the CO2(•­) aqueous species is significantly unfavored from an energetic standpoint and that its main fate, if formed, would be most likely that of getting adsorbed again on the Pt surface. The calculation of the pKa of adsorbed CO2(­) showed that its protonation reaction is thermodynamically favored in most electrochemical conditions used for CO2 reduction. Also, it was found that the free-energy difference between adsorbed formate and adsorbed COOH favors the latter, suggesting that the interconversion kinetics of these two species at a Pt surface may play an important role in determining the system reactivity. A tentative global mechanism able to describe the CO2 reactivity on Pt surfaces is proposed.

The diagnostic accuracy of colposcopy in previously treated cervical intraepithelial neoplasia.

OBJECTIVE: To determine whether colposcopy is reliable in diagnosing cervical intraepithelial neoplasia in women who have undergone a previous cervical excision biopsy. MATERIALS AND METHODS: A prospective study of women attending the colposcopy clinic at the University Hospital of North Staffordshire was performed between January 1998 and December 1999. RESULTS: A clear histological diagnosis of the grade of cervical intraepithelial neoplasia was available for 469 in the treatment-naive group and 58 in the treatment group. kappa coefficients comparing the colposcopic impression (negative, low-grade, high-grade, or invasion) with histological diagnosis showed that there was no difference between the treatment-naive group, weighted kappa=0.46, and the previous treatment group, weighted kappa=0.47. The sensitivity, specificity, positive predictive value, and negative predictive value of colposcopy for any cervical disease in the treatment-naive women were 93.9%, 51.9%, 96.7%, and 34.1%, respectively, compared with 77.6%, 66.7%, 86.4%, and 35.3% in previously treated women. The sensitivity of colposcopy fell when it was used to differentiate normal and low-grade disease from high-grade disease and invasion: 82.4%, 55.9%, 82.6%, and 49.6% for treatment-naive women, compared with 61.5%, 84.2%, 60.0% and 51.6%, respectively, for the previous treatment group. CONCLUSIONS: Previous treatment to the cervix does not seem to impair the ability of colposcopy to differentiate normal cervix from all grades of cervical abnormality in women where the squamocolumnar junction is visible. However, there is a suggestion that the sensitivity of colposcopy to differentiate negative/low-grade disease from high-grade disease/invasion is lower in previously treated women.

Is levonorgestrel intrauterine system effective for treatment of early endometrial cancer? Report of four cases and review of the literature.

BACKGROUND: Intrauterine progesterone therapy potentially provides a simple alternative treatment for women with Stage I Grade I endometrial cancers who are at high risk for surgery. The case histories of four women with early endometrial cancer primarily treated with levonorgestrel intrauterine system (Mirena) are reported and the literature reviewed. CASES: Four women had Stage I grade 1 endometrial adenocarcinoma with positive progesterone receptor. All were assessed to be in American Society of anaesthesiologists risk class IV. After insertion of mirena intrauterine system, one woman (25%) had complete histological regression of disease within 6 months. One of three women who did not respond to treatment subsequently had a vaginal hysterectomy, which showed endometrial cancer with superficial myometrial invasion. CONCLUSION: This report raises doubts about the effectiveness of intrauterine progesterone therapy as a definitive alternative for the treatment of early endometrial cancer.

Changes in the management of vulval cancer.

Vulval carcinoma is relatively rare. The disease spreads from the vulva through embolization to the locoregional lymphatic station, the inguinofemoral nodes. Prior to this event cure can be achieved, but rarely predicted with certainty. This chapter reviews current therapeutic knowledge and recognizes the increasing importance of individualization of a treatment plan. The adoption of these principles will hopefully evolve a pattern of care that leads to a decrease in morbidity for those women with early tumours and less morbid but more effective strategies for those with advanced disease.

Development of a clockwork light source to enable cervical inspection by village health workers.

BACKGROUND: Cervical cancer can often be prevented by screening and may be curable if identified and treated in its early stages. However, 80% of new cases occur in less-developed countries where cervical cancer screening programmes are small-scale or non-existent. This is a human tragedy of great proportion, with many of those affected being young mothers. There is some evidence that cancerous or precancerous lesions may be detected by visual inspection with acetic acid (VIA) and field studies indicate that this technique is effective, safe and acceptable to women. However, the provision of a light source for inspection of the cervix presents a major problem in less-developed countries, where candles and torches often provide the only means of illumination. Our objective was to develop a light source based on clockwork technology, that required no batteries or external power source. METHODS: We adapted the design of a commercially available clockwork torch to provide a light source for cervical inspection. The light source was then tested under laboratory conditions in a comparison with other illumination methods typically used in this application. RESULTS: The light source gave illuminance levels greater than those produced by any other method tested, and also had considerable advantages in terms of ease of use and safety. CONCLUSION: This design is small, compact, effective and safe to use and promises a better and more affordable means of visualising the cervix. Further field trials of VIA are now required which incorporate this light source.