Lorenzo Ferro Desideri

Inhibition of PI3K/AKT/mTOR pathway for the treatment of endometriosis

We read with great interest the article by Matsuzaki et al. (2018) entitled ‘In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: autophagymay be required for regrowth of endometriosis’ recently published in the British Journal of Pharmacology. The authors showed the efficacy of MK2206, an Akt inhibitor, in combination with chloroquine for inducing autophagy of endometriotic stromal and epithelial cells. Moreover, in their study, this double regimen succeeded in reducing the size of endometriotic implants in a xenograft mouse model of endometriosis. The rationale of this study is based on evidence of the important role displayed by PI3K/Akt/mTOR pathway in the pathogenesis of endometriosis. In fact, it has been suggested that this pathway may significantly modulate survival, proliferation of endometriotic cells and angiogenesis in endometriotic implants and that it may also be involved in resistance to progestins. To confirm its importance, some studies reported the overexpression of this pathway in women with endometriosis (Lee and Kim, 2014). The positive results of the study by Matsuzaki et al. (2018) are in line with the previous studies on temsirolimus and everolimus, two rapamycin-analogues that specifically inhibit mTORC1. In two preclinical studies on rats, these drugs were able to cause significant reduction of endometriosis implants growth (Kacan et al., 2017; Lee and Kim, 2014). Although Matsuzaki et al. (2018) should be congratulated for their laboratory findings, we would like to raise some concerns on the administration of PI3K/Akt/mTOR inhibitors and, in particular MK2206, in the clinical treatment of endometriosis. Currently, in oncology, several agents inhibiting key components of this pathway are being tested, such as mTOR (e.g. rapamycin analogues), PI3K (e.g. LY294002), PI3K/mTOR (e.g. BEZ235; dactolisib) or Akt inhibitors (e.g. MK2206). Specifically, MK2206 is being investigated for the treatment of patients with breast, non-small lung and pancreatic cancers (Janku et al., 2018). Although, in an oncological setting, patients with specific mutations (i.e. PIK3CA and PTEN) tend to have higher benefit receiving these inhibitors, a first non-negligible problem is that there are no validated predictive biomarkers for the selection of patients and for monitoring drug efficacy (Janku et al., 2018). More importantly, as the majority of these inhibitors are in early clinical development, there is a lack of solid clinical data on their efficacy and toxicity. However, a not negligible incidence of drug-related adverse events and treatment discontinuation has been reported, in patients receiving these compounds in clinical trials for advanced cancer. Their metabolic, haematological, respiratory, renal and dermatological related toxicities may be partly due to a broad activity profile and crossover inhibition of other ubiquitous lipid and protein kinases. Although some of these adverse events, such as oral stomatitis (30–60% of patients treated) or rash (30–40%), seem to increase with the dosage of the drug, they are often idiosyncratic and unpredictable, potentially occurring from days to years after the beginning of the therapy (Janku et al., 2018). Moreover, evaluating the double regimen administered in the study (Matsuzaki et al., 2018), it should be stated that also chloroquine itself is not free from gastrointestinal (12%), dermatological (3%) and less frequently ophthalmological adverse events (Rainsford et al., 2015). In conclusion, the administration of MK2206, eventually combined with chloroquine, may be acceptable for cancer therapy, in which the primary endpoints are represented by disease-free survival and overall survival. By contrast, it appears less reasonable to use them in youngwomenwith endometriosis where the goal is improving the quality of life. In fact, endometriosis needs a long-term therapy combining clinical efficacy, such as prevention of implants recurrence or control of disease-related pain, with acceptable costs and, more importantly, tolerability. Given this background, it seems unlikely that in the near future, MK2206 or its British Journal of Pharmacology British Journal of Pharmacology (2018) 175 3626–3627 3626

Retinal Detachment in Women with Eclampsia and Pre-Eclampsia

Dear editor, We read with great interest the article entitled ‘‘Serious visual (ocular) complications in pre-eclampsia and eclampsia’’ recently published by Radha Bai Prabhu [1] in The Journal of Obstetrics and Gynecology of India. In this study the author described the incidence and the clinical course of blindness in women with eclampsia and preeclampsia over a 4-year period follow-up and found the presence of visual loss in 16/9199 patients (0.17%), including 14 cases of cortical blindness and 2 retinal detachments [1]. The author should be congratulated for the prospective long-term design of the study, for having evaluated a large sample size of women and, nonetheless, for the multidisciplinary work with other specialists such as neurologists and ophthalmologists. However, we would like to point out some methodological concerns about the findings in this study from an ophthalmological point of view. Firstly, the author did not specify if, beside the funduscopy, the comprehensive ophthalmological examination included also multifocal electroretinography, optical coherence tomography (OCT) and fluorescein angiography, all diagnostic tools that have shown to better characterize ocular complications in (preeclamptic women) [2]. In a prospective study published in retina by Neudorfer et al., the authors examined retinal findings in a sample of pre-eclamptic women and demonstrated that the retinal nerve fibre layer (RFLN) thickness measured by OCT was significantly thicker in women with abnormal retinal findings in comparison with those with normal findings detected by slit-lamp examination [3]. Thus, OCT would provide a more detailed quantitative tool in the evaluation and follow-up of the neurological damage caused by (pre-)eclampsia in comparison with simple funduscopy. Secondly, in this study only 2/9199 cases of serous retina detachments were reported by the author, providing a very small incidence of the disease in (pre-)eclamptic women [1]. However, other studies have reported higher incidence rates of retinal detachment in these patients; In fact, Schultz et al. described an incidence rate of 1% in patients with pre-eclampsia and even 10% in eclamptic women [4]. Moreover, Saito et al. found investigating 71 Lorenzo Ferro Desideri, MD., Research fellow at the University of Genoa, postgraduate intern at the Department of Ophthalmology, University of Genoa; Fabio Barra, MD., postgraduate intern at the Department of Gynecology and Obstetrics, University of Genoa; Simone Ferrero, MD., PhD., Associate Professor of Gynecology and Obstetrics, University of Genoa.

Inhibitory kappa B alpha (IкB) expression in endometriosis

©Copyright 2018 by Turkish Society of Obstetrics and Gynecology Turkish Journal of Obstetrics and Gynecology published by Galenos Publishing House. Address for Correspondence/Yazışma Adresi: Simone Ferrero, MD, PhD Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy Phone: +39 010 511 525 E-mail: simoneferrero@me.com ORCID ID: orcid.org/0000-0003-2225-5568 Received/Geliş Tarihi: 03.05.2018 Accepted/Kabul Tarihi: 19.08.2018 To the Editor,

Choroidal thickness changes measured by enhanced depth imaging optical coherence tomography in third trimester pregnant women

Abstract The aim of this article is to underline the effect of pregnancy on the variations of choroidal thickness caused by hormonal and haemodynamic changes.

Prevention of Progression in Myopia: A Systematic Review

The prevalence of myopia has increased worldwide in recent decades and now is endemic over the entire industrial world. This increase is mainly caused by changes in lifestyle and behavior. In particular, the amount of outdoor activities and near work would display an important role in the pathogenesis of the disease. Several strategies have been reported as effective. Spectacles and contact lenses have shown only slight results in the prevention of myopia and similarly ortokerathology should not be considered as a first-line strategy, given the high risk of infectious keratitis and the relatively low compliance for the patients. Thus, to date, atropine ophthalmic drops seem to be the most effective treatment for slowing the progression of myopia, although the exact mechanism of the effect of treatment is still uncertain. In particular, low-dose atropine (0.01%) was proven to be an effective and safe treatment in the long term due to the lowest rebound effect with negligible side effects.

Congenital Nasolacrimal Duct Obstruction (CNLDO): A Review

Congenital nasolacrimal duct obstruction (CNLDO) is a common condition causing excessive tearing or mucoid discharge from the eyes, due to blockage of the nasolacrimal duct system. Nasolacrimal duct obstruction affects as many as 20% children aged <1 year worldwide and is often resolved without surgery. Available treatment options are conservative therapy, including observation, lacrimal sac massage and antibiotics, and invasive therapy. Observation, combined with conservative options, seems to be the best option in infants aged <1 year. Meanwhile, in children aged >1 year, nasolacrimal probing successfully addresses most obstructions. However, the most favorable timing for probing remains controversial. To alleviate persistent epiphora and mucous drainage that is refractory to probing, repeat probing, silicone tube intubation, balloon catheter dilation or dacryocystorhinostomy can be considered as available treatment options. Our review aims to provide an update to CNDO management protocols.