Transvaginal ligation of descending branch of uterine artery: could be the first surgical attempt to control post-partum haemorrhage?

Post-partum haemorrhage is the major cause of maternal death worldwide. This severe clinical condition can cause also physical morbidity and psychological distress (anemia, coagulopathy, blood transfusion, anterior pituitary ischemia with delay or failure of lactation, myocardial ischemia, postpartum depression). To date several efforts have been made to prevent and treat this severe condition mainly in three ways: medical, surgical, and interventional radiology even in combination. The surgical approach, needs the knowledge of anatomy of vascular distribution of the uterus. According to Palacios-Jaraquemada the feeding vessels of the body of the uterus is defined S1 area and the lower segment, uterine cervix and upper part of the vagina, S2 area. We report three cases in which the ligation of the descending branch of uterine artery (S2 area) helped the surgeon in the treatment of severe primary post-partum haemorrhage causing a significant reduction in blood loss

Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study

BACKGROUND: Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer. METHODS: 120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m(2)) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria. RESULTS: 55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy. CONCLUSION: A significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease

Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy

The “Sandwich” Schedule: A Well-Tolerated Adjuvant Treatment Both in Intermediate–High- and High-Risk Endometrial Cancer

(1) Background: In intermediate–high- and high-risk endometrial cancer (EC), radiotherapy (RT) and chemotherapy (CT) play a basic role. However, there is controversy regarding the optimal timing of their combination. The “sandwich” schedule involves adjuvant CT followed by RT and subsequent CT. The aim of this study is to assess the tolerability and efficacy of the “sandwich” schedule. (2) Methods: A retrospective study was conducted in two gynecological oncology units in Torino, Italy, from 1 January 2003 until 31 December 2021. Intermediate–high- and high-risk patients with available clinical data were included. Compliance with treatment, CT and RT toxicities, disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were analyzed. (3) Results: A total of 118 patients were selected: 27.1% FIGO I-II stages and 72.9% III-IV. Most of the patients (75.4%) received a carboplatin–paclitaxel combination, and as much as 94.9% of CT cycles were completed. Chemotherapy-related G3-4 toxicities were detected in 5.3% of the patients, almost half of which were hematological. Grade 2 gastrointestinal and genitourinary toxicities were reported in 8.4% and 4.2% of cases, respectively. With a median follow-up of 46 months, DFS was 77.6%, CSS was 70% and 5-year OS was 54%. (4) Conclusions: The “sandwich” schedule for CT and RT combination is an effective adjuvant treatment with low toxicity both in intermediate–high- and high-risk EC

Obstetric outcomes in patients who have undergone excisional treatment for high-grade cervical squamous intra-epithelial neoplasia

Objective: To evaluate the relationships between excisional treatment for high-grade cervical intraepithelial neoplasia (CIN2+) and obstetric outcomes in terms of preterm delivery risk, premature rupture of membrane (PROM) and type of delivery, and between pre-term delivery and the type of excisional technique (radio frequency excision, laser conization).Methods: This was a retrospective study of the obstetric outcomes of 2316 women aged 25-45 years who underwent excisional treatment for CIN2+ at the Obstetric and Gynecological Clinic of Ospedale Maggiore della Carita in Novara and at the Obstetric and Gynecological Department of Ospedale Sant'Anna in Torino in the period 2005-2014 and were evaluated until April 2016, and 57,937 untreated women of the same age, from the same centers.Results: After treatment, 320 women had at least one pregnancy leading to delivery after a mean of 3.35 years. Treatment significantly increased the risk of preterm delivery. Compared with no treatment, the risk of preterm birth was higher in women who had undergone treatment (33.13% vs. 6.60%). Techniques removing or ablating more tissue, such as large loop excision of the transformation zone, were associated with worse outcomes (OR 2.96, 95% IC 1.72-5.10).Smoking habits significantly increase the risk of preterm delivery in the treated women (OR 2.82, 95% IC 1.61-4.9).The risk of premature rupture of the membranes (PROM) (40% vs. 23.22%), the risk of preterm PROM (pPROM) (13.13% vs. 2.71%) and dystocic births (18.75% vs 4.48%) were also significantly increased after treatment.Caesarean sections were less frequent among the treated women (15.94% vs. 32.41%).Conclusions: Our findings reveal a relationship between cervical excisional treatment and pre-term delivery, PROM, and the method of delivery. In order to minimise risk and guarantee the best obstetric outcome, patient treatment and follow-up should be personalised. (C) 2019 Elsevier B.V. All rights reserved

Role of Mitochondria-Associated ER Membranes in Calcium Regulation in Cancer-Specific Settings

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcellular compartments that are shaped by ER subdomains juxtaposed to mitochondria but are biochemically distinct from pure ER and pure mitochondria. MAMs are enriched in enzymes involved in lipid synthesis and transport, channels for calcium transfer, and proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiological and pathophysiological processes. The term "cancer" denotes a group of disorders that result from uncontrolled cell growth driven by a mixture of genetic and environmental components. Alterations in MAMs are thought to account for the onset as well as the progression and metastasis of cancer and have been a focus of investigation in recent years. In this review, we present the current state of the art regarding MAM-resident proteins and their relevance, alterations, and deregulating functions in different types of cancer from a cell biology and clinical perspective

Cancer-Related Increases and Decreases in Calcium Signaling at the Endoplasmic Reticulum-Mitochondria Interface (MAMs)

Endoplasmic reticulum (ER)-mitochondria regions are specialized subdomains called also mitochondria-associated membranes (MAMs). MAMs allow regulation of lipid synthesis and represent hubs for ion and metabolite signaling. As these two organelles can module both the amplitude and the spatiotemporal patterns of calcium (Ca2+) signals, this particular interaction controls several Ca2+-dependent pathways well known for their contribution to tumorigenesis, such as metabolism, survival, sensitivity to cell death, and metastasis. Mitochondria-mediated apoptosis arises from mitochondrial Ca2+ overload, permeabilization of the mitochondrial outer membrane, and the release of mitochondrial apoptotic factors into the cytosol. Decreases in Ca2+ signaling at the ER-mitochondria interface are being studied in depth as failure of apoptotic-dependent cell death is one of the predominant characteristics of cancer cells. However, some recent papers that linked MAMs Ca2+ crosstalk-related upregulation to tumor onset and progression have aroused the interest of the scientific community.In this review, we will describe how different MAMs-localized proteins modulate the effectiveness of Ca2+-dependent apoptotic stimuli by causing both increases and decreases in the ER-mitochondria interplay and, specifically, by modulating Ca2+ signaling

Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer. Clin Breast Cancer

Abstract These are further data from a randomized controlled trial designed to test the effect of different doses of metformin in patients with breast cancer (BC) and without diabetes, with the aim of modifying the hormonal parameters linked to BC prognosis. A dose of 1500 mg/d of metformin causes significant reductions of the levels of free testosterone and estradiol. Introduction: Diabetic patients treated with metformin have a lower risk of developing BC or a better BC prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in natural menopause with high testosterone levels, we observed a significant decrease in insulin and in testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new analysis of our study on the effect of metformin on the bioavailability of sex hormones. Patients and Methods: One hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d. Results: Ninetysix women completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (À29%) and estradiol (À38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone sulfate. Conclusion: Metformin does not interfere with the production of dehydroepiandrosterone sulfate. Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal changes might have clinical relevance

Laparoscopic Nerve-Preserving Sacropexy

Study Objective To demonstrate our developed nerve-preserving technique during laparoscopic sacropexy (LSP) for multicompartment pelvic organ prolapse. Design A step-by-step demonstration of our surgical procedure on video (Canadian Task Force classification II-2). Informed consent was obtained from the subject, and the applicable Institutional Review Board provided approval. Setting Although sacropexy does remain the \ue2\u80\u98gold standard\ue2\u80\u99 procedure for apical prolapse [1], the subjective outcome of the procedure has been reported to be not so satisfactory as its anatomic outcome [2]. New onset bowel symptoms have been observed with voiding and sexual dysfunctions [3]. Published data revealed a correlation between iatrogenic denervation during LSP and postoperative dysfunctions [4-6. We adopted a nerve-preserving approach with the aim of reducing the iatrogenic morbidity. Interventions Our surgical nerve-preserving LSP technique from the promontory down to the right uterosacral ligament and the rectovaginal space proceeds in 3 steps: Step 1: Opening the peritoneum. The peritoneum is opened just medial to the right common iliac artery, approximately 20 to 30 mm above the sacral promontory, allowing a safe approach in an area far from nerves and vascular structures. Peritoneal incision is extended toward the promontory. The underlying presacral fascia containing the right hypogastric nerve (rHN) is identified and incised longitudinally. The presacral fascia and the rHN are then pushed medially to expose the longitudinal anterior vertebral ligament; the finding of the middle sacral veins represents the limit of any further medial dissection. Opening and displacement of the prevertebral fascia are not mandatory. Step 2: Opening the peritoneum of the right pelvic sidewall, respecting the integrity of the presacral fascia and of the rHN contained within it. An inverted L-shaped peritoneal incision extending from the sacral promontory up to the left uterosacral ligament is completed, with care taken to preserve the rHN identified previously. In proximity to the uterus, the dissection line crosses the upper edge of the right uterosacral ligament at its proximal third and extends medially. The rectovaginal space is opened and joined to the peritoneal tunnel with a section of the superficial layer of the right uterosacral ligament, preserving its deep nervous portion. Step 3: Dissection of the rectovaginal space, respecting the integrity of the rectal fascia. The rectovaginal space is fully dissected, and at its caudal edge the dissection is carried out laterally to the rectum upward to identify the pelvic parietal fascia covering the levator ani muscle, in the middle to the cranial edge of the perineal body. Preservation of the rectal fascia prevents possible injury to the middle rectal vessels and the rectal branches of the inferior hypogastric plexus, which runs close to the pelvic floor. The complete dissection of the rectovaginal space appears in an inverted V-shaped space covering approximately two-thirds of the posterior vaginal wall, with the apex at the convergence of the uterosacral ligaments. The procedure is completed with dissection of the vesicovaginal space through the creation of an avascular triangular-shaped space with the apex at the dorsal end of the bladder trigone and laterally limited by the superficial vascular layer of the vesicouterine ligaments. The bladder branches of the inferior hypogastric plexus run far from the surgical field in the deep portion of the vesicouterine ligaments. Conclusion A nerve-sparing approach to pelvic spaces during LSP is feasible following well-defined surgical steps, which allow the surgeon to visualize all of the nerve pathways and potentially dangerous anatomic structures