Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer

Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α–positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)–dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2’s cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19

Promises and challenges of adoptive T-cell therapies for solid tumours

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-09, rev-recd 2021-02-22, accepted 2021-03-04, registration 2021-03-04, pub-electronic 2021-03-29, online 2021-03-29, pub-print 2021-05-25Publication status: PublishedFunder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): RCF18/046Funder: Ovarian Cancer Action; doi: https://doi.org/10.13039/501100000299; Grant(s): HER000762Abstract: Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours

Promises and challenges of adoptive T-cell therapies for solid tumours.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours

Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study

Objective To evaluate the effect of a desogestrel progestogen-only pill (POP) compared to continuous combined oral contraception (COC) on migraine patterns in women with migraine without aura. Study design A retrospective analysis of prospective headache charts from migrainous women who used the POP or COC in our clinic between July 2009 and July 2013. The quality and quantity of migraine attacks and use of medications were evaluated at three and six months. Health related quality of life was evaluated after 6 months' treatment. Results Fifty-three patients were evaluable for the analysis (22 in the COC group and 31 in the POP group). Six months' POP treatment led to a statistical reduction in migraine days; headache days; pain intensity; number of days with severe pain and days with pain medication. The only statistical difference between the two groups was a reduction in the number of days with pain medication in the POP group compared to the COC group (p = 0.044). After 6 months' treatment a quality of life improvement was seen only in the POP group, but no statistical differences were found when comparing the two groups. Conclusions Our preliminary data confirm that POP therapy improves migraine patterns and quality of life after 6 months' treatment in women with migraine without aura and it decreases the analgesic consumption with respect to an extended COC therapy. As POP represents a healthier opportunity, in terms of vascular risk, than combined contraception, its role in migrainous women deserves to be further investigated

Endometriosis in menopause: a single institution experience

PURPOSE: This study aims to present the clinical characteristics of a series of postmenopausal women with endometriosis and to evaluate the preferential location, extension and histopathological features of the lesions. METHODS: We retrospectively examined the clinical records of 72 postmenopausal women with endometriosis who underwent surgery between January 1998 and December 2010. RESULTS: The median age of patients at the time of surgery was 58.5 years. Eleven patients (15.3 %) had previous history of endometriosis and five patients had previously undergone surgery for this reason. Only two patients included in the study were using hormone replacement therapy at the time of surgery. The most frequent location of endometriotic lesions was the ovary and among patients with endometriomas, 35 % (20/57) had different grades of metaplasia, hyperplasia, atypia and endometrioid carcinoma arising in endometriosis. The proportions of epithelium, stroma and hemorrhage in endometriotic lesions were higher in patients with concomitant endometrial or ovarian cancer. CONCLUSIONS: Endometriosis should be considered in the differential diagnosis of postmenopausal cystic lesions of the ovary. The administration of exogenous estrogen is not a prerequisite for the presence of endometriosis in postmenopausal women, and histological signs of functionally active lesions were also observed in the absence of exogenous hormone intake

Pharmacokinetic and toxicity considerations for the use of anthracyclines in ovarian cancer treatment

none4INTRODUCTION: Safe and effective treatments are needed for ovarian cancer. While there are many drugs currently available, there has recently been a renewed novel interest in the use of anthracyclines. AREAS COVERED: This review summarizes the available evidence on pharmacokinetic (PK) and toxicology implications of anthracyclines and pegylated liposomal doxorubicin (PLD) in the clinical management of women with epithelial ovarian cancer. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to September 2010. EXPERT OPINION: PLD is a liposomal formulation of doxorubicin (DXR), with a distinct pharmacokinetic profile, characterized by extended circulation time and a reduced clearance and volume of distribution with respect to the free drug. PLD is effective and well tolerated in relapsed ovarian cancer. The toxicity profile of PLD is characterized by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression and decreased cardiotoxicity compared to free DXR. The good response rate, toxicity profile and pharmacokinetic profile of PLD suggest that PLD could be an option in first-line and second-line treatment in ovarian cancer; especially in those who had experienced taxane-induced toxicity or had a poor performance status.Matteo Morotti;Mario Valenzano Menada;Pier Luigi Venturini;Simone FerreroMatteo, Morotti; VALENZANO MENADA, Mario; Venturini, PIER LUIGI; Ferrero, Simon