•The AR positive subtype has better prognosis and less chemotherapy responsiveness.•AR is involved in cell cycle regulation and Epithelial-to-Mesenchymal Transition.•Clinical data demonstrate the ...efficacy of antiandrogen therapies for AR positive TNBC.
Triple negative breast cancer (TNBC) represents the 15–20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC is not a single disease, but it is rather an umbrella for different ontology-profiles such as basal like 1 and 2, mesenchymal, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies.
Immune checkpoint inhibitors (i.e. anti-PD1, anti-PDL1, and anti-CTLA4) have revolutionized the therapeutic approach of several cancer types. In a subset of metastatic patients, the duration of the ...response is so long that a cure might be hypothesized, and a treatment discontinuation strategy could be proposed. Considering that long-term efficacy, some patients could also plan to have a child. Moreover, immunotherapy is moving to the early setting in several diseases including melanoma and breast cancer that are common cancers in young patients. However, there is a paucity of data about their potential detrimental effect on fertility, pregnancy, or sexuality. Herein, we conducted a systematic review with the aim to comprehensively collect the available evidence about fertility, pregnancy, and sexual adverse effects of checkpoint inhibitors in order to help clinicians in daily practice and trialists to develop future studies.
•This review collected the available evidence on the role of immunotherapy on fertility, hypogonadism, and sexuality.•Immune checkpoint inhibitors could impair fertility.•Immunotherapy can cause primary hypogonadism and secondary hypogonadism.•Immune checkpoint inhibitors have to be avoided during or shortly before pregnancy.•Immunotherapy might alter sexuality and libido.
In this letter, we propose a dispersion-aware program-verify algorithm to enable reliable multi-bit operations in HfO 2 -based RRAM. The significant intrinsic dispersion of the resistive states, ...typically hindering multi-bit operations, is exploited to devise a program-verify scheme which enables the multi-bit operations with unique properties of failure resilience and adaptability to degradation. We show that an appropriate choice of the algorithm parameters can minimize the average number of cycles needed to program the cell, enabling fast and reliable multi-bit operation. This maximizes the bit/cell ratio and minimizes the dispersion of targeted resistive states.
There is growing evidence about differences in metastatic spread among breast cancer (BC) biologic subtypes (BS). Aim of this study was to analyze the pattern of metastasization according to BS and ...to explore the corresponding prognosis. A series of 544 consecutive patients receiving anticancer therapy for metastatic BC from 2004 to 2013, was analyzed. BS were defined by immunohistochemistry according to St Gallen 2013 criteria. Association between BS and the different distant localizations was analyzed. Prognosis was described in terms of overall survival (OS), progression free survival (PFS) and post progression survival (PPS). Results were reported taking luminal A BC as reference. Triple negative BC showed a higher tropism for lung (OR 4.30 95 % CI 1.41–13.1), while non luminal HER2 subtype was associated with a higher rate of liver metastases (OR 3.61 95 % CI 1.36–9.58). All subtypes were associated with a lower risk of bone-only localization. Central nervous system (CNS) involvement was more common in HER2 positive BC (OR 6.3, 95 % CI 1.08–36.66). Liver, lung and CNS involvement influenced negatively OS (HR 1.64, 95 % CI 1.29–2.07; HR 1.49, 95 % CI 1.18–1.90; HR 2.891, 95 % CI 1.85–4.51, respectively) and PFS (HR 1.39, 95 % CI 1.13–1.71; HR 1.26, 95 % CI 1.02–1.55; HR 1.75, 95 % CI 1.12–2.71, respectively). Multivariate analysis confirmed liver involvement as independent predictor of worse OS (HR 1.64, 95 % CI 1.15–2.34). Stratification by metastatic pattern showed significant differences in terms of PPS but not in terms of PFS. The study suggests that BS may be characterized by typical patterns of metastatic spread and have different impact on clinical outcome.
The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical ...data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer.
Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS).
Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% 95% confidence interval (CI): 41.5–63.7 for combination therapy, and 60% (95% CI: 47.8–72.9) for monotherapy. Median PFS was 10.8months (95% CI: 5.6–12.7) for combination therapy, and 6.5months (95% CI: 5.4–8.5) for monotherapy hazard ratio (HR) 0.69; 95% CI: 0.4–1.1, exploratory P-value=0.12. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6months (HR 0.53; 95% CI: 0.3–0.9, exploratory P-value=0.02), but not in those who received prior ET for ≤6months.
Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET.
NCT02549430
To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 ...MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.
Highlights • The phenotype of BRCA wild-type TNBC often resembles the one of BRCA-related cancer. • BRCAness can be caused by epigenetic alterations or a RAD51 complex impairment. • Rearrangements ...analysis by high-throughput technologies predict response to platinum. • In neoadjuvant setting adding carboplatin improves pCR rates selectively in TNBC.
•PARP inhibitors have opened the era of targeted therapy in ovarian cancer;•Major therapeutic improvements have been limited to the high grade serous subtype;•The panorama of possible clinically ...actionable targets in ovarian cancer is wider.•New druggable alterations and matched drugs are under investigation.
After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.
Abstract Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic ...mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1+/− ) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1+/− mice, compared to their wild-type PINK1+/+ littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations. Mice were exposed to a range of concentrations of rotenone (0.01–1 mg/kg). Chronic treatment with concentrations of rotenone up to 0.8 mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1+/− and PINK1+/+ mice. Moreover, rotenone (up to 0.8 mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1+/− striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1+/− , a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1+/− mice treated with a low rotenone (0.1 mg/kg) concentration. Even lower concentrations (0.01 mg/kg) blocked LTP induction in heterozygous PINK1+/− MSNs compared to PINK1+/+ mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations. In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but profoundly impaired the expression of long-term plasticity at corticostriatal synapses in PINK1 heterozygous knockout mice, suggesting that disruption of synaptic plasticity may represent an early feature of a pre-manifesting state of the disease, and a potential tool to test novel neuroprotective agents.
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