ネオアジュバント化学療法後の残存疾患を有するトリプルネガティブ乳癌患者のための治療選択

要約のみTohoku University笹野　公伸課

The role of the prefrontal cortex in hypnotic and placebo analgesia.

Background: Prominent theoreticians have referred to hypnosis as a mega placebo (Kirsch, 1997) or “hypnobo” (Raz, 2007) suggesting that hypnosis and placebo are effectively the same phenomenon. However, there is evidence that their mechanisms of action are different (Parris, 2016a) and that whilst placebo effects rely on the prefrontal cortex (PFC; Benedetti, 2010), the role of the PFC in hypnosis and hypnotic suggestibility is inconclusive. Methods: Fifty-four participants (27 male) performed tasks known to tap either left (the Stroop Task; Stroop, 1938), right (the Hayling Task; Burgess & Shallice, 1996) or global PFC functions (Fluid IQ; Wechsler, 1939; 2008). Participants then completed the Cold Pressor Test (CPT), a commonly used test for pain-threshold (the time at which pain is first felt) and pain-tolerance (from pain threshold until hand removal), under three counterbalanced conditions: 1) After receiving a hypnotic suggestion for analgesia; 2) After receiving a placebo analgesia (hand cream); 3) After receiving “cleansing” hand cream. Results: Placebo analgesia was not effective on pain-tolerance, but did affect pain-threshold and was related to right and global Fluid IQ, which appeared to positively modify the relationship between the Hayling Task predictor, the right prefrontal cortex and placebo analgesic. Hypnotic analgesia was effective for both pain-threshold and pain-tolerance but was not related to performance on any PFC task. Conclusions: The findings showed that hypnotic analgesia was greater in magnitude than placebo analgesia. Additionally, placebo analgesia but not hypnotic analgesia was related to PFC function, indicating that participants with frontal atrophy through stroke or dementia would benefit from hypnotic analgesia but not from placebo analgesia. The results are discussed in terms of both cognitive and neural theories of hypnosis and placebo

Correction to: IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients

Purpose: Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design: Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results: Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions: The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments.</p

IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients

Purpose: Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design: Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results: Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions: The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments

BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells

Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549DOX) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-4685-FU) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549DOX and MDA-MB-4685-FU cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer

Identifying older people at risk of malnutrition and treatment in the community: prevalence and concurrent validation of the Patients Association Nutrition Checklist with ‘MUST’

BackgroundDespite policy guidance and quality standards, the majority of older adults with or at risk of malnutrition living in the community still remain under‐detected and under‐treated by health and social care professionals. The present study aimed to evaluate the concurrent validity of the Patients Association Nutrition Checklist against the ‘Malnutrition Universal Screening Tool’ (‘MUST’).MethodsThis cross‐sectional study involved 312 older adults recruited from 21 lunch and social groups. All participants were screened as per standard methodology for ‘MUST’. For the Patients Association Nutrition Checklist, they provided information about signs of unintentional weight loss in the past 3–6 months, experiencing loss of appetite or interest in eating. Chance‐corrected agreement (κ) was assessed.ResultsMean (SD) age of participants was 79.6 (8.3) years and body mass index was 27.8 (5.6) kg m–2. The majority (n = 197; 63%) were living alone. Using ‘MUST’, the overall prevalence of malnutrition was 9.9% (n = 31) comprising 6.7% at medium risk and 3.2% at high risk. There were 21.8% of participants (n = 68) rated at risk of overall malnutrition by the Patients Association Nutrition Checklist. Moderate agreement was observed between the two tools (κ = 0.47, P &lt; 0.001).ConclusionsThe Patients Association Nutrition Checklist has potential for early identification of malnutrition risk, attributed to unintentional weight loss and appetite changes with signposting to basic dietary advice and appropriate support. Further work is required to understand how this tool could be effectively used by stakeholders including volunteers, community workers and home care staff