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- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Pesce, S., et al.
(författare)
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Different Features of Tumor-Associated NK Cells in Patients With Low-Grade or High-Grade Peritoneal Carcinomatosis
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells. We show that while in the peritoneal fluid (PF) of low-grade PC most CD56dim NK cells show a relatively immature phenotype (NKG2A+KIR-CD57-CD16dim), in the PF of high-grade PC NK cells are, in large majority, mature (CD56dimKIR+CD57+CD16bright). Furthermore, in low-grade PC, PF-NK cells are characterized by a sharp down-regulation of some activating receptors, primarily NKp30 and DNAM-1, while, in high-grade PC, PF-NK cells display a higher expression of the PD-1 inhibitory checkpoint. The compromised phenotype observed in low-grade PC patients corresponds to a functional impairment. On the other hand, in the high-grade PC patients PF-NK cells show much more important defects that only partially reflect the compromised phenotype detected. These data suggest that the PC microenvironment may contribute to tumor escape from immune surveillance by inducing different NK cell impaired features leading to altered anti-tumor activity. Notably, after CRS/HIPEC treatment, the altered NK cell phenotype of a patient with a low-grade disease and favorable prognosis was reverted to a normal one. Our present data offer a clue for the development of new immunotherapeutic strategies capable of restoring the NK-mediated anti-tumor responses in association with the CRS/HIPEC treatment to increase the effectiveness of the current therapy.
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- Pesce, S., et al.
(författare)
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miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy
- 2020
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of certain forms of tumors has increased progressively in recent years and is expected to continue growing as life expectancy continues to increase. Tumor-infiltrating NK cells may contribute to develop an anti-tumor response. Optimized combinations of different cancer therapies, including NK cell-based approaches for targeting tumor cells, have the potential to open new avenues in cancer immunotherapy. Functional inhibitory receptors on NK cells are needed to prevent their attack on healthy cells. Nevertheless, disruption of inhibitory receptors function on NK cells increases the cytotoxic capacity of NK cells against cancer cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that target mRNA and thus regulate the expression of genes involved in the development, maturation, and effector functions of NK cells. Therapeutic strategies that target the regulatory effects of miRNAs have the potential to improve the efficiency of cancer immunotherapy. Interestingly, emerging evidence points out that some miRNAs can, directly and indirectly, control the surface expression of immune checkpoints on NK cells or that of their ligands on tumor cells. This suggests a possible use of miRNAs in the context of anti-tumor therapy. This review provides the current overview of the connections between miRNAs and regulation of NK cell functions and discusses the potential of these miRNAs as innovative biomarkers/targets for cancer immunotherapy.
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- Prudencio, Mercedes, et al.
(författare)
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Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
- 2020
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:566
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Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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| 9. |
- Serabyn, E, et al.
(författare)
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The W. M. Keck Observatory infrared vortex coronagraph and a first image of HIP79124 B
- 2017
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 153:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- An optical vortex coronagraph has been implemented within the NIRC2 camera on the Keck II telescope and used to carry out on-sky tests and observations. The development of this new L′-band observational mode is described, and an initial demonstration of the new capability is presented: a resolved image of the low-mass companion to HIP 79124, which had previously been detected by means of interferometry. With HIP 79124 B at a projected separation of 186.5 mas, both the small inner working angle of the vortex coronagraph and the related imaging improvements were crucial in imaging this close companion directly. Due to higher Strehl ratios and more relaxed contrasts in L′ band versus H band, this new coronagraphic capability will enable high-contrast, small-angle observations of nearby young exoplanets and disks on a par with those of shorter-wavelength extreme adaptive optics coronagraphs.
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