Summary In 2008, 72% of cancer deaths occurred in low-income and middle-income countries, where, although there is a lower incidence of cancer than in high-income countries, survival rates are also ...low. Many patients are sent home to die, and an even larger number of patients do not have access to treatment facilities. New constraint-adapted therapeutic strategies are therefore urgently needed. Metronomic chemotherapy—the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks—has recently emerged as a potential strategy to control advanced or refractory cancer and represents an alternative for patients with cancer living in developing countries. This low-cost, well-tolerated, and easy to access strategy is an attractive therapeutic option in resource-limited countries. Moreover, combined with drug repositioning, additional anticancer effects can be achieved, ultimately resulting in improved cancer control while maintaining minimum cost of treatment. In this Personal View, we will briefly review the rationale behind the combination of metronomic chemotherapy and drug repositioning—an approach we term metronomics. We assess the clinical experience obtained with this kind of anticancer treatment and describe potential new developments in countries with limited resources. We also highlight the need for adapted clinical study endpoints and innovative models of collaboration between for-profit and non-profit organisations, to address the growing problem of cancer in resource-limited countries.
Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and ...in some instances individual genetic aberrations such as
MYC
and
MYCN
amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including
MYC
and
MYCN
gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or
MYCN
-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with
TP53
mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 ...family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.
...targeted gene panel sequencing and RNA sequencing are being introduced into routine diagnostics and active drugs are being positioned as the standard of care by international collaborative groups ...(eg, the European Society for Paediatric Oncology also known as SIOPE). In addition to the biological explanations provided by Ian F Tannock, this absence of new efficacious treatments for most patients is also due to the fact that the myriad of associations between genetic and immunological alterations in patients who require specific drug combinations cannot be explored. ...we believe that clinical proof-of-concept trials and trials boosted by translational research exploring treatment combinations to match the biological diversity of cancer and patients with cancer, represent a step in the right direction.5 Ian F Tannock implies that new strategies are not necessarily grounded in firm biology. ...the option of evaluating these strategies in upfront window trials or as maintenance therapy for high-risk patients with poor prognoses should be better explored.5 Elsewhere, the systematic collection of real-world data for new drugs could generate evidence to support their further development. ...although we agree that reproducing the same clinical trials sets us up for possible failure, the rapidly evolving knowledge of paediatric cancer justifies comprehensive precision oncology trials paired with translational and basic research programmes.
Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, ...are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
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•FOLR2+ macrophages are tissue-resident cells found in healthy and malignant breasts•FOLR2+ macrophages reside in a perivascular niche in the tumor stroma•FOLR2+ macrophages interact with tumor-infiltrating CD8+ T cells•FOLR2+ macrophages positively correlate with T cell infiltration and better prognosis
A subset of macrophages marked by FOLR2 that interact with tumor-infiltrating CD8+ T cells are associated with favorable prognosis.
Developing precision medicine is a major trend in clinical oncology. The main adverse effects of ifosfamide, actinomycin D and vincristine (IVA) treatment for rhabdomyosarcoma are haematological ...toxicities such as neutropenia or thrombocytopenia. The severity of these effects vary among patients but their dynamic profiles are similar. A non-empirical adjustment of the chemotherapy dose to avoid severe toxicities could help secure the treatment administration. Twenty-four patients with rhabdomyosarcoma treated with IVA chemotherapy courses were selected. Before and during each cycle, routine multiple blood cell counts were performed allowing for a dynamic study of the haematological toxicities. We developed a machine learning analysis using a gradient boosting regression technique to forecast the ifosfamide induced haematological toxicities as a function of neutrophils and platelets initial levels and the initial ifosfamide dose. To validate models’ accuracy, predicted and observed neutrophils and platelets levels were compared. The model was able to reproduce the dynamic profiles of the haematological toxicities. Among all cycles, the mean absolute errors between predicted and observed neutrophils and platelets levels were 1.0 and 72.8 G/L, respectively. Adjusting a patient’s ifosfamide dose based upon the predicted haematological toxicity levels at the end of a treatment cycle could enable tailored treatment.
Metronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical ...development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynamic mathematical model that identifies
the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5-1 mg/kg gemcitabine as an optimal protocol to maximize antitumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation
, while standard gemcitabine did not. Furthermore, metronomic gemcitabine yielded a 40%-50% decrease in tumor mass at the end of treatment as compared with control mice (
= 0.002; ANOVA on ranks with Dunn test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67%-72% reduction in tumor growth at study conclusion,
< 0.001; ANOVA on ranks with Dunn test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors
.
The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft regularly observed the magnetospheric flanks of Mercury during its orbital phase. Data from the Magnetometer ...(MAG) and the Fast Imaging Plasma Spectrometer (FIPS) allow us to investigate the statistical properties of planetary ions (Na+) in the presence of Kelvin‐Helmholtz (KH) waves at the duskside magnetopause. We collect the data from orbits with clear signatures of KH waves under northward interplanetary magnetic field, as well as from adjacent orbits that do not have KH signatures, and we compare the energy characteristics between the KH and non‐KH events. Although low planetary counts in FIPS data make the comparison of these characteristics difficult, we find that in the presence of KH waves: (1) large counts of planetary ions are observed and (2) differences in Na+ energy spectra are only seen inside the magnetosphere, where they show a deceleration signature for ions with energies above 2.0 keV/e. These results suggest that planetary ions are not escaping from the magnetosphere and that electric field structures related to KH waves can decelerate planetary ions originating from the magnetotail region. The understanding of the energy distribution of planetary ions in the magnetospheric flanks of Mercury is important for a better understanding of plasma convection in the magnetosphere.
Key Points
We investigate the statistical characteristics of planetary ions derived from MESSENGER FIPS observations in the presence of KH waves
Large counts in FIPS data and a decelerating signature are observed above 2.0 keV/e for KH events
KH waves may play a role in the deceleration of planetary ions in the Hermean magnetosphere
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