Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the ...main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up.
Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires.
Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76–1.36 andP = 0.3, HR = 0.87; 95% CI, 0.66–1.15, respectively. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51–1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3–4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms.
The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.
The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional mode of hypoxia-inducible factor (HIF)-dependent ...transcriptional regulation, involving modulation of a specific set of micro RNAs (miRNAs), including miR-210, has emerged. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. Therefore, we hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed a non-small cell lung carcinoma (NSCLC)-derived cell line (A549) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). The miR-210-expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. Cells were subjected to radiation levels ranging from 0 to 10 Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of radioresistance as control cells in hypoxia. Under hypoxia, pmiR-210 cells showed a low mortality rate owing to a decrease in apoptosis, with an ability to grow even at 10 Gy. This miR-210 phenotype was reproduced in another NSCLC cell line (H1975) and in HeLa cells. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we have shown that genomic double-strand breaks (DSBs) foci disappear faster in pmiR-210 than in pmiR-Ctl cells, suggesting that miR-210 expression promotes a more efficient DSB repair. Finally, HIF-1 invalidation in pmiR-210 cells removed the radioresistant phenotype, showing that this mechanism is dependent on HIF-1. In conclusion, miR-210 appears to be a component of the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could be used by tumor cells in conditions where reoxygenation has occurred and suggests that strategies targeting miR-210 could enhance tumor radiosensitization.
Acting as GTPase activating proteins promoting the silencing of activated G-proteins, regulators of G protein signaling (RGSs) are generally considered negative modulators of cell signaling. In the ...CNS, the expression of RGS4 is altered in diverse pathologies and its upregulation was reported in astrocytes exposed to an inflammatory environment. In a model of cultured cortical astrocytes, we herein investigate the influence of RGS4 on intracellular calcium signaling mediated by type 5 metabotropic glutamate receptor (mGluR5), which is known to support the bidirectional communication between neurons and glial cells. RGS4 activity was manipulated by exposure to the inhibitor CCG 63802 or by infecting the cells with lentiviruses designed to achieve the silencing or overexpression of RGS4. The pharmacological inhibition or silencing of RGS4 resulted in a decrease in the percentage of cells responding to the mGluR5 agonist DHPG and in the proportion of cells showing typical calcium oscillations. Conversely, RGS4-lentivirus infection increased the percentage of cells showing calcium oscillations. While the physiological implication of cytosolic calcium oscillations in astrocytes is still under investigation, the fine-tuning of calcium signaling likely determines the coding of diverse biological events. Indirect signaling modulators such as RGS4 inhibitors, used in combination with receptor ligands, could pave the way for new therapeutic approaches for diverse neurological disorders with improved efficacy and selectivity.
•Glycolytic markers are highly expressed in triple negative breast cancers.•Lactate/H+ symporter MCT4 demonstrated the strongest deleterious impact on survival.•MCT4 should serve as a new prognostic ...factor in node-negative breast cancers.
18Fluor-deoxy-glucose PET-scanning of glycolytic metabolism is being used for staging in many tumors however its impact on prognosis has never been studied in breast cancer.
Glycolytic and hypoxic markers: glucose transporter (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 and 4 (MCT1, 4), MCT accessory protein basigin and lactate-dehydrogenase A (LDH-A) were assessed by immunohistochemistry in two cohorts of breast cancer comprising 643 node-negative and 127 triple negative breast cancers (TNBC) respectively.
In the 643 node-negative breast tumor cohort with a median follow-up of 124months, TNBC were the most glycolytic (≈70%), followed by Her-2 (≈50%) and RH-positive cancers (≈30%). Tumoral MCT4 staining (without stromal staining) was a strong independent prognostic factor for metastasis-free survival (HR=0.47, P=0.02) and overall-survival (HR=0.38, P=0.002). These results were confirmed in the independent cohort of 127 cancer patients.
Glycolytic markers are expressed in all breast tumors with highest expression occurring in TNBC. MCT4, the hypoxia-inducible lactate/H+ symporter demonstrated the strongest deleterious impact on survival. We propose that MCT4 serves as a new prognostic factor in node-negative breast cancer and can perhaps act soon as a theranostic factor considering the current pharmacological development of MCT4 inhibitors.
Les stratégies thérapeutiques anticancéreuses associant une radiothérapie et un traitement systémique incluant chimiothérapie, hormonothérapie mais aussi plus récemment immunothérapie et thérapie ...ciblée sont de pratique courante. Pourtant les traitements combinés concomitants ou séquentiels sont souvent à l’origine d’une augmentation de la toxicité. Pour augmenter le bénéfice d’une combinaison thérapeutique, la question d’une modulation de la dose délivrée aux organes à risque se pose afin de diminuer les effets indésirables. Une revue de la littérature sur les toxicités limitantes en lien avec les stratégies associant radiothérapie et traitements systémiques a été menée. Cette étude a permis de caractériser quatre situations parmi lesquelles 1) des contre-indications de certaines associations en raison de toxicité inacceptable ou recommandations de prudence avec limitations des indications, de la dose prescrite ou l’application de contraintes aux organes à risque plus sévères, 2) des traitements combinés sans toxicité surajoutée ne plaidant pas en faveur d’une modulation des contraintes de dose habituelles, 3) des associations semblant augmenter le risque de toxicité en faveur d’une modulation de la dose aux organe à risque, 4) des traitements combinés avec données de tolérance limitées ou inconnues, raison pour laquelle l’association n’est recommandée que dans le cadre d’un essai thérapeutique.
Therapeutic strategies combining irradiation and drugs including chemotherapy, hormonotherapy, but also more recently targeted therapy and immunotherapy are routinely used for cancer treatment. Nevertheless, combined treatments usually lead to a rise in toxicity. In order to increase the therapeutic ratio in favour of a multimodality treatment, adapting dose constraints to organs at risk may be the key to lower the risk of toxicity. A review of the literature was conducted, focusing on the toxicity in dose-limiting organs at risk when radiation therapy is associated with drugs. Four situations were differentiated, including : 1) some contraindicated combinations due to an inacceptable increased of toxicity, or recommendations of careful use with restricted indications, reduction in prescribed dose, or severe dose constraints to organs at risk, 2) combined treatments without increased toxicity with no arguments for adjusted dose constraints, 3) associations with higher risk of toxicity, for which dose constraints could be adapted, 4) combined therapies with limited tolerance data, prohibiting their use out of clinical trials.
Background: Treatment of metastatic breast cancer (MBC) remains palliative. Patients with MBC represent a heterogeneous group whose prognosis and outcome may be dependent on host factors. The purpose ...of the present study was dual: first, to draw up a list of factors easily available in everyday clinical practice requiring no sophisticated or costly methods and second, to provide results from a large cohort of women who underwent diagnostic and treatment at a single institution. Patients and methods: From 1975 to 2005, a total of 1038 women with MBC during their follow-up were included in this retrospective analysis. Patients were subsequently assigned to five groups according to the period of metastatic diagnosis. Results: It is shown that age at initial diagnosis, hormonal receptor status and site of metastasis are the most relevant prognostic factors for predicting survival from the time of metastastic occurrence. It is also shown that a metastasis-free interval is an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease. Conclusion: These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.
•Aim: To evaluate the benefit of discontinuous SBRT schedule on local control (LC) and overall survival (OS) in NSCLC patients.•Results: OS and LC were significantly higher for patients treated with ...a discontinuous schedule compared to a continuous one.•Interpretation: SBRT for early-stage NSCLC should be done leaving one day off between the consecutive fractions.
The duration of stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) may affect patient outcomes. We aimed to determine the impact of a continuous versus discontinuous SBRT schedule on local control (LC) and overall survival (OS) in NSCLC patients.
Consecutive NSCLC stage I patients (475) treated with SBRT in four centers were retrospectively analyzed. The delivered dose ranged from 48 to 75 Gy in 3–10 fractions. Based on the ratio between the treatment duration (TD) and number of fractions (n), patients were divided into two groups: continuous schedule (CS) (TD ≤ 1.6n; 239 patients) and discontinuous schedule (DS) (TD > 1.6n; 236 patients). LC and OS were compared using Cox regression analyses after propensity score matching (216 pairs).
The median follow-up period was 41 months. Multivariate analysis showed that the DS (hazard ratio (HR): 0.42; 95 % confidence interval (CI): 0.22–0.78) and number of fractions (HR: 1.24; 95 % CI: 1.07–1.43) were significantly associated with LC. The DS (HR: 0.67; 95 % CI: 0.51–0.89), age (HR: 1.02; 95 % CI: 1–1.03), WHO performance status (HR: 2.27; 95 % CI: 1.39–3.7), and T stage (HR: 1.4; 95 % CI: 1.03–1.87) were significantly associated with OS. The 3-year LC and OS were 92 % and 64 % and 81 % and 53 % for DS and CS treatments, respectively (p < 0.01). Cox analysis confirmed that the discontinuous SBRT schedule significantly increased LC and OS.
DS is associated with significantly improved LC and OS in early-stage NSCLC patients treated with SBRT.
Regulators of G-protein signaling (RGS) are major physiological modulators of G-protein-coupled receptors (GPCR) signaling. Several GPCRs expressed in both neurons and astrocytes participate in the ...central control of pain processing, and the reduced efficacy of analgesics in neuropathic pain conditions may rely on alterations in RGS function. The expression and the regulation of RGS in astrocytes is poorly documented, and we herein hypothesized that neuroinflammation which is commonly observed in neuropathic pain could influence RGS expression in astrocytes.
In a validated model of neuropathic pain, the spared nerve injury (SNI), the regulation of RGS2, RGS3, RGS4, and RGS7 messenger RNA (mRNA) was examined up to 3 weeks after the lesion. Changes in the expression of the same RGS were also studied in cultured astrocytes exposed to defined activation protocols or to inflammatory cytokines.
We evidenced a differential regulation of these RGS in the lumbar spinal cord of animals undergoing SNI. In particular, RGS3 appeared upregulated at early stages after the lesion whereas expression of RGS2 and RGS4 was decreased at later stages. Decrease in RGS7 expression was already observed after 3 days and outlasted until 21 days after the lesion. In cultured astrocytes, we observed that changes in the culture conditions distinctly influenced the constitutive expression of these RGS. Also, brief exposures (4 to 8 h) to either interleukin-1β, interleukin-6, or tumor necrosis factor α caused rapid changes in the mRNA levels of the RGS, which however did not strictly recapitulate the regulations observed in the spinal cord of lesioned animals. Longer exposure (48 h) to inflammatory cytokines barely influenced RGS expression, confirming the rapid but transient regulation of these cell signaling modulators.
Changes in the environment of astrocytes mimicking the inflammation observed in the model of neuropathic pain can affect RGS expression. Considering the role of astrocytes in the onset and progression of neuropathic pain, we propose that the inflammation-mediated modulation of RGS in astrocytes constitutes an adaptive mechanism in a context of neuroinflammation and may participate in the regulation of nociception.
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