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While radiomics analysis has been applied for localized cancer disease, its application to the metastatic setting involves a non-exhaustive lesion subsampling strategy which may sidestep the intrapatient tumoral heterogeneity, hindering the reproducibility and the therapeutic response performance. Our aim was to evaluate if radiomics features can capture intertumoral intrapatient heterogeneity, and the impact of tumor subsampling on the computed heterogeneity. To this end, We delineated and extracted radiomics features of all visible tumors from single acquisition pre-treatment computed tomography of patients with metastatic lung cancer (cohort L) and confirmed our results on a larger cohort of patients with metastatic melanoma (cohort M). To quantify the captured heterogeneity, the absolute coefficient of variation (CV) of each radiomics index was calculated at the patient-level and a sensitivity analysis was performed using only a subset of all extracted features robust to the segmentation step. The extent of information loss by six commonly used tumor sampling strategies was then assessed. A total of 602 lesions were segmented from 43 patients (median age 57, 4.9% female). All robust radiomics indexes exhibited at least 20% of variation with significant heterogeneity both in heavily and oligo metastasized patients, and also at the organ level. None of the segmentation subsampling strategies were able to recover the true tumoral heterogeneity obtained by exhaustive tumor sampling. Image-based inter-tumor intra-patient heterogeneity can be successfully grasped by radiomics analyses. Failing to take into account this kind of heterogeneity will lead to inconsistent predictive algorithms. Guidelines to standardize the tumor sampling step and/or AI-driven tools to alleviate the segmentation effort are required. [ABSTRACT FROM AUTHOR]

Age is an important feature at the time of early breast cancer diagnosis. Radiotherapy is a mandatory component of treatment for breast-conserving strategies in early disease stages. Breast radiotherapy has rapidly evolved in the last 20 years. A tendency to less treatment volume (partial-breast irradiation) and less treatment time (hypofractionation) is consolidated in modern radiation oncology practice. Age and risk for local recurrence guide the decision-making process to electro-optimal treatment. Radiotherapy technological versatility offers multiple options for individualized (risk-age adapted) recommendations. [ABSTRACT FROM AUTHOR]

Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers. [ABSTRACT FROM AUTHOR]

Background The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant preclinical antitumor activity. Methods This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin's lymphoma, or non-Hodgkin's lymphoma. EMD 534085 (starting dose 2 mg/m/day) was administered intravenously every 3 weeks. Doses were escalated in 100 % steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50 % until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25 %. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients. Results Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21-337). Thirty-eight patients (86 %) received ≥2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m/day). The maximum tolerated dose (MTD) was 108 mg/m/day. The most common treatment-related adverse events were asthenia (50 %) and neutropenia (32 %). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52 %). Conclusions EMD 534085 appeared to be well tolerated; MTD was 108 mg/m/day. Preliminary antitumor results suggested limited activity in monotherapy. [ABSTRACT FROM AUTHOR]

Background:Combined-modality therapy is a promising approach to improve the therapeutic index of radiotherapy. However, these improvements could come at the cost of increased toxicities. Clinical trials evaluating anti-tumour efficacy of bevacizumab combined with radiotherapy have encountered unexpected side effects. This study is the first systematic evaluation of normal tissue toxicity triggered by anti-angiogenic agents combined with radiation therapy in mice.Methods:Effect of a mouse anti-VEGF antibody was monitored on acute toxicity studying radiation-induced intestinal ulceration (12 Gy TBI); on subacute toxicity using a model of oral mucositis (16.5 Gy); on late radiation injuries by monitoring lung fibrosis (bleomycin and 19 Gy).Results:Combination of irradiation with anti-VEGF antibody enhanced intestinal damages with severe epithelial ulcerations, had no adverse impact on oral mucositis and dramatically worsened the fibrotic picture induced by bleomycin and irradiation to the lung.Interpretation:These reports bring to light the important questions about safety and underscore the need for appropriate preclinical modelling of the impact on normal tissues of novel drug-radiation regimens. Our findings also highlight the complexity of anti-VEGF action, which could in defined conditions exert tissue-specific protection. The findings indicate that the combination of targeted drugs with radiotherapy should be approached with caution. [ABSTRACT FROM AUTHOR]

Background: Non-small-cell lung cancer (NSCLC) is an aggressive disease in which vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are implicated in tumour growth, tumour resistance to radiation and chemotherapy, and disease relapse. We have investigated the anti-tumoural effects of BMS-690514, an inhibitor of both vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signalling pathways, as a single agent and in combination with ionising radiation (IR) on several NSCLC cell lines.Methods: Radiosensitisation of several NSCLC cell lines by BMS-690514 was assessed in vitro using clonogenic assay and in vivo using nude mice.Results: In vitro studies showed that BMS-690514 alone decreases clonogenic survival of NSCLC cells lines but no potential enhancement of IR response was observed in the combination. In tumour-bearing mice, BMS-690514 alone inhibits the growth of NSCLC xenografts, including the T790M mutation-harbouring H1975 tumour. The concomitant combination of BMS-690514 and radiation did not increase mice survival in comparison with treatment with IR alone. In contrast, BMS-690514 markedly enhances the anti-tumour effect of radiation in a sequential manner on H1299 and H1975 xenografts. Immunohistochemistry revealed a qualitative reduction in vessel area after administrations of BMS-690514, compared with vehicle-treated controls, suggesting that revascularisation may explain the schedule dependency of the tumour-growth delay observed.Conclusion: The results of association with radiation show that BMS-690514 may be a successful adjuvant to clinical radiotherapy. These findings are of translational importance because the clinical benefits of anti-EGFR and anti-VEGFR therapy might be schedule dependent. [ABSTRACT FROM AUTHOR]

Overexpression of the Aurora-B kinase correlates with oncogenic transformation and poor prognosis. We evaluated the effects of the bona fide Aurora-B kinase inhibitor AZD1152 on tumor responses to ionizing radiation (IR). When p53wt HCT116 and A549 cells were pretreated with AZD1152-HQPA prior to IR, additive effects were observed. Interestingly, more pronounced tumoricidal effects were observed in p53-deficient HCT116 and HT29 cells, as well as A549 cells treated with the p53 inhibitor cyclic pifithrin-α. In vivo studies on xenografted mice confirmed enhanced tumor growth delay after the combination of IR plus AZD1152-IR as compared to IR alone. Again, this effect was more pronounced with p53−/− HCT116 and p53-mutant xenografts. The AZD1152-mediated radiosensitization was mimicked by knockdown of Aurora-B with a short interference RNA or by inhibition of Aurora-B by transfection with an inducible kinase-dead Aurora-B. The radiosensitizing effect of AZD1152 was lost in CHK2−/− and 14-3-3−/− HCT116 cells. Altogether, these data indicate that AZD1152 can radiosensitize tumor cell lines in vitro and in vivo, the fact that these effects are exacerbated in p53-deficient cancer cells is of potential interest for further clinical development.Oncogene (2008) 27, 3244–3255; doi:10.1038/sj.onc.1210990; published online 17 December 2007 [ABSTRACT FROM AUTHOR]

Overexpression of Aurora-A kinase has been correlated with cancer susceptibility and poor prognosis in several human cancers. In this study, we evaluated the effect of inhibition of Aurora-A kinase on cell cycle progression and tumour cell survival after exposure to ionising radiation (IR). Combined IR and Aurora-A inhibition by short interfering RNA (siRNA) or by PHA680632 (a selective Aurora kinase inhibitor with submicromolar activity against Aurora-A) prior to IR led to an enhancement of radiation-induced annexin V positive cells, micronuclei formation, and Brca1 foci formation only in cells with deficient p53. However, the drug brought about additive to sub-additive interaction with radiation with regard to in vitro clonogenic survival. Cell cycle analysis revealed a high >4N DNA content 24 h after PHA680632 exposure. DNA content >4N was reduced dramatically when cells were irradiated combined with PHA680632 simultaneously. In vivo xenografts (p53-/- HCT116) of a mice study showed enhanced tumour growth delay (TGD) after the PHA680632-IR combinatorial treatment compared with IR alone. These results demonstrate that PHA680632 in association with radiation leads to an additive effect in cancer cells, especially in the p53-deficient cells, but does not act as a radiosensitiser in vitro or in vivo. [ABSTRACT FROM AUTHOR]

Colon carcinoma cells subjected to γ-irradiation (4 Gy) manifest signs of apoptosis (caspase activation, chromatin condensation, phosphatidylserine (PS) exposure on the cell surface, sub-diploid DNA content), correlating with their radiosensitivity, which is increased in cells lacking the 14-3-3σ protein as compared to wild-type controls. Inhibition of caspases by addition of Z-Val-Ala-DL-Asp (OMe)-fluoromethylketone, by stable transfection with the Baculovirus gene coding for p35, or by Bax knockout reduced all signs of apoptosis, yet failed to suppress radio-induced micro- and multinucleation. Moreover, pharmacological caspase inhibition, p35 expression or Bax knockout had no effect on the clonogenic survival that was reduced by γ-irradiation and caspase inhibition failed to abolish the increased radiosensitivity of 14-3-3σ-deficient cells. Micro- and multinucleation was detectable among non-apoptotic cells lacking PS exposure, as well as among cells undergoing apoptosis. Moreover, a fraction of micro- or multinucleated cells manifested caspase activation, and videomicroscopic analyses revealed that such cells could succumb to caspase-dependent apoptosis. Altogether, these results suggest that genomic instability induced by γ-irradiation can trigger apoptosis, although apoptosis is dispensable for radio-induced clonogenic death.Oncogene (2006) 25, 7758–7770. doi:10.1038/sj.onc.1209744; published online 24 July 2006 [ABSTRACT FROM AUTHOR]

Chronic myelogenous leukaemia (CML) is a clonal malignancy of the pluripotent haematopoietic stem cell, characterised by an uncontrolled proliferation and expansion of myeloid progenitors expressing a fusion oncogene, BCR-ABL, the molecular counterpart of the Ph1 chromosome. The tyrosine kinase (TK) activity of BCR-ABL is known to activate several major signalling pathways in malignant cells, including Ras, JAK/STAT and PI3K/Akt with evidence of proteasome-mediated degradation of other targets such as the DNA repair protein DNA-PKcs and cyclin-dependent kinases inhibitor p27. Targeting these abnormalities by blocking TK of BCR-ABL with STI571 provided a promising approach for the therapy of CML. The recent development of resistance to STI571 illustrates, however, that the use of other TK inhibitors could be of major interest for therapeutic purposes. To this end, the TK inhibitor Tyrphostin AG1024 was used to evaluate effect on regulation of BCR-ABL expression, inhibition of cell proliferation and tumour formation in vivo in human and murine BCR-ABL expressing cell lines. Tyrphostin AG1024 was shown to downregulate expression of BCR-ABL and P-Akt, and to upregulate DNA-PKcs expression. In addition, Tyrphostin AG1024 was able to inhibit cell proliferation, and delay tumour growth in vivo. Thus, AG1024 is able to interfere with three major targets of BCR-ABL in leukaemic cells. Interestingly, Tyrphostin AG1024 was also effective against cells resistant to STI571 by distinct mechanisms including Bcr-Abl mutation. Therefore, these data suggest that Tyrphostin AG1024 could represent the basis of a novel therapy for STI571 refractory CML.British Journal of Cancer (2004) 91, 1735-1741. doi:10.1038/sj.bjc.6602190 www.bjcancer.com Published online 19 October 2004 [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on normal tissue (lip mucosa) and tumour growth when combined with ionising radiation. The oral region (snout) of C57 black mice was irradiated with 16.5 Gy and n-3 PUFAs (100 microl) were injected intravenously for 2 weeks. After exposure to irradiation, the degree and duration of the acute reactions decreased significantly when mice were treated with n-3 PUFAs as compared to the control group. Interestingly, the range of the reactions in the n-3 PUFAs-treated group compared favourably to the group receiving amifostine (27.5 mg/kg i.v.). the effect of n-3 PUFAs was further evaluated in HEP-2 human carcinoma xenograft transplanted in nude mice. An inhibition of tumour growth was observed when mice were treated with n-3 PUFAs alone and this effect was maximal when combined with irradiation. Similar results were obtained using eicosapentaenoic acid. The effect of n-3 PUFAs was associated with inhibition of angiogenesis and tumour proliferation, and significantly decreased expression of cyclooxygenase-2. In conclusion, n-3 PUFAs administration decrease mucosal response, while moderately enhancing the antitumour effect of irradiation. The magnitude of the differential effect suggests that n-3 PUFAs need to be further investigated in the clinic. [ABSTRACT FROM AUTHOR]

Mantle cell lymphomas (MCL) are characterized by their aggressive behavior and poor response to chemotherapy regimens. We report here evidence of increased in vitro radiation sensitivity in two cell lines that we have generated from two MCL patients (UPN1 and UPN2). However, despite their increased radiation sensitivity, UPN2 cells were totally resistant to apoptotic cell death, whereas UPN1 cells underwent massive apoptosis 6?h after irradiation. The frequency of induced chromosomal abnormalities was higher in UPN1 as compared to UPN2. Distinct mechanisms have been found to contribute to this phenotype: a major telomere shortening (UPN1 and UPN2), deletion of one ATM allele and a point mutation in the remaining allele in UPN2, mutation of p53 gene (UPN1 and UPN2) with absence of functional p53 as revealed by functional yeast assays. After irradiation, Ku70 levels in UPN1 increased and decreased in UPN2, whereas in the same conditions, DNA-PKcs protein levels decreased in UPN1 and remained unchanged in UPN2. Thus, irradiation-induced apoptotic cell death can occur despite the nonfunctional status of p53 (UPN1), suggesting activation of a unique pathway in MCL cells for the induction of this event. Overall, our study demonstrates that MCL cells show increased radiation sensitivity, which can be the result of distinct molecular events. These findings could clinically be exploited to increase the dismal response rates of MCL patients to the current chemotherapy regimens.Oncogene (2003) 22, 5961-5968. doi:10.1038/sj.onc.1206826 [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) plays an important growth-promoting effect by activating the PI3K/Akt signalling pathway, inhibiting apoptotic pathways and mediating mitogenic actions. Tyrphostin AG 1024, one selective inhibitor of IGF-1R, was used to evaluate effects on proliferation, radiosensitivity, and radiation-induced cell apoptosis in a human breast cancer cell line MCF-7. Exposure to Tyrphostin AG 1024 inhibited proliferation and induced apoptosis in a time-dependent manner, and the degree of growth inhibition for IC20 plus irradiation (4 Gy) was up to 50% compared to the control. Examination of Tyrphostin AG 1024 effects on radiation response demonstrated a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Western blot analysis indicated that Tyrphostin AG 1024-induced apoptosis was associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. To our knowledge, this is the first report showing that an IGF-1 inhibitor was able to markedly increase the response of tumour cells to ionizing radiation. These results suggest that Tyrphostin AG 1024 could be used as a potential therapeutic agent in combination with irradiation. [ABSTRACT FROM AUTHOR]

Low-dose hyper-radiosensitivity (HRS) (below 0.5 Gy) has been extensively documented in the past few years. The molecular basis of this phenomenon remains largely unknown and the purpose of this study was to investigate the possible implication of the DNA repair DNA-PK complex. The activity of the DNA-PK complex, i.e. Ku DNA-end binding activity and kinase activity of the whole complex, was studied in 10 human cancer cell lines, 2 h after 0.2, 0.5 and 1 Gy irradiation. After low-dose irradiation (0.2 Gy), a marked decrease in DNA-PK activity was found in all six cell lines exhibiting HRS, whereas the DNA-PK activity was increased in the four cell lines which did not exhibit HRS. This modulation of DNA-PK activity was a rapid phenomenon occurring within the 2 h following low-dose radiation exposure. These data strongly suggest the implication of the DNA-PK repair complex in the HRS phenomenon. [ABSTRACT FROM AUTHOR]

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The pharmacodynamic effects of muzolimine and furosemide were compared in a single dose cross-over study in 8 patients on regular dialysis treatment, who had a residual diuresis of more than 300 ml/day. The study periods comprised two dialysis-free intervals of 3 days. On the second dialysis-free day either muzolimine 240 mg or furosemide 240 mg was administered orally. Urine was collected in 12-h periods on the pre-treatment, treatment and post-treatment days, and the excretion of sodium, potassium, urea and creatinine were measured. After administration of muzolimine 240 mg urine volume rose to twice that of the previous day, and sodium excretion increased approximately threefold. In contrast, the effect of furosemide 240 mg was not as pronounced; the diuresis was only 1.6 times that on the previous day and natriuresis was only 2.2 times as large. Excretion of potassium and creatinine was only slightly increased by either substance. The elimination of urea was increased by both substances to the same degree as the corresponding increase in diuresis. [ABSTRACT FROM AUTHOR]

In a double blind cross-over study of 11 patients suffering from advanced chronic renal failure, the diuretic effect of single oral dose of muzolimine 240 mg and furosemide 240 mg was compared. The patients were stratified according to a serum creatinine of approximately 4/8 and 12 mg/dl, or a mean endogenous creatinine clearance of 21.7 ml/min/1.73 m, 8.2 ml/min/1.73 m and 5.4 ml/min/1.73 m. Urine volume and sodium excretion were studied biometrically using a 3-factor variance analysis. Urine excretion in all groups tended to be greater after muzolimine than after furosemide. The cumulative sodium excretion after muzolimine was significantly greater. In the groups with a creatinine clearance of 8.2 or 5.4 ml/min/1.73 m, the duration of the time- response curve of muzolimine was greater than that of furosemide. Thus, even in advanced renal insufficiency, both substances had a saluretic effect. Muzolimine appeared to be significantly more effective than furosemide in causing natriuresis in patients with a serum creatinine of 4 to 8 mg/dl. [ABSTRACT FROM AUTHOR]

In a period of 5 years, 8 out of 77 renal transplant patients showed simultaneous fungal, bacterial and viral infections. Candida albicans was found in all cases. The most severe bacterial complications were infections with Klebsiella, Pseudomonas and Staphylococcus aureus. Cytomegalovirus, persistent HBsAg positive hepatitis, herpes zoster, and herpes simplex infections were also found. Seven patients died of bacterial superinfection and miliary tuberculosis. The data presented show that 'triple infections' are associated with high mortality and that miliary tuberculosis occurred frequently in immunosuppressed renal transplant recipients. [ABSTRACT FROM AUTHOR]

It is shown that the eigenvalue inclusion theorems for Gershgorin discs hold in a slightly weaker form also in the case of numerical ranges defined as the union of generalized Gershgorin discs in the sense of Bauer. The proof uses arguments similar to those of the Perron-Frobenius-theory but applied to matrices which are not necessarily nonnegative in the usual sense. [ABSTRACT FROM AUTHOR]

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Radiotherapy is a cornerstone of cancer management. The improvement of spatial dose distribution in the tumor volume by minimizing the dose deposited in the healthy tissues have been a major concern during the last decades. Temporal aspects of dose deposition are yet to be investigated. Laser-plasma-based particle accelerators are able to emit pulsed-proton beams at extremely high peak dose rates (~109 Gy/s) during several nanoseconds. The impact of such dose rates on resistant glioblastoma cell lines, SF763 and U87-MG, was compared to conventionally accelerated protons and X-rays. No difference was observed in DNA double-strand breaks generation and cells killing. The variation of the repetition rate of the proton bunches produced an oscillation of the radio-induced cell susceptibility in human colon carcinoma HCT116 cells, which appeared to be related to the presence of the PARP1 protein and an efficient parylation process. Interestingly, when laser-driven proton bunches were applied at 0.5 Hz, survival of the radioresistant HCT116 p53−/− cells equaled that of its radiosensitive counterpart, HCT116 WT, which was also similar to cells treated with the PARP1 inhibitor Olaparib. Altogether, these results suggest that the application modality of ultrashort bunches of particles could provide a great therapeutic potential in radiotherapy. [ABSTRACT FROM AUTHOR]

This article responds to a comment on a study about the flat maximum likelihood function related to the direct estimation of an Austrian constant elasticity of substitution (CES)-function. The neoclassical production functions of type Cobb-Douglas are preferred in mathematical economics for several reasons: First because of the simple functional representation, and because of its interpretation in terms of the neoclassical theory of distribution. The aim of the article was essentially to show, that the Cobb-Douglas function is a very special type among a set of functions of CES type with a nonlinear transformation of power λ in the variables capital, labor and energy. It has been shown by using Austrian data, that on the 95% level of significance the parameter λ = 0 cannot be rejected. But λ = 0 corresponds to the Cobb-Douglas function type. Since the 95 % confidence interval is (-0.4, 2.25) a wide variety of production functions is plausibly, including a linear function. One has to be aware of this fact, if one chooses the Cobb-Douglas function for traditional reasons. Based on the case of Leontief type production functions as has been suggested by the author of the comment. It remains to say that the choice of a value for the parameter is indeed a matter of goodness-of-fit in the model; the estimated coefficients of the production functions vary within wide intervals.