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Article ; Online: Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.

Basu, B / Krebs, M G / Sundar, R / Wilson, R H / Spicer, J / Jones, R / Brada, M / Talbot, D C / Steele, N / Ingles Garces, A H / Brugger, W / Harrington, E A / Evans, J / Hall, E / Tovey, H / de Oliveira, F M / Carreira, S / Swales, K / Ruddle, R /

Raynaud, F I / Purchase, B / Dawes, J C / Parmar, M / Turner, A J / Tunariu, N / Banerjee, S / de Bono, J S / Banerji, U

Annals of oncology : official journal of the European Society for Medical Oncology

2018 Volume 29, Issue 9, Page(s) 1918–1925

Abstract: ... to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 ...

Abstract	Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.
MeSH term(s)	Adult ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Benzamides/administration & dosage ; Benzamides/adverse effects ; Benzamides/pharmacokinetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Drug Administration Schedule ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Male ; Maximum Tolerated Dose ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors ; Middle Aged ; Morpholines/administration & dosage ; Morpholines/adverse effects ; Morpholines/pharmacokinetics ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/pathology ; Paclitaxel/administration & dosage ; Paclitaxel/adverse effects ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/pharmacokinetics ; Pyrimidines/administration & dosage ; Pyrimidines/adverse effects ; Pyrimidines/pharmacokinetics ; Response Evaluation Criteria in Solid Tumors ; Ribosomal Protein S6 Kinases/metabolism
Chemical Substances	Benzamides ; Morpholines ; Protein Kinase Inhibitors ; Pyrimidines ; vistusertib (0BSC3P4H5X) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases (EC 2.7.11.1) ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2018-07-16
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	1025984-3
ISSN	1569-8041 ; 0923-7534
ISSN (online)	1569-8041
ISSN	0923-7534
DOI	10.1093/annonc/mdy245
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Article ; Online: Improving Outcomes in NSCLC: Optimum Dose Fractionation in Radical Radiotherapy Matters.

Brada, Michael / Forbes, Helen / Ashley, Susan / Fenwick, John

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2022 Volume 17, Issue 4, Page(s) 532–543

Abstract: Introduction: We analyzed a comprehensive national radiotherapy data set to compare outcomes of the most frequently used moderate hypofractionation regimen (55 Gy in 20 fractions) and conventional fractionation regimen (60-66 Gy in 30-33 fractions).: ... ...

Abstract	Introduction: We analyzed a comprehensive national radiotherapy data set to compare outcomes of the most frequently used moderate hypofractionation regimen (55 Gy in 20 fractions) and conventional fractionation regimen (60-66 Gy in 30-33 fractions). Methods: A total of 169,863 cases of NSCLC registered in England from January 2012 to December 2016 obtained from the Public Health England were divided into cohort 1 (training set) diagnosed in 2012 to 2013 and cohort 2 (validation set) diagnosed in 2014 to 2016. Radiotherapy data were obtained from the National Radiotherapy Dataset and linked by National Health Service number to survival data from the Office of National Statistics and Hospital Episode Statistics, from which surgical data and Charlson comorbidity index were obtained. Of 73,186 patients with stages I to III NSCLC, 12,898 received radical fractionated radiotherapy (cohort 1-4894; cohort 2-8004). The proportional hazards model was used to investigate overall survival from time of diagnosis. Survival was adjusted for the prognostic factors of age, sex, stage of disease, comorbidity, other radical treatments, and adjuvant chemotherapy, and the difference between the treatment schedules was summarized by hazard ratio (HR) and 95% confidence interval. The significance of any difference was evaluated by the log likelihood test. Results: Of patients with stages I to III NSCLC, 17% to 18% received radical fractionated radiotherapy. After adjustment for independent prognostic factors of age, stage, comorbidity, and other radical and adjuvant treatments, patients in cohort 1 treated with the 2.75 Gy per fraction regimen had a median survival of 25 months compared with 29 months for patients treated with the 2 Gy per fraction regimen (HR = 1.16, p = 0.001). Similarly, in cohort 2, the respective median survival values were 25 and 28 months (HR = 1.10, p = 0.02). Conclusions: Big data analysis of a comprehensive national cohort of patients with NSCLC treated in England suggests that compared with a 4-week regimen of 55 Gy in 20 fractions, a 6-week regimen of conventional daily fractionation to a dose of 60 to 66 Gy at 2 Gy per fraction is associated with a survival benefit. Within the limitations of the retrospective big data analysis with potential selection bias and in the absence of randomized trials, the results suggest that conventional fractionation regimens should remain the standard of care.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/drug therapy ; Dose Fractionation, Radiation ; Humans ; Infant ; Lung Neoplasms/radiotherapy ; Radiotherapy Dosage ; Retrospective Studies ; State Medicine ; Treatment Outcome
Language	English
Publishing date	2022-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2022.01.006
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Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Robust Comprehensive Dataset Provides Pause for Thought.

Brada, Michael / Forbes, Helen / Ashley, Susan / Fenwick, John

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2022 Volume 17, Issue 6, Page(s) e56–e57

MeSH term(s)	Humans ; Lung Neoplasms
Language	English
Publishing date	2022-05-27
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2022.03.017
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Article: Proton radiotherapy: charging ahead without evidence

Brada, M.

Schweizer Krebs-Bulletin

2016 Volume 36, Issue 3, Page(s) 221

Language	English ; French ; German
Document type	Article
ZDB-ID	1340924-4
Database	Current Contents Medicine

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Zs.A 4528: Show issues

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Article ; Online: Integrated treatment of brain metastases.

Rosenfelder, Nicola / Brada, Michael

Current opinion in oncology

2019 Volume 31, Issue 6, Page(s) 501–507

Abstract: Purpose of review: Optimal treatment of brain metastases has been limited to local treatment with few systemic options. Increasing use of systemic targeted therapies, chemotherapy and immunotherapy and combination of local and systemic treatments has ... ...

Abstract	Purpose of review: Optimal treatment of brain metastases has been limited to local treatment with few systemic options. Increasing use of systemic targeted therapies, chemotherapy and immunotherapy and combination of local and systemic treatments has resulted in plethora of publications. We review the existing evidence for individual treatments and new evidence for the integration of systemic and combination of local treatments. Recent findings: Encouraging efficacy of systemic therapies supports combination of systemic and local treatment albeit with little randomized trial data. Efficacy particularly of targeted agents provides an opportunity to delay local treatments including radiosurgery and whole brain radiotherapy. Randomized trials testing the integration of surgery, radiotherapy and radiosurgery are reviewed with emphasis on patient relevant endpoints to guide the clinician in the choice and sequence of treatments and integrating systemic and local therapies. Summary: There is increasing tendency to use focused radiation for single and oligometastases with or without surgery and decline in whole brain radiotherapy which is limited to multiple metastases in tumours without effective systemic options. Systemic therapies have promising intracranial efficacy and the sequence and combination with localized radiation is awaiting trials. Changes in practice with a move to primary systemic treatment for brain metastases without radiation, should be undertaken with caution and close monitoring.
MeSH term(s)	Brain Neoplasms/drug therapy ; Brain Neoplasms/radiotherapy ; Brain Neoplasms/secondary ; Brain Neoplasms/therapy ; Combined Modality Therapy ; Humans ; Immunotherapy ; Molecular Targeted Therapy ; Radiosurgery ; Randomized Controlled Trials as Topic
Language	English
Publishing date	2019-08-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1049384-0
ISSN	1531-703X ; 1040-8746
ISSN (online)	1531-703X
ISSN	1040-8746
DOI	10.1097/CCO.0000000000000573
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Zs.A 3046: Show issues

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Article ; Online: Radiotherapy for benign brain tumours coming of age; example of vestibular schwannoma.

Brada, Michael

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

2013 Volume 106, Issue 2, Page(s) 157–160

MeSH term(s)	Brain Neoplasms/radiotherapy ; Dose Fractionation ; Humans ; Neuroma, Acoustic/radiotherapy ; Radiotherapy/adverse effects
Language	English
Publishing date	2013-02
Publishing country	Ireland
Document type	Editorial
ZDB-ID	605646-5
ISSN	1879-0887 ; 0167-8140
ISSN (online)	1879-0887
ISSN	0167-8140
DOI	10.1016/j.radonc.2013.01.009
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Article ; Online: Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter.

Meerwein, Christian M / Brada, Muriel D / Soyka, Michael B / Holzmann, David / Rupp, Niels J

Head and neck pathology

2022 Volume 16, Issue 3, Page(s) 670–678

Abstract: Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico- ... ...

Abstract	Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.
MeSH term(s)	Adenocarcinoma ; Colorectal Neoplasms ; Humans ; Paranasal Sinus Neoplasms ; Prognosis ; Retrospective Studies
Language	English
Publishing date	2022-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2407834-7
ISSN	1936-0568 ; 1936-055X
ISSN (online)	1936-0568
ISSN	1936-055X
DOI	10.1007/s12105-022-01410-3
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Article ; Online: Sorting lung tumor volumes from 4D-MRI data using an automatic tumor-based signal reduces stitching artifacts.

Warren, Mark / Barrett, Alexander / Bhalla, Neeraj / Brada, Michael / Chuter, Robert / Cobben, David / Eccles, Cynthia L / Hart, Clare / Ibrahim, Ehab / McClelland, Jamie / Rea, Marc / Turtle, Louise / Fenwick, John D

Journal of applied clinical medical physics

2024 Volume 25, Issue 4, Page(s) e14262

Abstract: Purpose: To investigate whether a novel signal derived from tumor motion allows more precise sorting of 4D-magnetic resonance (4D-MR) image data than do signals based on normal anatomy, reducing levels of stitching artifacts within sorted lung tumor ... ...

Abstract	Purpose: To investigate whether a novel signal derived from tumor motion allows more precise sorting of 4D-magnetic resonance (4D-MR) image data than do signals based on normal anatomy, reducing levels of stitching artifacts within sorted lung tumor volumes. Methods: (4D-MRI) scans were collected for 10 lung cancer patients using a 2D T2-weighted single-shot turbo spin echo sequence, obtaining 25 repeat frames per image slice. For each slice, a tumor-motion signal was generated using the first principal component of movement in the tumor neighborhood (TumorPC1). Signals were also generated from displacements of the diaphragm (DIA) and upper and lower chest wall (UCW/LCW) and from slice body area changes (BA). Pearson r coefficients of correlations between observed tumor movement and respiratory signals were determined. TumorPC1, DIA, and UCW signals were used to compile image stacks showing each patient's tumor volume in a respiratory phase. Unsorted image stacks were also built for comparison. For each image stack, the presence of stitching artifacts was assessed by measuring the roughness of the compiled tumor surface according to a roughness metric (Rg). Statistical differences in weighted means of Rg between any two signals were determined using an exact permutation test. Results: The TumorPC1 signal was most strongly correlated with superior-inferior tumor motion, and had significantly higher Pearson r values (median 0.86) than those determined for correlations of UCW, LCW, and BA with superior-inferior tumor motion (p < 0.05). Weighted means of ratios of Rg values in TumorPC1 image stacks to those in unsorted, UCW, and DIA stacks were 0.67, 0.69, and 0.71, all significantly favoring TumorPC1 (p = 0.02-0.05). For other pairs of signals, weighted mean ratios did not differ significantly from one. Conclusion: Tumor volumes were smoother in 3D image stacks compiled using the first principal component of tumor motion than in stacks compiled with signals based on normal anatomy.
MeSH term(s)	Humans ; Artifacts ; Tumor Burden ; Lung Neoplasms/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Lung ; Respiration
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2010347-5
ISSN	1526-9914 ; 1526-9914
ISSN (online)	1526-9914
ISSN	1526-9914
DOI	10.1002/acm2.14262
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Article: Radiotherapy in malignant glioma.

Brada, M

Annals of oncology : official journal of the European Society for Medical Oncology

2006 Volume 17 Suppl 10, Page(s) x183–5

MeSH term(s)	Brain Neoplasms/radiotherapy ; Glioma/radiotherapy ; Humans ; Radiotherapy Dosage
Language	English
Publishing date	2006-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1025984-3
ISSN	1569-8041 ; 0923-7534
ISSN (online)	1569-8041
ISSN	0923-7534
DOI	10.1093/annonc/mdl257
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Article: Combining immunotherapy and radiotherapy in lung cancer.

Bhalla, Neeraj / Brooker, Rachel / Brada, Michael

Journal of thoracic disease

2018 Volume 10, Issue Suppl 13, Page(s) S1447–S1460

Abstract: Immunotherapy has become standard of care in advanced non-small cell lung cancer (NSCLC) in a number of settings. Radiotherapy remains an important and potentially curative treatment for localized and locally advanced NSCLC not amenable to surgery. While ...

Abstract	Immunotherapy has become standard of care in advanced non-small cell lung cancer (NSCLC) in a number of settings. Radiotherapy remains an important and potentially curative treatment for localized and locally advanced NSCLC not amenable to surgery. While the principal cytotoxic effect of ionizing radiation is via DNA damage, the effect on tumour microenvironment, promoting dendritic cell presentation of tumour-derived antigens to T cells stimulating the host adaptive immune system to mount an immune response against tumours cells, has become of particular interest when combining immunomodulating agents with radiation. The 'abscopal effect' of radiation where non-irradiated metastatic lesions may respond to radiation may be immune-mediated, via radiation primed anti-tumour T cells. Immune priming by radiation offers the potential for increasing the efficacy of immunotherapy and this is subject to on-going clinical trials underpinned by immunological bioassays. Increasing understanding of the interaction between tumour, radiation and immune cells at a molecular level provides a further opportunity for intervention to enhance the potential synergy between radiation and immunotherapy. Applying the potential efficacy of combination therapy to clinical practice requires caution particularly to ensure the safety of the two treatment modalities in early phase clinical trials, many of which are currently underway. We review the biological basis for combining radiation and immunotherapy and examine the existing pre-clinical and clinical evidence and the challenges posed by the new combination of treatments.
Language	English
Publishing date	2018-05-28
Publishing country	China
Document type	Journal Article ; Review
ZDB-ID	2573571-8
ISSN	2077-6624 ; 2072-1439
ISSN (online)	2077-6624
ISSN	2072-1439
DOI	10.21037/jtd.2018.05.107
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