Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Inflammation

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Tanja Langsenlehner

Previous studies have reported that cancer survivors develop age-related chronic conditions like frailty, sarcopenia, cardiac dysfunction, and cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to cancer therapies.

However, the knowledge about aging-associated consequences of cancer treatment and the processes that underlie differential responses to therapy is very limited. In 2018, a think tank established by the National Cancer Institute has defined various research needs to expand the evidence base for aging-related consequences of cancer treatment, such as studies to examine aging-related processes that include regularly performed assessments capturing factors associated with physical function or studies to elucidate pathways that lead to the emergence of aging phenotypes and to understand the relationships between biomarkers of aging and functional outcomes in cancer survivors. In addition, study inclusion of older adults with comorbidities and higher levels of frailty has been proposed to achieve an improved understanding of functional outcomes at any age.

Hypotheses / objectives We hypothesize that prostate cancer radiotherapy accelerates aging-related processes, furthermore, aging-related biomarkers may predict functional outcomes and represent early indicators of aging phenotypes. Primary objectives of the proposed study are the determination of the aging-related consequences of radiotherapy in prostate cancer patients and the evaluation of the relationship between biomarkers of aging and age-related clinical conditions.

Systematic evaluations of functional and cognitive status, comorbidities, health status, mobility, nutritional status, psychological status, and social circumstances as well as measurements of cellular senescence and chronic inflammation will be performed in a cohort of prostate cancer patients at baseline (before radiotherapy), at the end of radiotherapy and at follow-up intervals thereafter. The evaluation of aging-related biomarkers will include determination of markers of cellular senescence and markers of systemic inflammation. The correlation between genetic variants modulating telomere length and the risk of developing age-related phenotypes will also be analyzed.

Influence of Prostate Cancer Radiation on Aging

Influence of Radiotherapy on the Dynamics of Aging in Prostate Cancer Patients

In is not planned to make individual participant data (IPD) available to other researchers.

Functional decline measured by Activities of Daily Living examination (range, 0-6; high values indicate high functionality and improved outcome)

Functional decline measured by the Instrumental Activities of Daily Living examination (range, 0-8; high values indicate high functionality and improved outcome)

Cognitive disorder measured by the Mini-Mental State Examination (range, 0-30; high values indicate normal cognition and improved outcome)

Comorbidities measured by the Charlson comorbidity index (range, 0-37; high score indicates high rate of comorbidities and worse outcome)

Mental disorder measured by the Geriatric depression scale (range, 0-30; higher values indicate depression and worse outcome)

Mobility measured by the Timed up and go test (≥12 seconds to complete the Timed up and go test indicates mobility impairment and worse outcome)

Polypharmacy represents an aging related condition (high number of medication taken indicates worse outcome)

Medical University of Graz

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Chia-Lin Hsu

Chien-Tai Hsu

Kuan-Yu Chen, PHD

Kuan-Yu Chen, PhD

The investigators hypothesize that the age-adjusted telomere length in lung cancer patients before chemotherapy may be correlated to comorbidity status and predict outcome. The change of telomere length shortening after chemotherapy may relate to treatment side effect and treatment response.

Except chemotherapy, telomere shortening were also related to a variety of cellular stress, including hydrogen peroxide, UV, and x-irradiation, transforming growth factor-beta, overexpression of oncogenes such as Ha-Ras. The cellular stress induced telomere shortening and/or telomere dysfunction and promote accelerated senescence in normal and malignant cells. Oxidative stress, which presented in several chronic inflammatory diseases, such as atherosclerosis, coronary artery disease, and chronic obstructive airway disease, was also found to be correlated with telomere shortening.

The Roles of Age, Comorbidity, and Telomere Length in Lung Cancer Treatment and Prognosis

The clinical data, including age, gender, clinical presentation, performance status, disease stage at diagnosis, initial treatment modality, progression-free survival of initial treatment, and survival duration will be recorded. Blood sample collection, quality of life, and cognitive function assessment will be performed before chemotherapy, one and four weeks after initial chemotherapy for telomere length measurement. Telomere length is measured by quantitative polymerase chain reaction(qPCR). Patients' characteristics are compared with chi-square test. Progression-free survival and survival time are analyzed by Kaplan-Meier with log rank test.

National Taiwan University Hospital

Gland and Hormone Related Diseases

Thyroid Neoplasms

Thyroid Diseases

Pharmaceutical Solutions

All Drugs and Chemicals

Micronutrients

Anti-Infective Agents

Iodine

Cadexomer iodine

Fresh semen treated without irradiation before cryopreservation

cryopreserved semen without irradiation (n=60)

Pelvis scanning : acute irradiation (1 or 2 second) using low dose (n=30),

Bone scintigraphy : long irradiation (3h) using low dose (n=30),

Radioactive Iodine 131 therapy (RAT) applied for thyroid cancer : long irradiation (3h) using medium dose (n=60),

sperm will be frozen in Cryosperm® cryoprotectant medium (Origio). The samples will be packaged in previously identified high security straws (Cryobiosystem). Slow freezing of the straws will be carried out using the Nanodigicool® programmable device (Cryobiosystem).

Cryopreserved semen

sperm sample will be placed on the scanner's processing table to be exposed for 1 to 2 seconds. Several dose levels will then be made in order to limit the value of 17 mGy

Acute and low irradiation

sperm sample will be exposed to gamma radiation by adding a solution of Tc99m for 3 hours.

Long and low irradiation

sperm sample will be exposed to gamma radiation by adding a solution of I131 for 3 hours

Long and medium irradiation

Lise Laclautre, PharmD

Hanaé PONS-REJRAJI, PhD

Florence BRUGNON, MD, PhD

Solène VORILHON, MD, PhD

Cyril BOUCHE, PhD

Aurélie VEGA, PhD

Philippe VAGO, MD, PhD

Andreï TCHIRKOV, MD, PhD

Céline PEBREL-RICHARD, MD

Gaëlle SALAUN, MD, PhD

Lauren VERONESE, MD, PhD

Laetitia GOUAS, MD, PhD

Carole GOUMY, MD, PhD

Hanae PONS-REJRAJI, PhD

Differentiated thyroid cancer is the third cause of cancer in young men of childbearing age. Its treatment by irradiation with Radioactive Iodine 131 therapy (RAT) could alter spermatogenesis and result in azoospermia and permanent infertility. A preventive gametes cryopreservation was recommended before RAT, but without mentioning a period of teratogenic risk transmissible to the offspring. To date, RAT impact on human sperm nucleus is poorly known or even unknown, notably on telomere length.

Our objective is to define RAT effects on human sperm nucleus by in vitro irradiation exposure of human spermatozoa to mimicking that of the gonads in the context of irradiation with iodine131 used for thyroid cancer. We will analyze standard sperm parameters, major DNA alterations and telomere length using molecular and cellular assays. Nucleus morphology and chromatin organization will also be analyzed using 3D bio-imaging. This study will permit to optimize the indications for the preservation of fertility.

Our main objective is to measure the in vitro impact of irradiation treatment on sperm nuclear quality such as DNA fragmentation and oxidation, chromatin condensation and organisation, nucleus morphology and notably sperm telomere length (STL).

The secondary objectives are :

* to measure RAT impact on sperm parameters (vitality, motility and morphology)
* to measure the impact of cryopreservation on chromatin organisation and nucleus morphology
* to evaluate RAT impact on human sperm cells in comparison with cryopreservation
* to evaluate the impact of different doses and types of irradiation on human sperm cells
* to establish relations between potential alterations of standards sperm parameters (vitality, motility and morphology) and nuclear sperm parameters (DNA fragmentation and oxidation, chromatin condensation and organisation, nucleus morphology and STL.

Our final goal is to provide a significant improvement of men fertility diagnosis and optimize our fertility preservation practices.

To this end, we will expose ejaculated human spermatozoa (n = 90) at different (low and moderate) doses of gamma or X photons to mimic gonads irradiation. Absorbed doses by the samples were calculated using the GATE Monte Carlo platform (version 8.2). Experiment geometry settings were modelled as three dimension voxelized volumes inside the software by assigning a shape, size, distance and density for all the volumes created. All measurements will be made on surplus samples from men undergoing routine semen analysis at the Center for Reproductive Medicine, after receiving their written informed consent. Semen samples are collected and subdivided into 3 arms to analyse sperm quality after:

* irradiation exposure (3 conditions);
* a freezing- thawing cycle;
* fresh state: negative control without treatment.

Before (fresh state) and after each treatment we will analyse:

* standard semen parameters (vitality, motility and morphology) in accordance with WHO, 2010;
* STL using Flow FISH, q-PCR and q-FISH;
* chromatin condensation (chromomycin A3);
* DNA oxidization (8-OHdG residues);
* DNA fragmentation (TUNEL);
* 3D nucleus structure using 3D bio-imaging.

Impact of Ionizing Treatment on the Nuclear Structure of Human Spermatozoa.

To achieve this goal, we will expose human sperm to an irradiation dose of I131 to mimic the irradiation of gonads and sperm. Reliquat of semen will be cryopreserved (control condition). After thawing, the same sample will be subdivised into 2 groups in order to analyze the sperm quality :

* After an irradiation dose of I131
* After a cryopreservation

All measurements are made on surplus samples from men undergoing routine semen analysis at the Center for Reproductive Medicine, after receiving their written informed consent. Semen samples will be collected and subdivided into 3 arms to analyse sperm quality after:

* irradiation exposure (3 conditions);
* a freezing- thawing cycle;
* fresh state: negative control without treatment.

Before (fresh state) and after each treatment we will analyse:

* STL using Flow FISH, q-PCR and q-FISH;
* chromatin condensation (chromomycin A3);
* DNA oxidization (8-OHdG residues);
* DNA fragmentation (TUNEL);
* 3D nucleus structure using 3D bio-imaging.

All measurements are made on surplus samples from men undergoing routine semen analysis at the Center for Reproductive Medicine, after receiving their written informed consent. Semen samples will be collected and subdivided into 3 arms to analyse sperm quality after:

* irradiation exposure (3 conditions);
* a freezing- thawing cycle;
* fresh state: negative control without treatment.
* a freezing- thawing cycle;
* fresh state: negative control without treatment. Before (fresh state) and after each treatment we will analyse standard semen parameters (vitality, motility and morphology) in accordance with WHO, 2010;

We will compare effects induced by RAT and cryopreservation on each sperm sample. In order to limit the bias, for each irradiation treatment, a sample of sperm cells (cryopreserved control) will be treated under identical conditions.

All measurements are made on surplus samples from men undergoing routine semen analysis at the Center for Reproductive Medicine, after receiving their written informed consent. Semen samples will be collected and subdivided into 3 arms to analyse sperm quality after:

* irradiation exposure (3 conditions);
* a freezing- thawing cycle;
* fresh state: negative control without treatment.

Irradiation exposure will be realised under 3 conditions:

* acute and low irradiation : sperm sample will be placed on the scanner's processing table to be exposed for 1 to 2 seconds. Several dose levels will then be made in order to limit the value of 17 mGy.
* long and low irradiation: sperm sample will be exposed to gamma radiation by adding a solution of Tc99m for 3 hours.
* long and medium irradiation : sperm sample will be exposed to gamma radiation by adding a solution of I131 for 3 hours

We will correlate the effects induced by on vitality, motility and morphology and nuclear sperm parameters (DNA fragmentation and oxidation, chromatin condensation and organisation, nucleus morphology and STL.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Influence of Prostate Cancer Radiation on Aging	NCT04321187	Prostate Cancer Aging Disorder Radiotherapy; C... Inflammation		70 Years - 100 Years	Medical University of Graz
Influence of Prostate Cancer Radiation on Aging	NCT04321187	Prostate Cancer Aging Disorder Radiotherapy; C... Inflammation		70 Years - 100 Years	Medical University of Graz
The Roles of Age, Comorbidity, and Telomere Length in Lung Cancer Treatment and Prognosis	NCT01963533	Lung Cancer		20 Years -	National Taiwan University Hospital
Influence of Prostate Cancer Radiation on Aging	NCT04321187	Prostate Cancer Aging Disorder Radiotherapy; C... Inflammation		70 Years - 100 Years	Medical University of Graz
Impact of Ionizing Treatment on the Nuclear Structure of Human Spermatozoa.	NCT04715828	Sperm Preservat... Irradiated Seme...	Cryopreserved s... Acute and low i... Long and low ir... Long and medium...	18 Years - 45 Years	University Hospital, Clermont-Ferrand
The Roles of Age, Comorbidity, and Telomere Length in Lung Cancer Treatment and Prognosis	NCT01963533	Lung Cancer		20 Years -	National Taiwan University Hospital
Impact of Ionizing Treatment on the Nuclear Structure of Human Spermatozoa.	NCT04715828	Sperm Preservat... Irradiated Seme...	Cryopreserved s... Acute and low i... Long and low ir... Long and medium...	18 Years - 45 Years	University Hospital, Clermont-Ferrand

Spots Global Cancer Trial Database for telomere length