Personalizing Medicine in Geriatric Oncology

Minimizing toxicity while maximizing efficacy is a common goal in the treatment of any condition but its importance is underscored in the discipline of oncology because of the serious nature of many chemotherapeutic toxicities and the risk of cancer recurrence or disease progression. The challenge of achieving an optimal therapeutic index is especially augmented in the elderly population because of age-related metabolism changes and interacting concurrent medications. Additional factors, such as germline mutations in drug-metabolizing enzymes and other pharmacogenomic alterations, may have more pronounced effects in elderly patients, given their predisposition to altered pharmacokinetics and pharmacodynamics with resulting increased risk of toxicity. Examples of the possible interplay of these factors will be discussed using tamoxifen, paclitaxel, codeine, and fluorouracil as starting points. Limited participation of the elderly in many cancer trials, especially trials assessing drug exposure, makes much knowledge on the interaction of these patient and environmental factors speculative in nature but presents an opportunity for future research to achieve better optimization of chemotherapeutic agents in the elderly.

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Abstract T P136: Potential Contributors to the Declining Impact of Stroke Risk Factors with Age: Implications for Stroke Epidemiology in the Elderly

Stroke ◽

10.1161/str.45.suppl_1.tp136 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

George Howard ◽

Mary Cushman ◽

Maciej Banach ◽

Brett M Kissela ◽

David C Goff ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Stroke Risk ◽

Multivariable Analysis ◽

The Elderly ◽

Stroke Risk Factors ◽

Age Related ◽

Increased Risk ◽

The Impact ◽

Age Related Changes

Purpose: The importance of stroke research in the elderly is increasing as America is “graying.” For most risk factors for most diseases (including stroke), the magnitude of association with incident events decreases at older ages. Potential changes in the impact of risk factors could be a “true” effect, or could be due to methodological issues such as age-related changes in residual confounding. Methods: REGARDS followed 27,748 stroke-free participants age 45 and over for an average of 5.3 years, during which 715 incident strokes occurred. The association of the “Framingham” risk factors (hypertension [HTN], diabetes, smoking, AFib, LVH and heart disease) with incident stroke risk was assessed in age strata of 45-64 (Young), 65-74 (Middle), and 75+ (Old). For those with and without an “index” risk factor (e.g., HTN), the average number of “other” risk factors was calculated. Results: With the exception of AFib, there was a monotonic decrease in the magnitude of the impact across the age strata, with HTN, diabetes, smoking and LVH even becoming non-significant in the elderly (Figure 1). However, for most factors, the increasing prevalence of other risk factors with age impacts primarily those with the index risk factor absent (Figure 2, example HTN as the “index” risk factor). Discussion: The impact of stroke risk factors substantially declined at older ages. However, this decrease is partially attributable to increases in the prevalence of other risk factors among those without the index risk factor, as there was little change in the prevalence of other risk factors in those with the index risk factor. Hence, the impact of the index risk factor is attenuated by increased risk in the comparison group. If this phenomenon is active with latent risk factors, estimates from multivariable analysis will also decrease with age. A deeper understanding of age-related changes in the impact of risk factors is needed.

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Abstract P329: White Matter Score Does Not Predict Post-tPA Hemorrhage in Elderly Patients Evaluated Acutely via Telestroke

Stroke ◽

10.1161/str.52.suppl_1.p329 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Muhammad Bilal Tariq ◽

Shekhar Khanpara ◽

Eliana Bonfante Mejia ◽

Liang Zhu ◽

Christy T Ankrom ◽

...

Keyword(s):

White Matter ◽

Elderly Patients ◽

The Elderly ◽

Periventricular White Matter ◽

Severe Stroke ◽

Age Related ◽

Increased Risk ◽

Symptomatic Intracranial Hemorrhage ◽

Relationship Of ◽

Patient Presentation

Background: While tPA may be safe in the elderly, increasing age appears to augment risk of post-tPA symptomatic intracranial hemorrhage (sICH). Age-related white matter changes (ARWMC) are associated with increased sICH. Patients evaluated for acute ischemic stroke (AIS) via telestroke (TS) may not have access to MRI to allow incorporation of microbleeds in tPA decisions. We assessed if increased CT-based ARWMC was associated with increased sICH in elderly patients. Methods: Patients 80 years and older who received tPA for AIS at spoke hospitals were selected from our TS network registry from 9/2015 to 12/2018. TS spoke CT scans from patient presentation were reviewed by three of the authors for periventricular white matter (PWMC) and deep white matter (DWMC) changes. Total ARWMC score, based on the Fazekas score, was collected. Total ARWMC score was either mild (0-2), moderate (3-4), or severe (5-6). PWMC and DWMC were either mild (0-1) or moderate-severe (2-3). Logistic regression adjusted for age, sex, race, ethnicity, NIHSS and premorbid mRS was used to analyze relationship of ARWMC scores with sICH and patient-outcomes. Results: Of 241 patients, median age overall was 86 years (IQR 83-90), and 66% were female. The overall median ARWMC score was 3 (IQR 2-5). Regression analysis showed that more severe ARWMC scores did not lead to higher frequency of post-tPA ICH (moderate OR 0.57, CI 0.19-1.71; severe OR 1.32, CI 0.48-3.65) including sICH (moderate OR 0.78, CI 0.21-2.94; severe OR 2.09, CI 0.62-7.02). Similarly, severe PWMC and DWMC were not associated with increased risk of post-tPA ICH (PWMC OR 1.31, CI 0.51-3.38; DWMC OR 1.25, CI 0.52-3.01), including sICH (PWMC OR 1.61, CI 0.51-5.08; DWMC OR 1.81, CI 0.65-5.01). In our cohort, older patients had no difference in hemorrhage (ICH OR 0.93 CI 0.85-1.00: sICH OR 0.95 CI 0.86-1.04), and patients with less severe stroke were more likely to have hemorrhage (ICH OR 1.06 CI 1.02-1.10; sICH OR 1.08 CI 1.03-1.13). IRR among the CT scan readers was moderate (k=0.504). Conclusions: ARWMC scores were not associated with post-tPA ICH in the elderly. Our analysis lends support for the use of tPA despite severity of white matter disease. ARWMC should not be used to assist in tPA decision-making in elderly patients via telestroke.

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Regenerative Medicine Approaches for Age-Related Muscle Loss and Sarcopenia: A Mini-Review

Gerontology ◽

10.1159/000479278 ◽

2017 ◽

Vol 63 (6) ◽

pp. 580-589 ◽

Cited By ~ 16

Author(s):

Juan Diego Naranjo ◽

Jenna L. Dziki ◽

Stephen F. Badylak

Keyword(s):

Regenerative Medicine ◽

Treatment Options ◽

The Elderly ◽

Signaling Molecules ◽

Current Treatment ◽

Muscle Physiology ◽

Age Related ◽

Increased Risk ◽

And Function ◽

Age Related Changes

Sarcopenia is a complex and multifactorial disease that includes a decrease in the number, structure and physiology of muscle fibers, and age-related muscle mass loss, and is associated with loss of strength, increased frailty, and increased risk for fractures and falls. Treatment options are suboptimal and consist of exercise and nutrition as the cornerstone of therapy. Current treatment principles involve identification and modification of risk factors to prevent the disease, but these efforts are of limited value to the elderly individuals currently affected by sarcopenia. The development of new and effective therapies for sarcopenia is challenging. Potential therapies can target one or more of the proposed multiple etiologies such as the loss of regenerative capacity of muscle, age-related changes in the expression of signaling molecules such as growth hormone, IGF-1, myostatin, and other endocrine signaling molecules, and age-related changes in muscle physiology like denervation and mitochondrial dysfunction. The present paper reviews regenerative medicine strategies that seek to restore adequate skeletal muscle structure and function including exogenous delivery of cells and pharmacological therapies to induce myogenesis or reverse the physiologic changes that result in the disease. Approaches that modify the microenvironment to provide an environment conducive to reversal and mitigation of the disease represent a potential regenerative medicine approach that is discussed herein.

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Low vitamin D status is associated with hearing loss in the elderly: a cross-sectional study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa310 ◽

2020 ◽

Author(s):

Betsy Szeto ◽

Chris Valentini ◽

Anil K Lalwani

Keyword(s):

Vitamin D ◽

Hearing Loss ◽

Low Frequency ◽

The Elderly ◽

Vitamin D Status ◽

Total Calcium ◽

Mineral Density ◽

Cross Sectional ◽

Age Related ◽

Increased Risk

ABSTRACT Background The elderly are at increased risk of both hearing loss (HL) and osteoporosis. Bone mineral density (BMD) has been putatively linked to HL. However, the roles of serum calcium concentrations and vitamin D status have yet to be elucidated. Objectives The purpose of this study was to examine the relation between vitamin D status, parathyroid hormone (PTH), total calcium, BMD, and HL in a nationally representative sample of elderly adults. Methods Using the NHANES (2005–2010), audiometry and BMD data of 1123 participants aged ≥70 y were analyzed in a cross-sectional manner. HL was defined as pure tone averages >25 dB HL at 500, 1000, and 2000 Hz (low frequency); 500, 1000, 2000, and 4000 Hz (speech frequency); and 3000, 4000, 6000, and 8000 Hz (high frequency) in either ear. Multivariable logistic regression was used to examine the relation between HL and total 25-hydroxyvitamin D [25(OH)D], PTH, total calcium, and BMD, adjusting for covariates. Results In multivariable analyses, total 25(OH)D < 20 ng/mL was found to be associated with greater odds of low-frequency HL (OR: 2.02; 95% CI: 1.28, 3.19) and speech-frequency HL (OR: 1.96; 95% CI: 1.12, 3.44). A 1-unit decrease in femoral neck BMD (OR: 4.55; 95% CI: 1.28, 16.67) and a 1-unit decrease in total spine BMD (OR: 6.25; 95% CI: 1.33, 33.33) were found to be associated with greater odds of low-frequency HL. Serum PTH and total calcium were not found to be associated with HL. Conclusions In the elderly, low vitamin D status was associated with low-frequency and speech-frequency HL. Low vitamin D status may be a potential risk factor for age-related HL.

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Sa1336 PREOPERATIVE CHOLANGITIS IN PATIENTS WITH PANCREATIC HEAD ADENOCARCINOMA IS ASSOCIATED WITH AN INCREASED RISK OF CANCER RECURRENCE AFTER PANCREATICODUODENECTOMY

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2019.03.193 ◽

2019 ◽

Vol 89 (6) ◽

pp. AB214

Author(s):

Thomas J. Wang ◽

Eli P. Darnell ◽

Melissa A. Lumish ◽

Yasmin G. Hernandez-Barco ◽

Maximilian Weniger ◽

...

Keyword(s):

Pancreatic Head ◽

Cancer Recurrence ◽

Increased Risk ◽

Risk Of Cancer

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Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium

Genetics ◽

10.1534/genetics.119.302268 ◽

2019 ◽

Vol 212 (3) ◽

pp. 655-665 ◽

Cited By ~ 1

Author(s):

Joseph Christopher ◽

Ann-Sofie Thorsen ◽

Sam Abujudeh ◽

Filipe C. Lourenço ◽

Richard Kemp ◽

...

Keyword(s):

Stem Cell ◽

Fold Increase ◽

Mutation Rates ◽

Wild Type ◽

Cell Dynamics ◽

Tissue Samples ◽

Age Related ◽

Increased Risk ◽

Microsatellite Mutation ◽

Risk Of Cancer

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10−2) compared to wild-type epithelium (6.2 × 10−5).

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Subjective Memory Complaints and Mild Cognitive Impairment

European Psychiatry ◽

10.1016/s0924-9338(09)71326-4 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1 ◽

Cited By ~ 2

Author(s):

M. Simoes ◽

L.C. Castro ◽

O. Ribeiro ◽

T. Salgado ◽

C. Paz

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

The Elderly ◽

Future Research ◽

Older Individuals ◽

Subjective Memory Complaints ◽

Subjective Memory ◽

Cross Sectional ◽

Memory Complaints ◽

Increased Risk

Background:Subjective Memory Complaints (SMC) are common in clinical practice. the clinical significance of these subjective complaints among older individuals is not well understood.Aim:To study and discuss the association between SMC and MCI, underlining the importance of an adequate clinical assessment of SMC in the elderly.Methods:Review of the literature.Results:There is no consistent definition of SMC in the literature. Some prospective studies showed an association with objective memory impairments, conceptualizing SMC as a Pre-Mild Cognitive Impairment. SMC are also currently considered to be a core feature of Mild Cognitive Impairment (MCI). Cross-sectional studies and longitudinal studies showed conflicting results concerning the association between SMC and MCI.Discussion:The understanding of the predictive value of SMC in cognitive decline is still poorly understood. It is important to define criteria aimed to increase specificity of memory complaints, allowing an earlier identification of populations with higher risk of MCI. Future research on this complex association is important to identify SMC individuals at increased risk of conversion to MCI and dementia.

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Rapidly Shifting Concepts Regarding Androgens and Prostate Cancer

The Scientific World JOURNAL ◽

10.1100/tsw.2009.80 ◽

2009 ◽

Vol 9 ◽

pp. 685-690 ◽

Cited By ~ 8

Author(s):

Abraham Morgentaler

Keyword(s):

Prostate Cancer ◽

Cancer Recurrence ◽

Serum Testosterone ◽

High Serum ◽

Prior History ◽

Minimal Risk ◽

Increased Risk ◽

History Of ◽

Dramatic Shift ◽

Risk Of Cancer

There has been a recent dramatic shift in our understanding of the relationship between androgens and prostate cancer (PCa). Whereas for several decades it had been assumed that higher serum testosterone (T) concentrations would lead to ever-greater PCa growth, current literature indicates that PCa growth is unaffected by changes in serum T throughout most of the naturally occurring range. A Saturation Model has been proposed to explain how prostate tissue can be exquisitely sensitive to changes in serum T at the very low end of the concentration range, but appears indifferent to such changes above the near-castrate range. This has special applicability to T-deficient men, since this means that T therapy may not be nearly as risky as once assumed. Indeed, one of the more interesting changes over the last several years has been the growing acceptance of the use of T therapy in men with a prior history of PCa, with early data indicating minimal risk of cancer recurrence or progression. Provocative new evidence suggests that it is not high serum T that is problematic for PCa, butlowserum T that is associated with worrisome cancer features and outcomes, such as high Gleason score, advanced stage of presentation, and increased risk of biochemical recurrence after surgery. It will be interesting to see what changes will occur in this rapidly changing field over the next several years.

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Incidence of Veno-Occlusive Disease with IV in Busulfan Children Is Higher Than Expected: Preliminary Results of the VOD-DF Trial.

Blood ◽

10.1182/blood.v114.22.3344.3344 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3344-3344

Author(s):

Selim Corbacioglu ◽

Simone Cesaro ◽

Maura Faraci ◽

Bernd Gruhn ◽

Jaap Jan Boelens ◽

...

Keyword(s):

Renal Failure ◽

Respiratory Failure ◽

Early Death ◽

Therapeutic Index ◽

Eligibility Criteria ◽

Age Related ◽

Increased Risk ◽

Life Threatening ◽

Intent To Treat ◽

Children Development

Abstract Abstract 3344 Poster Board III-232 Background: Hepatic VOD is a life-threatening complication following SCT with a high incidence in children. Development of VOD is one of the most common causes of early death after SCT. Busulfan (BU), an alkylating agent with a very narrow therapeutic index is a commonly used conditioning agent in pediatric stem cell transplantation (SCT) with a strong correlation between AUC and both efficacy and toxicity. Oral BU (poBU) has significant age-related and interpatient pharmacokinetic differences and was linked with an increased risk for VOD. IV busulfan (ivBU) yielded promising results in some studies to be associated with low toxicity profile, especially with a reduced incidence of VOD. Methods: Patients <18 years with myeloablative SCT were included in a prospective multicenter phase II/III trial to evaluate the efficacy of Defibrotide (DF). Eligibility criteria included conditioning with BU (iv and po) and melphalan (MEL). Pts were prospectively randomized to the control arm or to receive DF. Primary endpoint was the incidence of hepatic VOD by D+30 using modified Seattle criteria (2 or more of the following: bilirubin > 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by ultrasound. A blinded IRC of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. The additional analysis of the influence of BU on VOD was not planned and is therefore explorative. Results: 360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all pts who signed informed consent (n=356). 251 (71%) pts from the ITT population were conditioned with BU (64% ivBU; 36% poBU). 202 (55%) were treated with BU and Melphalan (MEL) (60% ivBU; 40% poBU). In 49 (14%) BU was used without MEL (80% ivBU; 20% poBU). In children <2yrs 44 (12%) were conditioned with BU/MEL (59% ivBU; 41% poBU) and 26 (7%) were conditioned without MEL (85% ivBU; 15% poBU). The median age of patients with iv BU was 3.65 yrs and 5,13 yrs with poBU; 28% infants, 50% children (ages 2-11 yrs) and 22% adolescents (evenly distributed). 45% female, 55% male (evenly distributed). Allo-SCT was performed in 69% with ivBU and 46% with poBU (remaining with auto-SCT). The diagnoses were evenly distributed between poBU and ivBU. Except in AML 18% were conditioned with ivBU and 32% with poBU. Preexisting liver disease was present in 23% ivBU and 9% poBU pts, of which 46% (17/37) ivBU and 37% (3/8) poBU had elevated transaminases. Overall VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The overall incidence of VOD in pts treated with BU was 18%. VOD was diagnosed in 24% ivBU vs 8% poBU pts. In pts treated with BU/MEL VOD was diagnosed in 16%. VOD in ivBU/MEL was 21% (26) vs 8% (6) in poBU/MEL. In BU without MEL VOD was diagnosed in 27% (13/49). 31% (12/39) in ivBU pts and 10% (1/10) in poBU pts. In infants treated with BU/MEL the incidence of VOD in the ivBU group was 23% (6/26) and 11% (2/18) in poBU. In BU without MEL in infants the incidences were 41% (9/22) ivBU versus none (0/4) in poBU. The diagnosis of VOD independent of severity was associated with a higher mortality and equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Respiratory failure was observed in 10% (16/161) of ivBU vs 2% (2/90) of poBU pts (9% (11/122) vs 1% (1/80) iv vs po BU/MEL); renal failure in 5% (8/161) ivBu vs 1% (1/90) poBU (5% (6/122) vs none in iv vs po BU/MEL). The incidence of multi-organ-failure (MOF) by day +100 was 12% (19/161) in ivBU vs 3% (3/90) in poBU (p=0.022). Compared to all other pts the risk to develop VOD in infants treated with allo-SCT and ivBU is 2.4 times higher (p=0.003). Conclusions: Although the scope of this trial was not to assess the influence of BU on the incidence of VOD and there was an imbalanced distribution of liver diseases and a potential bias for other risk factors the incidence of VOD in ivBU was unexpectedly high especially in infants. Inasmuch this is due to a high interpatient variability of the AUC should be explored prospectively. Disclosures: Corbacioglu: Gentium S.p.A.: Consultancy, Research Funding.

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Oxidative stress and cancer: have we moved forward?

Biochemical Journal ◽

10.1042/bj20061131 ◽

2006 ◽

Vol 401 (1) ◽

pp. 1-11 ◽

Cited By ~ 765

Author(s):

Barry Halliwell

Keyword(s):

Oxidative Damage ◽

Oxidation Products ◽

Cancer Development ◽

Malignant Tumours ◽

Age Related ◽

Dna Base ◽

Increased Risk ◽

Defence Enzymes ◽

Risk Of Cancer

‘Reactive species’ (RS) of various types are formed in vivo and many are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of RS can promote the development of malignancy, and the ‘normal’ rates of RS generation may account for the increased risk of cancer development in the aged. Indeed, knockout of various antioxidant defence enzymes raises oxidative damage levels and promotes age-related cancer development in animals. In explaining this, most attention has been paid to direct oxidative damage to DNA by certain RS, such as hydroxyl radical (OH•). However, increased levels of DNA base oxidation products such as 8OHdg (8-hydroxy-2′-deoxyguanosine) do not always lead to malignancy, although malignant tumours often show increased levels of DNA base oxidation. Hence additional actions of RS must be important, possibly their effects on p53, cell proliferation, invasiveness and metastasis. Chronic inflammation predisposes to malignancy, but the role of RS in this is likely to be complex because RS can sometimes act as anti-inflammatory agents.

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