Hospitalisation and adverse drug events in a geriatric oncology setting: A systematic review of the literature.

BACKGROUND: Geriatric Oncology is a specialty where a multidisciplinary approach can address the unmet needs of older adults with cancer. Older adults are at increased risk of adverse drug events (ADE) due to age-related changes in pharmacokinetics and pharmacodynamics, increasing treatment complexity, and medication burden. OBJECTIVES: To review the literature to determine the incidence of unplanned hospitalisation due to ADE for all medications, both systemic anticancer therapy (SACT) and non-SACT medications. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search included the following databases: PubMed, CINAHL, and Embase. A manual search of Scopus was then performed. Study quality was assessed using the Cochrane Handbook for Systematic Reviews of Interventions, Mixed Methods Appraisal Tool (MMAT) and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. RESULTS: Overall, three studies were included. One observational study reported 19 % of unplanned hospital admissions due to ADE in patients aged ≥70 years with cancer. The first retrospective study reported 24 % of unplanned hospital admissions are due to ADE in patients aged ≥70 years with cancer, and the second retrospective study reported 26 % of patients with metastatic melanoma treated with immune checkpoint inhibitors had an unplanned hospital admission due to an ADE. CONCLUSION: There is a paucity of studies assessing unplanned hospitalisation due to ADE in older adults with cancer. Future studies are needed and should account for the reporting of potential ADE relative to supportive care, ancillary medications, and indeed chronic medications used to treat long-standing comorbidities.

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

Statin use in older adults with cancer - Experience from a dedicated geriatric oncology service.

INTRODUCTION: The increase in statin use, since their introduction, has been rapid and the broadening of indications has occurred seemingly without restriction. Once established on statin therapy, there is sparse research on discontinuation. Trials do not often address benefit in later life, or the impact of a life-limiting diagnosis. Data on primary prevention suggest that 100 patients need treatment for 2.5 years to prevent one major adverse cardiovascular event. Acknowledging this, we sought to determine the use of statins in a cohort of older adults with cancer, to highlight prevalence, and suggest a role for deprescribing. MATERIALS AND METHODS: Data were retrospectively collected from a prospectively maintained database of patients attending a single centre Geriatric Oncology clinic. Data collected included sex, age, cancer type and stage, systemic anti-cancer therapy (SACT) recommendation, comorbidities, non-SACT medications, and overall survival. For those receiving statin therapy, data were separated into primary prevention and stage IV cancer. RESULTS: In the group studied (n = 230), 135 (59%) were prescribed a statin, with 79 (58%) for primary prevention. Ninety-three (40%) had stage IV cancer. Of the 230 patients, 134 (58%) were recommended SACT. Within the primary prevention group, the median age was 79 years. Twenty-seven patients (34%) had stage III disease, while 36 (46%) had stage IV disease. Thirteen (16%) had diabetes mellitus. The median number of medications was seven (Interquartile range 5). Fifty patients (63%) were recommended SACT. In terms of survival, 31 (50%) were alive at one year, 18 (29%) alive at two years, and 14 (23%) alive beyond two and a half years. Within the stage IV disease group, 59 out of 93 (63%) were receiving statin therapy; 35 (59%) for primary prevention and seven (8%) for diabetes mellitus. Fifty-eight (63%) were recommended SACT. Twenty-four (29%) were alive at one year, 17 (21%) alive at two years, and 13 (16%) alive beyond two and a half years. DISCUSSION: Statin therapy is prevalent and continues into older age. Available data regarding statin therapy in older adults and survival seen in this study support deprescribing in primary prevention and life-limiting illness, such as stage IV cancer.

Ageing-related considerations for medication used in supportive care in cancer.

Both randomized controlled trials (RCTs) and retrospective studies have shown that a comprehensive geriatric assessment (CGA) prior to a patient commencing systemic anti-cancer therapy (SACT) results in improved quality of life outcomes and is associated with a decreased risk of grade 3-5 toxicity; however, data are lacking in relation to adverse drug events (ADE) associated with supportive care medications. Supportive care medications are prescribed as prophylactic agents in a SACT regimen, for management of treatment related toxicity and for symptoms caused by the disease itself. While necessary, the commencement of SACT and supportive medications may cause, or exacerbate, a significant drug burden in older patients, some of whom may have existing comorbidities. For many medications, older adults are underrepresented in pharmacokinetic and pharmacodynamic modelling studies. In this article we will review ageing-related changes in pharmacokinetics and pharmacodynamics, as well as how these changes may impact supportive care medications. Additional considerations for prescribing these medications in older adults with cancer, such as polypharmacy, potentially inappropriate medications, drug-drug interactions, and anticholinergic burden, as well as ageing-related considerations and recommendations for supportive care medications commonly used in older adults with cancer are also reviewed.

Comprehensive pharmacological geriatric assessment compared to usual care in an older adult with cancer in the absence of polypharmacy.

INTRODUCTION: Medication reconciliation as part of a Comprehensive Geriatric Assessment by a specialist pharmacist is a process that has been shown to be beneficial in terms of medication adherence in patients taking oral anticancer medication and potentially cost-effective in cancer patients. Medication review guidelines in older adults with cancer suggest using polypharmacy (≥ 5 medications) as an indication for medication review in older adults with cancer. CASE REPORT: We present a case where a medication review as part of a Comprehensive Geriatric Assessment in the absence of polypharmacy resulted in two pharmacist interventions when standard care resulted in no intervention. A 71-year-old male prescribed capecitabine for rectal cancer had a medication reconciliation done as standard care before starting an oral anticancer medication. He then proceeded to get a medication review as part of a Comprehensive Geriatric Assessment and was deemed to have a potentially excessive anticholinergic burden and underprescribed gastro protection. This case is interesting as it occurred in a patient who would not have met the current inclusion criteria for a medication review as part of a Comprehensive Geriatric Assessment. MANAGEMENT AND OUTCOME: As a result of the Comprehensive Geriatric Assessment, a letter was written to the patient's general practitioner, recommending a change to anti-depressant therapy to optimise anticholinergic burden, as well as introducing a proton-pump inhibitor upon completion of the Capecitabine protocol concurrent with radiotherapy, to confer gastro-protection against the antidepressant medication, as per the START criteria. Upon discharge from medical oncology, neither of the changes had been adopted by the patient's general practitioner. This highlights one of the challenges facing clinical pharmacists in an outpatient setting, where evidence-based recommendations are not always implemented as care transitions from tertiary to primary care. CONCLUSION: Comprehensive Geriatric Assessment is a process that identifies potential issues in older adults with cancer that aren't identified with standard medication review. This is also evident for medication reviews as part of a Comprehensive Geriatric Assessment, and where resources allow, and recommendations are likely to be accepted, it should be offered to all older adults with cancer. Pharmacists are still faced with challenges in implementing recommendations from medication reviews, particularly in healthcare systems where pharmacist prescribing has yet to be introduced.

Hospitalization due to adverse drug events in older adults with cancer: A retrospective analysis.

INTRODUCTION: Geriatric oncology is a rapidly evolving field of practice, where comprehensive geriatric assessments (CGA) and multidisciplinary team (MDT) input have the potential to improve patient outcomes. Polypharmacy and potential drug interactions (PDI) have been associated with an increased risk of adverse outcomes in older adults with cancer, receiving systemic anti-cancer therapy (SACT). Our aim was to assess the incidence of unplanned hospitalization in older adults with cancer attending medical oncology outpatient clinics and to determine whether an unplanned hospitalization was potentially due to an adverse drug event (ADE). MATERIALS AND METHODS: We identified patients who attended a medical oncology outpatient appointment from January 1 to March 31, 2018. Medical records were examined to identify any unplanned hospital admissions between the clinic visit date and three and six months after initial clinic visit. Incidences of unplanned hospitalization were assessed to determine if an ADE potentially occurred. RESULTS: Data collected from 174 patients were analyzed. Over half (57%) were female, median age was 75 years and 53% had a favorable performance status. The most common malignancies were gastrointestinal (GI) at 31% (n = 54), breast 29% (n = 51), and genitourinary 22% (n = 37). Seventy-two percent had advanced disease (stage III/IV) and 61% had systemic therapy (SACT and hormonal therapy). Polypharmacy (≥5 medications) was observed in 77% of patients. The total number of admissions at six months was 99, with 55% of these potentially due to an ADE. On multivariate analysis breast cancer (p ≤0.001), lung cancer (p = 0.034), performance status (p ≤0.001), monochemotherapy (p = 0.012), polychemotherapy (p ≤0.001), and radiotherapy (p = 0.048) were independent predictors of unplanned hospitalization. Breast cancer (p = 0.008), GI cancer (p = 0.019), monochemotherapy (p = 0.039), and polychemotherapy (p ≤0.001) were independent predictors of unplanned hospitalization due to ADE on multivariate analysis. DISCUSSION: We observed that older adults with cancer have a high risk of unplanned hospitalization due to ADE. Medication review as part of a CGA in newly diagnosed older adults with cancer by a clinical pharmacist is recommended. This may identify opportunities to avoid medications that could potentially lead to unplanned hospitalization.

Mito-SiPE is a sequence-independent and PCR-free mtDNA enrichment method for accurate ultra-deep mitochondrial sequencing.

The analysis of somatic variation in the mitochondrial genome requires deep sequencing of mitochondrial DNA. This is ordinarily achieved by selective enrichment methods, such as PCR amplification or probe hybridization. These methods can introduce bias and are prone to contamination by nuclear-mitochondrial sequences (NUMTs), elements that can introduce artefacts into heteroplasmy analysis. We isolated intact mitochondria using differential centrifugation and alkaline lysis and subjected purified mitochondrial DNA to a sequence-independent and PCR-free method to obtain ultra-deep (>80,000X) sequencing coverage of the mitochondrial genome. This methodology avoids false-heteroplasmy calls that occur when long-range PCR amplification is used for mitochondrial DNA enrichment. Previously published methods employing mitochondrial DNA purification did not measure mitochondrial DNA enrichment or utilise high coverage short-read sequencing. Here, we describe a protocol that yields mitochondrial DNA and have quantified the increased level of mitochondrial DNA post-enrichment in 7 different mouse tissues. This method will enable researchers to identify changes in low frequency heteroplasmy without introducing PCR biases or NUMT contamination that are incorrectly identified as heteroplasmy when long-range PCR is used.

Chemotherapy Toxicity in Older Adults Optimized by Geriatric Assessment and Intervention: A Non-Comparative Analysis.

The Comprehensive Geriatric Assessment (CGA) is recommended to guide treatment choices in older patients with cancer. Patients ≥ 70 years referred to our oncology service with a new cancer diagnosis are screened using the G-8. Patients with a score of ≤14 are eligible to attend the Geriatric Oncology and Liaison (GOAL) Clinic in our institution, with referral based on physician discretion. Referred patients undergo multidimensional assessments at baseline. CGA domains assessed include mobility, nutritional, cognitive, and psychological status. Chemotherapy toxicity risk is estimated using the Cancer Aging and Research Group (CARG) calculator. We undertook a retrospective analysis of patients attending the GOAL clinic over a 30-month period to April 2021. The objective was to determine rates of treatment dose modifications, delays, discontinuation, and unscheduled hospitalizations as surrogates for cytotoxic therapy toxicity in these patients. These data were collected retrospectively. Ninety-four patients received chemotherapy; the median age was 76 (70-87) and 45 were female (48%). Seventy-five (80%) had an ECOG PS of 0-1. Seventy-two (77%) had gastrointestinal cancer, and most had stage III (47%) or IV (40%) disease. Chemotherapy with curative intent was received by 51% (n = 48) and 51% received monotherapy. From the CGA, the median Timed Up and Go was 11 s (7.79-31.6), and 90% reported no falls in the prior 6 months. The median BMI was 26.93 (15.43-39.25), with 70% at risk or frankly malnourished by the Mini Nutritional Assessment. Twenty-seven (29%) patients had impaired cognitive function. Forty-three (46%) had a high risk of toxicity based on the baseline CARG toxicity calculator. Twenty-six (28%) required dose reduction, 55% (n = 52) required a dose delay, and 36% (n = 34) had a hospitalization due to toxicity. Thirty-nine patients (42%) discontinued treatment due to toxicity. Despite intensive assessment, clinical optimization and personalized treatment decisions, older adults with cancer remain at high risk of chemotherapy toxicity.

Loss of the Vitamin B-12 Transport Protein Tcn2 Results in Maternally Inherited Growth and Developmental Defects in Zebrafish.

BACKGROUND: In humans, vitamin B-12 (cobalamin) transport involves 3 paralogous proteins: transcobalamin, haptocorrin, and intrinsic factor. Zebrafish (Danio rerio) express 3 genes that encode proteins homologous to known B-12 carrier proteins: tcn2 (a transcobalamin ortholog) and 2 atypical ß-domain-only homologs, tcnba and tcnbb. OBJECTIVES: Given the orthologous relation between zebrafish Tcn2 and human transcobalamin, we hypothesized that zebrafish carrying null mutations of tcn2 would exhibit phenotypes consistent with vitamin B-12 deficiency. METHODS: First-generation and second-generation tcn2-/- zebrafish were characterized using phenotypic assessments, metabolic analyses, viability studies, and transcriptomics. RESULTS: Homozygous tcn2-/- fish produced from a heterozygous cross are viable and fertile but exhibit reduced growth, which persists into adulthood. When first-generation female tcn2-/- fish are bred, their offspring exhibit gross developmental and metabolic defects. These phenotypes are observed in all offspring from a tcn2-/- female regardless of the genotype of the male mating partner, suggesting a maternal effect, and can be rescued with vitamin B-12 supplementation. Transcriptome analyses indicate that offspring from a tcn2-/- female exhibit expression profiles distinct from those of offspring from a tcn2+/+ female, which demonstrate dysregulation of visual perception, fatty acid metabolism, and neurotransmitter signaling pathways. CONCLUSIONS: Our findings suggest that the deposition of vitamin B-12 in the yolk by tcn2-/- females may be insufficient to support the early development of their offspring. These data present a compelling model to study the effects of vitamin B-12 deficiency on early development, with a particular emphasis on transgenerational effects and gene-environment interactions.