Androgen receptor pathway inhibitors, prostate cancer, and older adults: a global Young International Society of Geriatric Oncology drug review.

Prostate cancer is a disease of older adults that has undergone a significant therapeutic paradigm shift in the last decade with the emergence of novel androgen receptor pathway inhibitors (ARPis). One of the more commonly used ARPis is enzalutamide. This drug, along with darolutamide and apalutamide, initially received approvals in the metastatic castrate-resistant prostate cancer setting but is now utilized frequently in the metastatic castrate-sensitive and non-metastatic castration-resistant settings. Landmark phase III data illustrating ARPi efficacy in older adults are limited to those with excellent performance status. However, its role in unfit older prostate cancer patients remains to be explored in the context of a narrative review. This first-of-its-kind drug review aims to shed light on the most up-to-date evidence behind the unique toxicity profile of ARPis in the context of geriatric vulnerabilities such as cognitive and functional impairment, along with potential solutions and supporting evidence that exists to circumvent these issues in the vulnerable older adult.

Hypomethylating agent-based therapies in older adults with acute myeloid leukemia - A joint review by the Young International Society of Geriatric Oncology and European Society for Blood and Marrow Transplantation Trainee Committee.

Acute myeloid leukemia (AML) is associated with poor outcomes in older adults. A major goal of treatment is to balance quality of life and functional independence with disease control. With the approval of new, more tolerable regimens, more older adults are able to receive AML-directed therapy. Among these options are hypomethylating agents (HMAs), specifically azacitidine and decitabine. HMAs have become an integral part of AML therapy over the last two decades. These agents are used either as monotherapy or nowadays more commonly in combination with other agents such as the Bcl-2 inhibitor venetoclax. Biological AML characteristics, such as molecular and cytogenetic risk factors, play crucial roles in guiding treatment decisions. In patients with high-risk AML, HMAs are increasingly used rather than intensive chemotherapy, although further trials based on a risk-adapted approach using patient- and disease-related factors are needed. Here, we review trials and evidence for the use of HMA monotherapy and combination therapy in the management of older adults with AML. Furthermore, we discuss the use of HMAs and HMA combination therapies in AML, mechanisms of action, their incorporation into hematopoietic stem cell transplantation strategies, and their use in patients with comorbidities and reduced organ function.

Use of Single-Item Self-Rated Health Measure to Identify Frailty and Geriatric Assessment-Identified Impairments Among Older Adults with Cancer.

BACKGROUND: Poor self-rated health (SRH) is a known predictor of frailty and mortality in the general population; however, its role among older adults with cancer is unknown. We evaluated the role of SRH as a potential screening tool to identify frailty and geriatric assessment (GA)-identified impairments. MATERIALS AND METHODS: Adults ≥60 years diagnosed with cancer in the UAB Cancer & Aging Resilience Evaluation (CARE) registry underwent a GA at the time of initial consultation. We measured SRH using a single-item from the Patient-Reported Outcomes Measurement Information System global health scale and dichotomized responses as poor (poor, fair) and good (good, very good, and excellent). We evaluated the diagnostic performance of SRH in measuring frailty, and GA impairment (≥2 deficits among a set of seven GA domains). We examined the impact of SRH with survival using a Cox model adjusting for confounders, exploring the mediating role of frailty. RESULTS: Six hundred and three older adults with cancer were included, with a median age of 69 years. Overall, 45% (n = 274) reported poor SRH. Poor SRH demonstrated high sensitivity and specificity for identifying frailty (85% and 78%, respectively) and GA impairment (75% and 78%, respectively). In a Cox regression model, poor SRH was associated with inferior survival (HR = 2.26; 95% CI 1.60-3.18) after adjusting for confounders; frailty mediated 69% of this observed relationship. CONCLUSION: Self-rated health may be used as a screening tool to identify older adults with cancer with frailty and GA impairments. Poor SRH is associated with inferior survival, which is mediated by frailty.

Guideline Concordance With Durvalumab in Unresectable Stage III Non-Small Cell Lung Cancer: A Single Center Veterans Hospital Experience.

BACKGROUND: Durvalumab is recommended by national guidelines for patients with unresectable stage III non-small cell lung cancer (NSCLC) following concurrent chemoradiation therapy (CRT). Nonadherence to guidelines is associated with adverse outcomes. We studied the adherence and identified barriers to durvalumab usage at the Birmingham Veterans Affairs Medical Center (VAMC) Oncology Clinic in Alabama. METHODS: Using retrospective analysis, we assessed the use of consolidative durvalumab among veterans at Birmingham VAMC. The health records of all veterans with stage III unresectable NSCLC from October 2017 to August 2019 were reviewed. Data collected included demographics, barriers to CRT initiation and completion, durvalumab usage, and reasons for not prescribing durvalumab. RESULTS: In our data review, 34 patients were found to have stage III unresectable NSCLC. Twenty (58.8%) of those 34 initiated CRT, but only 16 (47.1%) completed CRT treatment and 7 (20.6%) underwent further treatment with durvalumab. Of the 14 patients who did not initiate CRT, the most common reasons were poor performance status and/or the presence of comorbidities. Of the evaluable cohort of 34, 11 (32.4%) patients with stage III NSCLC received durvalumab. Of the 9 eligible patients who did not receive durvalumab, the most common reasons cited were toxicities experienced during or following CRT (11.8%). CONCLUSIONS: Just one-third of patients were eligible to receive durvalumab at Birmingham VAMC. This was likely due to the difference between clinical trial and real-world patient populations. Interventions to address socioeconomic and system level barriers to improve our center's delivery of lung cancer treatment are planned.

Definity, an affinity for painful crisis: a case series describing vaso-occlusive pain crises in sickle cell patients undergoing echocardiogram with Definity contrast.

BACKGROUND: Individuals with sickle cell disease (SCD) are at risk for painful crises and long-term cardiopulmonary morbidity. Echocardiogram is recommended if signs or symptoms of cardiopulmonary disease develop in previously asymptomatic patients, or worsen in those with known disease. Second-generation echocardiogram contrast agents (ECAs) improve the diagnostic capacity of echocardiogram; however, these agents have risks in SCD populations that have yet to be investigated. CASE SUMMARY: We report a case series of two patients who experienced vaso-occlusive crises following administration of the ECA, Definity. Both patients were referred for echocardiogram from our institution's sickle cell clinic because of concern for SCD-related cardiopulmonary complications. Both patients were in their usual state of health at the time of their exams. The first patient experienced acute back and hip pain minutes after receiving Definity and was diagnosed with acute vaso-occlusive crisis requiring admission for 6 days for pain management. The second patient developed dyspnoea and chest pain within 90 min of her echocardiogram. She was diagnosed with acute chest syndrome and admitted for further management. Her hospitalization was complicated by hyper-haemolysis and multiple organ failure syndrome. After 13 days, she was discharged home. DISCUSSION: The safety profile of ECAs has not been fully evaluated and warrants further study in individuals with SCD. Proposed mechanisms for our observations include the release of pro-inflammatory metabolites from Definity contrast agent's shell and ultrasound-induced haemolysis secondary to ECA administration. Alternative imaging modalities and proper precautions should be considered when evaluating cardiopulmonary function in this patient population.

Understanding the andromeda strain - The role of cytokine release, coagulopathy and antithrombin III in SARS-CoV2 critical illness.

As the current coronavirus pandemic continues and cases of COVID-19 critical illness rise, physicians and scientists across the globe are working to understand and study its pathophysiology. Part of the pathology of this illness may result from its prothrombotic potential as witnessed from derangements in coagulation and thrombotic complications reported in observational studies performed in China and Europe to findings of microthrombosis upon autopsy analysis of patients who succumbed to COVID-19. Multiple organizations, including the American Society of Hematology (ASH), recommend the routine use of prophylactic heparin to temper the thrombotic complications of this illness given its mortality benefit in severe COVID-19 infections. Reductions in circulating levels of Antithrombin III (AT), the primary mediator of heparin's action, is present in cases of coronavirus related critical illness. AT's use as a prognostic marker, an important effector of heparin resistance, and a potential therapeutic target for COVID-19 remains to be explored.

Intraventricular metastatic melanoma: A case report and review of the literature.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.

Association of malnutrition with geriatric assessment impairments and health-related quality of life among older adults with gastrointestinal malignancies.

BACKGROUND: A majority of older adults with cancer develop malnutrition; however, the implications of malnutrition among this vulnerable population are poorly understood. The goal of this study was to quantify the prevalence of nutrition related-symptoms and malnutrition among older adults with gastrointestinal (GI) malignancies and the association of malnutrition with geriatric assessment (GA) impairment, health-related quality of life (HRQoL), and health care utilization. METHODS: We performed a cross-sectional study of older adults (≥60 years) who were referred to the GI Oncology clinic at the University of Alabama at Birmingham. Participants underwent the Cancer & Aging Resilience Evaluation survey that includes the abbreviated Patient-Generated Subjective Global Assessment of nutrition. Nutrition scores were dichotomized into normal (0-5) and malnourished (≥6), and multivariate analyses adjusted for demographics, cancer type, and cancer stage were used to examine associations with GA impairment, HRQoL, and health care utilization. RESULTS: A total of 336 participants were included (men, 56.8%; women, 43.2%), with a mean age of 70 years (standard deviation, ±7.2 years) and colorectal cancer (33.6%) and pancreatic cancer (24.4%) being the most common diagnoses. Overall, 52.1% of participants were identified as malnourished. Malnutrition was associated with a higher prevalence of several GA impairments, including 1 or more falls (adjusted odds ratio [aOR], 2.1), instrumental activities of daily living impairment (aOR, 4.1), and frailty (aOR, 8.2). Malnutrition was also associated with impaired HRQoL domains; both physical (aOR, 8.7) and mental (aOR, 5.0), and prior hospitalizations (aOR, 2.2). CONCLUSION: We found a high prevalence of malnutrition among older adults with GI malignancies that was associated with increased GA impairments, reduced HRQoL, and increased health care utilization.

Patient-reported cognitive complaints in older adults with gastrointestinal malignancies at diagnosis- Results from the Cancer & Aging Resilience Evaluation (CARE) study.

OBJECTIVES: Patient-reported cognitive complaint (CI) is poorly described in older adults with cancer. The purpose of this study was to quantify the prevalence and examine the associations of patient-reported CI in older adults with gastrointestinal (GI) malignancies at diagnosis. MATERIALS AND METHODS: Using participants ≥60 years with GI malignancies from the Cancer & Aging Resilience Evaluation (CARE) Registry that underwent a Geriatric Assessment (GA), we examined CI using the Patient-Reported Outcomes Measurement Information System (PROMIS®) Short Form 4a Cognitive Function. Cognition scores were dichotomized into normal (scores of 15-20) and impaired (4-14), and bivariate and multivariate analyses were used to examine associations. RESULTS: A total of 264 participants with GI malignancy were included, mean age of 70.0 ± 7.1, 55.7% male, pancreatic cancer was the most common cancer (24.2%) and majority were stage III/IV (68.2%). 29.3% of participants endorsed CI. CI was not associated with demographic and clinical domains, but was associated with many GA impairments including instrumental Activities of Daily Living (iADL) impairment (adjusted odds ratio [aOR] 6.0, 95% confidence interval 3.0-11.8), falls (aOR 2.7, 1.4-5.4), anxiety (aOR 10.3, 5.2-20.4), and depression (aOR 10.2, 5.2-20.4). CI was also associated with reduced global mental (aOR 18.7, 8.1-42.2) and physical (aOR 4.7, 2.4-8.9) quality of life, and prior hospitalizations (aOR 2.4, 1.2-4.8). CONCLUSION: We found a high prevalence of patient-reported CI in older adults with GI malignancies that was associated with increased GA impairments, reduced health-related quality of life, and increased healthcare utilization.

Epithelial-to-Mesenchymal Transition: A Mediator of Sorafenib Resistance in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients with advanced HCC, as it has proven to increase survival in these patients. However, clinical and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of drug resistance has gained increasing attention. EMT is a developmental multistep molecular and cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this review, we provide an overview of the currently available preclinical studies on the EMT mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights may facilitate rational development of combination therapies in the future to impact survival of patients with advanced HCC.

Nasal decongestants in monotherapy for the common cold.

BACKGROUND: Many treatments for the common cold exist and are sold over-the-counter. Nevertheless, evidence on the effectiveness and safety of nasal decongestants is limited. OBJECTIVES: To assess the efficacy, and short- and long-term safety, of nasal decongestants used in monotherapy to alleviate symptoms of the common cold in adults and children. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 6, June 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Specialised Register, MEDLINE (1946 to July 2016), Embase (2010 to 15 July 2016), CINAHL (1981 to 15 July 2016), LILACS (1982 to July 2016), Web of Science (1955 to July 2016) and clinical trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) and cluster-RCTs investigating the effectiveness and adverse effects of nasal decongestants compared with placebo for treating the common cold in adults and children. We excluded quasi-RCTs. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted and summarised data on subjective measures of nasal congestion, overall patient well-being score, objective measures of nasal airway resistance, adverse effects and general recovery. One review author acted as arbiter in cases of disagreement. We categorised trials as single and multi-dose and analysed data both separately and together. We also analysed studies using an oral or topical nasal decongestant separately and together. MAIN RESULTS: We included 15 trials with 1838 participants. Fourteen studies included adult participants only (aged 18 years and over). In six studies the intervention was a single dose and in nine studies multiple doses were used. Nine studies used pseudoephedrine and three studies used oxymetazoline. Other decongestants included phenylpropanolamine, norephedrine and xylometazoline. Phenylpropanolamine (or norephedrine) is no longer available on the market therefore we did not include the results of these studies in the meta-analyses. Eleven studies used oral decongestants; four studies used topical decongestants.Participants were included after contracting the common cold. The duration of symptoms differed among studies; in 10 studies participants had symptoms for less than three days, in three studies symptoms were present for less than five days, one study counted the number of colds over one year, and one study experimentally induced the common cold. In the single-dose studies, the effectiveness of a nasal decongestant was measured on the same day, whereas the follow-up in multi-dose studies ranged between one and 10 days.Most studies were conducted in university settings (N = eight), six at a specific university common cold centre. Three studies were conducted at a university in collaboration with a hospital and two in a hospital only setting. In two studies the setting was unclear.There were large differences in the reporting of outcomes and the reporting of methods in most studies was limited. Therefore, we judged most studies to be at low or unclear risk of bias. Pooling was possible for a limited number of studies only; measures of effect are expressed as standardised mean differences (SMDs). A positive SMD represents an improvement in congestion. There is no defined minimal clinically important difference for measures of subjective improvement in nasal congestion, therefore we used the SMDs as a guide to assess whether an effect was small (0.2 to 0.49), moderate (0.5 to 0.79) or large (≥ 0.8).Single-dose decongestant versus placebo: 10 studies compared a single dose of nasal decongestant with placebo and their effectiveness was tested between 15 minutes and 10 hours after dosing. Seven of 10 studies reported subjective symptom scores for nasal congestion; none reported overall patient well-being. However, pooling was not possible due to the large diversity in the measurement and reporting of symptoms of congestion. Two studies recorded adverse events. Both studies used an oral decongestant and each of them showed that there was no statistical difference between the number of adverse events in the treatment group versus the placebo group.Multi-dose decongestant versus placebo: nine studies compared multiple doses of nasal decongestants with placebo, but only five reported on the primary outcome, subjective symptom scores for nasal congestion. Only one study used a topical decongestant; none reported overall patient well-being. Subjective measures of congestion were significantly better for the treatment group compared with placebo approximately three hours after the last dose (SMD 0.49, 95% confidence interval (CI) 0.07 to 0.92; P = 0.02; GRADE: low-quality evidence). However, the SMD of 0.49 only indicates a small clinical effect. Pooling was based on two studies, one oral and one topical, therefore we were unable to assess the effects of oral and topical decongestants separately. Seven studies reported adverse events (six oral and one topical decongestant); meta-analysis showed that there was no statistical difference between the number of adverse events in the treatment group (125 per 1000) compared to the placebo group (126 per 1000). The odds ratio (OR) for adverse events in the treatment group was 0.98 (95% CI 0.68 to 1.40; P = 0.90; GRADE: low-quality evidence). The results remained the same when we only considered studies using an oral decongestant (OR 0.95, 95% CI 0.65 to 1.39; P = 0.80; GRADE: low-quality evidence). AUTHORS' CONCLUSIONS: We were unable to draw conclusions on the effectiveness of single-dose nasal decongestants due to the limited evidence available. For multiple doses of nasal decongestants, the current evidence suggests that these may have a small positive effect on subjective measures of nasal congestion in adults with the common cold. However, the clinical relevance of this small effect is unknown and there is insufficient good-quality evidence to draw any firm conclusions. Due to the small number of studies that used a topical nasal decongestant, we were also unable to draw conclusions on the effectiveness of oral versus topical decongestants. Nasal decongestants do not seem to increase the risk of adverse events in adults in the short term. The effectiveness and safety of nasal decongestants in children and the clinical relevance of their small effect in adults is yet to be determined.