Fewer severe infections with tranexamic acid in patients with hematologic malignancies.

Background: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty. Objectives: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies. Methods: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901). Results: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease. Conclusion: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.

Geriatric assessment-guided interventions for older adults with multiple myeloma: A feasibility and acceptability study.

INTRODUCTION: Geriatric assessment (GA)-guided supportive care programs have been successful in improving treatment outcomes for older adults with solid-organ cancers. This study aimed to evaluate the feasibility of a GA-guided supportive care program among older adults treated for multiple myeloma (MM). MATERIALS AND METHODS: The study utilized an existing registry of adults with plasma cell disorders at the University of North Carolina. Patients with MM, aged 60 or older, and having a GA-identified deficit in one or more problem area were offered referrals to supportive care resources during routine visits. Problem areas included physical function deficits, polypharmacy, and anxiety or depression. Patients with physical function deficits were offered referral to physical therapy (PT), those with polypharmacy to an Oncology Clinical Pharmacist Practitioner (CPP), and those with mental health symptoms to the Comprehensive Cancer Support Program (CCSP). RESULTS: Of the 58 individuals identified as having at least one deficit on the GA, PT was the most commonly identified relevant resource (79%), followed by CPP visits (57%). Among individuals that were offered referral(s) to at least one new supportive care resource, the acceptance rate was 50%. Referral acceptance rates were highest among those recommended for a CPP visit (55% of those approached) and lowest for CCSP (0%). DISCUSSION: The study examined the feasibility and acceptability of a referral program for supportive care resources among older adults with MM who have deficits on GA. The most commonly identified deficit was physical functioning, followed by polypharmacy and mental health. The study found that physical interventions and referrals to CPPs were the most accepted interventions. However, the low proportion of patients who accepted physical therapy referrals indicates the need for tailored and more personalized approaches. Further research is needed to explore the feasibility and impact of supportive care referral programs for older adults with MM.

Time spent at home among older adults with acute myeloid leukemia receiving azacitidine- or venetoclax-based regimens.

Time at home is a critically important outcome to adults with acute myeloid leukemia (AML) when selecting treatment; however, no study to date has adequately described the amount of time older adults spend at home following initiation of chemotherapy. We queried records from a multi-institution health system to identify adults aged ≥60 years newly diagnosed with AML who were treated with azacitidine or venetoclax and evaluated the proportion of days at home (PDH) following diagnosis. Days were considered "at home" if patients were not admitted or seen in the emergency department or oncology/infusion clinic. Assessed covariates included demographics and disease risk. Associations between PDH and baseline characteristics were evaluated via linear regression, adjusted for log length of follow-up. From 2015-2020, 113 older adults were identified. Most received azacitidine plus venetoclax (51.3%) followed by azacitidine monotherapy (38.9%). The mean PDH for all patients was 0.58 (95% confidence interval: 0.54-0.63, median 0.63). PDH increased among survivors over time. PDH did not differ between therapy groups (adjusted mean, azacitidine plus venetoclax: 0.68; azacitidine monotherapy: 0.66; P=0.64) or between disease risk categories (P=0.34). Compared to patients receiving azacitidine monotherapy, patients receiving azacitidine plus venetoclax had longer clinic visits (median minutes: 127.9 vs. 112.9, P<0.001) and infusion visits (median minutes: 194.3 vs. 132.5, P<0.001). The burden of care for older adults with AML treated with "less intense" chemotherapy is high. The addition of venetoclax to azacitidine did not translate into increased time at home. Future prospective studies should evaluate patient-centered outcomes, including time at home, to inform shared decision-making and drug development.

Longitudinal Analysis of Patient-Reported Cognitive Function in Multiple Myeloma.

BACKGROUND: Cancer-related cognitive impairment (CRCI) has been largely unstudied in patients with multiple myeloma (MM). This study describes patient-reported cognition over time and patient factors associated with adverse cognitive outcomes in MM. METHODS: Participants enrolled in a registry in which they completed a geriatric assessment at study entry, and 3 & 6 months after entry. Cognitive function was assessed using the EORTC QLQ-C30 Cognitive Function subscale, with CRCI defined as scores < 75. Generalized estimating equation (GEE) models were used to fit longitudinal models to investigate differences by group and differences in changes over time by group, with adjustment for time since diagnosis. RESULTS: One hundred and four adults with MM had mean age of 67 years and 30% identified as Black. Patient-reported CRCI was present in 18% of participants at enrollment, 21% at 3 months, and 30% at 6 months. Worse cognitive function was reported in those with impairments in physical function (P = .002), IADLs (P = .02), and performance status (P = .04), as well as in those who were prefrail/frail (P = .02) and depressed (P = .049). Greater cognitive decline over time was observed in patients without CRCI at enrollment (P < .0001) and those with lower levels of education (P = .04). CONCLUSION: This is one of the first studies to describe longitudinal changes in patient-reported cognition in patients with MM. Several potentially intervenable factors, including physical function impairment and depression, were associated with worse cognition at study entry, but only baseline CRCI status and education level were predictive of future decline.

Supportive Care and Symptom Management for Patients With Immunoglobulin Light Chain (AL) Amyloidosis.

Immunoglobulin light chain (AL) amyloidosis is a disorder of clonal plasma cells characterized by deposition of amyloid fibrils in a variety of tissues, leading to end-organ injury. Renal or cardiac involvement is most common, though any organ outside the central nervous system can develop amyloid deposition, and symptomatic presentations may consequently vary. The variability and subtlety of initial clinical presentations may contribute to delayed diagnoses, and organ involvement is often quite advanced and symptomatic by the time a diagnosis is established. Additionally, while organ function can improve with plasma-cell-directed therapy, such improvement lags behind hematologic response. Consequently, highly effective supportive care, including symptom management, is essential to improve quality of life and to maximize both tolerance of therapy and likelihood of survival. Considering the systemic nature of the disease, close collaboration between clinicians is essential for effective management.

Physical Function, Psychosocial Status, and Symptom Burden Among Adults with Plasma Cell Disorders and Associations with Quality of Life.

BACKGROUND: The plasma cell disorders (PCDs), multiple myeloma (MM), and light-chain amyloidosis (AL) are disproportionately diseases of older adults, whose care may be complicated by frailty associated with advancing age. We sought to evaluate the prevalence of functional deficits and symptoms in a cohort of persons with PCDs and associations of demographic, disease-related, functional, and psychosocial measures with quality of life (QoL). PATIENTS AND METHODS: Adults with PCDs were recruited into an observational registry in 2018-2020. Patients completed a functional assessment and European Organization for Research and Treatment of Cancer QoL questionnaire (QLQ-C30). Associations of covariates of interest with QoL were evaluated via univariate linear regression. RESULTS: Among 121 adults, the mean age was 68.6. Diagnoses were 74% MM, 14% AL, 7% both MM and AL, and 5% other PCDs. The median time from diagnosis was 34.9 months. Median lines of therapy were 2, with 11% having received ≥4th-line therapy.Patients with functional deficits had lower mean QoL scores: dependence in IADLs (66.3 vs. 79.9, P = .001) and recent falls (56.7 vs. 76.8, P = .001). Patients ≤6 months from diagnosis had lower QoL (66.7) than those ≥2 years from diagnosis (77.3, P = .03). However, patients on later lines of therapy (≥4th-line) had lower QoL (62.2) than those on 1st-line treatment (76.0, P = .04). CONCLUSIONS: Patients with physical impairments and more advanced PCDs had lower QoL than those without deficits or earlier in their disease course. Early identification of physical impairments may facilitate interventions that mitigate these deficits and thereby improve QoL for patients with PCDs.

Prevalence and clinical correlates of cognitive impairment in adults with plasma cell disorders.

INTRODUCTION: Older adults with plasma cell disorders (PCDs) experience cognitive dysfunction that may be attributable to the disease and associated therapies. Yet, this has seldom been reported in the literature. Our objectives were to describe cognitive function (objective and patient-reported) in adults with PCDs and to explore clinical correlates of cognitive impairment. MATERIALS AND METHODS: Participants completed a geriatric assessment between March 2018 and February 2020. Cognitive function was evaluated using two objective measures - Montreal Cognitive Assessment (MoCA, cutpoint <26) and Blessed Orientation Memory Concentration Test (BOMC, cutpoint >4) - and two patient-reported outcome (PRO) measures - Patient-Reported Outcomes Measurement Information System Cognitive Function (PROMIS-CF, cutpoint <45) and European Organization for Research and Treatment of Cancer Cognitive Functioning subscale (EORTC-CF, cutpoint <75). Spearman correlations examined relationships among these measures and log binomial regression was used to examine characteristics associated with cognitive impairment, as defined by the MoCA and PROMIS-CF measures. RESULTS: Among 86 participants with a mean age of 69 (range: 46-91), the prevalence of cognitive dysfunction was between 20% (BOMC) and 63% (MoCA). There was moderate correlation among objective measures (r = 0.51, p < 0.0001), moderate to high correlation among PRO measures (r = 0.69, p < 0.0001), but no correlation between objective and PRO measures. Factors associated with objective impairment included ≤ high school education (RR 1.46, p = 0.009), living alone (RR 1.42, p = 0.02), relapsed/refractory disease (RR 1.39, p = 0.04), empirically de-intensified induction therapy (RR 1.62, p = 0.008), frailty (RR 1.49, p = 0.04), and peripheral vascular disease (RR 1.54, p = 0.002). Factors associated with PRO impairment included social isolation (RR 3.43, p = 0.003), depression (RR 3.30, p = 0.004) and anxiety (RR 4.43, p = 0.0002), frailty (RR 3.60, p = 0.02), falls in the previous 6 months (RR 2.53, p = 0.02), and deficits in physical function (RR 4.44, p = 0.01). Older age was not associated with either objective or PRO impairment. DISCUSSION: Cognitive impairment, using objective and PRO screening measures, was relatively common in adults with PCDs. Cancer-related factors and medical comorbidities were associated with objective cognitive impairment whereas psychosocial and functional factors were associated with PRO impairment.

Geriatric-assessment-identified functional deficits among adults with multiple myeloma with normal performance status.

OBJECTIVES: Findings from a brief geriatric assessment (GA) in a cohort of adults with multiple myeloma (MM) are presented, with particular attention to the utility of the GA in identifying important deficits in adults judged to have a normal Karnofsky Performance Status (KPS ≥ 80). MATERIALS AND METHODS: Adults age 18 and older with MM were recruited into an observational study from 2018 to 2020. A modified Cancer and Aging Research Group (CARG) GA was administered at enrollment. Enrollees also completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients Core 30 questionnaire (QLQ-C30), with subscales of physical, social, role, and cognitive functioning (range 0-100; higher values indicate better function). Data were analyzed using descriptive statistics for the full cohort and stratified by concurrent KPS (score < 80 vs ≥ 80). RESULTS: Among 89 adults, the mean age was 69.1 years, 68% were aged ≥65 years, and 70% were white. In this cohort, 78% had KPS ≥ 80. Among those with KPS ≥ 80, functional impairments (Timed Up and Go ≥14 s and dependence in ≥1 instrumental activity of daily living) were seen in 30% and 21%, respectively, with 11% reporting ≥1 fall in the prior 6 months. At least two GA-identified deficits were detected in 50% of the overall cohort and in 41% of those with KPS ≥ 80. Among those with KPS ≥ 80, self-reported physical impairment on EORTC QLQ-C30 was noted by 34%. CONCLUSION: Using a modified CARG GA and EORTC questionnaire, functional impairments were identified among adults considered to have a good performance status based on a KPS (≥ 80). Future studies should focus on using GA measures for therapy assignment and identifying opportunities for intervening upon GA-identified deficits.

Cold agglutinin syndrome as a complication of Covid-19 in two cases.

BACKGROUND: Cold agglutinins are autoantibodies against RBC antigens, leading to hemolysis at less-than-physiological temperatures through complement fixation. Production can be triggered by infections, resulting in secondary cold agglutinin syndrome (CAS). This syndrome has been classically described in the setting of Mycoplasma pneumoniae infection, as well as with several viral pathogens. CASES: Here, we present two cases of cold agglutinins identified in the context of Covid-19 in critically ill patients treated at our institution. Each case was characterized by little in-vivo hemolysis, but these antibodies complicated laboratory assessment and renal replacement therapy. Management included anticoagulation and warming of dialysis circuit. CONCLUSIONS: Despite minimal in-vivo hemolysis, these antibodies are of clinical significance given their implications for laboratory assessment and renal replacement therapy, particularly with the frequency of multi-organ system dysfunction associated with severe Covid-19.

The Triage of Older Adults with Physiologic Markers of Serious Injury Using a State-Wide Prehospital Plan.

INTRODUCTION: In January of 2010, North Carolina (NC) USA implemented state-wide Trauma Triage Destination Plans (TTDPs) to provide standardized guidelines for Emergency Medical Services (EMS) decision making. No study exists to evaluate whether triage behavior has changed for geriatric trauma patients. HYPOTHESIS/PROBLEM: The impact of the NC TTDPs was investigated on EMS triage of geriatric trauma patients meeting physiologic criteria of serious injury, primarily based on whether these patients were transported to a trauma center. METHODS: This is a retrospective cohort study of geriatric trauma patients transported by EMS from March 1, 2009 through September 30, 2009 (pre-TTDP) and March 1, 2010 through September 30, 2010 (post-TTDP) meeting the following inclusion criteria: (1) age 50 years or older; (2) transported to a hospital by NC EMS; (3) experienced an injury; and (4) meeting one or more of the NC TTDP's physiologic criteria for trauma (n = 5,345). Data were obtained from the Prehospital Medical Information System (PreMIS). Data collected included proportions of patients transported to a trauma center categorized by specific physiologic criteria, age category, and distance from a trauma center. RESULTS: The proportion of patients transported to a trauma center pre-TTDP (24.4% [95% CI 22.7%-26.1%]; n = 604) was similar to the proportion post-TTDP (24.4% [95% CI 22.9%-26.0%]; n = 700). For patients meeting specific physiologic triage criteria, the proportions of patients transported to a trauma center were also similar pre- and post-TTDP: systolic blood pressure <90 mmHg (22.5% versus 23.5%); respiratory rate <10 or >29 (23.2% versus 22.6%); and Glascow Coma Scale (GCS) score <13 (26.0% versus 26.4%). Patients aged 80 years or older were less likely to be transported to a trauma center than younger patients in both the pre- and post-TTDP periods. CONCLUSIONS: State-wide implementation of a TTDP had no discernible effect on the proportion of patients 50 years and older transported to a trauma center. Under-triage remained common and became increasingly prevalent among the oldest adults. Research to understand the uptake of guidelines and protocols into EMS practice is critical to improving care for older adults in the prehospital environment.

Differences in overall survival and mutation prevalence between right- and left-sided colorectal adenocarcinoma.

BACKGROUND: Prior reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease, as well as differences in treatment response based on disease sidedness. Differences in prognosis remain even among patients with metastatic disease, indicating that anatomy or stage at diagnosis alone cannot explain all of these findings. While genetic differences between right- and left-sided CRC have long been described, the genetic and molecular drivers underlying differences in prognosis and treatment response remain incompletely understood. METHODS: We compared mutation prevalence between right- (cecum to splenic flexure) and left-sided (descending colon to rectum) CRC among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. RESULTS: Among 288 cases (167 left-sided, 103 right-sided, 18 synchronous or without clear primary), patients with left-sided primaries had a longer overall survival from pathologic diagnosis (median 1,823 days vs. 1,006 days for right-sided cases, P=0.004). Among the assessed genes, BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5-22.5%) compared to 4.8% (95% CI: 1.6-8.0%) (P=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (95% CI: 0.2-7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (P=0.01). CONCLUSIONS: This difference in mutation prevalence may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right- and left-sided CRC described in this and prior studies.

Rapid, Safe, and Simple Manual Bedside Nucleic Acid Extraction for the Detection of Virus in Whole Blood Samples.

The rapid diagnosis of an infection is essential for the outbreak management, risk containment, and patient care. We have previously shown a method for the rapid bedside inactivation of the Ebola virus during blood sampling for safe nucleic acid (NA) tests by adding a commercial lysis/binding buffer directly into the vacuum blood collection tubes. Using this bedside inactivation approach, we have developed a safe, rapid, and simplified bedside NA extraction method for the subsequent detection of a virus in lysis/binding buffer-inactivated whole blood. The NA extraction is directly performed in the blood collection tubes and requires no equipment or electricity. After the blood is collected into the lysis/binding buffer, the contents are mixed by flipping the tube by hand, and the mixture is incubated for 20 min at room temperature. Magnetic glass particles (MGPs) are added to the tube, and the contents are mixed by flipping the collection tube by hand. The MGPs are then collected on the side of the blood collection tube using a magnetic holder or a magnet and a rubber band. The MGPs are washed three times, and after the addition of elution buffer directly into the collection tube, the NAs are ready for NA tests, such as qPCR or isothermal loop amplification (LAMP), without the removal of the MGPs from the reaction. The NA extraction method is not dependent on any laboratory facilities and can easily be used anywhere (e.g., in field hospitals and hospital isolation wards). When this NA extraction method is combined with LAMP and a portable instrument, a diagnosis can be obtained within 40 min of the blood collection.

A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma.

BACKGROUND: The KRAS oncogene is a driver mutation and is present in greater than 90% of pancreatic ductal adenocarcinomas (PDAC). A subset of these tumors, however, do not harbor mutations in KRAS (wild type KRAS). Studies have shown that patients with mutated KRAS have a poorer survival on first-line gemcitabine-based chemotherapy compared to wild type KRAS. In this study, we examined a cohort of patients with PDAC at our institution who were either wild type or mutant for the KRAS gene and assessed for differences in survival and response to different chemotherapeutic regimens. METHODS: We examined clinical records of patients treated at the Abramson Cancer Center of the University of Pennsylvania from 2013 to 2017. Patients with a pancreatic mass and a histologic diagnosis of pancreatic or pancreaticobiliary adenocarcinoma were identified. Thirty-nine patients with PDAC who underwent tumor sequencing at Penn Medicine's Center for Personalized Diagnostics (CPD) were selected for further study. Twelve patients were identified whose tumors were KRAS wild type. Twenty-seven patients with PDAC whose tumors harbored KRAS mutations were selected as controls (KRAS mutant). RESULTS: We noted a longer overall survival (OS) among KRAS wild type patients compared to KRAS mutant patients (P=0.026). This was independent of the age at diagnosis, patient gender, stage of diagnosis, tumor morphology, mismatch repair (MMR) status, and chemotherapeutic regimen. CONCLUSIONS: Similar to previously reported studies, PDAC with a KRAS wild type mutational profile has a better prognosis with a longer OS. This improved prognosis is independent of the protocol utilized in therapy for these patients. Our findings suggest that future clinical trials in pancreatic cancer should take into consideration the presence of KRAS mutations in their pre-planned analysis when assessing the efficacy of a novel therapeutic approach. This may be a crucial factor in trial concepts and outcomes.

KDR Mutation as a Novel Predictive Biomarker of Exceptional Response to Regorafenib in Metastatic Colorectal Cancer.

This is the case of an 84-year-old woman diagnosed with Stage IVb colon adenocarcinoma (CRC) metastatic to the liver, retroperitoneum, anastomotic site, and distal rectal sigmoid colon. She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab, as well as disease progression. Next generation sequencing of her tumor was ordered, and further discussion of her malignancy's genomic information took place at a multidisciplinary molecular tumor board. The patient had mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) which made her ineligible for epidermal growth factor receptor (EGFR) inhibitors; however, a KDR p.R961W c.2881C>T mutation was noted as a variant of unknown significance (VUS). KDR (kinase insert domain receptor) is the human gene encoding for vascular endothelial growth factor receptor 2 (VEGFR-2). She was then considered a suitable candidate for regorafenib, which she could only tolerate at a low dose of 40 mg daily, with the intent of prolonging her survival and to optimize her quality of life. We report her excellent tolerance and exceptional response to low dose regorafenib, including symptomatic, tumor marker, and sustained partial metabolic radiological improvement. In the largest Phase III trial of regorafenib in CRC, only five patients (1%) of 760 experienced a partial response (versus one patient, 0.4%, receiving placebo). KDR R961W mutation has been described but no functional data has been reported. This mutation occurs in the tyrosine kinase domain of the VEGFR-2. Regorafenib targets VEGFR-2 (KDR). Hereby we hypothesize KDR mutation as a novel predictive biomarker to exceptional response to regorafenib in metastatic colorectal cancer. To our knowledge, this is the first reported case of the potential correlation between KDR mutation and regorafenib use for the successful management of a patient with advanced CRC, leading to what is considered an exceptional response. Further studies based on this preliminary data are warranted.

Immune checkpoint inhibitors for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and advanced HCC generally caries a poor prognosis. The treatment of advanced disease is limited to sorafenib, which provides only a limited improvement in survival, and novel therapies are, thus, sorely needed. Among emerging alternative approaches, immune checkpoint inhibitors are a particularly promising treatment modality. In this review, we summarize current knowledge of the mechanisms for the two primary targets of immune checkpoint inhibitors and discuss the relevance of these pathways to the immunology of HCC. We also review the state of ongoing and forthcoming trials of immune checkpoint blockade in HCC.