Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies.

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

Developing a measure of overall intensity of injury care: A latent class analysis.

BACKGROUND: While injury is a leading cause of death and debility in older adults, the relationship between intensity of care and trauma remains unknown. The focus of this analysis is to measure the overall intensity of care delivered to injured older adults during hospitalization. METHODS: We used Centers for Medicare and Medicaid Services Medicare fee-for-service claims data (2013-2014), to identify emergency department-based claims for moderate and severe blunt trauma in age-eligible beneficiaries. Medical procedures associated with care intensity were identified using a modified Delphi method. A latent class model was estimated using the identified procedures, intensive care unit length of stay, demographics, and injury characteristics. Clinical phenotypes for each class were explored. RESULTS: A total of 683,398 cases were classified as low- (73%), moderate- (23%), and high-intensity care (4%). Greater age and reduced injury severity were indicators of lower intensity, while males, non-Whites, and nonfall mechanisms were more common with high intensity. Intubation/mechanical ventilation was an indicator of high intensity and often occurred with at least one other procedure or an extended intensive care unit stay. CONCLUSION: This work demonstrates that, although heterogeneous, care for blunt trauma can be evaluated using a single novel measure. LEVEL OF EVIDENCE: For prognostic/epidemiological studies, level III.

Synergistic effect of hypoalbuminaemia and hypotension in predicting in-hospital mortality and intensive care admission: a retrospective cohort study.

OBJECTIVE: Hypoalbuminaemia is an important prognostic factor. It may be associated with poor nutritional states, chronic heart and kidney disease, long-standing infection and cancer. Hypotension is a hallmark of circulatory failure. We evaluated hypoalbuminaemia and hypotension synergism as predictor of in-hospital mortality and intensive care unit (ICU) admission. DESIGN: We retrospectively analysed emergency department (ED) visits from January 2011 to December 2019. SETTING: Data were retrieved from five Mount Sinai health system hospitals, New York. PARTICIPANTS: We included consecutive ED patients ≥18 years with albumin measurements. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinical outcomes were in-hospital mortality and ICU admission. The rates of these outcomes were stratified by systolic blood pressure (SBP) (<90 vs ≥90 mm Hg) and albumin levels. Variables included demographics, presenting vital signs, comorbidities (measured as ICD codes) and other common blood tests. Multivariable logistic regression models analysed the adjusted OR of different levels of albumin and SBP for predicting ICU admission and in-hospital mortality. The models were adjusted for demographics, vital signs, comorbidities and common laboratory results. Patients with albumin 3.5-4.5 g/dL and SBP ≥90 mm Hg were used as reference. RESULTS: The cohort included 402 123 ED arrivals (27.9% of total adult ED visits). The rates of in-hospital mortality, ICU admission and overall admission were 1.7%, 8.4% and 47.1%, respectively. For SBP <90 mm Hg and albumin <2.5 g/dL, mortality and ICU admission rates were 34.0% and 40.6%, respectively; for SBP <90 mm Hg and albumin ≥2.5 g/dL 8.2% and 24.1%, respectively; for SBP ≥90 mm Hg and albumin <2.5 g/dL 11.4% and 18.6%, respectively; for SBP ≥90 mm Hg and albumin 3.5-4.5 g/dL 0.5% and 6.4%, respectively. Multivariable analysis showed that in patients with hypotension and albumin <2.5 g/dL the adjusted OR for in-hospital mortality was 37.1 (95% CI 32.3 to 42.6), and for ICU admission was 5.4 (95% CI 4.8 to 6.1). CONCLUSION: Co-occurrence of hypotension and hypoalbuminaemia is associated with poor hospital outcomes.

Modifiable Failures in the Colorectal Cancer Screening Process and Their Association With Risk of Death.

BACKGROUND & AIMS: Colorectal cancer (CRC) deaths occur when patients do not receive screening or have inadequate follow-up of abnormal results or when the screening test fails. We have few data on the contribution of each to CRC-associated deaths or factors associated with these events. METHODS: We performed a retrospective cohort study of patients in the Kaiser Permanente Northern and Southern California systems (55-90 years old) who died of CRC from 2006 through 2012 and had ≥5 years of enrollment before diagnosis. We compared data from patients with those from a matched cohort of cancer-free patients in the same system. Receipt, results, indications, and follow-up of CRC tests in the 10-year period before diagnosis were obtained from electronic databases and chart audits. RESULTS: Of 1750 CRC deaths, 75.9% (n = 1328) occurred in patients who were not up to date in screening and 24.1% (n = 422) occurred in patients who were up to date. Failure to screen was associated with fewer visits to primary care physicians. Of 3486 cancer-free patients, 44.6% were up to date in their screening. Patients who were up to date in their screening had a lower risk of CRC death (odds ratio, 0.38; 95% confidence interval, 0.33-0.44). Failure to screen, or failure to screen at appropriate intervals, occurred in a 67.8% of patients who died of CRC vs 53.2% of cancer-free patients; failure to follow-up on abnormal results occurred in 8.1% of patients who died of CRC vs 2.2% of cancer-free patients. CRC death was associated with higher odds of failure to screen or failure to screen at appropriate intervals (odds ratio, 2.40; 95% confidence interval, 2.07-2.77) and failure to follow-up on abnormal results (odds ratio, 7.26; 95% confidence interval, 5.26-10.03). CONCLUSIONS: Being up to date on screening substantially decreases the risk of CRC death. In 2 health care systems with high rates of screening, most people who died of CRC had failures in the screening process that could be rectified, such as failure to follow-up on abnormal findings; these significantly increased the risk for CRC death.

Genetic Biomarker Prevalence Is Similar in Fecal Immunochemical Test Positive and Negative Colorectal Cancer Tissue.

BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening. METHODS: FIT-negative and FIT-positive colorectal cancer patients 50-77 years of age were matched on age, sex, and cancer stage. Adequate DNA was isolated from paraffin-embedded specimens in 210 FIT-negative and 211 FIT-positive patients. Quantitative allele-specific real-time target and signal amplification assays were performed for 7 K-ras mutations and 10 aberrantly methylated DNA biomarkers (NDRG4, BMP3, SFMBT2_895, SFMBT2_896, SFMBT2_897, CHST2_7890, PDGFD, VAV3, DTX1, CHST2_7889). RESULTS: One or more biomarkers were found in 414 of 421 CRCs (98.3%). Biomarker expression was not associated with FIT status, with the exception of higher SFMBT2_897 expression in FIT-negative (194 of 210; 92.4%) than in FIT-positive cancers (180 of 211; 85.3%; p = 0.02). There were no consistent differences in biomarker expression by FIT status within age, sex, stage, and cancer location subgroups. CONCLUSIONS: The biomarkers of a currently in-use multi-target stool DNA test (K-ras, NDRG4, and BMP3) and eight newly characterized methylated biomarkers were commonly expressed in tumor tissue specimens, independent of FIT result. Additional study using stool-based testing with these new biomarkers will allow assessment of sensitivity, specificity, and clinical utility.

Metformin use and risk of colorectal adenoma after polypectomy in patients with type 2 diabetes mellitus.

BACKGROUND: Existing literature suggests that metformin, the most commonly used biguanide, may lower colorectal cancer risk. Because most colorectal cancers originate in precancerous adenomas, we examined whether metformin use lowered colorectal adenoma risk after polypectomy in patients with type-2 diabetes. METHODS: Retrospective cohort study of 40- to 89-year-old Kaiser Permanente Northern California patients who had type 2 diabetes, and ≥1 adenoma detected at baseline colonoscopy during 2000 to 2009 and a repeat colonoscopy 1 to 10 years from baseline adenoma diagnosis through 2012. Cox models evaluated the association between metformin use during follow-up and subsequent adenoma diagnoses, controlling for age, race/ethnicity, sex, body mass index, and repeat examination indication. RESULTS: Study included 2,412 patients followed for a median of 4.5 years; cumulatively, 1,117 (46%) patients had ≥1 adenoma at repeat colonoscopy. Compared with patients not receiving diabetes medications (n = 1,578), metformin-only use (n = 457) was associated with lower adenoma recurrence risk [adjusted HR, 0.76; 95% confidence interval (CI), 0.65-0.89], and the association was stronger with increasing total metformin dose [quartile (Q) 1: HR, 0.90; 95% CI, 0.72-1.12; Q2: HR, 0.89; 95% CI, 0.70-1.12; Q3: HR, 0.80; 95% CI, 0.63-1.01; Q4: HR, 0.50; 95% CI, 0.42-0.60, Ptrend < 0.001]. Findings were unchanged in sensitivity analyses, including evaluating only outcomes during the 3- to 10-year period from baseline. CONCLUSION: Our study suggests a potential benefit of metformin use in lowering the risk of subsequent adenomas after polypectomy in patients with type 2 diabetes. IMPACT: Metformin may lower colorectal cancer risk by reducing the formation of precancerous lesions, reinforcing the potential additional benefits of its use.

Observational methods to assess the effectiveness of screening colonoscopy in reducing right colon cancer mortality risk: SCOLAR.

AIMS: Screening colonoscopy's effectiveness in reducing risk of death from right colon cancers remains unclear. Methodological challenges of existing observational studies addressing this issue motivated the design of 'Effectiveness of Screening for Colorectal Cancer in Average-Risk Adults (SCOLAR)'. METHODS: SCOLAR is a nested case-control study based on two large integrated health systems. This affords access to a large, well-defined historical cohort linked to integrated data on cancer outcomes, patient eligibility, test indications and important confounders. RESULTS: We found electronic data adequate for excluding ineligible patients (except family history), but not the detailed information needed for test indication assignment. CONCLUSION: The lessons of SCOLAR's design and implementation may be useful for future studies seeking to evaluate the effectiveness of screening tests in community settings.