Clinical Outcomes of Benign Concordant MRI-Guided Breast Biopsies.

INTRODUCTION: MRI-guided biopsy is the standard of care for breast imaging findings seen only by MRI. Although a non-zero false-negative rate of MRI-guided breast biopsy has been reported by multiple studies, there are varied practice patterns for imaging follow-up after a benign concordant MRI guided biopsy. This study assessed the outcomes of benign concordant MRI-guided biopsies at a single institution. PATIENTS AND METHODS: This IRB-approved, retrospective study included patients with MRI-guided biopsies of breast lesions from November 1, 2014, to August 31, 2020. Only image-concordant breast lesions with benign histopathology and those follow up with MRI imaging or excision were included in the study. RESULTS: Out of 275 lesions in 216 patients that met the inclusion criteria, 274 lesions were followed with MRI (range, 5-79 months; average, 25.5 months) and showed benign or stable features upon follow-up. One out of 275 lesions (0.4%), a 6 mm focal nonmass enhancement, was ultimately found to represent malignancy after initial MRI-guided biopsy yielded fibrocystic changes. The lesion was stable at a 6-month follow-up MRI but increased in size at 18 months. Repeat biopsy by ultrasound guidance yielded invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS). CONCLUSION: Breast MRI-guided biopsy has a low false-negative rate. Our single malignancy from a total of 275 lesions gives a false negative rate of 0.4%. This data also supports a longer follow-up interval than the commonly performed 6-month follow-up, in order to assess for interval change.

Association of Burnout and Other Factors Within Physicians and Advanced Practice Providers in an Academic Surgery Department.

BACKGROUND: Provider burnout is a work-related syndrome that is under-recognized, under-reported, and has negative repercussions on the individual, system, and patients. This study investigated burnout incidence and its association with wellness characteristics such as resilience, psychological safety, and perceptions of the workplace to inform future work in improving well-being. METHODS: Electronic surveys were sent to 153 physicians and advanced practice providers (APPs) in the department of surgery at a single institution. Survey topics included demographics, intention to stay, engagement, and items from validated measures for workplace perceptions including work pace/stress (Mini Z), burnout, psychological safety, and resilience. Descriptive statistics, bivariate associations, and logistic regression were used to evaluate responses. RESULTS: Overall response rate was 47%. The majority of providers reported feeling burned out (56%), and 48% indicated they would probably leave the organization within three years. Additionally, 61% reported being satisfied with their job and 55% felt that they contributed professionally in the ways they value most (meaningful work/engagement). Significant predictors for burnout included negative work environment perceptions (work pace/stress), low resilience, low meaningful work, and professional role (physician vs APP). DISCUSSION: Maintaining a healthy workforce requires investigation into the factors that support workplace well-being. The strongest predictors of burnout were work pace/stress. Protective factors against burnout were psychological safety and resilience. An organizational culture that promotes psychological safety, as well as workplace improvements to enhance providers' sense of meaning in work, and decreasing work pace and stress may contribute to the prevention of burnout and the retention.

NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage.

INTRODUCTION: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. METHODS: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. RESULTS: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs <20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. CONCLUSIONS: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.

Removal of the infrapatellar fat pad and associated synovium benefits female guinea pigs in the Dunkin Hartley model of idiopathic osteoarthritis.

Background: Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of sex, is the infrapatellar fat pad (IFP). We previously demonstrated that removal of the IFP had short-term beneficial effects for a cohort of male Dunkin-Hartley guinea pigs. The present project was designed to elucidate the influence of IFP removal in females of this OA-prone strain. It was hypothesized that resection of the IFP would reduce the development of OA in knees of a rodent model predisposed to the disease. Methods: Female guinea pigs (n=16) were acquired at an age of 2.5 months. Surgical removal of the IFP and associated synovium complex (IFP/SC) was executed at 3 months of age. One knee had the IFP/SC resected; a comparable sham surgery was performed on the contralateral knee. All animals were subjected to voluntary enclosure monitoring and dynamic weight-bearing, as well as compulsory treadmill-based gait analysis monthly; baseline data was collected prior to surgery. Guinea pigs were euthanized at 7 months. Knees from eight animals were evaluated via histology, mRNA expression, and immunohistochemistry (IHC); knees from the remaining eight animals were allocated to microcomputed tomography (microCT), biomechanical analyses (whole joint testing and indentation relaxation testing), and atomic absorption spectroscopy (AAS). Results: Fibrous connective tissue (FCT) replaced the IFP/SC. Mobility/gait data indicated that unilateral IFP/SC removal did not affect bilateral hindlimb movement. MicroCT demonstrated that osteophytes were not a significant feature of OA in this sex; however, trabecular thickness (TbTh) in medial femorae decreased in knees containing the FCT. Histopathology scores were predominantly influenced by changes in the lateral tibia, which demonstrated that histologic signs of OA were increased in knees containing the native IFP/SC versus those with the FCT. Similarly, indentation testing demonstrated higher instantaneous and equilibrium moduli in the lateral tibial articular cartilage of control knees with native IFPs. AAS of multiple tissue types associated with the knee revealed that zinc was the major trace element influenced by removal of the IFP/SC. Conclusions: Our data suggest that the IFP/SC is a significant component driving knee OA in female guinea pigs and that resection of this tissue prior to disease has short-term benefits. Specifically, the formation of the FCT in place of the native tissue resulted in decreased cartilage-related OA changes, as demonstrated by reduced Osteoarthritis Research Society International (OARSI) histology scores, as well as changes in transcript, protein, and cartilage indentation analyses. Importantly, this model provides evidence that sex needs to be considered when investigating responses and associated mechanisms seen with this intervention.

Modeling Sex-Bias in Anxiety: Pros and Cons of a Larval Zebrafish Model.

Anxiety disorders are the most prevalent psychiatric disorders, exhibiting strong female bias. Clinical studies implicate declining estradiol levels in the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle. This study aimed to simulate estradiol fluctuation-linked anxiety behavior in larval zebrafish, using an estradiol treatment withdrawal model. Contrary to model aims, estradiol treatment withdrawal decreased both basal activity and anxiety-like hyperlocomotion (ANOVA main effect of dose, P < 0.0001 and P < 0.01, respectively) in the light/dark transition test. The accuracy of the estradiol washout model was not improved by longer durations of treatment or withdrawal. Basal activity was slightly altered by supraphysiological concentrations of WAY-200070 in the absence of added estradiol. Estrogen receptor (ER) ß expression was not upregulated in larvae exposed to physiologically relevant, low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity (P < 0.01). In addition, acute exposure to low concentrations of estradiol increased basal activity. Data suggest that in the current models, estradiol-associated altered activity levels were linked to more favorable redox status, rather than reflecting altered anxiety levels. As such, it is recommended that zebrafish larval behavioral analysis be conducted in parallel with mechanistic studies such as redox indicators, for investigations focused on ER signaling.

Patient Utilization of Weekend and Evening Appointments for Screening Mammography: An 8-Year Observational Cohort Study.

OBJECTIVE: To characterize the patient population using weekend and evening appointments for screening mammography versus standard appointment times across four outpatient facilities in our academic health system. METHODS: In this institutional review board-approved retrospective cohort study, there were 203,101 screening mammograms from 67,323 patients who had a screening mammogram performed at outpatient centers at a multisite academic institution from January 1, 2015, to December 31, 2022. Screening appointments were defined as "standard appointment time" (between 8 am and 5 pm on Monday through Friday) or "weekend or evening appointment time" (scheduled after 5 pm on Monday through Friday or at any time on a Saturday or Sunday). Associations between appointment group and patient characteristics were analyzed using univariate and multivariate logistic regression. RESULTS: Most screening mammograms (n = 185,436, 91.3%) were performed at standard times. The remainder (n = 17,665, 8.7%) were performed during weekends or evenings. As we created additional weekend and evening appointments after the coronavirus disease 2019 pandemic, the annual percentage of all screening mammograms performed on evenings and weekends increased. On multivariate analysis, when compared with standard appointment times, we found that patients who were younger than age 50 (P < .001), a race other than non-Hispanic White (P < .001), non-English speakers (P < .001), and from less advantaged zip codes (P < .03) were more likely to use weekend and evening appointment times compared with those aged 70 and above, non-Hispanic White patients, English speakers, and those from the most advantaged zip codes. CONCLUSIONS: Weekend and evening appointment availability for screening mammograms might improve screening access for all patients, particularly for those younger than age 50, those of races other than non-Hispanic White, and those from less advantaged zip codes.

Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Safety, timing, and outcomes of early post-operative cardiac catheterisation following congenital heart surgery.

OBJECTIVE: The safety of early post-operative cardiac catheterisation has been described following congenital heart surgery. Optimal timing of early post-operative cardiac catheterisation remains uncertain. The aim of this study was to describe the safety of early post-operative cardiac catheterisation and its impact on cardiac ICU and hospital length of stay, duration of mechanical ventilation, and extracorporeal support. METHODS: This single-centre retrospective cohort study compared clinical and outcome variables between "early" early post-operative cardiac catheterisation (less than 72 hours after surgery) and "late" early post-operative cardiac catheterisation (greater than 72 hours after surgery) groups using Chi-squared, Student's t, and log-rank test (or appropriate nonparametric test). RESULTS: In total, 132 patients were included, 22 (16.7%) "early" early post-operative cardiac catheterisation, and 110 (83.3%) "late" early post-operative cardiac catheterisation. Interventions were performed in 63 patients (51.5%), 7 (11.1%) early and 56 (88.9%) late. Complications of catheterisation occurred in seven (5.3%) patients, two early and five late. There were no major complications. Patients in the late group trended towards a longer stay in the cardiac ICU (19 days [7, 62] versus 11.5 days [7.2, 31.5], p = 0.6) and in the hospital (26 days [9.2, 68] versus 19 days [13.2, 41.8], p = 0.8) compared to the earlier group. CONCLUSION: "Early" early post-operative cardiac catheterisation was associated with an overall low rate of complications. Earlier catheterisations trended towards shorter cardiac ICU and hospital length of stays. Earlier catheterisations may lead to earlier recovery for patients not following an expected post-operative course.

Effects of diets supplemented with bioactive peptides on nutrient digestibility, immune cell responsiveness, and fecal characteristics, microbiota, and metabolites of adult cats.

Bioactive peptides (BP) are recognized for their ability to function as antioxidants and maintain lipid stability. They may have positive health effects, including antihypertensive, anti-inflammatory, antimicrobial, osteoprotective, gut health, and immunomodulatory properties, but are poorly tested in cats. Our primary objective was to determine the apparent total tract digestibility (ATTD) of BP-containing kibble diets and assess how the fecal characteristics, metabolites, and microbiota were affected in adult cats. Our secondary objective was to test whether BP could impact blood oxidative stress markers and cytokine concentrations following transport stress. Twelve adult cats (4.83 ± 0.37 yr; 4.76 ± 0.14 kg) were used in a replicated 4 × 4 Latin square design to test four extruded kibble diets: Control (no BP), Chicken (4% chicken BP), Marine1 (2% marine BP), and Marine2 (4% marine BP). Each experimental period lasted 28 d, with a 20-d adaptation phase, 5 d for fecal collection, 2 d for blood collection, and 1 d for transport stress testing (driven in vehicle in individual carriers for 45 min). Salivary cortisol and blood oxidative stress markers and cytokines were measured after transport. Fecal microbiota data were evaluated using 16S rRNA gene amplicon sequencing and QIIME2. All other data were analyzed using the Mixed Models procedure of SAS, with P < 0.05 being considered significant and P < 0.10 considered trends. No differences were observed in animal health outcomes, with all cats remaining healthy and serum metabolites remaining within reference ranges. Cats fed the Marine2 diet had higher (P < 0.05) ATTD of dry matter (84.5% vs. 80.9%) and organic matter (88.3% vs. 85.8%) than those fed the control diet. The ATTD of protein and energy tended to be higher (P < 0.10) for cats fed the Marine2 diet. Fecal characteristics, metabolites, and bacterial alpha and beta diversity measures were not affected by treatment. However, the relative abundances of six bacterial genera were different (P < 0.05) and two bacterial genera tended to be different (P < 0.10) across treatments. Treatment did not alter salivary cortisol, blood oxidative stress markers, or blood cytokines after transport stress. Our data suggest that BP inclusion may increase nutrient digestibility and modify fecal microbiota and immune measures. More testing is required, however, to determine whether BP may provide additional benefits to cats.

Dietary bioactive peptides (BP) may have positive health effects, but are poorly tested in cats. Our primary objective was to determine the apparent total tract digestibility of BP-containing kibble diets and assess how fecal characteristics, metabolites, and microbiota were affected in adult cats. Our secondary objective was to test whether BP could impact blood oxidative stress markers and cytokines following transport stress. Adult cats were used in a replicated 4 × 4 Latin square design to test four extruded kibble diets containing different BP concentrations. After diet adaptation, fecal and blood samples were collected and transport stress testing was done in each experimental period. All cats remained healthy and serum metabolites remained within reference ranges. Cats fed one of the BP diets had higher dry matter and organic matter digestibilities and tended to have higher protein and energy digestibilities. Fecal characteristics, metabolites, and microbiota diversity measures were not different, but the relative abundances of eight bacterial genera differed or tended to differ across treatments. Treatments did not alter oxidative stress markers after transport stress. Our data suggest that BP inclusion may increase nutrient digestibility and modify fecal microbiota. Further testing is required to determine whether BP provides additional benefits to cats.

Rotational spectroscopy of methyl tert-butyl ether with a new Ka band chirped-pulse Fourier transform microwave spectrometer.

Chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy is a powerful tool for performing broadband gas-phase rotational spectroscopy, and its applications include discovery of new molecules, complex mixture analysis, and exploration of fundamental molecular physics. Here we report the development of a new Ka band (26.5-40 GHz) CP-FTMW spectrometer that is equipped with a pulsed supersonic expansion source and a heated reservoir for low-volatility samples. The spectrometer is built around a 150 W traveling wave tube amplifier and has an instantaneous bandwidth that covers the entire Ka band spectral range. To test the performance of the spectrometer, the rotational spectrum of methyl tert-butyl ether (MTBE), a former gasoline additive and environmental pollutant, has been measured for the first time in this spectral range. Over 1000 spectroscopic transitions have been measured and assigned to the vibrational ground state and a newly-identified torsionally excited state; all transitions were fit using the XIAM program to a root-mean-square deviation of 22 kHz. The spectrum displays internal rotation splitting, nominally forbidden transitions, and an intriguing axis-switching effect between the ground and torsionally excited state that is a consequence of MTBE's extreme near-prolate nature. Finally, the sensitivity of the spectrometer enabled detection of all singly-substituted 13C and 18O isotopologues in natural abundance. This set of isotopic spectra allowed for a partial r0 structure involving the heavy atoms to be derived, resolving a structural discrepancy in the literature between previous microwave and electron diffraction measurements.

Glucocorticoid receptor and specificity protein 1 (Sp1) or Sp3, but not the antibiotic Mithramycin A, stimulates human alphaherpesvirus 1 (HSV-1) replication.

Following acute human alphaherpesvirus 1 (HSV-1) infection of oral-facial mucosal surfaces, sensory neurons in trigeminal ganglia (TG) are important sites for life-long latency. Neurons in the central nervous system, including brainstem, also harbor viral genomes during latency. Periodically, certain cellular stressors trigger reactivation from latency, which can lead to recurrent HSV-1 disease: herpes labialis, herpes stromal keratitis, and encephalitis for example. Activation of the glucocorticoid receptor (GR) by stressful stimuli enhances HSV-1 gene expression, replication, and explant-induced reactivation. GR and certain stress-induced Krüppel like factors (KLF) cooperatively transactivate cis-regulatory modules (CRM) that drive expression of viral transcriptional regulatory proteins (ICP0, ICP4, and ICP27). These CRMs lack GR response elements (GRE); however, specificity protein 1 (Sp1) binding sites are crucial for GR and KLF15 or KLF4 mediated transactivation. Hence, we tested whether Sp1 or Sp3 regulate viral replication and transactivation of the ICP0 promoter. During early stages of explant-induced reactivation from latency, the number of Sp3+ TG neurons were significantly higher relative to TG from latently infected mice. Conversely, Sp1+ TG neurons were only increased in females, but not male mice, during explant-induced reactivation. Sp1 siRNA significantly reduced HSV-1 replication in cultured mouse (Neuro-2A) and monkey (CV-1) cells. Mithramycin A, an antibiotic that has anti-tumor activity preferentially interacts with GC-rich DNA, including Sp1 binding sites, significantly reduced HSV-1 replication indicating it has antiviral activity. GR and Sp1 or Sp3 transactivated the HSV-1 ICP0 promoter in Neuro-2A and CV-1 cells confirming these transcription factors enhance viral replication and gene expression.

Cancer patients with clonal hematopoiesis die from primary malignancy or comorbidities despite higher rates of transformation to myeloid neoplasms.

BACKGROUND: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood. METHODS: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed. RESULTS: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL. CONCLUSIONS: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities.

Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm.

ABSTRACT: Therapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome-7 abnormalities (4% vs 13%; P = .005) but not complex karyotype (3% vs 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs 12%; P = .04) and lower NRAS (6% vs 22%, P = .007) and CBL (4% vs 12%, P = .04) mutation frequency. Prior therapy with antimetabolites (odd ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42; P = .01) and mitotic inhibitors (OR, 1.24; 95% CI, 1.06-1.44; P = .009) was associated with NF1 and SETBP1 mutations whereas prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71; 95% CI, 0.55-0.92; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (hazard ratio, 1.76; 95% CI, 1.07-2.89; P = .026). Compared with a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P < .001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Arterial blood gas measurements are different for brachycephalic and nonbrachycephalic dogs acclimatized to an altitude of 1,535 meters.

OBJECTIVE: To define reference intervals (RIs) for arterial blood gas (aBG) measurements in healthy, nonsedated, dolichocephalic, and mesocephalic (nonbrachycephalic) dogs at approximately 1,535 m above sea level and compare these findings with healthy, nonsedated, brachycephalic dogs living at the same altitude. ANIMALS: 120 adult nonbrachycephalic dogs and 20 adult brachycephalic dogs. METHODS: Cases were prospectively enrolled from October 2021 to June 2022. Dogs were enrolled from the community or after presentation for wellness examinations or minor injuries including lacerations, nail injuries, and lameness. Physical examinations and systolic blood pressure (sBP) measurements were obtained before blood sample collection. Arterial blood was collected from the dorsal pedal artery or femoral artery. After data collection, brachycephalic dogs underwent pre- and postexercise tolerance assessments. RESULTS: The mean and RI values for arterial pH (7.442; 7.375 to 7.515), partial pressure of oxygen in arterial blood (Pao2; 78.3; 59.2 to 92.7 mm Hg), partial pressure of carbon dioxide in arterial blood (Paco2; 28.0; 21.5 to 34.4 mm Hg), saturation of arterial oxygen (Sao2; 98.4; 84.3% to 101.4%), HCO3 (18.9; 14.9 to 22.4 mmol/L), concentration of total hemoglobin (ctHb; 17.5; 13.4 to 21.1 g/dL), and sBP (133; 94 to 180 mm Hg) were established for healthy nonbrachycephalic dogs at 1,535-m altitude. All aBG measurements were statistically and clinically different from those previously reported for dogs at sea level. Brachycephalic dogs had significantly lower Pao2 and Sao2 (P = .0150 and P = .0237, respectively) and significantly higher ctHb (P = .0396) compared to nonbrachycephalic dogs acclimatized to the same altitude; the nonbrachycephalic RIs were not transferable to the brachycephalic dogs for Pao2. CLINICAL RELEVANCE: This study represents the first collation of aBG measurements for healthy nonbrachycephalic dogs acclimatized to an altitude of 1,535 m. Additionally, this study identified differences in arterial oxygenation measurements between brachycephalic and nonbrachycephalic dogs. RIs in brachycephalic dogs need to be established.

Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.

PURPOSE: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. METHODS: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). RESULTS: Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. CONCLUSION: The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.

Associations between Missed Colonoscopy Appointments and Multiple Prior Adherence Behaviors in an Integrated Healthcare System: An Observational Study.

BACKGROUND: Missed colonoscopy appointments delay screening and treatment for gastrointestinal disorders. Prior nonadherence with other care components may be associated with missed colonoscopy appointments. OBJECTIVE: To assess variability in prior adherence behaviors and their association with missed colonoscopy appointments. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients scheduled for colonoscopy in an integrated healthcare system between January 2016 and December 2018. MAIN MEASURES: Prior adherence behaviors included: any missed outpatient appointment in the previous year; any missed gastroenterology clinic or colonoscopy appointment in the previous 2 years; and not obtaining a bowel preparation kit pre-colonoscopy. Other sociodemographic, clinical, and system characteristics were included in a multivariable model to identify independent associations between prior adherence behaviors and missed colonoscopy appointments. KEY RESULTS: The median age of the 57,590 participants was 61 years; 52.8% were female and 73.4% were white. Of 77,684 colonoscopy appointments, 3,237 (4.2%) were missed. Individuals who missed colonoscopy appointments were more likely to have missed a previous primary care appointment (62.5% vs. 38.4%), a prior gastroenterology appointment (18.4% vs. 4.7%) or not to have picked up a bowel preparation kit (42.4% vs. 17.2%), all p < 0.001. Correlations between the three adherence measures were weak (phi < 0.26). The rate of missed colonoscopy appointments increased from 1.8/100 among individuals who were adherent with all three prior care components to 24.6/100 among those who were nonadherent with all three care components. All adherence variables remained independently associated with nonadherence with colonoscopy in a multivariable model that included other covariates; adjusted odds ratios (with 95% confidence intervals) were 1.6 (1.5-1.8) for outpatient appointments, 1.9 (1.7-2.1) for gastroenterology appointments, and 3.1 (2.9-3.4) for adherence with bowel preparation kits, respectively. CONCLUSIONS: Three prior adherence behaviors were independently associated with missed colonoscopy appointments. Studies to predict adherence should use multiple, complementary measures of prior adherence when available.