Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07-0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

Kidney transplantation in patients with multiple myeloma: narrative analysis and review of the last two decades.

There have been significant advances in the treatment of multiple myeloma in the last two decades. Approximately 25% of patients with newly diagnosed myeloma have some degree of kidney impairment. During the course of illness, nearly 50% of myeloma patients will develop kidney disease. Moreover, ∼10% of myeloma patients have advanced kidney disease requiring dialysis at presentation. Hemodialysis is associated with a significantly reduced overall survival (OS). In the setting of prolonged long-term OS due to the use of newer immunotherapeutic agents in the treatment of myeloma, patients with myeloma and advanced kidney disease may benefit from more aggressive management with kidney transplantation (KTx). Unfortunately, most data regarding outcomes of KTx in patients with myeloma come from single-center case series. With the advent of novel treatment choices, it remains unclear if outcomes of kidney transplant recipients with myeloma have improved in recent years. In this descriptive systematic review, we coalesced published patient data over the last 20 years to help inform clinicians and patients on expected hematologic and KTx outcomes in this complex population. We further discuss the future of KTx in patients with paraproteinemia.

SKP2 Activation by Thyroid Hormone Receptor ß2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells.

Germline RB1 mutations strongly predispose humans to cone precursor-derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type-specific circuitry that sensitizes these different cell types to the loss of RB1 has not been defined. Here we show that the cell type-restricted thyroid hormone receptor isoform TRß2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor-suppressive TRß1. TRß2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for RB1-mutant tumors, by enabling EMI1/FBXO5-dependent inhibition of SKP2 degradation. In RB1 wild-type neuroblastoma cells, endogenous Rb or ectopic TRß2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRß1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRß2 counteracts TRß1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies. Cancer Res; 77(24); 6838-50. ©2017 AACR.

Assessment of image quality in real time three-dimensional dobutamine stress echocardiography: an integrated 2D/3D approach.

BACKGROUND: Three-dimensional (3D) stress echocardiography is a relatively new technique offering the potential to acquire images of the entire left ventricle from 1 or 2 transducer positions in a time-efficient manner. Relative to two-dimensional (2D) imaging, the ability to quickly acquire full volume images during peak stress with 3D echocardiography can eliminate left ventricular (LV) foreshortening while reducing inter-operator variability. Our objectives were to (1) determine the practicality of a novel integrated 2D/3D stress protocol in incorporating 3D imaging into a standard 2D stress echocardiogram and (2) to determine whether the quality of imaging using the novel 2D/3D protocol was sufficient for interpretation. METHODS: Twenty-five patients referred for stress echocardiography underwent an integrated 2D/3D image acquisition protocol. LV segments were scored from 0 (absent or no clear endocardial visualization) to 3 (excellent/full visualization of endocardial border) with each modality. 2D segment quality scoring was compared with 3D. An integrated score was compared with either 2D or 3D imaging alone. RESULTS: Two-dimensional and 3D imaging were optimal for differing segments and the integrated protocol was superior to either modality alone. 3D imaging was superior in visualizing the anterior and anterolateral region of the base segments, compared to 2D imaging. 3D imaging was less useful for the base, the mid-inferior, and the inferoseptal segments, thus emphasizing the need to retain 2D imaging in stress echocardiography at this time. CONCLUSION: The integrated 2D/3D protocol approach to stress echocardiography is technically feasible and maximizes image quality of dobutamine stress echocardiography, improving patient assessment.

Can carotid bulb plaque assessment rule out significant coronary artery disease? A comparison of plaque quantification by two- and three-dimensional ultrasound.

BACKGROUND: Screening tools for the detection of coronary artery disease (CAD) are of considerable interest in light of skyrocketing risk factors. Recent work suggests that carotid plaque has a relatively unexplored role in CAD risk prediction but has previously been limited by the difficulty in quantifying its irregular architecture using two-dimensional (2D) ultrasound. The aim of this study was to investigate the utility of a novel automated three-dimensional (3D) ultrasound-based carotid plaque volume quantification technique as a negative predictor of CAD. METHODS: In this prospective study, 70 consecutive patients referred for coronary angiography underwent same-day 2D and 3D carotid ultrasound scans for the purpose of plaque quantification in the carotid bulbs. Two-dimensional plaque thickness was measured in its maximal value perpendicular to the vessel wall. Total 3D plaque volume was quantified using a stacked-contour method. Luminal narrowing of coronary arteries was analyzed using the established 16-segment model for coronary arteries to produce an overall angiographic score. Receiver operating characteristic curves, negative predictive value, and sensitivity of 2D and 3D plaque quantification relative to coronary angiography were determined. RESULTS: The novel 3D carotid ultrasound method resulted in a higher negative predictive value and sensitivity relative to 2D carotid ultrasound at their optimal thresholds as determined by Youden indices of receiver operating characteristic curves. In particular, total 3D plaque volumes less than the threshold of 0.09 mL accurately predicted the absence of significant CAD in 93.3% of patients (98.0% sensitivity), whereas maximal 2D plaque thickness less than the threshold of 1.35 mm provided significantly lower negative predictability at 75% (93.9% sensitivity). CONCLUSIONS: Using the determined threshold of 0.09 mL for plaque volumes, this feasibility study suggests that automated 3D ultrasound-based carotid plaque quantification may serve as an important clinical screening tool to help identify patients who are at low risk for significant CAD.

Development of BMP7-producing human cells, using a third generation lentiviral gene delivery system.

Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor ß (TGF-ß) superfamily, plays important roles in the development of various tissues and organs in mouse and human. In particular, BMP7 is critical for the formation of the nervous system and it is considered to have therapeutic potential in brain injury and stroke. One approach to make BMP7 more suitable for therapeutic purposes is the development of efficient vectors that allow the consistent, reliable and cost-effective production of the BMP7 protein. In this study, we developed an efficient BMP7 delivery system, using a third generation lentiviral vector to produce functional BMP7 protein. The lentiviral transduction of several human cell types, including human embryonic kidney 293 (HEK293) cells, amniotic fluid cells, NTera2 neurons (NT2-N) and primary neuronal cultures resulted in BMP7 expression. The production of BMP7 protein was achieved for at least 4 weeks post-transduction, as determined by enzyme-linked immunosorbent assay (ELISA). SMAD phosphorylation and neuronal differentiation assays verified the bioactivity and functionality of the lentiviral-based BMP7 protein, respectively. In addition, the intracerebroventricular injection of the lentivirus resulted in exogenous BMP7 expression in both neurons and astrocytes in the mouse brain. Taken together, this gene delivery system provides a reliable source of functional BMP7 protein for future in vitro and in vivo studies.

DNA barcoding of oomycetes with cytochrome c oxidase subunit I and internal transcribed spacer.

Oomycete species occupy many different environments and many ecological niches. The genera Phytophthora and Pythium for example, contain many plant pathogens which cause enormous damage to a wide range of plant species. Proper identification to the species level is a critical first step in any investigation of oomycetes, whether it is research driven or compelled by the need for rapid and accurate diagnostics during a pathogen outbreak. The use of DNA for oomycete species identification is well established, but DNA barcoding with cytochrome c oxidase subunit I (COI) is a relatively new approach that has yet to be assessed over a significant sample of oomycete genera. In this study we have sequenced COI, from 1205 isolates representing 23 genera. A comparison to internal transcribed spacer (ITS) sequences from the same isolates showed that COI identification is a practical option; complementary because it uses the mitochondrial genome instead of nuclear DNA. In some cases COI was more discriminative than ITS at the species level. This is in contrast to the large ribosomal subunit, which showed poor species resolution when sequenced from a subset of the isolates used in this study. The results described in this paper indicate that COI sequencing and the dataset generated are a valuable addition to the currently available oomycete taxonomy resources, and that both COI, the default DNA barcode supported by GenBank, and ITS, the de facto barcode accepted by the oomycete and mycology community, are acceptable and complementary DNA barcodes to be used for identification of oomycetes.