Ivosidenib to treat adult patients with relapsed or refractory acute myeloid leukemia.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to alpha-ketoglutarate (alphaKG). Somatic point mutations in IDH1/2 that are found in rare distinct subsets of cancers confer a gain of function in cancer cells which results in the accumulation and secretion in vast excess of the oncometabolite D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. High levels of D-2HG inhibit alphaKG-dependent dioxygenases including histone, DNA and RNA demethylases, resulting in histone, DNA and RNA hypermethylation and cell differentiation blockade. In addition, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis, and is also predictive of clinical response. The U.S. Food and Drug Administration (FDA) approved ivosidenib, a mutant-IDH1 enzyme inhibitor, for patients with relapsed or refractory IDH1-mutated acute myeloid leukemia (AML) in 2018, and also as front-line therapy for newly diagnosed elderly patients 75 years or older or who are ineligible to receive intensive chemotherapy in 2019. Ivosidenib represents a novel drug class for targeted therapy in AML.

Increasing the angular sensitivity of two-dimensional photonic crystal based sensors to arbitrary values.

A new design of photonic crystal (PhC) for optical sensing using guided mode resonance (GMR) is presented. We theoretically show that angular sensitivity is inversely proportional to the group velocity of the probed mode and can be made arbitrarily high in a properly designed PhC. PhCs made in polycrystalline diamond on insulator are fabricated. The angular sensitivity dependence is validated. We measured modes with group velocity of c/80 at a wavelength of 800 nm. A sensitivity in the order of 500 ° per refractive index unit is inferred, a value much larger than the one usually encountered in PhCs.

Neurotensin receptor type 2 protects B-cell chronic lymphocytic leukemia cells from apoptosis.

B-cell chronic lymphocytic leukemia (B-CLL) cells are resistant to apoptosis, and consequently accumulate to the detriment of normal B cells and patient immunity. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors drives cell transformation, and thus plays a critical role in malignancies. In this study, we identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed in B-CLL cells, whereas expression of its natural ligand, neurotensin (NTS), was minimal in both B-CLL cells and patient plasma. Surprisingly, NTSR2 remained in a constitutively active phosphorylated state, caused not by a mutation-induced gain-of-function but rather by an interaction with the oncogenic tyrosine kinase receptor TrkB. Functional and biochemical characterization revealed that the NTSR2-TrkB interaction acts as a conditional oncogenic driver requiring the TrkB ligand brain-derived neurotrophic factor (BDNF), which unlike NTS is highly expressed in B-CLL cells. Together, NTSR2, TrkB and BDNF induce autocrine and/or paracrine survival pathways that are independent of mutation status and indolent or progressive disease course. The NTSR2-TrkB interaction activates survival signaling pathways, including the Src and AKT kinase pathways, as well as expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. When NTSR2 was downregulated, TrkB failed to protect B-CLL cells from a drastic decrease in viability via typical apoptotic cell death, reflected by DNA fragmentation and Annexin V presentation. Together, our findings demonstrate that the NTSR2-TrkB interaction plays a crucial role in B-CLL cell survival, suggesting that inhibition of NTSR2 represents a promising targeted strategy for treating B-CLL malignancy.

Surface-sensitive diamond photonic crystals for high-performance gas detection.

Diamond slotted photonic crystal (PhC) cavities were fabricated and used for gas detection. They exhibit wavelength sensitivity reaching a 350 nm per unit change of the refractive index of the gaseous environment of the PhC. With a simple oxidized surface termination, diamond PhCs display an ultrahigh sensitivity to the surface adsorption of polar molecules. Gaseous concentrations as low as 80 parts per million (ppm) of hexanol vapor in nitrogen are probed, and a detection limit in the ppm range is inferred, demonstrating a high interest of such devices for trace sensing.

[Thrombopenia and the nature of the microorganism in infected critically ill children]. / Thrombopénie et nature des germes infectants en réanimation pédiatrique.

BACKGROUND: Thrombopenia is correlated with sepsis and mortality in pediatric intensive care units. The purpose of this study was to find an association between thrombopenia and the microorganism type to guide the choice of empiric antibiotic therapy in infected critically ill children. MATERIALS AND METHODS: We conducted a prospective descriptive study, including all newborns, infants, and children admitted to a pediatric surgical intensive care unit from 1st January to 31st December 2009. We identified patients who developed an infection and/or thrombopenia (platelet count less than 100,000/mm(3)) during hospitalization. RESULTS: One hundred ninety-seven patients were included (57 newborns, 41 infants, 99 children). Ninety patients developed 100 infectious episodes during the study period. Of the 57 newborns enrolled in the study, 31 (54%) developed 37 infections. Seventy-six microorganisms (55 Gram-negative bacilli [GNB], 17 Gram-positive cocci, two Gram-negative cocci, two fungal pathogens) were identified during 65 infectious episodes in 55 patients. Thirty-four episodes of thrombopenia were observed in 30 patients. Thrombopenia was observed only in infected patients (P<0.001). Thrombopenia was associated with infections caused by GNB (26/28 vs 20/37, P=0.001) and by Klebsiella (16/28 vs 6/37, P=0.001) and may be associated with infections caused by GNB producing extended-spectrum beta-lactamases (P=0.07). Gram-positive cocci infections were correlated to the non-occurrence of thrombopenia (P=0.02). Postoperative peritonitis was also significantly associated with thrombopenia (P=0.03). The mortality rate in our patients was 12.7% (22.8% in neonates). There was an association between thrombopenia and death in univariate analysis (11/25 vs 19/172, P<0.001). Multivariate logistic regression analysis did not confirm thrombopenia as an independent predictive factor of mortality in children. CONCLUSION: Because of the relatively high proportion of resistant GNB, an empiric antibiotic therapy combining a carbapenem and an aminoglycoside may be indicated in infected critically ill children developing thrombopenia.

A quality control program for acute pain management in out-of-hospital critical care medicine.

STUDY OBJECTIVE: This study was conducted to evaluate a quality control program for improving pain treatment in the out-of-hospital setting. METHODS: Pain was evaluated for all patients at the beginning (T(0)) and the end (T(end)) of out-of-hospital management. During the first part of the study (part 1, n=108), the administration and choice of analgesics was left to the physician's discretion. Pain protocols were then modified to encourage the use of opioids. The effectiveness of this new pain management was analyzed (part 2, n=105) using pain scales and quality of relief. RESULTS: Seventy percent of patients who expressed meaningful pain did not request analgesia, and 36% did not receive any analgesia in part 1 in contrast to 7% in part 2 of the study. The verbal rating scale and visual analog scale scores were substantially improved at T(end) versus T(0) in both periods, but the improvement was greater in part 2 (mean visual analog scale score at T(end) was 29.3+/-23 mm [+/-SD]) than in part 1 (38.6+/-25 mm). The percentage of patients who expressed satisfactory relief increased in part 2 (67% versus 49% in part 1). The mean dose of intravenous morphine was 7.2+/-6 mg. Adverse effects were rare and minor. CONCLUSION: This program focusing on pain treatment plus implementation of pain protocols (with intravenous morphine) improved pain management in the field.

Extracorporeal shock wave lithotripsy: multicenter study of kidney and upper ureter versus middle and lower ureter treatments.

Six institutions throughout the United States participated in this study. Each center used a multifunctional flat table lithotriptor (Dornier MFL-5000) to treat 658 patients with kidney and upper ureteral stones (766 treatments) and 323 with middle and lower ureteral stones (391 treatments), for a total of 925 patients (1,157 treatments). Some patients received more than 1 treatment (that is the kidney and ureter), for a total of 981 patient events. Complete followup was available for 81% of the patients. The overall stone-free rate at followup of approximately 90 days was greater in the middle and lower ureter group (83%) than in the kidney and upper ureter group (67%). The proportion of single stones treated was greater for the former group (89.5%) than for the latter group (72%). A larger proportion (18%) of the middle and lower ureter group required 2 or more treatments to the targeted stone than did the kidney and upper ureter group (13%). Anesthesia was required or selected in only 26.7% of the kidney and upper ureteral stone patients and in 18.5% of those with middle and lower ureteral calculi, usually at the request of the patient or physician, or for performance of an adjunctive procedure. The relative safety of this treatment is demonstrated by a low overall rate of complications reported during and after treatment, including a ureteral obstruction rate of 2.1% for kidney and upper ureteral stones and 2.5% for middle and lower ureteral stones. There were no demonstrated trends in a review of laboratory data to suggest significant treatment side effects. The diastolic blood pressure increased to more than 95 mm. Hg after extracorporeal shock wave lithotripsy (ESWL*) in 6% of the kidney and upper ureteral and 4% of the middle and lower ureteral stone patients, while pretreatment hypertension resolved after ESWL in 11% of both groups. The results of this clinical evaluation indicate somewhat greater effectiveness for the specified indications of ESWL of stones in the ureter below the upper rim of the bony pelvis, as opposed to those in the kidney and upper ureter, with a low incidence of complications and side effects.

Management of lower and middle ureteral calculi "in situ" using the Dornier MFL-5000 lithotripter.

A new successful approach in treating lower and middle ureteral calculi in situ was undertaken utilizing the Dornier MFL-5000. From August 19, 1989 to February 7, 1990, 46 consecutive cases were treated representing 60 stones (54 lower, 6 middle). The average size of treated stones was 12 mm. Ten cases (21.1%) had two stones and two cases (4.2%) had three stones. Stones were not displaced and no ureteral catheter was used except in one case, a female, 28 years of age, with a lower ureteral stone, where the stone had to be displaced proximally using a double balloon ureteral catheter to follow FDA protocol in order to avoid the ovaries. Minimal IV sedation was required in 97.7% of the patients and only 2.1% required general anesthesia. Different positioning techniques were implemented. One (2.1%) out of 46 cases required retreatment. The average length of stay in the hospital was 1.2 days. No complications occurred to date. Follow-up, 48 hours post-treatment, revealed 94.6% stone-free. At 3 month's follow-up, 100% were stone-free.