Citations

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

AbstractIntroductionReticulated platelet (RP) content is increased in nonvalvular atrial fibrillation (NVAF). The purpose of this study was to determine if platelet content, morphology, and RP proportion are modulated by platelet genes.Methods and resultsExpression of six platelet‐predominate genes impacting platelet formation and release, platelet count, and RP content was assessed in NVAF patients before and 3–4 months after pulmonary veins isolation (PVI) and compared to normal sinus rhythm (NSR) controls. RNA from isolated platelets was reverse‐transcribed assayed against selected genes utilizing real‐time qPCR, and expressed as mean cycle threshold (ΔCt) using beta‐2‐microglobulin as endogenous control. RP content was assessed by flow cytometry. A fourfold lower expression of CFL1 gene coding for nonmuscle cofilin (7.8 ± 0.9 vs. 5.7 ± 1.6, P < 0.001) and twofold lower expression of four other genes were associated with similar platelet counts but fourfold higher (28.7+7.0 vs. 6.7+5.4, P < 0.001) RP content (%) in 97 NVAF cases compared to 51 NSR controls. Three to 4 months after PVI, RP decreased by 28%, while CFL1 gene expression increased over twofold but TUBA4A gene expression decreased almost twofold; NFE2 and MYL6 gene expression remained unchanged.ConclusionsNVAF is associated with notable downregulation of genes directing platelet production and size but increased RP content. PVI impacts the expression of many of these genes, implying a direct relationship between atrial fibrillation and platelet biogenesis.

Objectives: To determine whether fixation of pertrochanteric hip fractures with cephalomedullary nails (CMNs) with a neck-shaft angle (NSA) less than the native NSA affects reduction and lag screw cutout. Design: Retrospective comparative study. Setting: Level I trauma center. Patients/Participants: Patients treated with a CMN for unstable pertrochanteric femur fractures (OTA/AO 31-A2.2 and 31-A2.3) between 2005 and 2014. Intervention: CMN fixation. Main Outcome Measurement: NSA reduction and lag screw cutout. Results: Patients fixed with a nail angle less than their native NSA were less likely to have good reductions [17% vs. 60%, 95% confidence interval (CI), −63% to −18%; P = 0.0005], secondary to more varus reductions (41% vs. 10%, 95% CI, 9%–46%; P = 0.01) and more fractures with ≥4 mm of displacement (63% vs. 35%, 95% CI, 3%–49%; P = 0.03). The cutout was not associated with the use of a nail angle less than the native NSA (60% vs. 76%, 95% CI, −56% to 18%; P = 0.5), varus reductions (60% vs. 32%, 95% CI, −13% to 62%; P = 0.3), or poor reductions (20% vs. 17%, 95% CI, −24% to 44%; P = 1.0). Conclusions: The fixation of unstable pertrochanteric hip fractures with a nail angle less than the native NSA was associated with more varus reductions and fracture displacement but did not affect the lag screw cutout. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Key Points RP2D of PEV 20 mg/m2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT. In treatment-naive older AML patients, the intent-to-treat ORR was 50%.

SEEK and you may find cancer earlier Many cancers can be cured by surgery and/or systemic therapies when detected before they have metastasized. This clinical reality, coupled with the growing appreciation that cancer's rapid genetic evolution limits its response to drugs, have fueled interest in methodologies for earlier detection of the disease. Cohen et al. developed a noninvasive blood test, called CancerSEEK that can detect eight common human cancer types (see the Perspective by Kalinich and Haber). The test assesses eight circulating protein biomarkers and tumor-specific mutations in circulating DNA. In a study of 1000 patients previously diagnosed with cancer and 850 healthy control individuals, CancerSEEK detected cancer with a sensitivity of 69 to 98% (depending on cancer type) and 99% specificity. Science , this issue p. 926 ; see also p. 866

New Findings What is the central question of this study? Premenopausal women have an attenuated inspiratory muscle metaboreflex‐induced increase in arterial blood pressure compared with men. It is unclear whether sympathetic vasomotor outflow during dynamic exercise with increased inspiratory muscle activation is less in young women than in men. What is the main finding and its importance? The magnitude of increased sympathetic vasomotor outflow during leg cycling with inspiratory resistance was smaller in women than in men. Less sympathetic vasomotor outflow with inspiratory muscle metaboreflex activation could be one of the mechanisms for the attenuated inspiratory muscle‐induced metaboreflex during exercise in young women. AbstractWe compared changes in muscle sympathetic nerve activity (MSNA) and cardiovascular variables during leg cycle exercise with increased inspiratory muscle resistance in men and women. We hypothesized that sympathetic vasomotor outflow during exercise with increased inspiratory resistance would be attenuated in young women compared with age‐matched men. Eight women and seven men completed the study. The subjects performed two 10 min exercise bouts at 40% peak oxygen uptake using a cycle ergometer in a semirecumbent position [spontaneous breathing for 5 min and voluntary hyperventilation with or without inspiratory resistive breathing for 5 min (breathing frequency 50 breaths min−1 with a 50% duty cycle; inspiratory resistance 30% of maximal inspiratory pressure)]. Mean arterial blood pressure (MAP) was acquired using finger photoplethysmography. The MSNA was recorded via microneurography of the right median nerve at the cubital fossa. During leg cycle exercise with inspiratory resistive breathing, MSNA burst frequency was increased, accompanied by an increase in MAP in both men and women. Women, compared with men, had less of an increase in MAP (women +22.8 ± 12.3 mmHg versus men +32.2 ± 5.4 mmHg; P < 0.05) and MSNA burst frequency (women +9.6 ± 2.9 bursts min−1 versus men +14.6 ± 6.4 bursts min−1; P < 0.05). These results suggest that the attenuated inspiratory muscle‐induced metaboreflex during exercise in young women is attributable, in part, to a lesser sympathetic vasomotor outflow compared with men.

scikit-image is an image processing library that implements algorithms and utilities for use in research, education and industry applications. It is released under the liberal "Modified BSD" open source license, provides a well-documented API in the Python programming language, and is developed by an active, international team of collaborators. In this paper we highlight the advantages of open source to achieve the goals of the scikit-image library, and we showcase several real-world image processing applications that use scikit-image.

scikit-image is an image processing library that implements algorithms and utilities for use in research, education and industry applications. It is released under the liberal "Modified BSD" open source license, provides a well-documented API in the Python programming language, and is developed by an active, international team of collaborators. In this paper we highlight the advantages of open source to achieve the goals of the scikit-image library, and we showcase several real-world image processing applications that use scikit-image.

Acquired angioedema due to C1 inhibitor deficiency (C1INH-AAE) is a rare and potentially fatal syndrome of bradykinin-mediated angioedema characterized by episodes of angioedema without urticaria. It typically manifests with nonpitting edema of the skin and edema in the gastrointestinal (GI) tract mucosa or upper airway. Edema of the upper airway and tongue may lead to life-threatening asphyxiation. C1INH-AAE is typically under-diagnosed because of its rarity and its propensity to mimic more common abdominal conditions and allergic reactions. In this article, we present the case of a 62-year-old male with a history of recently diagnosed chronic lymphocytic leukemia (CLL) who presented to our hospital with recurrent abdominal pain, initially suspected to haveClostridium difficilecolitis and diverticulitis. He received a final diagnosis of acquired angioedema due to C1 esterase inhibitor deficiency due to concomitant symptoms of lip swelling, cutaneous nonpitting edema of his lower extremities, and complement level deficiencies. He received acute treatment with C1 esterase replacement and icatibant and was maintained on C1 esterase infusions. He also underwent chemotherapy for his underlying CLL and did not experience further recurrence of his angioedema.