Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.     

Type II enteropathy-associated T-cell lymphoma: a multicenter analysis from the Asia Lymphoma Study Group

Enteropathy‐associated T‐cell lymphoma (EATL) is a rare primary gastrointestinal T‐cell lymphoma. A multicenter study from the Asia Lymphoma Study Group identified 38 EATL patients within a 19‐year period. All cases were type II EATL. Men were affected twice as common as women, at a median age of 59 (23–89) years. None had a history of celiac disease. The sites of involvement were small bowel and stomach (5%), small bowel (63%), small and large bowel (16%), and large bowel (18%). Common presenting features were bowel perforation (34%), pain (32%), and obstruction (21%). Lymphomas showed monomorphic neoplastic lymphoid infiltrates that were CD3⁺ (100%), CD56⁺ (91%), TIA‐1⁺ (96%), CD4^–CD8⁺ (63%), CD4⁺CD8⁺ (19%), CD4^–CD8^– (16%), and CD4⁺CD8^– (3%). Epstein Barr virus was demonstrable in three cases. Despite chemotherapy and/or surgical resection, the overall response and complete response rates were poor at 46% and 38%. The median overall survival (OS) was 7 months and progression‐free‐survival (PFS) 1 month. Five patients underwent hematopoietic stem cell transplantation all were alive. Age and the prognostic index for peripheral T‐cell lymphoma were not prognostically significant. Good performance status was associated with better OS (P = 0.03), and response to initial treatment led to better OS and PFS (P < 0.001). Am. J. Hematol. 87:663–668, 2012. © 2012 Wiley Periodicals, Inc.     

Prognostic role of adjuvant radiotherapy in triple‐negative breast cancer: A historical cohort study

The value of adjuvant radiotherapy in triple‐negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast‐conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23–96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node‐negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline‐based regimes. In 775 women with T1‐2, N0‐1, M0 TNBCs, 5‐year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8–98.8%), followed by BCT (90.8%, 95% CI: 85.0–94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4–88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3‐4, N2‐3, M0 TNBCs, BCT was associated with highest 5‐year RSR (94.1%, 95% CI: 81.3–99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3–70.1%), and mastectomy only (58.6%, 95% CI: 43.5–71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.     

“It ain't over … till it's over!” Risk-mitigation strategies for patients with gastrointestinal diseases in the aftermath of the COVID-19 pandemic

The available COVID-19 literature has focused on specific disease manifestations, infection control, and delivery or prioritization of services for specific patient groups in the setting of the acute COVID-19 pandemic. Local health systems aim to contain the COVID-19 pandemic and hospitals and health-care providers rush to provide the capacity for a surge of COVID-19 patients. However, the short, medium-term, and long-term outcomes of patients with gastrointestinal (GI) diseases without COVID-19 will be affected by the ability to develop locally adapted strategies to meet their service needs in the COVID-19 setting. To mitigate risks for patients with GI diseases, it is useful to differentiate three phases: (i) the acute phase, (ii) the adaptation phase, and (iii) the consolidation phase. During the acute phase, service delivery for patients with GI disease will be curtailed to meet competing health-care needs of COVID-19 patients. During the adaptation phase, GI services are calibrated towards a “new normal,” and the consolidation phase is characterized by rapid introduction and ongoing refinement of services. Proactive planning with engagement of relevant stakeholders including consumer representatives is required to be prepared for a variety of scenarios that are dictated by thus far undefined long-term economic and societal impacts of the pandemic. Because substantial changes to the delivery of services are likely to occur, it is important that these changes are embedded into quality and research frameworks to ensure that data are generated that support evidence-based decision-making during the adaptation and consolidation phases.     

Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics

With noncommunicable diseases (NCDs) now constituting the majority of global mortality, there is a growing need for low-cost, noninvasive methods to diagnose and treat this class of diseases, especially in resource-limited settings. Molecular biomarkers combined with low-cost point-of-care assays constitute a potential solution for diagnosing NCDs, but the dearth of naturally occurring, predictive markers limits this approach. Here, we describe the design of exogenous agents that serve as synthetic biomarkers for NCDs by producing urinary signals that can be quantified by a companion paper test. These synthetic biomarkers are composed of nanoparticles conjugated to ligand-encoded reporters via protease-sensitive peptide substrates. Upon delivery, the nanoparticles passively target diseased sites, such as solid tumors or blood clots, where up-regulated proteases cleave the peptide substrates and release reporters that are cleared into urine. The reporters are engineered for detection by sandwich immunoassays, and we demonstrate their quantification directly from unmodified urine; furthermore, capture antibody specificity allows the probes to be multiplexed in vivo and quantified simultaneously by ELISA or paper lateral flow assay (LFA). We tailor synthetic biomarkers specific to colorectal cancer, a representative solid tumor, and thrombosis, a common cardiovascular disorder, and demonstrate urinary detection of these diseases in mouse models by paper diagnostic. Together, the LFA and injectable synthetic biomarkers, which could be tailored for multiple diseases, form a generalized diagnostic platform for NCDs that can be applied in almost any setting without expensive equipment or trained medical personnel.In the last several decades, global health challenges have dramatically shifted, with substantial reductions in the burden of infectious diseases (e.g., HIV, tuberculosis, and malaria) and simultaneous growth in the prevalence of noncommunicable diseases (NCDs) such as stroke, heart disease, and cancer, which constitute an increasing majority of global mortality (1, 2). Strikingly, NCDs disproportionately affect the developing world: low- and middle-income countries bear nearly 80% of the world’s NCD burden (3), and cardiovascular diseases and cancer have been the first and second, respectively, highest causes of mortality in the developing world since 2001 (4). Diagnosing NCDs in remote and/or poor settings is difficult without access to costly imaging modalities [e.g., computed tomography (CT)/MRI], well-equipped clinical laboratories (e.g., for histopathology), and trained medical personnel. Consequently, developing diagnostics for NCDs that are cost effective and can be easily implemented remains an important goal in global health. One promising approach is to detect disease biomarkers from readily accessible bodily fluids with point-of-care (POC) devices that are inexpensive, noninvasive, and do not require trained medical personnel. Despite widespread interest, the lack of predictive, validated biomarkers significantly limits the types of NCDs that can be detected at the POC (5–7).Rather than searching for endogenous biomarkers, a promising strategy is to engineer exogenous agents that can specifically probe for the presence of diseased tissue. Radiolabeled glucose is an example of a common exogenous agent used with PET to reveal the location of metabolically active tumors. Inspired by engineered approaches, our group recently outlined a framework whereby protease-sensitive nanoparticles (NPs) called “synthetic biomarkers” are administered to detect NCDs including liver fibrosis, cancer, and thrombosis noninvasively (8, 9). These peptide-coated NPs probe diseased sites and, in response to cleavage by local dysregulated proteases, release mass-encoded reporters that then filter into the urine for analysis by mass spectrometry. In practice, administering NPs and collecting urine samples are both well-suited for the POC, but the need for a mass spectrometer to analyze the urinary cleavage fragments limits the utility of mass-encoded synthetic biomarkers for global health applications.To address these difficulties, we reformulated our synthetic biomarkers to release ligand-encoded reporters designed for detection by a companion POC diagnostic comprised of paper test strips, a well-established technology used to screen and monitor diseases with readily available biomarkers (10, 11). The benefits of paper testing include low cost, rapid diagnosis, and no need for complex equipment or technical expertise (11, 12). Paper tests operate by wicking a biological specimen (commonly urine, saliva, or blood) containing a target analyte to regions where subsequent chemical or antibody-mediated analyses are detected by direct observation (13) or inexpensive and accessible quantitative imaging (14–16). Recently, paper diagnostics have been developed for quantitative assays like monitoring transaminases released by liver damage (13) or detecting infectious diseases like HIV-1, malaria, or trichinellosis (17). Unfortunately, the scarcity of naturally occurring biomarkers has limited use of paper diagnostics for NCDs. Consequently, combining paper diagnostics with synthetic biomarkers that sensitively and specifically indicate disease from the urine may provide a simple and low-cost method to diagnose NCDs in resource-limited settings.To pursue the goal of developing affordable POC tests for NCDs, we engineer synthetic biomarkers to detect thrombosis and colorectal cancer (CRC) from the urine by custom lateral flow assay (LFA), a variant of paper tests. Thrombosis, the formation of obstructive blood clots, occurs in many cardiovascular-associated disorders (e.g., stroke and heart attack) and is characterized by the activation of the plasma protease thrombin that mediates fibrin clot formation. In CRC and most solid cancers, tumors produce matrix metalloproteinases (MMPs) to facilitate growth, angiogenesis, and metastatic spread (18). To detect these diseases, we develop thrombin- and MMP-sensitive NPs by conjugating substrate–reporter tandem peptides to the surface of NPs (Fig. 1A). When administered, these NPs probe diseased tissues (blood clots or tumors) where local up-regulated proteases (thrombin or MMPs, respectively) cleave their surface coat of peptides, releasing reporters that are concentrated into the urine. The urinary reporters are functionalized with structurally distinct ligands for capture onto paper test strips adsorbed with ligand-binding antibodies (Fig. 1B). Beyond thrombosis and CRC, this approach may be amenable to many noncommunicable and infectious diseases in which aberrant protease activities are implicated.Open in a separate windowFig. 1.Protease-sensitive NPs for POC urinary monitoring of disease. (A) Synthetic biomarkers were synthesized by conjugating substrate–reporter tandem peptides to carrier iron oxide NWs. Proteolytic cleavage of the linking peptide substrate liberates ligand-encoded reporters that filter into urine. (B) (I) A patient suspected of harboring a disease receives a disease-tuned diagnostic nanoworm (NW) mixture. (II) NWs infiltrate the disease site and release reporters upon proteolytic cleavage of peptide substrates. Although intact NWs are too large to pass the glomerular basement membrane, liberated reporters passively filter through the kidney. (III) The patient collects a urine sample. (IV) Application of unprocessed urine to a low-cost POC paper lateral flow assay (LFA) enables diagnosis.     

Endomyocardial Implantation of Autologous Bone Marrow Mononuclear Cells in Advanced Ischemic Heart Failure: a Randomized Placebo-Controlled Trial (END-HF)

Prior studies suggest that endomyocardial implantation of autologous bone marrow (BM) mononuclear cell therapy improves symptoms and left ventricular (LV) function in patients with refractory angina; however, the therapeutic efficacy in patients with ischemic cardiomyopathy is unclear. In a randomized, double-blind, placebo-controlled trial, 28 patients with advanced ischemic cardiomyopathy [New York Heart Association III-IV, LV ejection fraction (LVEF) <40 %] were assigned in 2:1 ratio to receive endomyocardial injection of BM cells (100 million, n?=?19) or placebo (n?=?9), guided by electroanatomical mapping. After 6 months, there was no significant difference between the two groups in LV ejection fraction (LVEF) and LV end-systolic volume (LVESV), LV infarct volume, and LV peri-infarct ischemic volume as determined by cardiac magnetic resonance imaging or exercise capacity. In conclusion, endomyocardial implantation of autologous BM mononuclear cells did not improve LV function or remodeling in patients with advanced ischemic cardiomyopathy.     

Prevention and caries risk management in teenage and orthodontic patients

As patients progress from childhood through to teenage years, they progress through periods of high caries risk as they undergo changes in lifestyle and oral microflora. Removable or fixed orthodontic treatment also alters the oral microflora and can dramatically increase caries risk. This paper outlines ways to identify the transition to higher caries risk, and practical ways to lower the risk of hard tissue loss from dental caries during orthodontic treatment across the teenage years, including tooth surface protection, optimised use of mechanical and chemical plaque control, and appropriate delivery of remineralising agents over time.