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The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes.We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects.The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16%; PR was 6%; Median OS was 16.4 months; median DOR was 10.1 months; median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%.The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS.

Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy.We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing.Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed.The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response.Takeda Oncology and Amgen.

Single-agent hypomethylating agents remain the cornerstone of treatment for patients with high-risk myelodysplastic syndromes. Although these agents have clinical activity and can improve the overall survival of these patients, their impact on the natural history of myelodysplastic syndromes is only partial. Therefore, we need either newer agents or combinations that could have a greater impact on the survival of our patients. Over the past decade there has been an increased effort in drug development for myelodysplastic syndromes. Hypomethylating agent combinations that have been explored over the past decade include agents that block mutant TP53, NEDD inhibitors, BCL-2 inhibitors, and antibodies such as sabatolimab or magrolimab. Despite initial encouraging results, two registration trials from 2021 and 2022 have not been successful in improving outcomes when compared with single-agent hypomethylating agents. Here, I summarise the current status of ongoing phase 3 trials for patients with untreated high-risk myelodysplastic syndromes and provide some suggestions for future designs.

Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes.We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients.Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related.Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia.Amgen.

Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival.The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13).Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials.None.

Epigenetic dysregulation leads to aberrant DNA hypermethylation and is common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). A large number of clinical trials in AML, MDS, and other hematologic malignancies have assessed hypomethylating agents (HMAs), used alone or in combination with other drugs, in the frontline, maintenance, relapsed/refractory, and peritransplant settings. Effective maintenance therapy has long been a goal for patients with AML in remission. Previous large, randomized clinical trials of maintenance with HMAs or other agents had not shown meaningful improvement in overall survival. Oral azacitidine (Oral-AZA [CC-486]) is approved in the United States, Canada, and European Union for treatment of adult patients with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy who are ineligible for hematopoietic cell transplant. Regulatory approvals of Oral-AZA were based on outcomes from the randomized, phase III QUAZAR AML-001 trial, which showed a median overall survival advantage of 9.9 months with Oral-AZA versus placebo. Oral-AZA allows convenient extended AZA dosing for 14 days per 28-day treatment cycle, which is not feasible with injectable AZA. Focusing on AML and MDS, this report reviews the rationale for the use of orally bioavailable AZA and its potential use in all-oral combination therapy regimens; the unique pharmacokinetic and pharmacodynamic profile of Oral-AZA compared with injectable AZA; the clinical safety and efficacy of Oral-AZA maintenance therapy in patients with AML in first remission and for treatment of patients with active MDS; and ongoing Oral-AZA clinical trials.

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders. The 2020 Surveillance, Epidemiology, and End Results data demonstrates the incidence rate of MDS increases with age especially in those greater than 70 years of age. Risk stratification that impact prognosis, survival, and rate of acute myeloid leukemia (AML) transformation in MDS is largely dependent on revised International Prognostic Scoring System along with molecular genetic testing as a supplement. Low risk MDS typically have a more indolent disease course in which treatment is only initiated to ameliorate symptoms of cytopenias. In many, anemia is the most common cytopenia requiring treatment and erythroid stimulating agents, are considered first line. In contrast, high risk MDS tend to behave more aggressively for which treatment should be initiated rapidly with Hypomethylating Agents (HMA) being in the frontline. In those with high risk MDS and eligible, evaluation for allogeneic stem cell transplant should be considered as this is the only potential curative option for MDS. With the use of molecular genetic testing, a personalized approach to therapy in MDS has ensued. As the treatment landscape in MDS continues to flourish with novel targeted agents, we ambitiously seek to improve survival rates especially among the relapsed/refractory and transplant ineligible.

We evaluated the interlaboratory agreement, the essential agreement, and the categorical agreement between the Sensititre YeastOneTM panel and the reference methods M27 4th Edition of the Clinical and Laboratory Standards Institute (CLSI), and the EDef 7.3.1 of the European Committee on Antifungal Susceptibility Testing (EUCAST). We studied 67 Candida strains isolated from different clinical samples and 9 Candida strains with resistance to fluconazole and echinocandins. The highest percentage of interlaboratory agreement was observed with amphotericin B (96.8%), and the lowest percentage with voriconazole (77.2%). Caspofungin showed 5.8% of very major errors when compared with the CLSI reference method. For EUCAST, itraconazole, posaconazole, and anidulafungin showed high percentages of major errors: 17.6%, 18.1%, and 19.6%, respectively. Sensititre YeastOneTM is a reliable alternative, and easy to perform for detecting Candida species resistant to antifungal drugs, with some limitations for echinocandins. Results are comparable to those of the reference methods.

Introduction Myelodysplastic syndromes (MDS) are genomically complex clonal hematopoietic stem cell neoplasms leading to myelodysplasia and ineffective hematopoiesis.1,2 MDS is a disease of older age, clinically manifesting as symptomatic cytopenias with an added propensity for transformation to acute myeloid leukemia (AML).3 The treatment of MDS is based on a risk-adapted approach per the International Prognostic Scoring System (IPSS)4 or the modified IPSS-R.5 Allogeneic stem cell transplantation (ASCT) is the only curative strategy, but most patients are not eligible due to their age or other comorbidities.6 In these patients, hypomethylating agents (HMA, either decitabine or azacitidine) are the mainstay of therapy to either alleviate cytopenias or impede disease progression. 7 Decitabine (DEC) and azacitidine (AZA) are approved to treat patients with MDS, including previously treated and untreated, de novo, and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk IPSS groups.7

The COVID-19 pandemic has drawn attention to food insecurity in developed countries. Despite adequate levels of agricultural production, consumers experienced demand-induced scarcity. Understanding the effects on nutrition and the environment is limited, yet critical to informing ecologically embedded mitigation strategies. To identify mitigation strategies, we investigated wheat flour and egg retail shortages in the United Kingdom (UK), focusing on consumer behavior during the COVID-19 lockdown. The 6 Steps for Quality Intervention Development (6SQuID) framework informed the methodology. Mixed qualitative and quantitative methods were used to pinpoint the causes of the shortages, and ecological impacts of consumer behavior were related using survey results (n = 243) and environmental and nutritional databases. This research confirmed consumers’ narrowed consideration set, willingness to pay, and significant reliance on processed foods which indicates agronomic biofortification, breeding strategies, selective imports and improved processed food quality are important mitigation strategies. We identified positive and negative synergies in consumer, producer and retailer behavior and related these to mitigation strategies in support of a circular bio-economy for food production. We found that the substitutes or alternative foods consumed during the COVID-19 lockdown were nutritionally inadequate. We identified the most ecological substitute for wheat flour to be corn flour; and for eggs, yogurt. Our findings also indicate that selenium deficiency is a risk for the UK population, especially to the increasing fifth of the population that is vegetarian. Due to the need to implement short-, medium-, and long-term mitigation strategies, a coordinated effort is required by all stakeholders.

t(6;9)(p22;q34.1)/DEK-NUP214 is a recurrent genetic abnormality that occurs in 1-2% of patients with acute myeloid leukemia (AML), and rarely in myelodysplastic syndrome (MDS). It has been suggested by others that all myeloid neoplasms with t(6;9)/DEK-NUP214 may be considered as AML, even when blast count is

The food industry is responsible for significant impacts on the environment, such as climate change, water depletion and land use. Although these environmental impacts, along with socio-economic ramifications, are generally difficult to monitor and control, there is a significant interest from the food industry to assess the sustainability of their activities and wider supply chains. However, new food products are being continuously designed and manufactured, for instance complex foods made with a number of ingredients such as sandwiches, prepared salads and ready meals. Most sustainability analyses are currently done after the food product is designed and not during the food product development process. Nevertheless, embedding sustainability considerations in the new food product development (NFPD) process has significantly more potential to improve the overall sustainability of the food business. This paper discusses how the food industry could be more sustainable by identifying methodologies and tools to support such sustainability assessments in food businesses. A case study with a prepared food manufacturer is used to discuss where each sustainability methodology and tool could be used in the NFPD process to optimize the design of more sustainable food products. The main conclusion of this paper is that such methodologies and tools should be applied in the first stages of the NFPD process, and then be continuously used when more information on the production processes and wider data on its food supply chain is obtained.

There are a number of shortcomings for currently-available technologies for ammonia production, such as carbon dioxide emissions and water consumption. We simulate a novel model for ammonia production from hydrogen sulfide through membrane technologies. The proposed production process decreases the need for external water and reduces the physical footprint of the plant. The required hydrogen comes from the separation of hydrogen sulfide by electrochemical membrane separation, while the required nitrogen is obtained from separating oxygen from air through an ion transport membrane. 10% of the hydrogen from the electrochemical membrane separation along with the separated oxygen from the ion transport membrane is sent to the solid oxide fuel cell for heat and power generation. This production process operates with a minimal number of processing units and in physical, kinetic, and thermal conditions in which a separation factor of ~99.99% can be attained.

Background Simulation allows surgical trainees to acquire surgical skills in a safe environment. With the aim of reducing the use of animal experimentation, different alternative nonliving models have been pursued. However, one of the main disadvantages of these nonliving models has been the absence of arterial flow, pulsation, and the ability to integrate both during a procedure on a blood vessel. In the present report, we have introduced a microvascular surgery simulation training model that uses a fiscally responsible and replicable pulsatile flow system. Methods We connected 30 human placentas to a pulsatile flow system and used them to simulate aneurysm clipping and vascular anastomosis. Results The presence of the pulsatile flow system allowed for the simulation of a hydrodynamic mechanism similar to that found in real life. In the aneurysm simulation, the arterial flow could be evaluated before and after clipping the aneurysm using a Doppler ultrasound system. When practicing anastomosis, the use of the pulsatile flow system allowed us to assess the vascular flow through the anastomosis, with verification using the Doppler ultrasound system. Leaks were manifested as “blood” pulsatile ejections and were more frequent at the beginning of the surgical practice, showing a learning curve. Conclusions We have provided a step-by-step guide for the assembly of a replicable and inexpensive pulsatile flow system and its use in placentas for the simulation of, and training in, performing different types of anastomoses and intracranial aneurysms surgery.

Background Prognosis of patients with relapsed or refractory AML has been poor as no standard salvage therapy exists. Most trials of investigational agents begin in r/r AML and accrue a wide range of patients with different characteristics. Historical context for outcomes can be used as a reference for the development of future protocols and novel agents. The objective of this study was to evaluate outcomes of patients presenting with r/r AML in a single institution. Methods We analyzed the outcomes of patients who were treated for r/r AML for at least one treatment course at our institution between the years 2002 and 2016. At the time of inclusion in this study, patients had at least one prior treatment failure, were ≥18 years old at time of AML diagnosis, and had no central nervous system (CNS) involvement. Patients with acute promyelocytic leukemia were excluded. Descriptive characteristics of patients were summarized by proportions. Complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) rates were described as proportion with Wald 95% confidence intervals. Time to event analyses was estimated using the Kaplan-Meier method. Univariate and multivariate Cox models estimated p-values from Wald chi-square. Results A total of 1021 patients were included. Median age was 60 years (range, 18 - 87). At least one cytogenetic abnormality was present in 53.3% (n=546) of the population, 34.5% (n=352) had a history of an antecedent hematologic disease, and 10.5% (n=107) were therapy-related AML. For patients with available induction records, approximately 46% (295/635) were refractory. Among patients who achieved a CR after induction, 45% (118/264) had a CR duration Overall, only a small proportion of all r/r AML patients achieved a CR2 and CR rates decreased with each subsequent salvage attempt (Table 1). Rates were lower among patients >60 years of age (1st salvage p=0.05, 2nd salvage p=0.003, 3rd salvage p=0.09). Among various types of salvage regimens, the range of CR was from 0 to 36%. Regimens based on high dose cytarabine (HDAC) were the most common (n=297). Although sample size was modest, HDAC regimens that additionally contained a FLT3 inhibitor induced the highest CR and CR/CRi rates (33% CR2, 44% CR3) (Table 2). Age (p=0.0006), cytogenetics (p Overall survival and event free survival were modest and decreased with subsequent salvage (Table 3). Age (p Conclusion Overall, most patients were unable to achieve a CR2+. Fewer patients were able to achieve subsequent CR after a second treatment failure or relapse. EFS was short due to most patients failing to achieve CR. Even at first salvage, OS was less than 1 year. These data demonstrate that patients with relapsed or refractory AML have poor overall outcomes and further emphasizes the need for additional options for these patients. These data can be used to help guide the development of novel therapeutic options in AML. Disclosures Ravandi: Sunesis: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy. DiNardo:Celgene: Honoraria; Abbvie: Honoraria; Bayer: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Karyopharm: Honoraria. Daver:Pfizer: Consultancy; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; ARIAD: Research Funding; Pfizer: Research Funding; Kiromic: Research Funding; Sunesis: Research Funding; Karyopharm: Research Funding; ImmunoGen: Consultancy; BMS: Research Funding; Novartis: Consultancy; Incyte: Consultancy; Sunesis: Consultancy; Alexion: Consultancy; Otsuka: Consultancy; Incyte: Research Funding. Short:Takeda Oncology: Consultancy. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Kim:Amgen: Employment, Equity Ownership. Kelsh:Amgen: Employment, Equity Ownership. Katz:Amgen: Other: Former employee and stockholder; Kite, a GILEAD Company: Consultancy. Yang:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen: Employment, Equity Ownership.

We studied the characteristics of the provisional category de novo acute myeloid leukemia (AML) with mutated RUNX1 (AML-RUNX1mut) proposed by the World Health Organization (WHO). Until now, most published studies have combined de novo and secondary AML-RUNX1mut. We compared the clinicopathologic characteristics and outcomes of WHO-defined de novo AML-RUNX1mut with de novo AML without RUNX1 alterations (AML-RUNX1wt). We performed sequential NGS to assess RUNX1 mutation stability over disease course. We identified 46 de novo AML-RUNX1mut patients [32 (70%) men, 14 (30%) women; median age, 66.5 years] with 54 RUNX1 mutations [median VAF, 32% (2–97%)]. Point mutations clustered within the runt-homology-domain and frame-shift mutations within the transactivation domain. Compared with AML-RUNX1wt, AML-RUNX1mut showed male predominance (p = 0.02), higher frequency of SRSF2 (p = 0.02), and ASXL1 (p = 0.0004) mutations and normal karyotype (p = 0.01), and absent NPM1 mutations (p = 0.0002). De novo AML-RUNX1mut showed no significant difference in overall survival (OS) compared with AML-RUNX1wt (median: 26 vs. 32 months) (p = 0.71). AML-RUNX1mut with clonal RUNX1 mutation (≥20% VAF) had shorter OS than subclonal

Background An outbreak of post-kidney transplant cutaneous mucormycosis (PK-CM), a severe and even fatal complication in immunocompromised patients, occurred in our institution. The objective of this study was to compare the usual fixation of sterile wound dressings with non-sterile elastic bandages and fixation with sterile bandages processed at our centralized sterile services department with regard to PK-CM prevention. Methods We conducted a before-and-after trial in a private tertiary care hospital. The pre-intervention cohort (n = 16) included all patients who had undergone kidney transplant (KT) during the outbreak (June 2010-April 2011), and the post-intervention cohort (n = 49) included all patients who had undergone KT between May 2011 and October 2013. From May 2011, only bandages sterilized by the centralized sterile services department were used to fix wound dressings of KT patients. Results Differences in age (50.2 years vs 51.3 years), sex (43.8% male vs 59.2% female), weight (63.3 kg vs 69.7 kg), hemodialysis vintage (55.6 months vs 47.8 months), and other risk factors were not observed between the pre- and post-intervention cohorts, respectively. PK-CM incidence dropped from 25% in the pre-intervention cohort (4/16) to 0% in the post-intervention cohort (0/49). Relative risk was 0 (P = .003). Conclusions With regard to KT patients and sterile wound dressing fixation with non-sterile bandages versus the use of autoclaved bandages, fixation with autoclaved bandages proved to be effective for cutaneous mucormycosis outbreak control and prevention in our institution.

The prevalence of chronic kidney disease and its risk factors is increasing worldwide, and the rapid rise in global need for end-stage kidney disease care is a major challenge for health systems, particularly in low- and middle-income countries. Countries are responding to the challenge of end-stage kidney disease in different ways, with variable provision of the components of a kidney care strategy, including effective prevention, detection, conservative care, kidney transplantation, and an appropriate mix of dialysis modalities. This collection of case studies is from 15 countries from around the world and offers valuable learning examples from a variety of contexts. The variability in approaches may be explained by country differences in burden of disease, available human or financial resources, income status, and cost structures. In addition, cultural considerations, political context, and competing interests from other stakeholders must be considered. Although the approaches taken have often varied substantially, a common theme is the potential benefits of multi-stakeholder engagement aimed at improving the availability and scope of integrated kidney care.

Hepatitis C, a liver inflammation caused by the hepatitis C virus (HCV), is treated with antiviral drugs. In this context, simeprevir (SIM) is an NS3/4A protease inhibitor used in HCV genotypes 1 and 4. It is orally administered and achieves high virological cure rates. Among adverse reactions associated with SIM treatment, photosensitivity reactions have been reported. In the present work, it is clearly shown that SIM is markedly phototoxic, according to the in vitro NRU assay using BALB/c 3T3 mouse fibroblast. This result sheds light on the nature of the photosensitivity reactions induced by SIM in HCV patients, suggesting that porphyrin elevation in patients treated with SIM may not be the only mechanism responsible for SIM-associated photosensitivity. Moreover, lipid photoperoxidation and protein photooxidation assays, using human skin fibroblasts (FSK) and human serum albumin (HSA), respectively, reveal the capability of this drug to promote photodamage to cellular membranes. Also, DNA photo lesions induced by SIM are noticed through comet assay in FSK cells. Photochemical and photobiological studies on the mechanism of SIM-mediated photodamage to biomolecules indicate that the key transient species generated upon SIM irradiation is the triplet excited state. This species is efficiently quenched by oxygen giving rise to singlet oxygen, which is responsible for the oxidation of lipids and DNA (Type II mechanism). In the presence of HSA, the photobehavior is dominated by binding to site 3 of the protein, to give a stable SIM@HSA complex. Inside the complex, quenching of the triplet excited state is less efficient, which results in a longer triplet lifetime and in a decreased singlet oxygen formation. Hence, SIM-mediated photooxidation of the protein is better explained through a radical (Type I) mechanism., Financial support from the Spanish Ministry of Science and Innovation [PID2020-115010RB-I00/AEI/10.13039/501100011033 (I.A), PID2019-105512RB-I00/AEI/10.13039/501100011033 (CG-B) and FPU predoctoral fellowship for M. El O.], Axencia Galega de Innovaci´on (2020-PG067, CG-B), the Xunta de Galicia [ED431C 2021/29 and the Centro singular de investigaci´on de Galicia accreditation 2019–2022 (ED431G 2019/03),], and the European Regional Development Fund (ERDF) is gratefully acknowledged. All authors are grateful to the Centro de Supercomputaci´on de Galicia (CESGA) for use of the Finis Terrae computer.

Fish and other seafood products represent a valuable source of many nutrients and micronutrients for the human diet and contribute significantly to global food security. However, considerable amounts of seafood waste and by-products are generated along the seafood value and supply chain, from the sea to the consumer table, causing severe environmental damage and significant economic loss. Therefore, innovative solutions and alternative approaches are urgently needed to ensure a better management of seafood discards and mitigate their economic and environmental burdens. The use of emerging technologies, including the fourth industrial revolution (Industry 4.0) innovations (such as Artificial Intelligence, Big Data, smart sensors, and the Internet of Things, and other advanced technologies) to reduce and valorize seafood waste and by-products could be a promising strategy to enhance blue economy and food sustainability around the globe. This narrative review focuses on the issues and risks associated with the underutilization of waste and by-products resulting from fisheries and other seafood industries. Particularly, recent technological advances and digital tools being harnessed for the prevention and valorization of these natural invaluable resources are highlighted.

espanolAntecedentes: Los pacientes con neumonia viral grave reciben altas dosis de farmacos inmunomodu-ladores para prevenir el empeoramiento clinico. Los pacientes con influenza grave que reciben esteroidestienen neumonias secundarias causadas por Aspergillus con una frecuencia relativamente alta. Lospacientes con COVID-19 ingresados en la unidad de cuidados intensivos (UCI) reciben dicha medicacioncomo parte de su tratamiento, y comparten con otro tipo de pacientes muchas de las caracteristicas clini-cas de otras neumonias virales graves. Estos pacientes deberian considerarse como un grupo de riesgode aspergilosis invasiva. Caso clinico: Se presenta un caso de coinfeccion por SARS-CoV-2 y Aspergillus de la seccion Fumigatien un paciente intubado de edad avanzada con antecedentes de embolia pulmonar y tratado con cor-ticosteroides. El diagnostico siguio las definiciones ad hoc descritas para pacientes ingresados en laUCI con gripe grave. El paciente cumplia varios criterios clinicos (fiebre durante 3 dias refractaria altratamiento antibiotico apropiado, disnea, friccion pleural, empeoramiento del estado respiratorio a pesardel tratamiento antibiotico y la necesidad de soporte respiratorio), el criterio radiologico (infiltrado pul-monar) y un criterio micologico (test de galactomanano positivo en suero, (ratio ≥ 0,5). Ademas, se detectoADN de Aspergillus de la seccion Fumigati en muestras de suero y sangre del paciente. Estas pruebas fueronpositivas 4 semanas despues de que el paciente ingresara en la UCI. El paciente recibio tratamiento convoriconazol, y despues de 2 meses en la UCI mejoro su estado pulmonar; fue dado de alta despues de 6semanas de tratamiento antifungico.Conclusiones: Los pacientes gravemente enfermos con COVID-19 deberian considerarse un nuevo grupode riesgo para la aspergilosis. La deteccion de galactomanano y ADN de Aspergillus son metodos utiles parael diagnostico de infeccion por este hongo al evitar los problemas de bioseguridad en estos pacientes. EnglishBackground: Patients with severe viral pneumonia are likely to receive high-dose immunomodulatorydrugs to prevent clinical worsening. Aspergillus species have been described as frequent secondary pneu-monia agents in severely ill influenza patients receiving steroids. COVID-19 patients admitted to IntensiveCare Unit (ICU) are receiving steroids as part of their treatment and they share clinical characteristics withother patients with severe viral pneumonias. COVID-19 patients receiving steroids should be considereda putative risk group of invasive aspergillosis.Case report: We are reporting a SARS-CoV-2/Aspergillus section Fumigati coinfection in an elderly intu-bated patient with a history of pulmonary embolism treated with corticosteroids. The diagnosis was madefollowing the ad hoc definitions described for patients admitted to ICU with severe influenza, includingclinical criteria (fever for 3 days refractory to the appropriate antibiotic therapy, dyspnea, pleural fric-tion rub, worsening of respiratory status despite antibiotic therapy and need of ventilator support), aradiological criterion (pulmonary infiltrate) and a mycological criterion (several positive galactomannantests on serum with ratio ≥0.5). In addition, Aspergillus section Fumigati DNA was found in serum andblood samples. These tests were positive 4 weeks after the patient was admitted to the ICU. The patientreceived voriconazole and after two month in ICU his respiratory status improved; he was dischargedafter 6 weeks of antifungal treatment.Conclusions: Severely ill COVID-19 patients would be considered a new aspergillosis risk group. Galac-tomannan and Aspergillus DNA detection would be useful methods for Aspergillus infection diagnosis asthey allow avoiding the biosafety issues related to these patients

Most food manufacturers in industrialised countries produce significant amounts of food wastes during their manufacturing activities. Due to the serious environmental consequences of managing these materials, environmental impact analyses have become popular to identify more sustainable practices for food waste management. Life-Cycle Assessment (LCA) is a useful methodology to assess such environmental impacts. This paper presents the main results obtained using the LCA methodology to analyse the potential environmental impacts of waste management for a brewery in the UK. Initially, the main waste types are identified for this industry: barley straw, malt waste and spent grain, and then barley straw is selected to study its environmental impact in detail. An alternative, more sustainable way to manage barley straw by extracting its wax with supercritical CO2 is discussed. SimaPro software is used to both quantify potential environmental impacts and evaluate the overall environmental performance of this valorisation opportunity, and to compare its modelled environmental impacts to the current impacts of managing barley straw. Results show that valorising barley straw by this method generates a high environmental impact due to the energy requirements of the processes involved, principally for human toxicity (cancer effects), human toxicity (non-cancer effects) and freshwater ecotoxicity impact categories. Using more energy-efficient processes or an alternative energy source would reduce this environmental impact. The analysis used in this paper allows an objective comparison between different scenarios with the final aim of supporting the use of sustainable solutions for waste management in the food industry.

In food and drink manufacturing, costs must be relentlessly minimised because margins for most products are low. At the same time, the business case for biorefining of lignocellulosic feedstocks has been positive in only a small number of cases. Since the two industries use similar feedstocks and processing equipment, there should be potential for significant sharing of resources for economic and environmental gain, particularly with regard to energy, if they were co-located. This paper reviews the nature, issues and opportunities for this sort of resource sharing between food industries and biorefineries. It then illustrates the opportunity by modelling a food product (coffee bean roasting) co-located with lignocellulosic biorefining of its downstream by-product (spent coffee grounds) where biofuels are not the target output, identifying and evaluating the resource efficiencies and economics involved. The analysis shows that there can be significant benefits, but that the exact nature of the food and biorefinery products and the biorefining pathways are the key dependencies. Further research should produce a comprehensive league table of co-location opportunities for the benefit of both industries to enhance both their economics and their sustainability metrics through well-targeted synergies.

[EN] Phototoxic effects of 6,8 dihalogenated quinolones confers to this type of molecules a potential property as photochemotherapeutic agents. Two photodehalogenation processes seem to be involved in the remarkable photoinduced cellular damage. In this context, a new 6,8 dihalogenated quinolone 1 (1-methyl-6,8-difluoro-4-oxo-7-aminodimethy1-1,4-dihydroquinoline-3-carboxylic acid) was synthesized looking for improving the phototoxic properties of fluoroquinolones (FQ) and to determine the role of the photodegradation pathways in the FQ phototoxicity. With this purpose, fluorescence emissions, laser flash photolysis experiments and photodegradation studies were performed with compound 1 using 1-ethyl-6,8-difluoro-4-oxo-7-aminodimethy1-1,4-dihidroquinoline-3-carboxylic acid (2) and lomefloxacin (LFX) as reference compounds. The shortening of alkyl chain of the N(1) of the quinolone ring revealed a lifetime increase of the reactive aryl cation generated from photolysis of the three FQ and a significant reduction of the FQ photodegradation quantum yield. The fact that these differences were smaller when the same study was done using a hydrogen donor solvent (ethanol-aqueous buffer, 50/50 v/v) evidenced the highest ability of the reactive intermediate arising from 1 to produce intermolecular alkylations. These results were correlated with in vitro 3T3 NRU phototoxicity test. Thus, when PhotoIrritation-Factor (PIF) was determined for 1, 2 and LFX using cytotoxicity profiles of BALB/c 3T3 fibroblasts treated with each compound in the presence and absence of UVA light, a PIF more higher than 30 was obtained for 1 while the values for 2 and LFX were only higher than 8 and 10, respectively. Thereby, the present study illustrates an approach to modulate the photosensitizing properties of FQ with the purpose to improve the chemotherapeutic properties of antitumor quinolones. Moreover, the results obtained in this study also evidence that the key pathway responsible for the phototoxic properties associated with dihalogenated quinolones is the aryl cation generation., Financial support from Spanish government (MINECO grant CTQ2014-54729-C2-2-P and Severo Ochoa fellowship for C. A., Carlos III Institute of Health grant PI16/01877), and the Generalitat Valenciana (PROMETEO program, 2017-075). We thank M.P. Marin of IIS La Fe Microscopy Unit for confocal microscopy.

Summary Background Guadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes. Methods This phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m2 on days 1–5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings Between July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m2 (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m2 (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8–3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27–54] with 60 mg/m2 and 27 of 49 [55%, 95% CI 40–69] with 90 mg/m2; p=0·16). 25 of 49 (51%, 95% CI 36–66) patients who were treatment-naive and 23 of 53 (43%, 30–58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m2 group and 28 [57%] of 49 in the 90 mg/m2 group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m2 and four with 60 mg/m2), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m2; pneumonia with 90 mg/m2). Interpretation Guadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m2 on a 5-day schedule for these patients. Funding Astex Pharmaceuticals and Stand Up To Cancer.