Improved Treatment Outcomes With Modified Induction Therapy in Acute Myeloid Leukemia (AML): A Retrospective Observational Study From a Regional Cancer Center.

BACKGROUND: The aggressive, genetically diverse group of malignant illnesses known as acute myeloid leukemia (AML) is characterized by clonally related myeloblast invasion of the bone marrow, blood, and other organs. The treatment regimen plays a crucial role in the management of AML, and it is associated with poor overall survival and enhanced risk of relapse. Induction therapy with a 7+3 DA regimen (daunorubicin + ara-C) has been the treatment of choice for young and fit patients. OBJECTIVE: To evaluate the effect of dose modification in young and fit patients for a modified treatment regimen. METHODS: This was a retrospective, observational study of AML patients to analyze the outcomes of modified induction therapy in AML patients enrolled at Dr. B. Borooah Cancer Institute, Guwahati, Assam, India, from October 2021 to March 2022. The outcomes of modified induction therapy with intensive chemotherapy (modified 7+3 DA) and low-intensity chemotherapy decitabine (10 days) and venetoclax + azacytidine (seven days) were considered after the first two cycles or 60 days, whichever was earlier. RESULTS: Data from 31 patients with de-novo AML was analyzed; the median age of the patients was 41 years (range: 2-71 years), and the male-to-female ratio was 1.8. There were seven patients in the pediatric age group (2-13 years), and 19%, 65%, and 13% of patients belonged to favorable, intermediate, and high-risk groups, respectively. With regards to modified induction therapy (n=31), 20 (65%) patients received modified "7+3 DA", nine (29%) received hypomethylating agents (HMA, decitabine only), and two patients received HMA (azacitidnie) + venetoclax. Additionally, 23/31 patients completed at least two cycles of induction therapy. Overall, 60 day-induction mortality was 13%, and the complete remission (CR) and partial remission (PR) rates were 48% and 26%, respectively. In patients who received modified "7+3 DA", the CR rate was 55%. CONCLUSIONS: The notable reduction in deaths due to infections observed in our study suggests that centers with limited resources for preventing neutropenic complications during induction therapies in AML patients could consider adopting this modified regimen.

Real-Life Multicenter Experience of Venetoclax in Combination with Hypomethylating Agents in Previously Untreated Adult Patients with Acute Myeloid Leukemia in Greece.

BACKGROUND: The landscape of first-line treatment for acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy has changed remarkably after venetoclax approval. Accumulating real-world data further apprises us with more knowledgeable use. To assess the efficacy and safety challenges in the real-life setting of the combination of hypomethylated agent (HMA) and venetoclax, we conducted a multi-center retrospective study. METHODS: Forty adult AML patients treated with the combination of HMA and venetoclax as a first-line treatment after full approval (2020) were included. To confirm VIALE-A results, this group was compared to a historical cohort of 17 chemotherapy-ineligible AML patients treated with HMA monotherapy before 2020. RESULTS: The combination of HMA-venetoclax achieved a composite complete response rate of 86.8% (p < 0.001), median overall survival, and event-free survival of 33.8 and 19.7 months, respectively, in a median follow-up of 17.8 months (pos < 0.001, HR = 0.276, CI: 0.132-0.575, pEFS = 0.004, HR = 0.367, CI: 0.174-0.773). High rates of neutropenia (90%) and consequent infection rates (57.5%) were noted. Only 55% of our patients received antifungal prophylaxis, as its use remains controversial, and invasive fungal infections were presented in 7.5%. CONCLUSIONS: Evidently, venetoclax-HMA yields high response rates and profound survival benefits in real life and has changed our approach to alternative chemotherapy options.

An unusual response to 5-azacitidine by a patient with chronic myelomonocytic leukemia.

Key Clinical Message: Hypomethylating agents may be useful in some but not all cases of myelodysplastic syndromes. In some versions of these conditions, this treatment may yield deleterious results. Abstract: Chronic myelomonocytic leukemia (CMML) is considered to be a heterogeneous group of hematopoietic neoplasms. Usually it shares the features of myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) and is known as MDS/MPN. It occurs mostly in the elderly and has an inherent tendency to transform to acute myeloid leukemia. FDA has approved hypomethylating agents (HMAs) such as 5-azacitidine (AZA) and decitabine (DEC) for the treatment of this disorder. The extent of response rate to AZA varies considerably among patients. Our report describes a patient with CMML who not only did not respond to a conventional dose of intravenous (IV) therapy with AZA, but showed marked progression of the disease with the leucocyte count rising exponentially while undergoing the aforesaid treatment. We believe this is the first such case reported in the currently extant literature.

Analysis and clinical characteristics of acute myeloid leukemia developing with prior or concurrent tumors in non cyto- or radiotherapy exposure patients in a single center.

ABSTRACTAcute myeloid leukemia (AML) that develops along with prior or concurrent tumors without previous cyto- or radiotherapy (pc-AML) is an essential subset of AML but is often ignored and ambiguous. The biological and genetic characteristics of pc-AML remain largely unknown. Moreover, it is unclear whether pc-AML should be treated as de novo or secondary AML, whereas most clinical trials exclude it due to comorbidities. We performed a retrospective study of 50 patients with multiple neoplasms over five years. We focused on characteristics, treatment regimens, response rate, and prognosis of pc-AML, compared with therapy-related AML (tAML) and AHD-AML (AML discovered following prior hematologic disorders) as controls. We report the first detailed distribution of secondary tumors associated with hematological disorders. The incidence of pc-AML was 30% of all multiple neoplasms, and it was predominantly found in male and older participants. Nearly three-quarters of gene mutations affected epigenetic regulation and signaling pathways, and NPM1, ZRSR2, and GATA2 occurred exclusively in pc-AML. No significant differences were in CR, and pc-AML had an inferior OS similar to that of tAML and AHD-AML. More patients received hypomethylation agents (HMAs) in combination with venetoclax (HMAs + VEN) than intensive chemotherapy (IC) (65.7% vs 31.4%), and there was a trend toward improved OS in HMAs + VEN-based than in IC-based patients, whose 2-year estimated OS times were 53.6% and 35.0%, respectively. In conclusion, our results collectively support pc-AML as a biologically and genetically distinct entity with high-risk and dismal outcomes, and HMAs in combination with venetoclax-based regimens may benefit patients with pc-AML.

Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances.

Angioimmunoblastic T-cell lymphoma (AITL) is the second most frequent subtype of mature T-cell lymphoma (MTCL) in the Western world. It derives from the monoclonal proliferation of T-follicular helper (TFH) cells and is characterized by an exacerbated inflammatory response and immune dysregulation, with predisposition to autoimmunity phenomena and recurrent infections. Its genesis is based on a multistep integrative model, where age-related and initiator mutations involve epigenetic regulatory genes, such as TET-2 and DNMT3A. Subsequently, driver-mutations, such as RhoA G17V and IDH-2 R172K/S promote the expansion of clonal TFH-cells ("second-hit"), that finally begin to secrete cytokines and chemokines, such as IL-6, IL-21, CXCL-13 and VEGF, modulating a network of complex relationships between TFH-cells and a defective tumor microenvironment (TME), characterized by expansion of follicular dendritic cells (FDC), vessels and EBV-positive immunoblasts. This unique pathogenesis leads to peculiar clinical manifestations, generating the so-called "immunodysplastic syndrome", typical of AITL. Its differential diagnosis is broad, involving viral infections, collagenosis and adverse drug reactions, which led many authors to use the term "many-faced lymphoma" when referring to AITL. Although great advances in its biological knowledge have been obtained in the last two decades, its treatment is still an unmet medical need, with highly reserved clinical outcomes. Outside the setting of clinical trials, AITL patients are still treated with multidrug therapy based on anthracyclines (CHOP-like), followed by up-front consolidation with autologous stem cell transplantation (ASCT). In this setting, the estimated 5-year overall survival (OS) is around 30-40%. New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.

Transcriptional analysis of heavy metal P1B-ATPases (HMAs) elucidates competitive interaction in metal transport between cadmium and mineral elements in rice plants.

Cadmium (Cd) pollution has become a major threat to crop production and quality globally. The heavy metal P1B-ATPases (HMAs) play a crucial role in metal transport in plants. In the present study, we investigated the interaction in metal transport by HMAs between Cd and mineral elements in rice plants. Rice seedlings were treated with cadmium nitrate either in the nutrient solution ("Cd+M") or in the ultrapure water ("Cd-M"). Result showed that phytotoxicity of Cd to rice seedlings was evident from both Cd treatments, judged by relative growth rate (RGR), where more severe repression (p < 0.05) of RGR was observed in the "Cd-M" treatments than the "Cd+M" treatments. More Cd (p < 0.05) was accumulated in rice tissues from the "Cd-M" treatments than the "Cd+M" treatments, while there is a significant difference (p < 0.05) in distribution and translocation of mineral elements in rice tissues between the "Cd+M" and the "Cd-M" treatments. RT-qPCR analysis displayed that the expression patterns of HMAs related genes were quite different between "Cd+M" and "Cd-M" treatments, suggesting their different regulatory effects during the transport of Cd and mineral elements within rice plants. The competition in metal transport by HMAs mainly occurs between Cd and micro-elements of Zn and Cu in rice tissues during Cd exposure. Overall, this study provides new evidence to clarify the different translocation mechanisms of HMAs in metal transport between Cd and mineral elements in rice seedlings during Cd exposure.

Improving clinical trials in higher-risk myelodysplastic syndromes.

Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival and are in need of more effective therapy options. Hypomethylating agents (HMAs) are the current standard of care and are being studied in combination with a number of novel therapies. Recent evidence, however, has delivered sub-optimal results, prompting the need to revisit patient selection criteria, treatment schedules, and clinical endpoints to better inform future studies and steer endpoints towards those that are clinically meaningful to patients.

MYB43 as a novel substrate for CRL4PRL1 E3 ligases negatively regulates cadmium tolerance through transcriptional inhibition of HMAs in Arabidopsis.

Controlled stability of proteins is a highly efficient mechanism to direct diverse processes in plants. A key regulatory system for protein stability is given by the CULLIN-RING E3 ligases (CRLs). In this work, MYB43 is identified as a novel target of a CUL4-DDB1-PRL1 (PLEIOTROPIC REGULATORY LOCUS 1)-RING E3 ligase (CRL4PRL1 E3 ligase). Its stability depends on the presence of PRL1, a WD40-containing protein functioning as a substrate receptor of the CRL4 E3 ligases. Genetic studies have indicated that MYB43 is a negative regulator of cadmium (Cd) tolerance in Arabidopsis by transcriptional inhibition of important Cd transporters (HMA2, HMA3 and HMA4), while PRL1 and CUL4 positively regulate Cd tolerance. Expression of CUL4 and PRL1 was enhanced in response to Cd stress, and PRL1 can interact with and target MYB43 for degradation depending on assembly of CRL4PRL1 E3 ligase, and consequently increase the expression of HMA2, HMA3 and HMA4 through attenuating the transcriptional inhibition. HMA2 and HMA4 are shown to transport cadmium ion (Cd2+ ) from the roots of plants to the shoots through the xylem, ultimately increasing the plants' tolerance to Cd stress.

Log reduction of leukemic cells and minimal residual disease by flow cytometry represent effective predictors of clinical outcome in elderly patients with acute myeloid leukemia.

BACKGROUND: Nowadays minimal residual disease (MRD) and log-reduction of leukemic cells are poorly investigated in elderly patients with acute myeloid leukemia (AML) treated with hypometilating agents (HMAs). Studies focusing on MRD in elderly AML patients who received HMAs are scant and devoid of rigorous criteria for both enrollment and monitoring. Log-reduction has never been investigated in these patients. Thus, the purpose of our study was to compare the prognostic impact of MRD and log-reduction of leukemic cells at the optimal time of assessment in older AML patients. METHODS: Elderly patients who completed at least six cycles of HMAs and showed suitable leukemia-associated immunophenotypes (LAIPs) for the MRD and log-reduction assessment by flow cytometry were enrolled in the study. RESULTS: After comparing the times of assessment C4 (4-cycles) and C6 (6-cycles), C6 has been chosen as optimal. Patients who achieved MRD negativity or 2-log-reduction of leukemic cells at C6 had a significantly longer DFS. Particularly, results of 2-log-reduction were confirmed a multivariate analysis. Patients with MRD negativity or 2-log reduction of leukemic cells showed an improvement of their OS, although not significantly. CONCLUSIONS: Our data confirmed the predictive role of MRD and 2-log reduction also in older AML patients treated with HMAs.

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia.

Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent used in the treatment of acute myeloid leukemia (AML). Decitabine inhibits DNA methyltransferases, causing DNA hypomethylation, and leading amongst others to re-expression of silenced tumor suppressor genes. Decitabine is indicated for the treatment of adult patients with newly diagnosed de novo or secondary AML who are not eligible for standard induction chemotherapy. The initial authorization in 2012 was based on the results of the open-label, randomized, multicenter phase 3 DACO-016 trial, and supported by data from the supportive phase 2 open-label DACO-017 trial. Compared with standard care, decitabine significantly improved overall survival, event-free survival, progression-free survival, and response rate. Decitabine was generally well tolerated, offering a valuable treatment option in patients with AML irrespective of age, especially for patients achieving a complete response. Several observational "real-life" studies confirmed these results. In contrast to standard chemotherapy, the presence of adverse-risk karyotypes or TP53 mutations does not negatively impact sensitivity to hypomethylating therapy albeit with lower durability. Data suggest a potential positive effect of decitabine in patients with monosomal karyotype-positive AML. For the time being, decitabine is an appropriate option as monotherapy for patients with AML who are unfit to receive more intensive combination therapies, but emerging data suggest that decitabine-based doublet or triplet combinations may be future treatment options for patients with AML.

How do molecular aberrations guide therapy in MDS?

Myelodysplastic syndromes (MDS) represent a cluster of genetically and phenotypically heterogeneous hematological disorders. While molecularly targeted therapies have entered the standard of care for other hematological malignancies like acute myeloid leukemia, this approach has been elusive in MDS. This review has summarized recent evidence to determine how molecular aberrations can be used to guide therapy in MDS and improve outcomes among patients.

The Real-Life Efficacy of Fixed-Dose Hypomethylating Agents in Older Patients With Acute Myeloid Leukemia: A 10-Year Experience.

BACKGROUND: Hypomethylating agent (HMA) is one of recommended treatment for elderly patients with acute myeloid leukemia (AML); however, their high cost precludes their general use, especially in developing countries. Therefore, the fixed-dose HMAs approach was adopted to reduce the expenses. This study focuses on the clinical outcome of various treatment protocols, including intensive chemotherapy, fixed-dose HMAs, and palliative treatment in Thai elderly patients with AML. Fixed-dose HMAs include 5-azacitidine given at 100 mg per day for seven days and decitabine given at 30 mg per day for 5 days. PATIENTS AND METHODS: We conducted a 10-year cohort study focused on elderly AML patients aged over 60 years. The exclusion criteria were acute promyelocytic leukemia. RESULTS: A total of 243 AML patients were enrolled. Comparing 3 groups of treatment regimens (intensive chemotherapy, fixed-dose HMAs, and palliative treatment), the proportions of patients in each category accounted for 23.5%, 21.4%, and 55.1%, respectively. The median overall survival (OS) in each therapeutic option was 7.7, 11, and 2.5 months, respectively. From multivariate analysis, palliative treatment was significantly inferior OS comparing to the fixed-dose HMAs and intensive treatment (hazard ratio [HR]: 0.42; 95% CI, 0.29-0.60; P value <.001 and HR: 0.41; 95% CI, 0.28-0.61; P value <.001, respectively). Nevertheless, the OS outcome in patients with fixed-dose HMAs was comparable to those who received intensive treatment. CONCLUSION: Our study demonstrates that the fixed-dose regimen of HMAs is the reasonable treatment for these patients, and this approach is not inferior to intensive therapy. Thai Clinical Trials Registry identifier: TCTR20210514007.

Comparison of Azacitidine and Decitabine in Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Network Meta-analysis.

BACKGROUND: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that mostly affect the elderly and have a poor prognosis. Azacitidine (AZA) and decitabine (DAC) are the most widely used hypomethylating agents. However, few randomized controlled trials (RCTs) have compared AZA and DAC head to head in MDS or AML. This study intended to conduct a network meta-analysis to compare the 2 drugs to provide more guidance using evidence-based medicine. PATIENTS AND METHODS: A comprehensive search for RCTs was performed till July 31, 2020. The network meta-analysis was conducted using the Markov chain Monte Carlo method. The primary endpoints were overall survival (OS) and the incidence of adverse events, and the secondary endpoints were complete remission (CR) rate, overall remission rate (ORR), and AML-free survival. There were 6 RCTs with 1072 MDS patients, and 3 RCTs with 1256 AML patients. RESULTS: In MDS, AZA showed better AML-free survival (hazard ratio = 0.62; 95% CI, 0.43-0.9), whereas DAC had the possibility of achieving better CR and ORR, and AZA had the possibility of obtaining better OS with lower toxicity. As for elderly AML patients, DAC had the possibility of achieving superior CR, ORR, and OS, while the toxicity was relatively higher. Furthermore, subgroup analysis for patients ≥ 75 years old or of high risk in MDS suggested that AZA achieved better OS. CONCLUSION: For MDS, especially patients with intermediate or high risk disease with advanced age and poor general condition, AZA may be a better choice, while DAC may be of more benefit in elderly AML patients.

The use of hypomethylating agents in hematologic malignancies: treatment preferences and results.

Aim: The objective of this article was to compare the efficiency of azacitidine (AZA) and decitabine (DAC) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are not suitable for high-dose chemotherapy. Materials and methods: MDS and AML patients who were treated with hypomethylating agents (HMAs) between January 2005 and 2020 were evaluated retrospectively. Results: No statistically significant difference was found between the patients who received AZA or DAC in AML patients. In MDS group, the rate of patients who achieved remission was statistically significantly higher in patients who received DAC (p = 0.032). Conclusion: The advantage in terms of response for MDS and no survival difference between AZA and DAC for AML and MDS patients will be an important contribution to the literature.

Pre-transplant hypomethylating agents do not influence post-transplant survival in myelodysplastic syndrome.

Information on the use of hypomethylating agents (HMAs) as a pre-transplant cytoreductive therapy in MDS is limited. We retrospectively evaluated outcomes of 172 adult MDS patients, who underwent allogeneic hematopoietic stem cell transplantation between January 2000 and December 2016. Patients were divided into three groups: group 1 - pre-transplant blasts <5% with HMA (n = 42), group 2 - pre-transplant blasts ≥5% with HMA (n = 38), group 3 - no HMA (n = 92). With a median follow up of 4.08 years, 1-year survival and relapse rates for groups 1, 2, and 3 were 75%, 40.2%, and 60.71%, respectively; and 17.6%, 26.6%, and 9.8%, respectively. Multivariate analysis revealed adverse relapse (HR 3.54; p = .03) in group 2 compared to groups 1 and 3, while no difference in overall survival was noticed. Our study shows no survival association with pre-transplant HMA; although, higher relapse rate was observed in the non-responding patients indicating possible chemotherapy resistant disease.

Bacterial bifunctional chorismate mutase-prephenate dehydratase PheA increases flux into the yeast phenylalanine pathway and improves mandelic acid production.

Mandelic acid is an important aromatic fine chemical and is currently mainly produced via chemical synthesis. Recently, mandelic acid production was achieved by microbial fermentations using engineered Escherichia coli and Saccharomyces cerevisiae expressing heterologous hydroxymandelate synthases (hmaS). The best-performing strains carried a deletion of the gene encoding the first enzyme of the tyrosine biosynthetic pathway and therefore were auxotrophic for tyrosine. This was necessary to avoid formation of the competing intermediate hydroxyphenylpyruvate, the preferred substrate for HmaS, which would have resulted in the predominant production of hydroxymandelic acid. However, feeding tyrosine to the medium would increase fermentation costs. In order to engineer a tyrosine prototrophic mandelic acid-producing S. cerevisiae strain, we tested three strategies: (1) rational engineering of the HmaS active site for reduced binding of hydroxyphenylpyruvate, (2) compartmentalization of the mandelic acid biosynthesis pathway by relocating HmaS together with the two upstream enzymes chorismate mutase Aro7 and prephenate dehydratase Pha2 into mitochondria or peroxisomes, and (3) utilizing a feedback-resistant version of the bifunctional E. coli enzyme PheA (PheAfbr) in an aro7 deletion strain. PheA has both chorismate mutase and prephenate dehydratase activity. Whereas the enzyme engineering approaches were only successful in respect to reducing the preference of HmaS for hydroxyphenylpyruvate but not in increasing mandelic acid titers, we could show that strategies (2) and (3) significantly reduced hydroxymandelic acid production in favor of increased mandelic acid production, without causing tyrosine auxotrophy. Using the bifunctional enzyme PheAfbr turned out to be the most promising strategy, and mandelic acid production could be increased 12-fold, yielding titers up to 120 mg/L. Moreover, our results indicate that utilizing PheAfbr also shows promise for other industrial applications with S. cerevisiae that depend on a strong flux into the phenylalanine biosynthetic pathway.

Hypomethylating Agents-associated Infections-Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The reported data regarding the effects of hypomethylating agents (HMAs) on the risk of infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all randomized controlled trials comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms. MATERIALS AND METHODS: A comprehensive search was conducted until February 2018. Two reviewers appraised the quality of the trials and the extracted data. The primary outcome was grade 3/4 infections. The secondary outcomes included febrile neutropenia, fever of unknown origin, grade 3/4 neutropenia, infection-related mortality, and all-cause mortality. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool the data unless significant heterogeneity was present, in which case a random-effects model was used. RESULTS: We identified 9 trials reported from 2002 to 2016 and randomizing 2184 patients. HMAs were associated with an increase in grade 3/4 infections compared with the comparator (RR, 1.30; 95% CI, 1.02-1.66). This was true for the subgroup of patients aged >60 years (RR, 1.19; 95% CI, 1.01-1.39). In addition, HMAs resulted in an increase in the rate of fever of unknown origin and neutropenia (RR, 1.48; 95% CI, 1.15-1.92; RR, 1.48; 95% CI, 1.22-1.78, respectively). Although no difference was found in the incidence of fatal infections (RR, 1.44; 95% CI, 0.72 to 2.89), treatment with HMA reduced the incidence of all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88). CONCLUSION: Treatment with HMAs was associated with an increase in the grade 3/4 infection rate.

More is less, less is more, or does it really matter? The curious case of impact of azacitidine administration schedules on outcomes in patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) encompass a diverse group of hematologic disorders characterized by ineffective and malignant hematopoiesis, peripheral cytopenias and significantly increased risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine induce meaningful clinical responses in a significant subset of patients with MDS. Though never compared directly with decitabine, only azacitidine has improved overall survival (OS) compared to conventional care in a randomized trial in patients with higher-risk MDS. The azacitidine regimen used in this pivotal trial AZA-001 included administration at 75 mg/m2/day for 7 consecutive days in 28-day cycles (7-0 regimen). Given the logistical difficulties of weekend administration in the 7-0 regimen, as well as in efforts to improve response rates, alternative dosing schedules have been used. In a typical 28-day cycle, administration schedules of 3, 5, 10, and (with the oral version of azacitidine) 14 and 21 days have been used in clinical trials. Most trials that evaluated alternative administration schedules of azacitidine did so in lower-risk MDS and did not directly compare to the 7-0 schedule. Given the lack of randomized prospective studies comparing the 7-0 schedule to the other regimens of azacitidine in MDS, Shapiro et al. conducted a systematic review in an attempt to answer this question. Here we place the findings of this important work in clinical context and review the current knowledge and unresolved issues regarding the impact of administration schedules of azacitidine on outcomes of patients with both lower-risk and higher-risk MDS.

The medical officer's journal: HMAS Sydney 1913-1922. An Australian Naval record of surgery and anaesthesia at the time of the outbreak of World War I.

The Medical Officer's Journal of HMAS Sydney was a record kept by the ship's Surgeon, Leonard Darby, of the conditions on the ship and the health, diseases, injuries and treatment of the sailor's under his care. Records of anaesthesia and surgery indicate chloroform was mostly administered as was ether occasionally. There was some use of intravenous and subcutaneous fluids for resuscitation. The journal also provides an eyewitness account of the Sydney-Emden battle on 9 November 1914 which occurred off the Cocos Keeling Islands and was a famous first victory for the young Australian Navy, making headlines around the world. The treatment of the many injured, mostly Germans, is described; with the two Australian surgeons and the surviving German surgeon working together.