Does IPSS-R down staging before transplantation improve the prognosis of patients with Myelodysplastic neoplasms?

In MDS patients higher IPSS-R at transplant is associated with worse transplant outcome. Thus, it may seem beneficial to improve IPSS-R by therapeutic intervention prior to transplantation in order to "down-stage" the disease risk. However, there is no evidence to date to support this approach. A retrospective analysis of the EBMT transplant registry was performed to investigate the role of therapeutic interventions prior to transplantation with regard to changes in IPSS-R and transplant outcomes. A total of 1482 MDS patients with sufficient data to calculate IPSS-R at diagnosis and at time of transplantation were selected and analysed for transplant outcome in a multivariable Cox model including IPSS-R at diagnosis, treatment intervention, change in IPSS-R before transplant and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R change in untreated patients and moderately superior in chemotherapy-treated patients with improved IPSS-R at transplant. Improved IPSS-R after hypomethylating agents (HMA) or other therapies showed no beneficial effect. However, when IPSS-R progressed after chemotherapy, (HMA) or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R down staging or reduction of BM blasts after chemotherapy and no benefit for HMA or other treatments and thus question the role of prior therapy in MDS patients scheduled for transplantation. The model-based survival estimates should help inform decision making for both doctors and patients.

An Approach to Evaluate the Costs and Outputs of Academic Biobanks.

Academic biobanks commonly report sustainability challenges, which may be exacerbated by a lack of information on biobank value. To better understand the costs and supported outputs that contribute to biobank value, we developed a systematic, generalizable methodology to determine biobank inputs and publications arising from biobank-supported research. We then tested this in a small cohort (n = 12) of academic cancer biobanks in New South Wales, Australia. A proforma was developed to capture monetary and in-kind biobank costing data from biobank managers and publicly available sources. Participating biobanks were grouped and compared according to the following two classifications: open- versus restricted-access and high versus low total annual costs. Our methodology provides a feasible approach for capturing comprehensive costing data for a defined period. Characterization of biobanks using this approach showed that median total costs, as well as median staffing and in-kind costs, were comparable for open- and restricted-access biobanks, as were the quantity and journal impact metrics of supported publications. High- and low-cost biobanks supported similar median numbers of publications; however, high-cost biobanks supported publications with higher median journal impact factor and Altmetric scores. Overall, 9 of 10 biobanks had higher Field-Weighted Citation Impact scores than the global average for similar publications. This is the first tested, generalizable approach to analyze the costs and publications arising from biobank-supported research. By determining explicit cost and output data, academic biobanks, funders, and policymakers can engage in or support informed redirection of resourcing and/or benchmark setting with the aim of improving biobank support of research.

Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.

The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001-2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd-3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Applying Findable, Accessible, Interoperable, and Reusable Principles to Biospecimens and Biobanks.

The importance of stimulating greater sharing of data for use and reuse in health research is widely recognized. To this end, the findable, accessible, interoperable, and reusable (FAIR) principles for data have been developed and widely accepted in the research community. Research biospecimens are a resource that leads to much of this health research data but are also a form of data. Therefore, the FAIR principles should apply to biospecimens. Nevertheless, there is a widespread problem of not sharing biospecimen resources that is clearly visible within the research arena. The impacts of this are likely to include diversion of precious research funds into compiling duplicate biospecimen cohorts, detraction from research productivity as researchers compete for and create duplicate resources, and deterrence of attempts to assess research reproducibility. This article explores some of the barriers that may limit availability of FAIR biospecimens. These barriers relate to the type of biospecimen collections and the characteristics of the custodians that influence their intention and interest in sharing. Barriers also relate to the ethical, legal, and social issues concerning collections, the research context of the collections, and cost and expertise involved in repurposing collections to enable sharing. Several solutions to increase sharing are identified. Some have recently been implemented, including enhancing biospecimen locators with tools to guide researchers and facilitating transfer of research collections to centralized biobank infrastructures at the conclusion of projects. New proposed solutions include improving search capabilities within publication databases, and introduction of evidence-based justifications for all new collections into peer-reviewed grant competition processes. It is recognized that there are both scientific factors and practical reasons that can impose limits to sharing biospecimens. However, funding availability, productivity, and progress in health research all stand to benefit from improved sharing of research biospecimen collections.

Verification of nucleotide sequence reagent identities in original publications in high impact factor cancer research journals.

Human gene research studies that describe wrongly identified nucleotide sequence reagents have been mostly identified in journals of low to moderate impact factor, where unreliable findings could be considered to have limited influence on future research. This study examined whether papers describing wrongly identified nucleotide sequences are also published in high-impact-factor cancer research journals. We manually verified nucleotide sequence identities in original Molecular Cancer articles published in 2014, 2016, 2018, and 2020, including nucleotide sequence reagents that were claimed to target circRNAs. Using keywords identified in some 2018 and 2020 Molecular Cancer papers, we also verified nucleotide sequence identities in 2020 Oncogene papers that studied miRNA(s) and/or circRNA(s). Overall, 3.8% (251/6647) and 4.0% (47/1165) nucleotide sequences that were verified in Molecular Cancer and Oncogene papers, respectively, were found to be wrongly identified. Wrongly identified nucleotide sequences were distributed across 18% (91/500) original Molecular Cancer papers, including 38% (31/82) Molecular Cancer papers from 2020, and 40% (21/52) selected Oncogene papers from 2020. Original papers with wrongly identified nucleotide sequences were therefore unexpectedly frequent in two high-impact-factor cancer research journals, highlighting the risks of employing journal impact factors or citations as proxies for research quality.

Palliation of Intractable Cancer-Related Pain With Low-Dose Epidural Bupivacaine.

Introduction: Patients with advanced cancer nearing end of life often present with complex multifactorial pain. Although epidural analgesia is routinely used in inpatient hospital settings for targeted pain control, there is scant description in the literature of the use of low-dose epidural analgesia for relief of cancer-related pain at end of life. In this study, we present a case of difficult to control cancer-related rectal and pelvic pain in a patient who responded well in her last days of life to a low-dose bupivacaine epidural. Case Description: A 66-year-old woman presented for inpatient hospital admission for pain control from home hospice with intractable cancer-related pain from metastatic colorectal adenocarcinoma marked by extensive erosive lesions extending from the anterior perineum to the posterior rectum, with rectovaginal fistula. The patient reported poor tolerance of medications and described spiritual beliefs (based in Buddhism) that caused her and her family to prioritize maintaining a lucid, clear mind above nearly all else while seeking symptom management. The patient was so debilitated by pain at the time of presentation that she was bedbound in a quadruped position. Case Management and Outcome: After 2 weeks of poor pain control in the hospital with multiple failed attempts at palliation-including bilateral pudendal block, as well as opioids and other routine, but potentially sedating or deliriogenic, medications to treat her pain-the patient permitted administration of a low-dose bupivacaine epidural that significantly reduced her pain and allowed the patient to remain clear-headed up until the time of her death. Twenty-three days after admission, and 5 days after initiation of low-dose bupivacaine epidural for pain control, the patient died peacefully in the hospital. Conclusion: Low-dose epidural analgesia for cancer-related pain at end of life from malignancy involving the pelvis-perineum, rectum, or vagina-may be a viable option for patients, particularly those who wish to avoid the risk of somnolence or confusion from systemic opioids and other analgesics.

Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.

PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Biobanking and research quality: think locally, act globally.

Although biobanks can support research across geographic and governance boundaries, biomedical researchers consistently describe preferences for either collaborating with local biobanks or establishing their own biobanks. This article summarizes the potential research impacts of local biobank use and suggests how descriptions of biospecimen provenance can be improved in research publications.

Protection of the human gene research literature from contract cheating organizations known as research paper mills.

Human gene research generates new biology insights with translational potential, yet few studies have considered the health of the human gene literature. The accessibility of human genes for targeted research, combined with unreasonable publication pressures and recent developments in scholarly publishing, may have created a market for low-quality or fraudulent human gene research articles, including articles produced by contract cheating organizations known as paper mills. This review summarises the evidence that paper mills contribute to the human gene research literature at scale and outlines why targeted gene research may be particularly vulnerable to systematic research fraud. To raise awareness of targeted gene research from paper mills, we highlight features of problematic manuscripts and publications that can be detected by gene researchers and/or journal staff. As improved awareness and detection could drive the further evolution of paper mill-supported publications, we also propose changes to academic publishing to more effectively deter and correct problematic publications at scale. In summary, the threat of paper mill-supported gene research highlights the need for all researchers to approach the literature with a more critical mindset, and demand publications that are underpinned by plausible research justifications, rigorous experiments and fully transparent reporting.

Dexmedetomidine Continuous Infusion for Refractory Cancer Pain at End of Life: A Case Report.

Refractory cancer-related pain at end-of-life (EoL) is multifaceted and may require utilizing medications with different mechanism of actions beyond opioids. We report the successful use of dexmedetomidine in a 63-year old female with recurrent breast cancer and intractable left arm pain and swelling admitted to University of California, San Diego, Health (UC San Diego Health), palliative care unit. Patient's pain and agitation continued to persist and she declined clinically despite efforts to start methadone, continuous infusion opioids, continuous infusion lidocaine and intravenous chlorpromazine by the palliative care team. On hospital day (HD) 11 patient was started on dexmedetomidine continuous infusion for refractory pain per our protocol at UC San Diego Health. The next day the patient appeared much improved in terms of pain and agitation with grimacing and moaning completely resolved. She was able to have some lucid periods and interacting with her family. With the addition of dexmedetomidine to her pain regiment, the patient was able to peacefully die 5 days later. This case report highlights the clinical utility of demedetomidine in a palliative care unit for refractory pain at EoL.

Is the future of peer review automated?

The rising rate of preprints and publications, combined with persistent inadequate reporting practices and problems with study design and execution, have strained the traditional peer review system. Automated screening tools could potentially enhance peer review by helping authors, journal editors, and reviewers to identify beneficial practices and common problems in preprints or submitted manuscripts. Tools can screen many papers quickly, and may be particularly helpful in assessing compliance with journal policies and with straightforward items in reporting guidelines. However, existing tools cannot understand or interpret the paper in the context of the scientific literature. Tools cannot yet determine whether the methods used are suitable to answer the research question, or whether the data support the authors' conclusions. Editors and peer reviewers are essential for assessing journal fit and the overall quality of a paper, including the experimental design, the soundness of the study's conclusions, potential impact and innovation. Automated screening tools cannot replace peer review, but may aid authors, reviewers, and editors in improving scientific papers. Strategies for responsible use of automated tools in peer review may include setting performance criteria for tools, transparently reporting tool performance and use, and training users to interpret reports.

The Availability of Human Biospecimens to Support Biomarker Research.

Preserved biospecimens held in biobank inventories and clinical archives are important resources for biomarker research. Recent advances in technologies have led to an increase in use of clinical archives in particular, in order to study retrospective cohorts and to generate data relevant to tissue biomarkers. This raises the question of whether the current sizes of biobank inventories are appropriate to meet the demands of biomarker research. This commentary discusses this question by considering data concerning overall biobank and biospecimen numbers to estimate current biospecimen supply and use. The data suggests that biospecimen supply exceeds current demand. Therefore, it may be important for individual biobanks to reassess the targets for their inventories, consider culling unused portions of these inventories, and shift resources towards providing prospective custom biobanking services.

Ultrasound screening protocol for osteochondrosis at selected predilection sites in thoroughbred yearlings.

BACKGROUND: Osteochondrosis is a common condition of young horses where there is a failure of endochondral ossification, usually at predisposed sites. The estimated prevalence of osteochondrosis is 33-44%, with radiographic screening of yearlings being used to identify lesions. Radiography has two major limitations: poor sensitivity in detecting cartilaginous lesions and secondly, the exposure of the horse and personnel to ionising radiation. Ultrasonography allows imaging of the articular cartilage and subchondral bone margins and has been shown to be more sensitive in identifying osteochondrosis lesions. However, the ultrasonographic technique for examining joints is operator dependant, resulting in highly variable examinations, thus affecting its reliability and reproducibility as a screening test. RESULTS: A prospective observational clinical population study was undertaken involving twenty-two clinically normal weanling thoroughbred horses on-farm, describing a detailed protocol of the ultrasonographic examination technique for on-farm screening of common sites of osteochondral disease in the young horse, namely the carpal, metacarpophalangeal, stifle, tarsal and metatarsophalangeal joints. CONCLUSION: Two veterinary practitioners used the technique to illustrate the repeatability of the protocol. The step-by-step protocol provides a valuable, reliable, repeatable technique for veterinary professionals performing screening ultrasound in the field.

Autologous hematopoietic cell transplantation for relapsed multiple myeloma performed with cells procured after previous transplantation-study on behalf of CMWP of the EBMT.

Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.

Trends in autologous stem cell transplantation for newly diagnosed multiple myeloma: Changing demographics and outcomes in European Society for Blood and Marrow Transplantation centres from 1995 to 2019.

Multiple myeloma (MM) accounts for 10% of haematological malignancies. Overall survival (OS) has improved in recent years due to increased use of autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed MM and the advent of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. To assess trends in ASCT including patient selection, choice of induction regimen, depth of response and survival, we performed a retrospective analysis of all patients undergoing first ASCT for MM in European Society for Blood and Marrow Transplantation centres between 1995 and 2019. A total of 117 711 patients across 575 centres were included. The number of transplants performed increased sevenfold across the study period. The median age increased from 55 to 61 years, and the percentage of patients aged >65 years rose from 7% to 30%. Use of chemotherapy-based induction fell significantly, being largely replaced by bortezomib-based regimens. The two-year complete response rate increased from 22% to 42%. The five-year progression-free survival and OS rates increased from 28% to 31% and from 52% to 69%, respectively. Transplant mortality fell from 5.9% to 1.5%. Ongoing advances in MM treatment may challenge the future role of ASCT. However, at the current time, ASCT remains central to the MM treatment paradigm.

Identification of human gene research articles with wrongly identified nucleotide sequences.

Nucleotide sequence reagents underpin molecular techniques that have been applied across hundreds of thousands of publications. We have previously reported wrongly identified nucleotide sequence reagents in human research publications and described a semi-automated screening tool Seek & Blastn to fact-check their claimed status. We applied Seek & Blastn to screen >11,700 publications across five literature corpora, including all original publications in Gene from 2007 to 2018 and all original open-access publications in Oncology Reports from 2014 to 2018. After manually checking Seek & Blastn outputs for >3,400 human research articles, we identified 712 articles across 78 journals that described at least one wrongly identified nucleotide sequence. Verifying the claimed identities of >13,700 sequences highlighted 1,535 wrongly identified sequences, most of which were claimed targeting reagents for the analysis of 365 human protein-coding genes and 120 non-coding RNAs. The 712 problematic articles have received >17,000 citations, including citations by human clinical trials. Given our estimate that approximately one-quarter of problematic articles may misinform the future development of human therapies, urgent measures are required to address unreliable gene research articles.