Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma.

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study.

BACKGROUND: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. METHODS: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. RESULTS: A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose-limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3-64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. CONCLUSIONS: Nivolumab has a safety profile in PLWH similar to HIV-negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02408861.

IL-27-engineered CAR.19-NK-92 cells exhibit enhanced therapeutic efficacy.

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells has shown promising results in early-phase clinical studies. However, advancing CAR-NK cell therapeutic efficacy is imperative. In this study, we investigated the impact of a fourth-generation CD19-targeted CAR (CAR.19) coexpressing IL-27 on NK-92 cells. We observed a significant improvement in NK-92 cell proliferation and cytotoxicity activity against B-cell cancer cell lines, both in vitro and in a xenograft mouse B-cell lymphoma model. Our systematic transcriptome analysis of the activated NK-92 CAR variants further supports the potential of IL-27 in fourth-generation CARs to overcome limitations of NK cell-based targeted tumor therapies by providing essential growth and activation signals. Integrating IL-27 into CAR-NK cells emerges as a promising strategy to enhance their therapeutic potential and elicit robust responses against cancer cells. These findings contribute substantially to the mounting evidence supporting the potential of fourth-generation CAR engineering in advancing NK cell-based immunotherapies.

Roxadustat versus placebo for patients with lower-risk myelodysplastic syndrome: MATTERHORN phase 3, double-blind, randomized controlled trial.

In patients with lower-risk myelodysplastic syndromes/neoplasms (MDS), response to first-line therapy is limited and transient. The MATTERHORN randomized, double-blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion-dependent, lower-risk MDS. Eligible patients had very low-, low-, or intermediate-risk MDS with or without prior erythropoiesis-stimulating agent treatment, and a transfusion burden of 1-4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders (p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p-nominal = .047). The seven on-study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment.

Quality use of publicly subsidised tapentadol in Australia: a population-based analysis.

BACKGROUND: Sustained-release (SR) tapentadol was listed on Australia's Pharmaceutical Benefits Scheme (PBS) in 2014 for chronic severe pain requiring long-term opioid treatment. Dispensings have increased since listing despite declining trends in other PBS-listed opioids. Preferential prescribing of SR opioids may increase the risk of dependence and accidental overdose, particularly when used to treat acute pain. AIMS: To explore the quality use of publicly subsidised tapentadol in Australia. METHODS: We examined annual initiation rates and patterns of use of tapentadol (SR) in the dispensing records of a 10% random sample of PBS-eligible Australians (2014-2021). We used national tapentadol sales data to assess the proportion of sales attributable to the PBS. RESULTS: Tapentadol initiation increased from 2014, peaking at 7.5/1000 adult population in 2019 before declining to 5.3/1000 in 2021. We identified 63 766 new users between 2014 and 2020, of whom 92.8% discontinued in the first year following initiation, 58.0% had only a single dispensing and 34.3% had no other opioids dispensed in the 3 months before or after initiation. 27.8% of new users were dispensed tapentadol on the same day as potentially interacting medicines. There was a sustained drop in the proportion of sales attributable to the PBS from June 2020 onwards, from an average of 69.1%, to 63.9% of pack sales. CONCLUSIONS: Patterns of use suggest tapentadol (SR) is generally used for short duration. Although most tapentadol sold in Australia is subsidised, there is evidence of a shift towards private sales.

Exact Solutions Modelling Nonlinear Atmospheric Gravity Waves.

Exact solutions to the governing equations for atmospheric motion are derived which model nonlinear gravity wave propagation superimposed on atmospheric currents. Solutions are explicitly prescribed in terms of a Lagrangian formulation, which enables a detailed exposition of intricate flow characteristics. It is shown that our solutions are well-suited to modelling two distinct forms of mountain waves, namely: trapped lee waves in the Equatorial f-plane, and vertically propagating mountain waves at general latitudes.

Open-label, Phase 2 study of roxadustat for the treatment of anemia in patients receiving chemotherapy for non-myeloid malignancies.

Anemia is a common side effect of myelosuppressive chemotherapy; however, chemotherapy-induced anemia (CIA) management options are suboptimal. We evaluated the efficacy and safety of roxadustat in this setting. This open-label Phase 2 study included patients with non-myeloid malignancies and CIA (hemoglobin [Hb] ≤10 g/dL) who had planned concurrent myelosuppressive chemotherapy for ≥8 additional weeks. Oral roxadustat was administered for ≤16 weeks (starting dose 2.0 or 2.5 mg/kg, then titrated every 4 weeks). The primary efficacy endpoint was mean maximum change in Hb within 16 weeks of baseline without red blood cell (RBC) transfusion. Patients were assigned to roxadustat 2.0 (n = 31) or 2.5 mg/kg (n = 61) starting doses, and 89 were assessed for efficacy. The mean (standard deviation) maximum Hb change from baseline without RBC transfusion was 2.4 (1.5) and 2.5 (1.5) g/dL in the roxadustat 2.0 and 2.5 mg/kg groups, respectively. Median (range) time to Hb increase of ≥2 g/dL was 71 (57-92) days. Twelve patients (14.5%) had RBC transfusions (Week 5 to the end of treatment). Roxadustat was efficacious regardless of tumor type and chemotherapy regimen. Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 14 (15.2%) and nine (9.8%) patients, respectively, and three had serious adverse events attributed to roxadustat in the opinion of the investigators (PE: n = 2 [2.2%]; DVT: n = 1 [1.1%]). Roxadustat increased Hb in patients with CIA regardless of tumor type and chemotherapy regimen. Adverse events were consistent with observations in patients with advanced-stage malignancies.

Wound inflammation post-orchiectomy affects the social dynamic of Nelore bulls.

BACKGROUND: Confinement of cattle imposes spatial restrictions and predisposes to aversive social encounters that can lead to contusions, wounds, pain, stress, fright, and reduced productivity. Although endogenous testosterone concentrations are linked to agonistic dominance behaviors in males, it is unknown whether decreased blood testosterone concentrations after castration alter social hierarchy rank in Nelore bulls. Therefore, in this study, we investigated the impact of the surgical would inflammation post-orchiectomy on social dynamics in a group of Nelore bulls (Bos indicus). Fourteen Nelore (Bos indicus) bulls were castrated and assessed pre- and post-surgically. Parameters evaluated were agonistic (mounting, headbutting, and fighting) and affiliative (head-play) behavior, plasma testosterone concentrations, average daily weight gain (ADG), and a score for severity of post-surgical infection. Exploratory statistics included social network analysis (SNA), hierarchy rank delta (Δ), and principal component analysis (PCA). Furthermore, statistical inferences included the Wilcoxon test, multiple logistic regression models, and Spearman's correlation. RESULTS: The social dynamic of Nelore bulls was modified after castration based on the findings of the SNA and the PCA. The moderate correlation between the postoperative inflammation level with the Δ, and the significant effect of this level in the logistic model post-castration were partially attributed to effects of pain on social relations. CONCLUSIONS: Our findings suggest the severity of post-surgical inflammation, which has an association with pain intensity, was closely associated with changes in the social hierarchy.

Stakeholder Perspectives of Clinical Artificial Intelligence Implementation: Systematic Review of Qualitative Evidence.

BACKGROUND: The rhetoric surrounding clinical artificial intelligence (AI) often exaggerates its effect on real-world care. Limited understanding of the factors that influence its implementation can perpetuate this. OBJECTIVE: In this qualitative systematic review, we aimed to identify key stakeholders, consolidate their perspectives on clinical AI implementation, and characterize the evidence gaps that future qualitative research should target. METHODS: Ovid-MEDLINE, EBSCO-CINAHL, ACM Digital Library, Science Citation Index-Web of Science, and Scopus were searched for primary qualitative studies on individuals' perspectives on any application of clinical AI worldwide (January 2014-April 2021). The definition of clinical AI includes both rule-based and machine learning-enabled or non-rule-based decision support tools. The language of the reports was not an exclusion criterion. Two independent reviewers performed title, abstract, and full-text screening with a third arbiter of disagreement. Two reviewers assigned the Joanna Briggs Institute 10-point checklist for qualitative research scores for each study. A single reviewer extracted free-text data relevant to clinical AI implementation, noting the stakeholders contributing to each excerpt. The best-fit framework synthesis used the Nonadoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework. To validate the data and improve accessibility, coauthors representing each emergent stakeholder group codeveloped summaries of the factors most relevant to their respective groups. RESULTS: The initial search yielded 4437 deduplicated articles, with 111 (2.5%) eligible for inclusion (median Joanna Briggs Institute 10-point checklist for qualitative research score, 8/10). Five distinct stakeholder groups emerged from the data: health care professionals (HCPs), patients, carers and other members of the public, developers, health care managers and leaders, and regulators or policy makers, contributing 1204 (70%), 196 (11.4%), 133 (7.7%), 129 (7.5%), and 59 (3.4%) of 1721 eligible excerpts, respectively. All stakeholder groups independently identified a breadth of implementation factors, with each producing data that were mapped between 17 and 24 of the 27 adapted Nonadoption, Abandonment, Scale-up, Spread, and Sustainability subdomains. Most of the factors that stakeholders found influential in the implementation of rule-based clinical AI also applied to non-rule-based clinical AI, with the exception of intellectual property, regulation, and sociocultural attitudes. CONCLUSIONS: Clinical AI implementation is influenced by many interdependent factors, which are in turn influenced by at least 5 distinct stakeholder groups. This implies that effective research and practice of clinical AI implementation should consider multiple stakeholder perspectives. The current underrepresentation of perspectives from stakeholders other than HCPs in the literature may limit the anticipation and management of the factors that influence successful clinical AI implementation. Future research should not only widen the representation of tools and contexts in qualitative research but also specifically investigate the perspectives of all stakeholder HCPs and emerging aspects of non-rule-based clinical AI implementation. TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews) CRD42021256005; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=256005. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/33145.

Safety and Tolerability of Carboplatin and Paclitaxel in Cancer Patients with HIV (AMC-078), an AIDS Malignancy Consortium (AMC) Study.

BACKGROUND: Persons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer. METHODS: Eligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles. RESULTS: Sixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/µL) compared with baseline values (median: 389/µL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts. CONCLUSION: Full doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT01249443.

Interface between Two Immiscible Electrolyte Solutions Electrodes for Chemical Analysis.

The interface between two immiscible electrolyte solutions (ITIES) plays vital roles in various fields, such as neuroscience, environmental science, analytical chemistry, separation, catalysis, and nanoparticle synthesis. ITIES emerges as a unique approach in chemical analysis due to its sensitivity to both redox-active and redox-inactive analytes. Neurotransmitters, metal ions, drug molecules, and other complex molecules such as proteins have been detected using ITIES. The detection of redox-inactive species at the ITIES has opened a door to understanding a wide range of complex systems that are less suited to probing by solid electrodes. In this feature article, we present the history of electrochemistry at the ITIES; charge transfer reactions, thermodynamics, and kinetics at the ITIES; electrode-solution interfacial structure; and a diverse range of applications enabled by ITIES.

Roxadustat for the treatment of anemia in patients with lower-risk myelodysplastic syndrome: Open-label, dose-selection, lead-in stage of a phase 3 study.

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.

Patterns of primary prophylactic granulocyte colony-stimulating factor use in older Medicare patients with cancer receiving myelosuppressive chemotherapy.

PURPOSE: Guidelines recommend primary prophylactic (PP) granulocyte colony stimulating factor (G-CSF) for prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy with high risk (HR: > 20%), or intermediate risk (IR:10-20%) of FN and ≥ 1 patient risk factor (e.g., age ≥ 65y). The current retrospective cohort study describes patterns of PP-G-CSF in older Medicare patients undergoing myelosuppressive chemotherapy with HR/IR of FN. METHODS: Patients aged ≥ 66y initiating chemotherapy regimens with HR/IR of FN to treat breast, colorectal, lung, or ovarian cancer, or Non-Hodgkin's Lymphoma were selected using Medicare 20% sample (2013-2015) and 100% cancer patient (2014-2017) data. PP-G-CSF use was identified in the first cycle. Timing of pegfilgrastim pre-filled syringe (PFS) administration, proportion of patients completing all cycles (adherence) with pegfilgrastim PFS or on-body injector (OBI), and duration of short-acting G-CSF (sG-CSF) was described across all cycles. RESULTS: Of 64,893 patients receiving HR/IR for FN, 71% received HR and 29% IR regimens. Overall, PP-G-CSF use in the first cycle was 53% (HR: 74%; IR: 44%) and varied across cancers. Adherence with pegfilgrastim was slightly higher among OBI initiators (78%) than PFS (74%). Number of PP-sG-CSF administrations (mean [SD]) per cycle was 5.1 (SD: 2.7) overall, 5.4 (2.6) for HR, and 4.9 (2.7) for IR. CONCLUSION: Despite cancer treatment guidelines recommending PP-G-CSF use to reduce risk of FN associated with HR and IR (with ≥ 1 patient risk-factor) regimens, PP-G-CSF remains underutilized in older patients, across cancer types and regimens. Opportunities exist for improvement in use of PP-G-CSF.

Incidence of heterotopic ossification following hip arthroscopy is low: considerations for routine prophylaxis.

PURPOSE: This scoping review aims to map and summarise the available literature on heterotopic ossification (HO) following hip arthroscopy, with particular focus on incidence, distribution as per Brooker classification, efficacy of prophylactic measures and factors that may influence the likelihood of production of HO. METHODS: A computer-based search was performed on PubMed, Embase, Emcare, Cinahl, ISI web of science and Scopus using the terms 'heterotopic ossification' and 'hip arthroscopy'. Articles reporting heterotopic ossification following hip arthroscopy for any condition were included after two-stage title/abstract and full-text screening. RESULTS: Of the 663 articles retrieved, 45 studies were included. The proportion of patients with HO ranged from 0 to 44%. The majority of the cases were either Brooker grade I or II. Of the six studies investigating the effect of NSAID prophylaxis, five reported a significantly lower incidence of heterotopic ossification associated with its use. Weak evidence suggests that an outside-in arthroscopic approach, no capsular closure, male sex and mixed cam and pincer resection may be associated with an increased risk of HO. CONCLUSION: Although there is a large variation in rates of HO following hip arthroscopy in the current literature, the majority of studies report a low incidence. Evidence exists advocating the administration of post-operative NSAIDs to reduce the incidence of HO following hip arthroscopy. This, combined with the low risk of complications, means there is a favourable risk-benefit ratio for prophylactic NSAID used in HA. Future research should work to identify patient clinical and demographic factors which may increase the risk of development of HO, allowing clinicians to risk stratify and select only specific patients who would benefit from receiving NSAID prophylaxis.

Metoprolol Impairs ß1-Adrenergic Receptor-Mediated Vasodilation in Rat Cerebral Arteries: Implications for ß-Blocker Therapy.

The practice of prescribing ß-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of ß-blocker therapy primarily relies on preventing activation of cardiac ß1-adrenergic receptors (ARs). However, we reported that ß1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that ß-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed ß1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1-10 µmol/l) prevented ß1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The ß1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted ß1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent ß1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on ß-blockers relates in part to adrenergic dysregulation of cerebrovascular tone. SIGNIFICANCE STATEMENT: ß-Blocker therapy using second-generation, cardioselective ß-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardioselective ß-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.

Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in HIV-associated, B-cell non-Hodgkin's lymphoma.

Four cycles of rituximab plus CHOP chemotherapy is as effective as 6 cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with HIV-associated DLBCL and high-grade lymphoma treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy. 106 evaluable patients with HIV-associated DLBCL or high-grade CD20-positive non-Hodgkin's lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. 64 of 106 evaluable patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms. The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) because a CR was first documented after cycle 4. A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in patients with HIV-associated lymphoma treated with EPOCH plus rituximab, which merits further evaluation in additional prospective trials. Clinical Trials.gov identifier NCT00049036.

Intravenous ferric derisomaltose for the treatment of iron deficiency anemia.

Intravenous (IV) iron is the therapy of choice when oral iron is ineffective or poorly tolerated, yet use has been limited by fears of hypersensitivity reactions (HSRs). Newer formulations that bind iron more tightly and release it more slowly have made the risk of serious or severe HSRs very low. One such formulation, ferric derisomaltose, has been approved in the United States for delivery of 1000 mg iron in a single IV infusion. Ferric derisomaltose rapidly repletes iron parameters with low rates of serious or severe HSRs. Single-infusion iron repletion offers convenience, eliminates adherence concerns, and reduces healthcare resource utilization.

Efficacy and safety of ferric carboxymaltose infusion in reducing anemia in patients receiving chemotherapy for nonmyeloid malignancies: A randomized, placebo-controlled study (IRON-CLAD).

Erythropoiesis-stimulating agents (ESA) are effective for chemotherapy-induced anemia (CIA) but associated with serious adverse events. Safer alternatives would be beneficial in this population. The efficacy and safety of ferric carboxymaltose (FCM) as monotherapy for CIA was evaluated. This Phase 3, 18-week, double-blind, placebo-controlled study randomized adults with ≥ 4 weeks of chemotherapy remaining for treatment of nonmyeloid malignancies with CIA to FCM (two 15 mg/kg infusions 7 days apart; maximum dose, 750 mg single/1500 mg total) or placebo. The primary efficacy endpoint was percentage of patients with decreases in hemoglobin (Hb) ≥ 0.5 g/dL from weeks 3 to 18; the key secondary efficacy endpoint was change in Hb from baseline to week 18. Inclusion criteria included: (Hb) 8-11 g/dL, ferritin 100-800 ng/mL, and transferrin saturation (TSAT) ≤35%. In 244 patients (n = 122, both groups), the percent of patients who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs. 35.3%; p = 0.01). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs. 0.87 g/dL) but significantly greater with FCM with baseline Hb ≤ 9.9 g/dL (1.08 vs. 0.42 g/dL; p = 0.01). The percent with ≥ 1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs. 54%; p = 0.01), occurring in a median 43 versus 85 days (p = 0.001). Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). FCM monotherapy effectively maintained Hb and was well tolerated in CIA.

Cancer in First Nations people in Ontario, Canada: Incidence and mortality, 1991 to 2010.

BACKGROUND: This study aims to measure cancer incidence and mortality rates of Registered First Nations people in Ontario and compare them with those of other people in Ontario from 1991 to 2010. DATA AND METHODS: The federal Indian Register, the Ontario Cancer Registry and the Registered Persons Database were linked to develop a cohort of First Nations people diagnosed with cancer in Ontario. Sex-and site-specific age-standardized cancer incidence and mortality rates, and selected trends over time, were calculated. Rate ratios (RRs) were used to compare rates in First Nations peoples with those of other people in Ontario. RESULTS: The First Nations cohort comprised 194,392 people, with 6,859 cancer diagnoses. First Nations people had higher rates for certain cancers than others in Ontario: lung (males RR 1.19; females RR 1.47), colorectal (males RR 1.36; females RR 1.34) and kidney (males RR1.95; females RR 2.23). While lung cancer rates rose in First Nations females (annual percent change [APC] +2.67), they fell at a similar rate (APC -2.28) in males. Cervical cancer rates fell (APC -9.53) and approached the rate among other females in Ontario. Kidney cancer rates increased in First Nations people. DISCUSSION: First Nations people in Ontario have higher incidence and mortality for certain cancers compared with other people in Ontario. However, the declines in cervical cancer rates in First Nations females and lung cancer rates in First Nations males illustrate the likely impact of Pap test uptake and smoking cessation programs. Community-led efforts to develop culturally appropriate prevention and screening programs are essential to further reduce cancer rates in First Nations people.

Over one third of patients with symptomatic femoroacetabular impingement display femoral or acetabular version abnormalities.

PURPOSE: The aim of this study was investigate the relationship between version and torsional abnormalities of the acetabulum, femur and tibia in patients with symptomatic FAI. METHODS: A systematic review was performed according to PRISMA guidelines using the EMBASE, MEDLINE, PubMed and Cochrane databases. Original research articles evaluating the described version and torsional parameters in FAI were included. The MINORS criteria were used to appraise study quality and risk of bias. Mean version and torsion values were displayed using forest plots and the estimated proportion of hips displaying abnormalities in version/torsion were calculated. RESULTS: A total of 1206 articles were identified from the initial search, with 43 articles, involving 8861 hips, meeting the inclusion criteria. All studies evaluating femoral or acetabular version in FAI reported 'normal' mean version values (10-25 °). However, distribution analysis revealed that an estimated 31% and 51% of patients with FAI displayed abnormal central acetabular and femoral version, respectively. CONCLUSION: Up to 51% of patients presenting with symptomatic FAI show an abnormal femoral version, whilst up to 31% demonstrate abnormal acetabular version. This high percentage of version abnormalities highlights the importance of evaluating these parameters routinely during assessment of patients with FAI, to guide clinical decision-making. LEVEL OF EVIDENCE: IV.