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Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.

Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0–45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. After a median follow-up of 5.6 years [interquartile range (IQR) 3.6–7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6–3.8%] for patients aged 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 − 3.0 × 109/L. Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p

Objectives: Explore patient adherence and physician compliance to protocol guidelines during maintenance therapy, including the association with survival in adults with acute lymphoblastic leukemia (ALL). Methods: Blood counts, aminotransferase levels and prescribed 6-mercaptopurine (6MP)/methotrexate (MTX) doses were compared with the protocol guidelines to assess compliance. Non-adherence to the prescribed medication was confirmed in patients with unmeasurable 6MP metabolite levels and suspected in patients with low 6MP metabolites concurrent with aminotransferase and white blood cell count within normal ranges, while potential intermittent non-adherence was defined by >1.9 fold fluctuating 6MP metabolites. Results: Physicians’ non-compliance with insufficient dose increments of 6MP/MTX despite white blood cell counts above the target level comprised a median of 20.1% (interquartile range 9.7-39.3%) of the observed time in maintenance therapy, yet no association to relapse was found (P =.17). Non-adherence to 6MP was confirmed in 9.8% (5 of 51 patients), suspected in an additional 9.8% (5 of 51 patients), and intermittent non-adherence was suspected in 52.6% (20 of 38 patients). Conclusion: Although no association between non-compliance and leukemic relapse was found, likely due to lack of power, increased attention to this phase of ALL therapy is indicated.

Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs.We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study.After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex.Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Hepatotoxicity was recognised as a complication of 6-thioguanine (6TG) in 1976. Since then, 6-TG associated hepatotoxicity in the form of acute sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), has notably been reported in childhood acute lymphoblastic leukaemia (ALL), whereas chronic nodular regenerative hyperplasia (NRH) has been reported in adults with inflammatory bowel disease (IBD) as well as in childhood ALL. However, SOS and NRH should be considered part of a spectrum of microvascular disorders caused by endothelial injury. Nevertheless, the cellular mechanisms responsible for the sinusoidal damage, being pivotal to their development, remain to be established. 6TG-related SOS and NRH have been hypothesised to be dose-related, since they do not seem to occur with low cumulative doses. The recent finding that higher levels of thioguanine nucleotides incorporated into leucocyte DNA (DNA-TGN) correlate to a lower relapse risk, calls for reappraisal of the feasibility of prolonged 6TG treatment for childhood ALL, while avoiding the risk of SOS and NRH. Objectives - Primary objective: To assess the incidence of hepatotoxicity in patients treated with 6TG compared to 6MP or standard care. - Secondary objective: To explore if a safe dose of 6TG can be established.

BackgroundThe recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity.ObjectivesTo assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.Data sourcesDatabases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018.MethodsWe included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included.Results and conclusionsWe included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients; SOS has not been reported. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe.

Objective In the present hypothesis-generating study, we investigated whether spontaneous blood pressure oscillations are suppressed to lower frequencies, and whether abolished oscillations are associated with an adverse outcome in mechanically ventilated patients with sepsis. Methods We retrospectively subjected invasive steady-state blood pressure recordings from 65 mechanically ventilated patients with sepsis to spectral analysis. Modified spectral bands were visually identified by plotting spectral power against frequency. Results Modified middle-frequency and low-frequency (MF' and LF') oscillations were absent in 9% and 22% of the patients, respectively. In patients in whom spontaneous blood pressure oscillations were preserved, the MF' oscillations occurred at 0.021 Hz (median, interquartile range 0.013-0.030), whereas the LF' oscillations occurred at 0.009 Hz (median, interquartile range 0.006-0.010). The absence of LF' oscillations was associated with a higher 30-day mortality [50 vs. 18%, hazard ratio, 3.6 (95% confidence interval: 1.4-9.8), P=0.01]. Conclusion Spontaneous blood pressure oscillations in mechanically ventilated septic patients may be suppressed to lower frequencies than previously reported for spontaneously breathing, healthy humans. Patients in whom the resultant changes in blood pressure (MF' and LF' oscillations) are abolished may have a higher risk of an adverse outcome. This may reflect suppression of the pressor area in the brainstem with subsequent sympathetic dysfunction.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.PROCEDURE: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.RESULTS: Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia CONCLUSIONS: PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

We evaluated whether a classic article on haemorheology would lead to better learning when integrated with a collaborative rather than an individual teaching strategy in the undergraduate physiology classroom setting. A total of 88 2nd-year medical students were randomised to solve assignments based on the classic article individually (n=42) or in groups (n=46) during a 45-minute lesson on basic haemorheology. At the end of the lesson, students completed a test and an evaluation form. There were no differences between the two intervention groups with regard to the total test score, but students who had worked in groups rated their own effort during the lesson higher. In the present study, a collaborative teaching strategy did not lead to higher test scores than an individual teaching strategy. However, our findings suggest that students working in groups may feel a greater level of involvement during class.

Summary Background Continuous monitoring of cerebral blood flow (CBF) may be valuable in critically ill patients with sepsis. In this study, we compared spatially resolved near-infrared spectroscopy (NIRS) to transcranial Doppler ultrasound (TCD)-derived estimates of noradrenaline-associated changes in CBF in such patients. Methods Mean arterial blood pressure (MAP) was elevated by increasing the noradrenaline infusion rate in eight mechanically ventilated, critically ill patients diagnosed with severe sepsis or septic shock. The associated changes in CBF were assessed by simultaneous ipsilateral NIRS (ScO2) and TCD (middle cerebral artery blood flow velocity, MCAv) measurements. Results A total of fifteen simultaneous NIRS- and TCD-derived assessments of noradrenaline-associated changes in CBF were obtained. MAP was increased from 74 (median; interquartile range (IQR), 71–90) to 100 (median; IQR, 93–115) mmHg (P

“The viscosity of the blood in narrow capillary tubes” by Robin Fåhraeus and Torsten Lindqvist ( Am J Physiol 96: 562–568, 1931) can be a valuable opportunity for teaching basic hemorheological principles in undergraduate cardiovascular physiology. This classic paper demonstrates that a progressive decline in apparent viscosity occurs when blood flows through glass capillary tubes of diminishing radius, which was later designated as the “Fåhraeus-Lindqvist effect.” Subsequent studies have shown that apparent viscosity continues to decline at diameters that correspond to the arteriolar segments of the systemic vascular tree, where the majority of the total peripheral resistance resides and is actively regulated in vivo. The Fåhraeus-Lindqvist effect thus reduces microvascular resistance, thereby maintaining local tissue perfusion at a relatively lower blood pressure. The paper by Fåhraeus and Lindqvist can be used as a platform for a plenary discussion of these concepts as well as of the relationships among hematocrit, vessel diameter, red blood cell deformability, and resistance to blood flow and how these factors may affect the work of the heart.

the ability to recognize and diagnose acid-base disorders is of the utmost importance in the clinical setting. However, in our experience, medical students often have difficulties learning the basic principles of acid-base physiology in the respiratory physiology curriculum, particularly when

Anesthesia-related central anticholinergic syndrome (CAS) is most commonly associated with administration of atropine or scopolamine, whereas glycopyrrolate is an extremely rare cause of CAS. Here, we report a case of CAS in a 5-year-old boy admitted to the intensive care unit. Immediately after the administration of glycopyrrolate, he became agitated and developed apnea, hypertension, tachycardia, and anuria. Although the present case describes a rare cause of CAS, it is an important reminder of an iatrogenic condition that is presumably underdiagnosed in the operating theater as well as the intensive care unit.

SUMMARY We report a case of cerebral aspergilloma in a 25-yearold immunoincompetent man admitted to a general intensive care unit. Monitoring of intracranial pressure was instigated and revealed hour-long epochs of severe intracranial hypertension, despite a normal opening pressure, with decreases in cerebral perfusion pressure. We documented that this was associated with cerebral hypoperfusion by transcranial Doppler ultrasound. The present case illustrates that severe intracranial hypertension may evolve despite a normal opening pressure; it furthermore shows that continuous monitoring of intracranial pressure may be used to predict changes in cerebral haemodynamics in critically ill patients with neuroinfection.

When teaching the cardiac cycle to second-year medical students, we have often experienced that students are puzzled by the occurrence of the dicrotic notch (or aortic incisura) and dicrotic wave ([Fig. 1][1]), which is observed in the aortic blood pressure signal as the aortic valve closes and left