Higher Cumulative Dose Research Articles

Effect of dose adjustments on overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with NALIRIFOX: A post hoc analysis of NAPOLI 3.

716 Background: NALIRIFOX is approved by the US Food & Drug Administration and European Medicines Agency for the first-line treatment of adults (no upper age limit) with mPDAC. Approval was based on the results of NAPOLI 3 (NCT04083235), in which NALIRIFOX demonstrated significant improvements in OS (primary outcome) and progression-free survival compared with nab-paclitaxel plus gemcitabine. In this exploratory post-hoc analysis of NAPOLI 3, we examined the impact of NALIRIFOX dose adjustments on OS in patients treated in North America. Methods: Patients (N = 770) with confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m 2 + oxaliplatin 60 mg/m 2 + leucovorin 400 mg/m 2 + 5-fluorouracil 2400 mg/m 2 (NALIRIFOX) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 28-day cycle. In this analysis, liposomal irinotecan dose reductions, delays, and exposure were examined descriptively in patients who received NALIRIFOX at centers in North America. OS was evaluated using Kaplan–Meier methods; no statistical tests were performed. Results: Overall, 120 patients were randomized to receive NALIRIFOX at centers in North America (intention-to-treat [ITT] population) and 112 received treatment (safety population). Dose adjustments (dose reductions and dose delays) occurred in a higher proportion of patients presenting with longer OS. Patients with the longest duration of liposomal irinotecan exposure and highest cumulative dose had the longest OS. Conclusions: This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes and suggests a path forward to further optimize the OS of patients with mPDAC receiving NALIRIFOX. Clinical trial information: NCT04083235 .

Predictors of revision endoscopic sinus surgery in Finnish patients with chronic rhinosinusitis with nasal polyps.

Although patients with chronic rhinosinusitis with nasal polyps (CRSwNP) may benefit from endoscopic sinus surgery (ESS), some patients will experience polyp recurrence, adding to the overall disease burden of CRSwNP. We aimed to investigate predictors of revision ESS in patients with CRSwNP. A nationwide population-based study including all adults diagnosed with CRSwNP who had surgical procedure codes for ESS (N=3506), followed up between January 2012 and December 2019. Logistic regression models provided adjusted odds ratios (OR) with 95% confidence intervals (CIs) for the odds of revision surgery within one and 3years post-index surgery. 559 (15.9%) of the patients had at least one revision surgery during the follow-up. Median time to revision of ESS was 425days (interquartile range: 213-898). Baseline asthma (OR=1.58, 95% CI 1.17-2.12) and antibiotic use (OR=1.61, 95% CI 1.27-2.04) were associated with higher odds of revision ESS, particularly within 3years post-index surgery, whereas Increasing age was inversely associated with the odds of ESS revision (OR=0.82, 95% CI 0.76-0.88). The highest odds of revision ESS were observed within 3years post-index surgery in patients who had undergone extensive surgery at index (OR=14.13, 95% CI 3.41-95.64) compared with those who had undergone limited surgery. OCS use was frequent among CRSwNP patients, with a higher cumulative dose in patients undergoing multiple ESS revisions (63%, n=97, median daily dose 3.29mg, IQR: 1.64-3.70) compared with patients without revisions (49%, n=1361 and 1.64mg, IQR: 1.64-3.29, respectively. p-value <0.001). A small proportion of CRSwNP patients require revision ESS with associated high cumulative OCS doses, highlighting the need for additional therapies to achieve disease control and reduce the corticosteroid burden. A few simple baseline characteristics can predict the need for recurrent surgery among the patients with CRSwNP.

Isotretinoin and Hepatotoxicity in Patients with Acne: A Narrative Review

Acne vulgaris is a prevalent dermatological condition that is often treated with isotretinoin, a potent medication effective in moderate to severe cases. However, its use requires careful monitoring because of its potential hepatotoxic effects. Isotretinoin has been associated with transient elevations in liver enzyme levels, with mild abnormalities observed in up to 11% of cases. Severe elevations (grade ≥ 3), indicating potential liver dysfunction, occur infrequently, with an incidence of approximately 0.2% to 0.5%. The mechanisms underlying isotretinoin-induced liver injury involve oxidative stress and genetic susceptibility, primarily manifesting as idiosyncratic drug-induced liver injury. Most enzyme abnormalities occur within the initial months of treatment, and their clinical significance varies, with many cases resolving without intervention. A review of large cohort studies highlighted the incidence of abnormal liver function tests, including elevated alanine aminotransferase and aspartate aminotransferase levels. These abnormalities are often present within the first 3 months of therapy, particularly at higher cumulative doses. The role of routine liver function monitoring is debated, with recommendations favoring baseline and early follow-up tests and further testing guided by clinical indicators. Alanine aminotransferase may serve as a more specific marker for liver injury compared to other markers, such as aspartate aminotransferase. This review highlights the importance of evidence-based guidelines to balance effective acne treatment with the risk of isotretinoin-induced hepatotoxicity. Standardizing monitoring protocols and integrating genetic and oxidative stress markers may enhance safety and therapeutic outcomes. Further research is essential to refine these strategies and address gaps in long-term hepatotoxicity data.

Metformin use and pancreatic ductal adenocarcinoma outcomes: a narrative review.

Metformin is a diabetes medication with anti-mitotic properties. A narrative review was performed to investigate people using metformin and the risk of developing pancreatic ductal adenocarcinoma (PDAC) as well as survival outcomes in established PDAC. Relevant studies on metformin use and PDAC were retrieved from PubMed including observational studies on metformin and the risk of developing PDAC and survival outcomes in PDAC, and randomized controlled trials of metformin as a treatment in PDAC. Of the 367 studies searched, 26 studies fulfilled the criteria for this review. Metformin was not consistently associated with a reduced risk of developing PDAC. However, metformin use, especially higher cumulative doses, in some studies was associated with longer survival in patients with established PDAC, especially in the subgroup with resectable PDAC. Metformin use was not associated with longer survival in more advanced (non-resectable metastatic) PDAC. Metformin was not consistently associated with a reduced risk of developing PDAC. Metformin may be associated with overall survival benefits in patients with PDAC including the resectable PDAC subgroup but not in the metastatic PDAC subgroup. The evidence to date does not support the routine use of metformin as an adjuvant therapy for advanced PDAC.

Acne Relapse and Isotretinoin Retrial in Patients With Acne

Isotretinoin is the only medical acne treatment capable of inducing acne remission; however, some patients experience acne relapse and require retrials of isotretinoin. There is a need to understand who is most at risk and how daily dose and cumulative dosage can influence outcomes. To assess rates of acne relapse and isotretinoin retrial and to identify associated factors among patients with acne who received an isotretinoin treatment course. This cohort study used data from the MarketScan commercial claims database from January 1, 2017, to December 31, 2020, to identify patients with acne who were 12 years or older and had received isotretinoin for 4 months or longer, with at least 1 year of continuous enrollment after completion of isotretinoin. Data analyses were performed from June 30, 2024, to August 1, 2024. Multivariable Cox proportional hazards regression was used to quantify associations of patient demographic and treatment characteristics with acne relapse and isotretinoin retrial. A total of 19 907 patients (mean [SD] age, 20.6 [7.8] years; 10 504 females [52.8%]) were included, among whom 4482 (22.5%) had acne relapse and 1639 (8.2%) had isotretinoin retrial. Female sex (hazard ratio [HR], 1.43; 95% CI, 1.35-1.52) was significantly associated with increased rates of acne relapse, and isotretinoin cumulative dosage (mg/kg) was associated with a decreased rate of acne relapse (HR, 0.996; 95% CI, 0.995-0.997). Furthermore, daily dose was not associated with decreased risk of acne relapse or isotretinoin retrial among those with conventional and high cumulative dosages. Female sex (HR, 0.68; 95% CI, 0.62-0.76) and isotretinoin cumulative dosage (HR, 0.99; 95% CI, 0.98-0.99) were associated with decreased rates of isotretinoin retrial. Stratification by cumulative dosage indicated that higher cumulative dosage was associated with decreased rates of retrial among patients with low (<120 mg/kg) and conventional (120-220 mg/kg), but not high (>220 mg/kg) cumulative dosage. Maximum daily dose (mg/kg/d) was not negatively associated with acne relapse or isotretinoin retrial in patients with cumulative dosage of 120 mg/kg or more. The findings of this cohort study suggest that higher cumulative dosage may potentially reduce risk of acne relapse and isotretinoin retrial. Furthermore, daily dose was not associated with decreased risk of the outcomes for conventional and high cumulative dosage; therefore, daily dosing could be individualized to patient goals and preferences.

Corticosteroid therapy for treating acute exacerbation of interstitial lung diseases: a systematic review.

Acute exacerbation of interstitial lung disease (AE-ILD) often results in death and poses significant challenges in clinical management. While corticosteroids are frequently employed, the optimal regimen and their clinical efficacy remain uncertain. To address this knowledge gap, we undertook a systematic review to evaluate the impact of steroid therapy on clinical outcomes in patients experiencing AE-ILD. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched multiple databases, identifying 12 454 articles. After removing duplicates and screening titles and abstracts, 447 articles were selected for full-text review. Ultimately, nine studies met inclusion criteria, comparing high-dose corticosteroids with low-dose or non-steroidal interventions in treating AE-ILD. Key outcomes included in-hospital and long-term mortality, as well as AE recurrence. Analysis of nine studies (total n=18 509) revealed differential treatment effects based on the ILD subtype. In non-idiopathic pulmonary fibrosis (IPF) ILD, high-dose corticosteroid therapy (>1.0 mg/kg prednisolone) demonstrated improved survival (adjusted HR 0.221, 95% CI 0.102 to 0.480, p<0.001) and reduced 90-day mortality. Early tapering of high-dose corticosteroids (>10% reduction within 2 weeks) reduced in-hospital mortality (adjusted HR 0.37, 95% CI 0.14 to 0.99). Higher cumulative doses in the first 30 days (5185±2414 mg/month vs 3133±1990 mg/month) were associated with lower recurrence rates (adjusted HR 0.61, 95% CI 0.41 to 0.90, p=0.02). In IPF patients, however, high-dose therapy showed inconsistent benefits, with some studies reporting increased mortality risk (OR 1.075, 95% CI 1.044 to 1.107, p<0.001). This review emphasises the potential benefits of individualised treatment approaches for AE-ILD but highlights the need for caution in making definitive recommendations. Although high-dose corticosteroids may show promise, particularly in non-IPF cases, the current evidence is inconsistent, and the lack of robust supporting literature makes it difficult to draw firm conclusions. Further research through randomised controlled trials is necessary to refine and optimise therapeutic strategies for AE-ILD.

Graves' Disease and the Risk of Type 2 Diabetes: A Korean Population-Based Study.

Background: Several meta-analyses have found no association between Graves' disease (GD) and an increased risk of incident diabetes; however, the intricate relationship between thyroid dysfunction and diabetes remains underexplored. In this study, we aimed to evaluate the risk of incident type 2 diabetes (T2DM) in a population newly diagnosed with GD, focusing on different treatment methods and treatment duration. Methods: This was a retrospective population-based study utilizing data from the Korean National Health Insurance database. We included 36,243 patients with GD and 36,243 controls, matched with age and sex. We calculated the incidence of T2DM among patients and controls based on treatment methods, such as medical therapy, radioactive iodine therapy (RAIT), and surgery. We examined the cumulative dose and duration of antithyroid drug (ATD) use for each patient. Results: The majority of patients (34,867, 96.2%) were treated with ATDs, followed by RAIT (1093 patients, 3%), and surgery (283 patients, 0.8%). After adjusting for age; sex; income; comorbidities, including hypertension, dyslipidemia, and cancer; body mass index; smoking; drinking; and exercise, patients with GD exhibited a higher risk of developing diabetes (hazard ratio [HR] = 1.13 [95% confidence interval 1.06-1.21]) than controls (5.1% vs. 4.5%, respectively). While the risk was the highest within the first six months after GD diagnosis (HR = 3.21), it was significant between six months and two years (HR = 1.36) and was comparable with the controls two years after GD diagnosis (HR = 0.93). A longer duration of ATD treatment and a higher cumulative dose were associated with an increased risk of diabetes. However, the risks for T2DM did not differ according to treatment modality or clinical outcomes, which was probably related to the small number of patients in each subgroup. Conclusions: Our findings highlight the negative impact of GD on the development of T2DM. Patients newly diagnosed with GD can be considered for diabetes screening to facilitate early detection and intervention.

Metformin lowers risk of hearing loss and mortality in type 2 diabetes.

To assess the association between metformin use and the risk of sudden sensorineural hearing loss (SSNHL) in patients with Type 2 diabetes (T2D), a population at elevated risk for SSNHL. This cohort study utilized data from Taiwan's National Health Insurance Research Database, following T2D patients from 2008 to 202 database's baseline. Metformin use was defined as achieving ≥80% of the medication possession ratio (MPR) and ≥28 cumulative defined daily doses (cDDD) within three months. The control group included patients with ≥80% MPR from other antidiabetic agents, ensuring active treatment comparability. Propensity score matching was applied to balance covariates, while competing risk models accounted for mortality. Hazard ratios (HRs), incidence rates (IRs), and incidence rate ratios (IRRs) were calculated. Metformin users demonstrated a lower SSNHL incidence (IR: 11.48 per 10,000 person-years) compared to non-users (IR: 15.66 per 10,000 person-years), with an IRR of 0.73 (95% CI: 0.66-0.82; p < 0.0001). Adjusted HRs indicated a 27% reduction in SSNHL risk (HR: 0.73; 95% CI: 0.66-0.82). Higher cumulative doses (Q4: HR 0.36; 95% CI: 0.29-0.46) and daily doses ≥1 DDD (HR: 0.78; 95% CI: 0.69-0.87) were linked to further risk reductions. Metformin use was also associated with lower overall mortality. Metformin use is associated with a dose-dependent reduction in SSNHL risk and lower mortality in T2D patients. The rigorous definitions of metformin exposure and an actively treated comparator group emphasize these findings, suggesting metformin's potential role in SSNHL prevention and improved survival.

Effectiveness of Bisphosphonates in Young Adults with Fragility Fractures: Representative Population-Based Cohort Study.

Fragility fractures in young adults present significant clinical challenges due to the limited evidence on the effectiveness of bisphosphonates in preventing subsequent fractures. To evaluate the effectiveness of bisphosphonate therapy in reducing the fracture risk among premenopausal women with a history of osteoporotic fractures. A population-based retrospective cohort study was conducted using data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) in South Korea, covering the years 2003 to 2014. A nationwide healthcare setting utilizing a representative cohort database. Among 2,087 premenopausal women with osteoporotic fractures, participants were propensity score-matched based on age and body mass index at a 1:3 ratio, resulting in 132 bisphosphonate users and 396 non-users. Bisphosphonate treatment. The incidence of osteoporotic fractures. Bisphosphonate users had a significantly lower risk of major osteoporotic fractures (HR 0.618, 95% CI 0.396 - 0.963) compared to non-users. Ibandronate users showed significant reductions in both major osteoporotic (HR 0.376, 95% CI 0.164 - 0.861) and nonvertebral fractures (HR 0.214, 95% CI 0.052 - 0.877). Also, longer duration of bisphosphonate use (≥180 days) was associated with a significantly lower risk of major osteoporotic and nonvertebral fractures (HR 0.528, 95% CI 0.300 - 0.929; HR 0.409, 95% CI 0.187 - 0.895, respectively). Bisphosphonate therapy significantly reduces fracture risk in premenopausal women with previous osteoporotic fractures, especially at higher cumulative doses. These findings support considering bisphosphonates as a treatment option in premenopausal women at high risk of fractures.

Bullous pemphigoid. New directions of therapy, prospects for the future (literature review)

Bullous pemphigoid (BP) is an autoimmune subepidermal bullous dermatosis that significantly affects the quality of life of patients due to pronounced subjective symptoms, affecting mainly the elderly. Autoantibodies against hemidesmosomal proteins BP180 and BP230 are involved in the pathogenesis of BP, which leads to detachment at the junction of the dermis and epidermis, as well as the formation of blisters. The severity, prevalence of the pathological process and painful itching require the appointment of high doses or constant use of systemic glucocorticoids, which is not always possible due to extensive concomitant pathology and a large list of side effects. The article presents modern methods of bullous pemphigoid therapy using monoclonal antibodies (rituximab, dupilumab, omalizumab). The mechanisms of therapeutic effect of the drugs described in the article are aimed at various pathways of immunopathogenesis of bullous pemphigoid. The new treatment methods described in the article offer alternative ways of helping patients who have contraindications to the appointment of systemic glucocorticosteroids, demonstrating the lack of effect from the use of basic therapy, with a recurrent process. New therapeutic techniques will improve results and reduce high cumulative doses of systemic corticosteroids and their associated toxic effects.

Transitional Cell Carcinoma Arising From the Renal Allograft: A Case Series and Review of the Literature.

Transitional cell carcinoma (TCC) of the urinary tract appears more commonly amongthe transplant population. The increased incidence of TCC has been primarily associated with the male gender, BK virus (BKV), and smoking.We report a case series and comprehensive review of the literature. The comprehensive literature review was conducted via Pubmed using the keywords "transitional cell carcinoma" and "renal allograft."At our institution, all of our cases presented with hematuria, and hydronephrosis was present in 50% (two) of our cases. BKV was detected in 75% (three) of our cases. The average time from BKV detection to TCC diagnosis was 5.6 years. The average time from transplant to TCC diagnosis was 11.25 years. Upon review of the literature, a total of 20 cases were reported of TCC arising within the renal allograft. Of those patients, 55% (11) presented with hematuria, 30% (six) had BKV, and 35% (seven) were found to have hydronephrosis. The average time from BKV detection to TCC diagnosis was 3.4 years and the average time from transplant to TCC diagnosis was 9.5 years. Given the relatively increased incidence of neoplasm among solid organ transplant recipients, painless hematuria in a renal transplant recipient should raise concern for malignancy, especially in those with prior oncogenic viral infections, history of smoking, other environmental exposures, or in those with high cumulative doses of immunosuppressive medications.

Reirradiation in Paediatric Tumours of the Central Nervous System: Outcome and Side Effects After Implementing National Guidelines

AimsReirradiation is becoming more frequently used in paediatric tumours of the central nervous system (CNS). To fill the void of clinical guidelines, the Swedish Working Group of Paediatric Radiotherapy compiled consensus guidelines on reirradiation in 2019. The aim of this study was to evaluate the outcome of children reirradiated for CNS tumours since implementing the guidelines. Material and methodsAll children in Sweden who were reirradiated for CNS tumours between 2019 and 2023 were retrospectively analysed. Data were collected on patient and treatment characteristics, outcome, and severe side effects. Radiation treatment plans were reviewed, and cumulative doses to organs at risk at reirradiation were extracted following rigid registration. ResultsThirty-one patients (male 55%, female 45%) were included, and the median age at start of reirradiation was 10.2 years. The median time between primary irradiation and reirradiation was 19 months (range 2–141). The most common treatment intent at reirradiation was palliative (68%), followed by curative (32%). With a median follow-up of 8.5 months (range 0–49), the median overall survival from the end of reirradiation was 11.4 months. In the 8 patients where the treatment goal at reirradiation was symptom relief, 6 patients (75%) had relief of symptoms. The median cumulative near maximum doses (D2%) to the brain, brainstem, and chiasm/optic nerves were 71 GyEQD2 (range 44–102), 72 GyEQD2 (range 0–94), and 40 GyEQD2 (range 0–76), respectively. Following reirradiation, only 2 patients had grade ≥3 side effects. One with transient neurological deficit and one with rapid onset of blindness that persisted. ConclusionThe implementation of national guidelines has harmonised the way paediatric patients are reirradiated for CNS tumours in Sweden. A structured follow-up shows that severe side effects are rare despite high cumulative doses to organs at risk, and that reirradiation can offer relief of symptoms and/or local control for selected patients.

MO48-2 Cardiotoxicity after high cumulative dose of anthracyclines in adults with advanced soft tissue sarcomas: a meta-analysis

MO48-2 Cardiotoxicity after high cumulative dose of anthracyclines in adults with advanced soft tissue sarcomas: a meta-analysis

Prevalence of Low Bone Mineral Density and Associated Risk Factors among Patients with Systemic Lupus Erythematosus: A Retrospective Observational Study

Abstract Objectives: The objective of this study was to determine the prevalence of low bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE) and evaluate potential risk factors. Methods: A retrospective observational study of 144 patients with SLE who had at least one BMD test through dual-energy X-ray absorptiometry (DEXA) scan was conducted at King Saud Medical City and Prince Sultan Military Medical City in Riyadh, Saudi Arabia, between April 19, 2022, and April 18, 2023. Multivariate linear regression analyses were performed to determine the risk factors for low BMD. Results: The study included 144 SLE patients. The prevalence of low BMD was 53.3%. Low bone mass prevalence (defined as a Z-score &lt;−2.0 in premenopausal women and men younger than 50 years), osteopenia, and osteoporosis were 29.9%, 13.2%, and 10.4%, respectively. There were 5.6% patients with fragility fractures, 75% vertebral fractures, and 25% peripheral fractures. Older age, postmenopausal status, arthritis, and high cumulative glucocorticoid dose were associated with low BMD. Immunosuppressive agents are protected against low BMD. In multivariate linear regression analyses, postmenopausal status remained a risk factor for low BMD. Conclusions: Patients with SLE are at a high risk of having low BMD. The majority exhibit low bone mass rather than osteopenia or osteoporosis, with the most common fractures occurring in the vertebrae. Notably, postmenopausal status represents a major risk factor for low BMD in patients with SLE.

1750P Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis

1750P Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis

Symptomatic osteonecrosis in children treated for Hodgkin lymphoma: A population-based study in Sweden, Finland, and Denmark.

Osteonecrosis (ON) is a potentially disabling skeletal complication of cancer treatment. Although symptomatic osteonecrosis (sON) is well-known in acute lymphoblastic leukemia (ALL), with an incidence around 6%, studies on sON in pediatric Hodgkin lymphoma (HL) are scarce. The aim of this study was to examine the incidence, risk factors, and outcome of sON in children treated for HL. A total of 490 children under 18, diagnosed with HL between 2005 and 2019 in Sweden, Finland, and Denmark were eligible for the study. Data on patient characteristics, HL treatment, and development of sON were collected from patients' medical records. Magnetic resonance imaging scans were used to establish ON diagnosis and grade ON according to the Niinimäki grading system. Cumulative 2-year incidence of sON among the 489 included patients was 5.5% (n=30). The risk for developing sON was higher for those with older age (odds ratio [OR] 1.25, 95% confidence interval [CI]: 1.05-1.49, p<.010), female sex (OR 4.45, CI 1.87-10.58, p<.001), high total cumulative glucocorticoid (GC) doses (OR 1.76, 95% CI: 1.21-2.56, p=0.003), and advanced HL (OR 2.19, 95% CI: 1.03-4.65, p=.042). Four (13.3%) patients underwent major surgical procedures and 13 (43.3%) had persistent symptoms due to ON at follow-up. This study shows that sON is as common in pediatric HL as in pediatric ALL, with risk factors such as older age, female sex, high cumulative GC doses, and advanced HL. Future HL protocol development should aim to reduce the burden of ON by modifying GC treatment.

Cognitive performance and brain volume among survivors of pediatric hematological malignancies: a case-control study.

Cognitive dysfunction may be one of the hazardous late effects among survivors of pediatric hematological malignancies. Our study aimed to explore cognitive performance and assess the global and regional brain volume changes in survivors of hematological malignancies. This case-control study was conducted on 68 survivors of hematological malignancies, with a median follow-up period of 2years (ranging from 1 to 6.2years). Stanford-Binet Testwas used for cognitive assessment. A quantitative volumetric assessment of the brain was done using the NeuroQuant Brain Magnetic Resonance. Age and sex-matched 68 children were selected as a comparison group. Cancer survivors showed significantly lower levels of IQ and their subtests than the control group. Global brain atrophy was observed in the majority of the survivors. Many risk factors significantly affected different IQ subtests, such as radiotherapy (RTH), high cumulative doses of methotrexate (MTX), and prednisone. At the same time, low white matter volume (WMV) was observed with higher cumulative doses of MTX and anthracyclines. Hematological malignancies have a negative impact on cognition. Neurocognitive impairment and related brain changes were evident in those who received RTH, HDMTX, or high cumulative doses of steroids.

Asbestos Surveillance Program Aachen (ASPA): Cancer mortality among asbestos exposed power industry workers

BackgroundThe time between initial asbestos exposure and asbestos-related disease can span several decades. The Asbestos Surveillance Program aims to detect early asbestos-related diseases in a cohort of 8,565 power industry workers formerly exposed to asbestos. Research questionHow does asbestos exposure patterns affect cancer mortality and the duration of latency until death? MethodsA mortality follow-up was conducted with available vital status for 8,476 participants (99 %) and available death certificates for 89.9 % of deceased participants. Standardised mortality ratios (SMR) were calculated for asbestos-related cancers. The SMR of mesothelioma and lung cancer were stratified by exposure duration, cumulative asbestos exposure and smoking. The effect of age at first exposure, cumulative asbestos exposure and smoking on the duration of latency until death was examined using multiple linear regression analysis. ResultsThe mortality risk of mesothelioma (n = 104) increased with cumulative asbestos exposure but not with exposure duration; the highest mortality (SMR: 23.20; 95 % CI: 17.62–29.99) was observed in participants who performed activities with short extremely high exposures (steam turbine revisions). Lung cancer mortality (n = 215) was not increased (SMR: 1.03; 95 % CI: 0.89–1.17). Median latency until death was 46 (15–63) years for mesothelioma and 44 (15–70) years for lung cancer and deaths occurred between age 64 and 82 years. Latency until death was not influenced by age at first exposure, cumulative exposure, or smoking. ConclusionCumulative dose seems to be more appropriate than exposure duration for estimating the risk of mesothelioma death. Additionally, exposure with high cumulative doses in short time should be considered. Since only lung cancer mortality, not incidence, was recorded in this study, lung cancer risk associated with asbestos exposure could not be assessed and the lung cancer mortality was lower than expected probably due to screening effects and improved treatments. The critical time window of death from asbestos-related cancer is between the seventh and ninth decade of life. Future studies should further explore the concept of latency, especially since large ranges are reported throughout the literature.

Prochlorococcus marinus responses to light and oxygen.

Prochlorococcus marinus, the smallest picocyanobacterium, comprises multiple clades occupying distinct niches, currently across tropical and sub-tropical oligotrophic ocean regions, including Oxygen Minimum Zones. Ocean warming may open growth-permissive temperatures in new, poleward photic regimes, along with expanded Oxygen Minimum Zones. We used ocean metaproteomic data on current Prochlorococcus marinus niches, to guide testing of Prochlorococcus marinus growth across a matrix of peak irradiances, photoperiods, spectral bands and dissolved oxygen. MED4 from Clade HLI requires greater than 4 h photoperiod, grows at 25 μmol O2 L-1 and above, and exploits high cumulative diel photon doses. MED4, however, relies upon an alternative oxidase to balance electron transport, which may exclude it from growth under our lowest, 2.5 μmol O2 L-1, condition. SS120 from clade LLII/III is restricted to low light under full 250 μmol O2 L-1, shows expanded light exploitation under 25 μmol O2 L-1, but is excluded from growth under 2.5 μmol O2 L-1. Intermediate oxygen suppresses the cost of PSII photoinactivation, and possibly the enzymatic production of H2O2 in SS120, which has limitations on genomic capacity for PSII and DNA repair. MIT9313 from Clade LLIV is restricted to low blue irradiance under 250 μmol O2 L-1, but exploits much higher irradiance under red light, or under lower O2 concentrations, conditions which slow photoinactivation of PSII and production of reactive oxygen species. In warming oceans, range expansions and competition among clades will be governed not only by light levels. Short photoperiods governed by latitude, temperate winters, and depth attenuation of light, will exclude clade HLI (including MED4) from some habitats. In contrast, clade LLII/III (including SS120), and particularly clade LLIV (including MIT9313), may exploit higher light niches nearer the surface, under expanding OMZ conditions, where low O2 relieves the stresses of oxidation stress and PSII photoinhibition.

Clinical factors associated with hyponatremia correction during treatment with oral urea.

Oral urea is being used more commonly to treat hyponatremia, but factors contributing to the correction rate are unknown. We hypothesized that clinically relevant factors can be identified to help guide hyponatremia correction with oral urea. This was a retrospective study in two university hospitals including hospitalized patients with hyponatremia (plasma sodium <135mmol/L) treated with oral urea. Linear mixed-effects models were used to identify factors associated with hyponatremia correction. Rates of overcorrection, osmotic demyelination and treatment discontinuation were also assessed. We included 161 urea treatment episodes in 140 patients (median age 69years, 46% females, 93% syndrome of inappropriate antidiuresis). Oral urea succeeded fluid restriction in 117 treatment episodes (73%), was combined with fluid restriction in 104 treatment episodes (65%) and was given as the only treatment in 27 treatment episodes (17%). A median dose of 30g/day of urea for 4days (interquartile range 2-7days) increased plasma sodium from 127 to 134mmol/L and normalized hyponatremia in 47% of treatment episodes. Older age (β 0.09, 95% CI 0.02-0.16), lower baseline plasma sodium (β -0.65, 95% CI -0.78 to -0.62) and higher cumulative urea dose (β 0.03, 95% CI -0.02 to -0.03) were independently associated with a greater rise in plasma sodium. Concurrent fluid restriction was associated with a greater rise in plasma sodium only during the first 48h of treatment (β 1.81, 95% CI 0.40-3.08). Overcorrection occurred in 5 cases (3%), no cases of osmotic demyelination were identified and oral urea was discontinued in 11 cases (11%) due to side effects. During treatment with oral urea, older age, higher cumulative dose, lower baseline plasma sodium and initial fluid restriction are associated with a greater correction rate of hyponatremia. These factors may guide clinicians to achieve a gradual correction of hyponatremia with oral urea.