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Supplementary Information | The online version contains supplementary material available at 10.1007/s10549-023-07054-3. | PMC10460747 |
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Keywords | Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. | PMC10460747 |
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Introduction | hormone receptor-positive breast cancer, cancer relapse [In postmenopausal women, cancers, breast cancer | CANCERS, RECURRENCE, BREAST CANCER RECURRENT, BREAST CANCER | Hormone receptor-positive [i.e., estrogen (ER) and/or progesterone (PR) receptor-positive] cancers account for 75 percent of all breast cancer cases. Adjuvant endocrine therapy blocks ER function or lowers estrogen levels, reduces the risk of recurrence, and improves survival among women with hormone receptor-positive early breast cancer.Aromatase inhibitors (AIs) suppress plasma estrogen levels by inhibiting peripheral conversion of androgens to estrogens and reduce breast cancer recurrence and mortality. AIs are the preferred adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer [Adjuvant AI treatment is often recommended for five to ten years according to the risk of cancer relapse [In postmenopausal women, levels of circulating E2 are typically within the range of 10 to 60 pmol/L [The primary aim of the present study was to analyze the effects of letrozole treatment on serum estrogens, especially E2, in postmenopausal breast cancer patients, using a highly sensitive and specific LC–MS/MS method. The aim was also to assess our routine chemiluminescent E2 method for monitoring of serum estradiol in post-menopausal patients and compare it to our sensitive LC–MS/MS. Secondary objectives were to analyze the effects of letrozole on serum E1 and to investigate the impact of baseline demographics, E2, E1, and FSH on QoL and treatment tolerability during adjuvant letrozole treatment. | PMC10460747 |
Patients and methods | amenorrhea, Cancer | CANCER | This study was carried out at the Helsinki University Central Hospital Comprehensive Cancer Center from October 2015 to January 2017. Eligible patients were postmenopausal women with hormone receptor-positive early-stage breast cancer for whom adjuvant letrozole treatment was planned. Prior adjuvant chemotherapy was not allowed. The patients were classified as postmenopausal if they were either ≥ 60 years of age or had a history of amenorrhea for at least 12 months with serum E2 and FSH levels within the postmenopausal range. Adjuvant treatment with letrozole 2.5 mg daily was started in all patients.The levels of E2 and FSH were analyzed by a solid-phase, enzyme-labeled chemiluminescent immunoassay in an Immulite 2000 Xpi analyzer (Siemens Healthineers, Tarrytown, NY USA) at three and 12 months during letrozole treatment. After the completion of the trial the levels of serum E2 and E1 were studied by a highly sensitive LC–MS/MS using duplicate serum samples taken at the same time as routine monitoring samples during baseline and at three and 12 months of letrozole treatment and stored in a deep freezer (− 80 C) until analysis.The patients filled structured QoL and side-effect questionnaires at the start of letrozole treatment and after 12 months. The scores at the start of treatment and after 12 months were calculated.The study was approved by the local ethics committee at the Helsinki University Hospital. Informed consent was obtained from each participant. | PMC10460747 |
Quantification of estrogens by LC–MS/MS | SEPARATION | Serum E1 and E2 concentrations were analyzed by a LC–MS/MS: Agilent 1200 high-performance liquid chromatography (Agilent Technologies Inc., Santa Clara, CA, USA) coupled with an AB Sciex Triple Quad 5500 mass spectrometer controlled by Analyst Software 1.6.2 (AB Sciex, Concord, ON, Canada). Slight modifications of our previous method were included [Assay calibrators and blank solutions of 0.0–1000 pmol/L E1 (Vetranal, Sigma-Aldrich, St. Louis, MO, USA) and 0.0–1275 pmol/L E2 (Sigma-Aldrich) were prepared in water:methanol (1:1, v/v). To 300 µL of calibrator or 300 µL of serum 30 µL of internal standard (IS) containing 3 nmol/L One hundred µl of the calibrator or the sample extract was measured in one LC–MS/MS run. Chromatographic separation was performed on a tandem column where a Discovery HS F5-3 column (2.1 × 100 mm, 3 µm; Supelco, Bellefonte, PA, USA) was coupled with a SunFire C18 column (2.1 × 50 mm, 3.5 µm; Waters, Milford, MA, USA). The mobile phase was a linear gradient consisting of 40 µmol/L ammonium fluoride in water (A) and methanol (B) at a flow rate of 300 µL/min. The gradient was 0 min 50% B, 4.5–10 min 100% B, and 10.5–19 min 50% B.E1, E2, and corresponding Using Analyst Software 1.6.2 data processing tools for assay calibrators and sample quantifications we estimated the lower limits of quantification (LLOQ) to 5 pmol/L for E1 and E2 with signal to noise ratios | PMC10460747 |
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Assessments of health-related Quality of Life (QoL) and menopausal symptoms | Breast Cancer, nausea/vomiting, dyspnea, fatigue, diarrhea, pain, constipation, insomnia, Cancer | APPETITE LOSS, BREAST CANCER, CANCER | QoL data were obtained using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) and the EORTC Breast Cancer Module questionnaire (QLQ-BR23).The EORTC QLQ-C30 is composed of a global health status/QoL scale, five scales measuring physical, role, emotional, cognitive, and social functioning, three symptom scales (fatigue, nausea/vomiting, and pain), and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) [The Women’s Health Questionnaire (WHQ) was used to measure health-related quality of life, psychological well-being, and emotional well-being. This questionnaire which has been validated in Finnish language is a commonly used instrument for measuring climacteric-related symptoms [Menopausal symptoms during the past two weeks were assessed with a modified Kupperman Index [ | PMC10460747 |
Statistical methods | REGRESSION | The data was analysed using SPSS statistic Version 28. Baseline demographics and characteristics of the patients were summarized using median and range, or mean and standard deviation. The association between baseline hormone levels, and between hormone levels and demographic characteristics (age, BMI, weight, waist circumference) was tested with the Pearson correlation coefficient. The association between treatment discontinuation and baseline hormone levels was tested with the unpaired t-test. A Bonferroni correction for multiple testing was used when appropriate.We tested the effect of the magnitude of change of E2 levels during letrozole treatment in two steps. Firstly, we determined the significance of changes in QoL and symptom scores from baseline to 12 months by a paired t-test. Due to the large number of testable variables a Bonferroni correction was applied, and the level of significance was set as < 0.001. Only scales with significant change during letrozole treatment were tested for association with E2 changes during treatment. The analysis was done by linear regression on score change during treatment by hormone level. In addition to significantly changed single items we also tested the impact of E2 on change in global QoL assessed by the EORTC QLQ-C30 questionnaires. | PMC10460747 |
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Discussion | pain, muscle pain, breast cancer | SECONDARY, BREAST CANCER | The aim of the present study was to analyze the effects of letrozole on serum estradiol (E2) and estrone (E1) levels in postmenopausal breast cancer patients by using a highly sensitive and specific LC–MS/MS method. Quality of life and tolerability of the treatment were secondary outcome measures.AIs suppress plasma estrogen levels in postmenopausal women. At menopause, mean plasma E2 levels vary from 10 to 60 pmol/L [As expected, mean E2 levels measured by routine chemiluminescent immunoassay were higher than levels obtained with LC–MS/MS. E2 measured by immunoassay at three or 12 months did not differ compared to baseline levels which is in line with our findings from a previous study [Baseline levels for E1 measured by a sensitive LC–MS/MS ranged from less than 5 pmol/L (LLOQ < 5 pmol/L) to 226 pmol/L with a mean of 66 pmol/L. Levels of serum E1 also decreased below the LLOQ level in 89 of 90 patients during letrozole treatment. Only in one patient, serum E1 level remained above 5 pmol/L at three months and decreased below LLOQ at 12 months.Adjuvant AI treatment is recommended for at least five years and extended treatment for up to ten years especially for patients with high-risk features [There was no change in global health status, and all functional scales scores remained stable during the first year of adjuvant letrozole treatment. The reported overall QoL was higher than 70 points and all functional scales were higher than 80 points, which is similar to the QoL of the general population [Women with higher pre-treatment E2 levels experienced more joint and muscle pain during letrozole treatment. However, we did not find any association between pre-treatment hormone levels and the other significant side-effects. The relationship between sensitivity to pain and estrogen levels is poorly understood. However, pain sensitivity decreases during high estrogen phases of the menstrual cycle [The main strength of the current study is the use of the sensitive LC–MS/MS estrogen assay for monitoring changes in the levels of postmenopausal E2 during AI treatment. Another strength is the systematic assessment of QoL and symptoms with relevant questionnaires during AI treatment. Limitations include the relatively small number of patients, the lack of a control group, and the short one- year follow-up time. | PMC10460747 |
Conclusion | muscle pain | In conclusion, letrozole treatment caused complete suppression of both E2 and E1 when measured by our highly sensitive LC–MS/MS assay. A high pretreatment E2 level was associated with more frequent joint and muscle pain during letrozole treatment. Our commercial chemiluminescent immunoassay for serum E2 had no value in assessing these low estrogen levels. | PMC10460747 |
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Acknowledgements | We are grateful to all participating patients, without whom it will be not have been possible to do this study. We also like to thank the Clinical Research Institute Helsinki University Hospital and Foundation for Promoting Laboratory Medicine for supporting this project. | PMC10460747 |
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Funding | Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. | PMC10460747 |
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Data availability | Enquiries about data availability should be directed to the authors. | PMC10460747 |
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Declarations | PMC10460747 |
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Conflict of interest | The authors report no conflict of interest. The authors are responsible for the content and writing of the paper. | PMC10460747 |
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References | PMC10460747 |
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ABSTRACT | CAP, lower respiratory tract, Pneumonia | PNEUMONIA, COMMUNITY-ACQUIRED PNEUMONIA | The authors declare no conflict of interest.Syndromic PCR-based analysis of lower respiratory tract (LRT) samples in patients with community-acquired pneumonia (CAP) improves the bacterial yield and time-to-results compared to culture-based methods. However, obtaining adequate sputum samples can be challenging and is frequently not prioritized in the emergency department (ED). In this study, we assess the concordance of microbiological detections between oropharyngeal- (OP) and LRT samples from patients presenting to the ED with CAP using a syndromic PCR-based respiratory panel [Biofire FilmArray Pneumonia | PMC10512787 |
KEYWORDS | PMC10512787 |
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INTRODUCTION | CAP, deaths | COMMUNITY-ACQUIRED PNEUMONIA | Community-acquired pneumonia (CAP) is one of the leading causes of hospital admissions and deaths in the world (The introduction of syndromic molecular assays with broad panels targeting common respiratory tract pathogens improves the microbiological yield and time to results when analyzing specimens from the lower respiratory tract (LRT) (Three recent studies have evaluated the performance of syndromic PCR panels for CAP on samples from the upper respiratory tract (URT) (OP samples are easier and faster to obtain than both LRT- and NP samples. OP samples have demonstrated a higher sensitivity than NP samples for detection of atypical bacteria, but only a few studies with discordant results have examined the utility of OP samples for the detection of other CAP-related bacteria ( | PMC10512787 |
MATERIALS AND METHODS | PMC10512787 |
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Patients and study design | We analyzed samples from prospectively enrolled CAP patients at Haukeland University Hospital, a tertiary care referral center in Bergen, Norway. The patients had been included in a randomized controlled trial (RCT) (CAPNOR, NCT04660084) or a following observational study on ED patients with suspected CAP, between October 1, 2020, and September 19, 2022. The criteria for eligibility were the same in both cohorts ( | PMC10512787 |
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Microbiological methods and sampling | Pneumonia | PNEUMONIA | Study nurses collected microbiological samples shortly after presentation to the ED. First, an OP sample was collected using an OP swab (Sigma VCM MW910PF) as part of routine hospital care (swabbing the OP back wall for approximately five seconds). Subsequently, an LRT sample was obtained from all patients (Both LRT samples and the OP samples were analyzed with the Biofire FilmArray Pneumonia | PMC10512787 |
Statistical analysis | Descriptive statistics for continuous variables are reported as medians with interquartile range (IQR). Fisher’s exact test was used for analyzing categorical data, by use of contingency tables. A two-tailed | PMC10512787 |
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RESULTS | PMC10512787 |
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DISCUSSION | Pneumonia | FAP, PNEUMONIA | In this study, we evaluated the performance of a commercial rapid syndromic multiplex PCR panel on OP samples and high-quality LRT samples obtained from a well-characterized cohort of patients presenting to the ED with CAP. The PCR panel is validated for LRT samples, which can be difficult and time-consuming to obtain, especially in an ED setting. We demonstrated high NPAs and PPAs between OP- and high-quality LRT samples for the most common bacterial pathogens involved in CAP. To our knowledge, this study is the first to evaluate syndromic PCR testing on OP samples from CAP patients.In previous CAP studies, an LRT sample has been obtained from only 30%–60% of the included patients, often after transfer from the ED (Pneumonia is a heterogeneous condition, with differences in microbiological etiology. The FAP Most divergent results between OP- and LRT samples were caused by detections of various Enterobacterales, which are of uncertain clinical importance in uncomplicated CAP (The strengths of this study include a well-characterized study population with a CAP diagnosis based on predefined criteria, and the use of the FAP In conclusion, our study demonstrated that the FAP | PMC10512787 |
ETHICS APPROVAL | RECRUITMENT | The study is approved by the Regional Committee for Medical and Health Research Ethics in South East Norway (REK ID: 31935) and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants or from their legal guardian/close relative at the time of recruitment. | PMC10512787 |
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SUPPLEMENTAL MATERIAL | The following material is available online at | PMC10512787 |
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jcm.00505-23-s0001.pdf | Tables S1 and S2.Click here for additional data file.ASM does not own the copyrights to Supplemental Material that may be linked to, or accessed through, an article. The authors have granted ASM a non-exclusive, world-wide license to publish the Supplemental Material files. Please contact the corresponding author directly for reuse. | PMC10512787 |
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REFERENCES | PMC10512787 |
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Background | Erectile dysfunction, metabolic syndrome, MeTS | ERECTILE DYSFUNCTION, METABOLIC SYNDROME, PLAQUE PSORIASIS | Erectile dysfunction (ED) and metabolic syndrome (MeTS) are highly prevalent in chronic plaque psoriasis (CPP). | PMC10808673 |
Objective | OBESE | The aim of this lifestyle modification study is to explore the response of MeTS components and ED to a 12-week lifestyle modification program (low-calorie diet and moderate-intensity treadmill walking) in 60 obese men with CPP, mild and moderate ED, and MeTS. | PMC10808673 |
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The design, settings, participants, and intervention | OBESE, RECRUITMENT | In this lifestyle modification randomized study, a university-based hospital recruitment of 60 obese men with CPP, mild and moderate ED, and MeTS was randomly performed. Men were randomly assigned to the lifestyle modification group ( | PMC10808673 |
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Results | Trends of significant improvements in all outcomes were documented in favor of the lifestyle modification group. All outcomes of the waitlist group did not show the same reported significant improvements of the lifestyle modification group. | PMC10808673 |
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Conclusion | psoriasis-associated, weight loss, psoriasis | OBESE, PSORIASIS | A 12-week lifestyle modification program as a tool for weight loss in obese men with CPP is a good therapeutic method to improve psoriasis severity and psoriasis-associated ED and MeTS. | PMC10808673 |
Keywords | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10808673 |
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Introduction | chronic vascular inflammation, psoriasis, MeTS, MetS, LCD, CPP-associated cardiovascular comorbidities, erectile dysfunction | ENDOTHELIAL DYSFUNCTION, DYSFUNCTION, PSORIASIS, VASCULAR INSUFFICIENCY, ERECTILE DYSFUNCTION, CHRONIC INFLAMMATION, INFLAMMATORY SKIN DISEASE, PLAQUE PSORIASIS, ENDOTHELIAL DYSFUNCTION | The autoimmune-mediated inflammatory skin disease in 2 to 3% of the general adult population is chronic plaque psoriasis (CPP). In men, CPP is strongly associated with erectile dysfunction [The prevalence of CPP-associated MetS ranges from 20 to 50%. Compared with non-psoriatic age-matched control subjects, the risk of having MetS is at least double in psoriatic sufferers [The mechanism links between ED, MeTS, and CPP might be contributed to the chronic systemic inflammatory nature of CPP. This chronic inflammation is a predisposing factor to the development of endothelial dysfunction in CPP. Endothelial dysfunction—chronic vascular inflammation combined with nitric oxide dysfunction and vascular insufficiency—is the same pathogenic mechanism that explains the highly prevalent ED and MeTS in CPP [Recently, published psoriatic reports confirm that patients’ correct lifestyle (proper diet with increased physical activity levels) may positively affect the clinical signs/symptoms, severity/progression, outcomes of CPP [Low-calorie diets (LCD) seem to result in an improved body mass index (BMI), CPP activity, pharmacotherapies’ efficacy, and CPP-associated cardiovascular comorbidities such as MeTS, especially in sufferers who are overweight or obese [Since there are no published studies to clarify the effect of lifestyle changes (exercise and diet intervention) on ED in psoriasis patients [ | PMC10808673 |
Materials and methods | PMC10808673 |
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Settings | MeTS | RECRUITMENT | The men diagnosed with CPP, ED, and MeTS were randomly recruited from Cairo University Hospitals. Recruitment of the subjects was conducted during the period between 16th October 2022 and 16th April 2023. | PMC10808673 |
Men’s inclusion criteria | MeTS, Psoriatic | RECRUITMENT | With ages ranging from 32 to 49 years old (because these age ranges were the available age ranges of CPP men who visited the recruitment settings during the recruitment period), this lifestyle modification trial included 60 mild-to-severe CPP married men with ED. The erectile function in psoriatic men was evaluated using the Arabic version of the five-item international index of erectile function questionnaire (IIEFQ-5). Psoriatic men with IIEFQ-5 scores ≥ 8 to < 21 (i.e., mild to moderate ED) were included. Men’s BMI ranged from 30 to 34.9 kg/mThe psoriatic men who showed at least three MeTS components were included in this lifestyle modification study. The components were men’s waist circumference (WC) ≥ 102 cm, blood pressure (BP) ≥ 130/85 mmHg or regular administration of pharmacological therapies to high BP, the value of serum high-density lipoprotein (SHDL) < 40 mg/dl, value of serum triglycerides (STG) ≥ 150 mg/dl, and serum fasting blood glucose (SFBG) level—tested after 6-h fasting— ≥ 110 mg/dl [All ethical issues concerned with Helsinki recommendations, institutional approval, and men’s consent were followed by the two authors. This single-blinded lifestyle modification approach in CPP men with MeTS and ED received local institutional approval (P.T.REC/012/004117). | PMC10808673 |
Men’s exclusion criteria | autoimmune or neurological disorders, prostatic disorders, hypogonadism, lower limb arthritic disorders, mental disorders, hepato-renal or respiratory disorders, deformations, tumors, weight loss | HYPOGONADISM, TUMORS, VASCULAR DISORDERS | Men who received phototherapeutic interventions, weight loss prescriptions (diet, exercise, or drugs), biologic therapies, and pharmacological inhibitors of phosphodiesterase-type 5 (Is-PDET5) within the last 12 weeks were excluded. CPP men with autoimmune or neurological disorders, hypogonadism (low testosterone levels), hepato-renal or respiratory disorders, penile implants, cardiopulmonary or vascular disorders, structural deformations of the penile shaft, lower limb arthritic disorders, prostatic disorders, mental disorders, drinking or smoking habits, or tumors were excluded from this lifestyle modification study. | PMC10808673 |
Randomization | MeTS, metabolic syndrome, psoriasis | METABOLIC SYNDROME, OBESE, ERECTILE DYSFUNCTION, PSORIASIS | The consented psoriatic men with MeTS and ED were divided by the simple randomization technique, a closed envelope technique conducted by a physiotherapy assistant who was unaware of the lifestyle changes that would be executed, into two 30-men groups. Men in the first group (lifestyle modification group, LMG) were treated with a low-calorie diet (LCD) and supervised moderate-intensity exercise program for 12 weeks, while men in the second group (control group, CG) were ordered not to change their lifestyle habits (Fig. Consort flow chart of the lifestyle modification approach in obese men with psoriasis, erectile dysfunction, and metabolic syndrome | PMC10808673 |
Lifestyle modification program | ’ basal metabolic rate | OBESE | Harris–Benedict equation—[(10 × weight of men in kilograms) + (6.25 × height of men in centimeters) − (5 × age of men in years) + 5]—was utilized to calculate participants’ basal metabolic rate (BMR) before involving them in the low-calorie-diet protocol. To start the low-calorie diet, the value of BMR was subtracted from 500 kilocalories per day [The LMG received a supervised 40-min on-treadmill walking program. Day after day (3 times weekly), the session was constituted of 3 stages in all obese men with CPP, ED, and MeTS. Warming-up and cooling-down walking stages conducted at 40–50% of men’s maximal heart rate, 5 min for each, were done before and after the main exercise stage (a 30-min walking on the treadmill at 60–70% of men’s maximal heart), respectively. | PMC10808673 |
Main outcome (Arabic version of IIEFQ-5) | A hard copy of IIEFQ-5 was given to every psoriatic man to fill it before and after the 12-lifestyle-modification program. | PMC10808673 |
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Secondary outcomes | ’s head, neck, upper/low limbs, and trunk, psoriasis | PSORIASIS | Besides BMI, MeTS components of all psoriatic men were tested. The components included men’s BP (systolic and diastolic pressures were assessed with a manual sphygmomanometer), WC (evaluated via in elastic tape at men’s umbilicus level), SFBG (assessed with a glucose blood meter after overnight fasting), and overnight fasting STG and SHDL. Also, the psoriasis area and severity index (PASI) was evaluated in all participating men.The second author used the validated PASI to assess psoriasis severity before and after this 12-week lifestyle modification study. With a score ranging from 0 to 72, PASI assessed men’s erythema/scaliness levels and the density of CPP in men’s head, neck, upper/low limbs, and trunk. If there was a decrease in PASI scores after ending the lifestyle modification protocol, it was considered an improvement in CPP severity. | PMC10808673 |
Blinding | MeTS | SECONDARY | Assessors of the primary outcome (IIEFQ-5) or secondary outcomes (BMI, MeTS components, and PASI) were not informed of the details of the 12-week lifestyle modification program introduced to the examined 60 CPP men with MeTS and ED. | PMC10808673 |
G*power sample size | OBESE | Sixteen obese men with CPP, MeTS, and ED were the pilot test that was used to extract the needed sample size calculation at a power of 80%. The effect size of IIEFQ-5 ( | PMC10808673 |
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Statistical analysis (SPSS 18) | SECONDARY | The Smirnov test—used to examine the distribution of primary outcome (IIEFQ-5) or secondary outcomes (BMI, MeTS components, and PASI)—confirmed the normal distribution of CPP men’s primary and secondary outcomes, so ANOVA test (repeated measure) was used to assess the statistical changes within and between groups, respectively in this 12-week lifestyle modification study. | PMC10808673 |
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Discussion | MeTS.The exercise-induced decrease, overactivity of the sympathetic nervous system, psoriasis, MeTS, overweight, diabetic, hypertensive, penile erection, diabetes | DIABETES, OBESE, PATHOGENESIS, PSORIASIS | This is the first lifestyle modification study that reported an improvement in ED, MeTS components, and PASI after a 12-week randomized-controlled program of exercise and diet restriction in men with CPP, ED, and MeTS.The exercise-induced decrease in psoriatic severity may be in part due to a decrease in obesity-associated high mass of adipose tissue. Decreased mass of adipose tissue is associated with a decreased release of inflammatory cytokines involved in the pathogenesis of psoriasis. Decreased production of cytokines not only restricts the causative role in the induction of CPP [The suggested mechanisms that explain the improvement in MeTS components in this CPP study reduction may be reported as follows: reduction in overactivity of the sympathetic nervous system; improvement in elastic and endothelial properties/functions of vessels; enhancement functions of micro- and macrocirculation; increased production of vasodilating substances such as nitric oxide (NO), reduced production of plasma vasoconstrictors/catecholamines [Supporting us, treatment with a low-calorie diet (a reduced food intake reaching 800–1000 kcal/day for 2 months followed by a reduced food intake reaching 1200 kcal/day for 2 months) in overweight/obese patients with CPP showed a trend in favor of clinically important improvements in BMI, WC, SFBG, PASI [The 24-week low-calorie diet produced significant changes in BMI, WC, STG, and SHDL, but SFBG did not show significant changes despite the decrease in its level due to the small number (In obese patients with CPP, despite non-significant improvements in SHDL and STG, PASI improvement could be increased by adding diet restriction protocols, mainly the low-calorie diet, to the course of pharmacological therapies [Regarding ED improvement, adherence to weight-loss programs including diet restriction and/or increased physical activity augments a strong penile erection in ED sufferers, likely via improving mood and self-esteem, increasing serum testosterone levels [Esposito et al. [Esposito et al. [The response of IIEFQ-5 to an 8-week interval exercise in hypertensive men with ED was compatible with our results because IIEFQ-5 significantly increased after the interval exercise program [Except for WC and diastolic BP, comparing the post results of obese men with ED who followed a Mediterranean diet protocol with the post results of obese men with ED who did not follow any calorie restriction diet showed significant improvements in systolic BP, SHDL, STG, blood glucose, and IIEFQ-5 in favor of Mediterranean diet men [The results of the random assignment of overweight and obese diabetic men with ED to a group of an intensive lifestyle-modification program (diet restriction with exercise) or a group of diabetes education/support program were compatible with our results due to the trend of improvement in tested outcomes (weight, glycosylated hemoglobin, BP, IIEFQ-5, and SHDL) was in favor of the group of the intensive lifestyle modification program [Opposite to us, despite augmenting the high efficacy of ED pharmacotherapies in the treatment of ED in MeTS men with ED, adding exercise to ED pharmacotherapies did not augment significant improvements in BP, WC, SHDL, STG, and blood glucose due to including a small number ( | PMC10808673 |
Limitations | psoriasis-associated, MeTS, psoriasis | PSORIASIS | Comparing the effect of different types of calorie restriction diets on psoriasis severity and psoriasis-associated ED and MeTS is the main limitation of this study. The two authors invite researchers of CPP to cover this limitation in future studies. | PMC10808673 |
Authors’ contributions | OBESE | Ismail AMA and Hamed DE contributed equally in all parts of this lifestyle modification study conducted on 60 obese men with CPP, MeTS, and ED. Both authors authorize the responsibility of the content of this lifestyle modification study. | PMC10808673 |
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Funding | Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). | PMC10808673 |
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Data availability | Data (age, WC, BMI, IIEFQ-5, PASI, BP, STG, SFBG, and SHDL) will be available on request. | PMC10808673 |
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Declarations | PMC10808673 |
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Ethics approval | MeTS | All ethical issues concerned with Helsinki recommendations, institutional approval, and men’s consent were followed by the two authors. This single-blinded lifestyle-modification approach in CPP men with MeTS and ED received local institutional approval (P.T.REC/012/004117). | PMC10808673 |
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Consent to participate | MeTS | All CPP men with MeTS and ED consented. | PMC10808673 |
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Consent for publication | This is not applicable. | PMC10808673 |
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Conflict of interests | The authors declare no competing interests. | PMC10808673 |
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References | PMC10808673 |
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Research Design and Methods | PMC9983122 |
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Design | This post hoc subgroup analysis of a single-center open-label randomized controlled trial included 13 participants undergoing total or partial pancreatic surgery at the University Hospital Bern (6 in the FCL group, 7 in the UC group). Details can be found in the original publication.All participants provided written informed consent and the protocol was approved by the Ethics Committee Bern, Switzerland (2020-01024). The trial was done in accordance with the principles of the Declaration of Helsinki. The data sets analyzed during this study are not publicly available, but are available from the corresponding author on reasonable request. | PMC9983122 |
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Procedures | RS, UC | The SC FCL system consisted of an Android smartphone, running the Cambridge adaptive model predictive control algorithm (version 0.3.71; HX variant) on the CamAPS HX mobile application (CamDiab Ltd., Cambridge, UK), an SC real-time continuous glucose monitoring (CGM) sensor (Dexcom G6; Dexcom, San Diego, CA), and the SC insulin pump (Dana Diabecare RS, Sooil, South Korea). The CamAPS HX app received CGM glucose values and communicated through Bluetooth with the pump, which modulated the SC delivery of faster acting insulin aspart (Fiasp; Novo Nordisk, Bagsværd, Denmark) every 8–12 min. The FCL insulin therapy was initialized upon hospital admission using the participants' body weight and estimated total daily insulin dose.The nominal glucose target was set to the default of 5.8 or 7.0 mmol/L, based on individual circumstances. Participants were treated with FCL insulin therapy until hospital discharge or a maximum of 20 days. The glucose levels (recorded through a masked Dexcom G6 CGM) of the UC group were managed by the clinical team in accordance with local guidelines. The study did not interfere or specify the perioperative care plans and activities. All study devices were managed by the study team. | PMC9983122 |
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Outcomes | Outcomes of this subgroup analysis were the level of glucose control (% time spent with CGM values in predefined ranges and mean glucose concentration) and glucose variability (defined as standard deviation [SD] and coefficient of variation of sensor glucose). We further assessed insulin doses in the UC group and investigated the evolution of the insulin requirements in the FCL group after pancreatic resection. Glucose control was evaluated from the time of hospital admission until discharge (or a maximum of 20 days). Results are reported for the overall period as well as separately for the time from admission to end of anesthesia (immediate perioperative period) and from end of anesthesia to discharge (postoperative period). | PMC9983122 |
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Statistical analysis | Aggregated period-specific summary measures (overall, perioperative, and postoperative periods) were calculated and are presented by treatment. Outcomes were compared between treatments using unpaired Welch's | PMC9983122 |
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Discussion | hypoglycemia, UC | STILL, POSTOPERATIVE COMPLICATIONS, TYPE 1 DIABETES, HYPOGLYCEMIA, COMPLICATIONS | In this exploratory post hoc analysis, we compared the perioperative glycemic efficacy and insulin requirements of SC FCL insulin delivery with UC insulin therapy in patients undergoing pancreatic surgery. We observed that FCL substantially improved glycemic control by increasing time spent in the glycemic target range and lowering mean sensor glucose without increasing the risk of hypoglycemia.Although we have recently shown the feasibility and superior performance of the FCL approach over UC insulin regimes in various types of elective surgery, the present analysis provides evidence that an FCL insulin-only approach effectively controls glucose levels in clinical situations with maximum glycemic lability as is the case after total pancreatectomy (five out of six patients in the FCL group received total pancreatectomy in this study). The absolute insulin deficiency that is also the pathophysiological hallmark of type 1 diabetes makes these two populations comparable in terms of complexity of their glucose control.However, the concomitant lack of glucagon secretion is mainly pertinent to patients with total pancreatectomy, thereby further challenging glucose management in this population. In this context, the present results are encouraging as previous efforts to control glucose levels by an FCL approach in people with type 1 diabetes have shown insufficient performanceHowever, it is important to note that the algorithm used in this study has a considerably enhanced adaptivity to allow for more responsive insulin dosing compared with currently available hybrid closed-loop systems for the treatment of type 1 diabetes. In addition, the amount of oral dietary intake in the perioperative setting is likely lower than in usual outpatient conditions.We are not aware of any other study that analyzed the use of an SC FCL insulin-only system to manage perioperative glucose levels in patients undergoing pancreatic surgery. Nevertheless, observational studies and a nonrandomized clinical trial investigated the efficacy of STG-55 (Nikkiso, Inc.) FCL that uses the intravenous route for both glucose sensing and insulin delivery.Although these small studies reported benefits in terms of reducing postoperative complications in pancreatic surgery patients, evidence from randomized controlled trials is still lacking. The advantages in terms of facilitation of care by FCL systems, however, are more apparent. Pancreatic resections are high-risk procedures with frequently experienced complications (30%–73%) and high complexity of postoperative care.FCL insulin therapy may, therefore, not only contribute to improved quality and safety of blood glucose control in this challenging population, but also reduce the work load of hospital staff. Of note, a recently published study reported increased time in euglycemia and reduced time in hypoglycemia using a bihormonal SC FCL system modulating both insulin and glucagon compared with UC in 12 outpatients after total pancreatectomy.We acknowledge the limitations that are inherent to any post hoc analysis and the fact that the FCL insulin treatment was managed by the study team rather than the hospital staff. In addition, the small sample size needs to be considered. Still, we believe that these early findings provide an important steppingstone for future larger and well-designed studies in the field of perioperative and possibly postoperative glucose management in patients undergoing pancreatic surgery. | PMC9983122 |
Supplementary Material | PMC9983122 |
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Supplemental data | PMC9983122 |
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Acknowledgments | Diabetes | DIABETES | We are grateful to all study participants for their contribution, time, and support. We acknowledge administrative support from Laura Goetschi and data management support from Markus Huber, University Hospital Bern. We thank R. Dragulin, D. Studer, A. Goerg, M. Somasundaram, and study nurses (all University Hospital Bern) who contributed to patient care, study logistics, and data management. We are also grateful to the Diabetes Center Bern for providing working and storage space. We acknowledge support by the clinical staff at the University Hospital Bern. | PMC9983122 |
Authors' Contributions | D.H. and L.B. | G.K. contributed to writing—original draft (equal), formal analysis (support), and writing—review and editing (equal). J.R. was involved in data curation (equal) and writing—review and editing (equal). D.S. carried out data curation (equal) and writing—review and editing (equal). C.C. contributed to writing—review and editing (equal). M.E.W. took care of formal analysis (support) and writing—review and editing (equal). P.Y.W. was involved in writing—review and editing (equal). D.H. was in charge of conceptualization (support), methodology (support), writing—original draft (equal), formal analysis (lead), and writing—review and editing (equal).R.H. oversaw formal analysis (support), software (lead), and writing—review and editing (equal). A.V. carried out conceptualization (support) and writing—review and editing (equal). B.G. took charge of conceptualization (support) and writing-review and editing (equal). L.B. was in charge of conceptualization (lead), writing—original draft (lead), methodology (lead), and writing—review and editing (equal). D.H. and L.B. had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors made the decision to submit the article for publication. | PMC9983122 |
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Author Disclosure Statement | hypoglycemia, Diabetes | HYPOGLYCEMIA, DIABETES | M.E.W. reports receiving license fees from B. Braun, patents related to closed-loop, and being a consultant at CamDiab Ltd. R.H. reports receiving speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk; receiving license fees from B. Braun and Medtronic; declares consulting fees from Abbott Diabetes Care; patent issued in closed-loop field (glucose monitoring and control using multimodel approach, patent number CA2702345C) with University of Cambridge and patent issued in closed-loop field (methods for reducing false hypoglycemia alarm occurrence during closed-loop, patent number US9579456B2) with University of Cambridge and Abbott Diabetes Care; being director and stockholder at CamDiab; and leadership/fiduciary role for ATTD. A.P.V. reports advisory board fees from MSD Merck. All other authors declare no competing interests associated with this article. | PMC9983122 |
Funding Information | The study was funded by the Swiss Helmut Horten Foundation and the Swiss Foundation of Anaesthesiology and Intensive Care. Dexcom provided product support (CGM equipment). Company representatives had no role in study design, data collection, data analysis, data interpretation, or writing of the report. | PMC9983122 |
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Supplementary Material | PMC9983122 |
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References | PMC9983122 |
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Subject terms | T cell lymphopenia, death, SARS-CoV-2 infection | SYNDROME, SARS-COV-2 INFECTION, CYTOKINE RELEASE SYNDROME, SECONDARY | The clinical course of COVID-19 may show severe presentation, potentially involving dynamic cytokine storms and T cell lymphopenia, which are leading causes of death in patients with SARS-CoV-2 infection. Plasma exchange therapy (PLEX) effectively removes pro-inflammatory factors, modulating and restoring innate and adaptive immune responses. This clinical trial aimed to evaluate the impact of PLEX on the survival of patients with severe SARS-CoV-2 and the effect on the cytokine release syndrome. Hospitalized patients diagnosed with SARS-CoV-2 infection and cytokine storm syndrome were selected to receive 2 sessions of PLEX or standard therapy. Primary outcome was all-cause 60-days mortality; secondary outcome was requirement of mechanical ventilation, SOFA, NEWs-2 scores modification, reduction of pro-inflammatory biomarkers and hospitalization time. Twenty patients received PLEX were compared against 40 patients receiving standard therapy. PLEX reduced 60-days mortality (50% vs 20%; OR 0.25, 95%CI 0.071–0.880; p = 0.029), and this effect was independent from demographic variables and drug therapies used. PLEX significantly decreased SOFA, NEWs-2, pro-inflammatory mediators and increased lymphocyte count, accompanied with a trend to reduce affected lung volume, without effect on SatO | PMC9812351 |
Introduction | infection, death, tumor necrosis | VIRUS, TUMOR NECROSIS, DISEASE, CYTOKINE RELEASE SYNDROME, INFECTION, ACUTE RESPIRATORY FAILURE, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME, MULTI-ORGAN FAILURE | Since December 2019, health workers and governments around the world have been fighting a virus that changed our lives. COVID-19 is an infection caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)Coronavirus disease is characterized by a wide spectrum of manifestations, ranging from asymptomatic to acute respiratory failure, multi-organ failure, and death, the result of macrophage activation and cytokine stormThe severity of COVID-19 is associated with host response and increased release of inflammatory mediators including cytokines and chemokines such as interleukin (IL) -2, IL-6, IL-7, IL-10, tumor necrosis factor (TNF), C-reactive protein (CRP), ferritin, and D-dimer in blood after SARS-CoV-2 replicationEffective antiviral treatment and measures to modulate the innate immune response and restore the adaptive immune response are imperative to break the cycle and enhance the effect of treatment. Some drug therapies would take weeks or months to remove these pro-inflammatory factors, while plasma exchange therapy (PLEX) is able to effectively remove these large moleculesThe effectiveness of PLEX depends on the plasma volume (PV) removed from the patient, on the distribution of the pathogen to be removed. One exchange (1:1) is equivalent to 65% of the initial component removed from the intravascular space. The first session of PLEX, which is prescribed with 1.5 plasma volume, removes approximately 75% of target molecules from the intravascular compartment, while the second session achieves a removal of 85% of target moleculesThis trial aimed to evaluate the impact of plasmapheresis therapy on the survival of patients with severe SARS-CoV-2 and cytokine release syndrome who received at least two sessions during their hospitalization compared against standard therapy. | PMC9812351 |
Methods | lymphopenia, bleeding, NLV, hypofibrinogenemia | ACUTE RESPIRATORY DISTRESS SYNDROME, BLEEDING, LUNG, SARS-COV-2 INFECTION, CYTOKINE RELEASE SYNDROME, LYMPHOPENIA, HYPOFIBRINOGENEMIA, BLOOD, OPACITIES | Study design. Our trial was designed to evaluate the impact of plasmapheresis therapy in the outcome of severe COVID-19 and cytokine release syndrome at one medical center in Mexico City. The study was designed and performed according to ethical guidelines of the 1975 Declaration of Helsinki, and approved by the Local Committees of Research, Ethics in Research and Biosafety of the Centro Médico Nacional ‘20 de Noviembre’ ISSSTE, Mexico City (Protocol ID No. 09-136.2021). All participants provided written informed consent.Study population. Hospitalized patients between April-August 2020. Patients were aged 16 to 65 years old, diagnosed with SARS-CoV-2 infection, as confirmed by typical tomographic findings according to Radiological Society of North America and/or qRT-PCR confirmation. Clinical presentation of Acute Respiratory Distress Syndrome and increased levels of interleukine-6 > 40 pg/mL, ferritin > 500 ng/mL, C reactive protein (CRP) > 60 mg/L, erythrocyte sedimentation rate > 40 m/s; and/or lymphopenia < 1.0 × 10/L. Patients were excluded if they had SOFA score > 11 points, active bleeding, platelet count < 50,000 cels and/or hypofibrinogenemia < 80 mg/dL. Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent.Standard therapy. It was based on the use of chloroquine, azithromycin, dexamethasone, supplementary oxygen; as well as tocilizumab and intravenous immunoglobulin. This therapy was common for the control and PLEX group, while PLEX group received tocilizumab and immunoglobulin before PLEX therapy.Plasmapheresis. A double lumen central venous catheter was placed, either at jugular or femoral vein approaches. The plasmapheresis therapy was performed with a membrane-based system, using PrismaFlex CRRT and a TPE 1000–2000 filter according to body surface. Exchange plasma volumes of 1.5 times the estimated circulating plasma volume, according to Kapplan’s formula (Plasma volume (lts) = 0.065 × Weight (kg) × (1 Hematocrit [%])). The blood flow rate was set at range 75–150 ml/min. Replacement solution consisted of 3% albumin, at a flow rate started at 100 mL/h, and increased up to maximum of 1500 mL/h; while 2 fresh frozen plasma were transfused at the end of each session. Anticoagulation was performed at doses of 30–40 IU/Kg/h of unfractionated heparin. A second plasmapheresis session was systematically performed 48 h after the first session. Blood samples were obtained from catheter blood before and after every session, for cytokine determination.Cytokine determination. Blood samples were centrifuged and 500 mcL of serum are used for cytokine determination. Briefly, serum was combined with surface-bound capture anti-IL6 polyclonal antibody and alkaline phosphatase system developer as tracer (IL6 Bead Pack, Diagnostic Products Corporation, LA Cal. USA), in a immulite 2000 automatized immunoassay (Siemens), working within a range of 3–870 pg/mL. This system works under certification ISO 13485:2003.Lung damage determination. One day before starting treatment and ten days after the last PLEX, the volume of lung involvement was calculated through tomographic volumetric assessment. Non-contrast enhanced chest CT imaging was performed using 2 CT scanners (Siemens SOMATOM drive and Siemens SOMATOM emotion scanners, Siemens Healthineers, Germany). Imaging reconstructions were performed with a 1-mm thickness slices without interstice gap. Lung segmentation was performed using the Alma Medical workstation version 5.0. For determination of non-affected lung parenchyma volume (NLV), automated segmentation tool was selected, and a reference attenuation range between − 1000 and − 600 HU was designated. Vascular structures, airways, and pathologic opacities were excluded. For determination of Lung Opacities Segmentation-Lung Opacities Volume (LOV): Initial automated segmentation was attempted using thresholding-based methods. A reference attenuation range between − 500 HU and 20 HU was selected. Then, the semi-automated option was selected to perform a region-based segmentation to adjust lesion boundaries. Volumes from each side were added to calculate total NLV and LOV. Total lung volume was calculated adding NLV + LOV.Outcomes. The primary outcome was all-cause mortality within 60 days after inclusion. Secondary outcomes were the free mechanical-ventilation days, changes in SOFA score, decrease of pro-inflammatory markers at day 7, hospital length-of-stay, and decrease of lung’s volume involvement.Statistical analysis. Data distribution was assessed by Kolmogorov–Smirnoff test. Then, qualitative and quantitative data were resumed as n(%) and mean±SD, respectively. Inferential analyses were performed by either chi square, one-way independent T-test, or U-Mann–Whitney. Kaplan–Meyer curves were constructed. Risk estimation was evaluated through OR and CI 95%. Statistical significance was considered at p < 0.05. | PMC9812351 |
Ethics approval and consent to participate | The study was designed and performed according to ethical guidelines of the 1975 Declaration of Helsinki, and approved by the Local Committees of Research, Ethics in Research and Biosafety of the Centro Médico Nacional ‘20 de Noviembre’ ISSSTE, Mexico City (Protocol ID No. 09-136.2021). All participants provided written informed consent. | PMC9812351 |
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Discussion | bleeding, pneumonia, inflammation, ARDS, lymphopenia, empyema | BLEEDING, PNEUMONIA, SARS-COV-2 INFECTION, INFLAMMATORY RESPONSE, ADVERSE EVENTS, INFLAMMATION, CYTOKINE RELEASE SYNDROME, INFECTIONS, DISORDERS, LYMPHOPENIA, SECONDARY, SYNDROME, EMPYEMA, ARDS, PULMONARY FAILURE | In our study, plasmapheresis (PLEX) showed to improve survival from patients with severe COVID-19, as compared with control group. Consistently, several case-series have reported a reduction of 28-days mortality associated with PLEX, which ranges between 10% and 28% in patients with SARS-Cov2, ARDS and cytokine release syndromeIndeed, one study achieved zero mortality in patients with severe COVID that received 5 sessions of PLEX (0% vs 35%, PLEX vs not PLEX), without adverse events reportedIt is possible that the effect of PLEX be mediated by the clearance of pro-inflammatory mediators and toxic biological substances with molecular weights bigger than 15,000 daltons, representing a therapeutic option in patients with hyperinflammatory state secondary to SARS-CoV-2 infection. In our study PLEX was effective to clear pro-inflammatory mediators and to reduce mortality; however, it did not prevent mechanical ventilation, suggesting that additional disorders may underlie pulmonary failure.A point to highlight is the selectivity of patients with potential benefit from PLEX therapy, which include particular features like severe course of COVID and evidence of cytokine storm syndrome. Similarly, several trials using such indications for PLEX were registered during the present pandemicInterestingly, there is not a current accepted definition for cytokine release syndrome, and whether this syndrome represents an appropriate inflammatory response is still controversialIn the present study, cytokine release syndrome was considered as IL-6 cutoff value higher than 40 pg/mL, accompanied by elevation of other markers of inflammation and lymphopenia. Previously, Guiaro et al, found that an IL-6 cut-off value higher than 35 pg/mL was associated with increased mortality and higher risk for ICU admissionAlong clearance of pro-inflammatory mediators, PLEX showed to improve lymphopenia in our study, potentially representing a prognosis modification, since severe lymphopenia (< 500/mmRegarding adverse events, potential mechanisms related to PLEX has been described to clearance of procoagulant factors, immunoglobulins and cytokines, leading to risk of bleeding and/or immunosuppression. In our study only 4 patients developed hospital-acquired infections like pneumonia and one subject developed empyema. Finally, the length of hospital stay was significantly longer in the group with PLEX. Comparatively, PLEX therapy during Faqihi’s trial significantly reduced length of ICU stay. This difference may be explained because institutional CT scan programming was performed at day 10 after the first session of PLEX, independently from severity scoresLimitations of the present study include a single-center design with a limited sample size that may have caused a statistical overestimation of effect size. In addition, control-case match was uncomplete, which may be explained by the reduced number of candidates for PLEX, who also had incomplete information for adequate analysis. Likewise, the heterogeneity of pharmacologic therapy, which was inherent to the available scientific evidence during the course of pandemia. For example, PLEX and control group received the same non-specific therapy, which included immunoglobulin; but we cannot rule out potential effect of PLEX on immunoglobulin clearance. | PMC9812351 |
Conclusion | ADVERSE EVENTS | PLEX therapy provided significant benefits of pro-inflammatory clearance and reduction of 60-days mortality in selected patients with COVID-19, without significant adverse events. These results are relevant to better characterize the effect of PLEX in patients with COVID-19; which may contribute to establish more specific therapeutic protocols, based in selection of potential candidates and expected benefits. | PMC9812351 |
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Acknowledgements | The authors acknowledge all the medical team and Nephrology residents who participated in the application of PLEX therapy. | PMC9812351 |
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Author contributions | J.H.-A. | G.F.-G. and M.A.-S. conceived the design and experiments. V.G.-M., J.H.-A., M.V.-B., E.T.-R., D.M.-T., M.L.-M., J.H.C.-C., J.O.-V., D.T.-M., S.C.-M., M.E.-S., S.M.-L. and L.M.-L. collected data and analyzed the results. P.M.-T. and J.A.S.-C. critically revised the manuscript. All authors reviewed the manuscript. All the authors revised the final manuscript and agreed to be published. | PMC9812351 |
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Data availability | The datasets generated and analyzed during the current study are not publicly available due to privacy policies of the hospital and patients information; but are available from the corresponding author on reasonable request. | PMC9812351 |
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Competing interests | The authors declare that they have no competing interests. | PMC9812351 |
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References | PMC9812351 |
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Supplementary Information | toxicity | SOLID TUMORS | To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/mThe online version contains supplementary material available at 10.1007/s10637-022-01307-6. | PMC10030450 |
Keywords | PMC10030450 |
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Introduction | SCLC, cancers, cancer, malignant tumors, toxic alkylating, tumors | CANCERS, SCLC, CANCER, SOLID TUMORS, MALIGNANT TUMORS, SMALL CELL LUNG CANCER, TUMORS, METASTATIC BREAST CANCER | Drug therapies for malignant tumors include chemotherapy, hormone therapy, and molecular-targeted therapy, and a combination of these therapies has been used in clinical settings. Chemotherapy has long been used to treat cancer and remains the backbone of systemic treatment in most cancers. Bendamustine hydrochloride (bendamustine) is a less toxic alkylating agent composed of three structures: a nitrogen mustard skeleton, benzimidazole ring, and butyric acid side chain. It was first synthesized in the German Democratic Republic in 1963 [The alkylation activity of bendamustine was found to be more potent than that of other alkylating agents in previous studies [Bendamustine has also been extensively evaluated for the treatment of solid tumors, and its activity has been observed in patients with metastatic breast cancer (mBC) and small cell lung cancer (SCLC) [Oral administration of bendamustine to humans was first reported by Preiss et al. in 1985, and a moderate bioavailability of 57% was reported [The development of a new oral dosing schedule for orally-administered bendamustine that ensures a balance between efficacy and safety will provide a new treatment option for patients with advanced solid tumors. In this study, we employed a standard 3 + 3 dose escalation design to evaluate the safety and pharmacokinetics (PK) and to determine the recommended dose (RD) and optimal dosing schedule of orally-administered bendamustine in patients with advanced solid tumors. Furthermore, we explored the types of tumors that were sensitive to orally-administered bendamustine. | PMC10030450 |
Materials and methods | PMC10030450 |
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Study design | toxicity, diarrhea, anemia, nausea, vomiting | ADVERSE EVENTS, MAY, ANEMIA | This study (NCT03604679) was conducted from May 16, 2018 to May 12, 2020 in Japan as a two-center, open-label, standard 3 + 3 dose escalation study, according to Good Clinical Practice, the Declaration of Helsinki, and other applicable regulations. A 3-week treatment period was considered as one cycle, and the maximum tolerated dose (MTD) and RD were assessed in Cohort 1 (once daily for 7 days), 2 (once daily for 14 days), and 3 (once daily for 21 days). Patient enrollment began with Cohort 1-Level 1 and was increased using a 3 + 3 design based on the dose-limiting toxicity (DLT). The starting dose was determined to be 25 mg/mDose escalation schedule of orally-administered bendamustine per cohort and level. Thick frame indicates the evaluated dosage, and gray highlight indicates the unexamined dosage at each level in each cohort; MTD, maximum tolerated dose. *Total dose of bendamustine per cycle (3-week schedule)Three to six patients were enrolled at each level in each cohort, starting with Cohort 1-Level 1 (25 mg/mThe daily doses at each level in each cohort are shown in Fig. DLT was defined as the following adverse events (AEs) for which a causal relationship to the study drug could not be ruled out: 1) Grade 4 neutrophil count decrease, lasting for more than 8 days; 2) FN; 3) grade ≥ 3 platelet count decrease, requiring platelet transfusion; 4) grade ≥ 3 anemia requiring red blood cell transfusion; 5) Grade 4 platelet count decrease; 6) Grade ≥ 3 non-hematologic toxicity except in grade ≥ 3 nausea, vomiting, and diarrhea controlled with appropriate supportive care or grade ≥ 3 abnormalities in laboratory test results controlled with appropriate supportive care or without clinically significant symptoms; and 7) unresolved hematologic toxicity (platelet count < 75,000/μL, ANC < 1000/μL) or bendamustine-related non-hematologic toxicity that prevented starting of the next cycle within 8 days. DLT evaluation was performed only during cycle 1. If AEs equivalent to DLT were observed even outside the evaluation period, the decision of DLT was left to the Data and Safety Monitoring Board (DSMB). | PMC10030450 |
Patients | idiopathic or drug-induced pneumonitis, pneumonitis, emphysema, pain | PNEUMONITIS, PULMONARY FIBROSIS, INTERSTITIAL PNEUMONIA, BONE LESIONS, SOLID TUMORS, CENTRAL NERVOUS SYSTEM METASTASES, EMPHYSEMA, HEPATIC METASTASIS, ONCOLOGY | Patients aged ≥ 20 years diagnosed with advanced solid tumors and resistant to standard therapy or no standard therapy and met the selection criteria were included in the study. The main inclusion criteria were:1) patients with an Eastern Clinical Oncology Group performance status of 0–1; 2) preserved organ and bone marrow functions (absolute neutrophil count ≥ 1500/μL, platelet count ≥ 100,000/μL, hemoglobin ≥ 9 g/dL; serum creatinine ≤ 1.5 × the upper limit of the normal range or estimated creatinine clearance ≥ 50 mL/min; total serum bilirubin ≤ 1.5 × the upper limit of the normal range, AST and ALT ≤ 3.0 × the upper limit of the normal range (≤ 5.0 × the upper limit of the normal range in the case of hepatic metastasis). The main exclusion criteria were:1) active, uncontrolled, or symptomatic central nervous system metastases; 2) interstitial pneumonia, pulmonary fibrosis, or severe emphysema; 3) a history of radiation pneumonitis or idiopathic or drug-induced pneumonitis; 4) major surgery performed or scheduled, or receiving immunotherapy, antibody therapy, or other biologic or radiation therapy within 4 weeks of enrollment.; 5) receiving cytotoxic chemotherapy or hormone therapy within 14 days of enrollment and palliative radiation therapy for pain management of bone lesions within 7 days of enrollment. | PMC10030450 |
Study drug | An LFHC formulation (orally-administered bendamustine) containing 10 or 30 mg of bendamustine (as a free base) in one capsule was administered once daily in the fasted state (fasting for 2 h before administration and 1 h after administration). The individual nominal dose at each level was calculated using the body surface area (BSA), and the nearest available dose was selected using 30 mg capsules in Cohort 1 and using a combination of 10 and 30 mg capsules in Cohorts 2 and 3. | PMC10030450 |
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Study evaluation | Tumors, PD, tumor, SD | DISEASE, SECONDARY, TUMORS, TUMOR | The primary endpoint was the identification of DLT in cycle 1 and the number of patients with DLT. The MTD, RD, and recommended dosing schedules were estimated based on the primary endpoints. The secondary endpoints were safety, PK, and efficacy. Efficacy was assessed as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not evaluable as an objective tumor assessment based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1). In addition, progression-free survival (PFS) was evaluated. If DLT occurred in one of three patients at each level in each cohort, another three patients were added to the relevant cohort/level; MTD was defined as the highest level with DLT occurring in ≤ one of six patients. The RD and recommended dosing schedule were determined by an independent DSMB based on a comprehensive evaluation. | PMC10030450 |
Pharmacokinetics | BLOOD | Blood samples were collected at 8 time points: immediately before administration and 0.5, 1, 1.5, 2, 4, 6, and 8 h after administration. Plasma concentrations of unchanged bendamustine were determined using liquid chromatography-tandem mass spectrometry. The individual PK parameters, maximum concentration (C | PMC10030450 |
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Safety | ADVERSE DRUG REACTIONS | At each observation time point, AEs were evaluated based on factors, such as subjective and objective symptoms, vital signs, laboratory tests, and general condition and graded using the NCI CTCAE (version 4.03). A causal relationship with bendamustine was assessed, and AEs, wherein a causal relationship could not be ruled out, were classified as adverse drug reactions. | PMC10030450 |
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Statistical analysis | Continuous variables were summarized using the number of patients, mean, and standard deviation. Categorical variables were summarized using frequencies and percentages. PFS was estimated using the Kaplan–Meier method. All analyses were performed using SAS version 9.4. | PMC10030450 |
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Results | PMC10030450 |
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Dose-limiting toxicity and maximum tolerated dose | None of the patients at 25 mg/mDLT occurred in one of three patients at 37.5 mg/m | PMC10030450 |
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Efficacy | As the best overall response, no patients were assessed as having CR; however, PR was observed in two patients at 75 mg/mCT imaging in patients who experienced partial response. Findings for each patient (swimmer plot). *The colors in the bar chart indicate dose reductions of bendamustine | PMC10030450 |
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Pharmacokinetics | PK parameters were calculated for all 18 patients who received orally-administered bendamustine. The CMean concentration–time profiles of bendamustine in plasma | PMC10030450 |
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Discussion | tBendamustine-based, death, thymic carcinoma, prostatic small cell carcinoma | DRUG INTERACTIONS, SOLID TUMORS | After administering bendamustine orally to 18 patients with advanced solid tumors, FN (n = 1) and a decrease in platelet count (n = 2) were observed as DLT; however, no AEs led to death or discontinuation of orally-administered bendamustine. PR was obtained in one patient each with prostatic small cell carcinoma and thymic carcinoma. As two of six patients had PR at 75 mg/mAs shown in Table S2, the bioavailability of orally-administered bendamustine was sufficiently high, and the individual variability in PK parameters was generally similar to that of bendamustine injection. The tBendamustine-based regimens have been recommended in the NCCN guidelines [Bendamustine is rapidly eliminated from the blood, and mono-hydroxylated and di-hydroxylated bendamustine are primarily formed by rapid hydrolysis. A portion of the bendamustine is metabolized via CYP1A2 into demethylated bendamustine. Therefore, drug interactions with CYP1A2 inhibitors or inducers are unlikely because of the limited contribution of CYP1A2 to bendamustine metabolism. The effect of bendamustine exposure is not dependent on age, ethnicity, sex, or differences in liver and kidney function [The MTD, RD, and recommended treatment schedule were determined to be 75 mg/m | PMC10030450 |
Acknowledgements | The authors express their gratitude to the patients and their families who participated in this study. The authors are grateful to Accerise, Inc. for supporting the preparation of this manuscript. | PMC10030450 |
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