Total Cumulative Dose Research Articles

MicroRNA-34a-5p as a promising early circulating preclinical biomarker of doxorubicin-induced chronic cardiotoxicity.

Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present study was designed to address a knowledge gap concerning a lack of circulating biomarkers capable of predicting the risk of cardiotoxicity induced by DOX. Profiling of 2083 microRNAs (miRNAs) in mouse plasma revealed 81 differentially expressed miRNAs 1 week after 6, 9, 12, 18, or 24 mg/kg total cumulative DOX doses (early-onset model) or saline (SAL). Among these, the expression of seven miRNAs was altered prior to the onset of myocardial injury at 12 mg/kg and higher cumulative doses. The expression of only miR-34a-5p was significantly (false discovery rate [FDR] < 0.1) elevated at all total cumulative doses compared with concurrent SAL-treated controls and showed a statistically significant dose-related response. The trend in plasma miR-34a-5p expression levels during DOX exposures also correlated with a significant dose-related increase in cardiac expression of miR-34a-5p in these mice. Administration of a cardioprotective drug, dexrazoxane, to mice before DOX treatment, significantly mitigated miR-34a-5p expression in both plasma and heart in conjunction with attenuation of cardiac pathology. This association between plasma and heart may suggest miR-34a-5p as a potential early circulating marker of early-onset DOX cardiotoxicity. In addition, higher expression of miR-34a-5p (FDR < 0.1) in plasma and heart compared with SAL-treated controls 24 weeks after 24 mg/kg total cumulative DOX dose, when cardiac function was altered in our recently established delayed-onset cardiotoxicity model, indicated its potential as an early biomarker of delayed-onset cardiotoxicity.

Association of androgen excess and bone mineral density in women with classical congenital adrenal hyperplasia with 21-hydroxylase deficiency.

This study aims to assess BMD and its association with androgen excess in women with CAH. We enrolled 92 women with CAH with 21-OH deficiency and retrospectively reviewed their clinical features, hormone concentrations, body composition, glucocorticoid (GC) dose, and BMD. BMD was not different according to the subtypes of CAH. BMD at the lumbar spine was lower in women with CAH with regular menstruation than those with irregular menstruation (1.081 vs. 1.165g/cm2, P < 0.05). BMD was lower in women with CAH with 17-hydroxyprogesterone (17-OHP) < 10ng/mL than in those with ≥ 10ng/mL (lumbar spine, 1.019 vs. 1.150g/cm2; femur neck, 0.806 vs. 0.899g/cm2; total hip, 0.795 vs. 0.943g/cm2; all P < 0.05). After adjusting for age and BMI in correlation analyses, testosterone concentrations were positively correlated with lumbar spine, femur neck, and total hip BMD (r = 0.46, r = 0.38, and r = 0.35, respectively; all P < 0.05), while 17-OHP was positively correlated with lumbar spine BMD (r = 0.38, P < 0.01). In subgroup analysis, 17-OHP was positively correlated with BMD (lumbar spine, r = 0.22; femur neck, r = 0.22; total hip, r = 0.24; all P < 0.05) only in the group with a total cumulative dose of GC ≥ 156.0g/m2. Androgen excess may have a protective effect on BMD in women with classic CAH and high cumulative doses of GC.

Major vault protein attenuates cardiomyocyte injury in doxorubicin-induced cardiomyopathy through activating AKT

BackgroundDoxorubicin (DOX) has limited chemotherapy application for malignancies due to cardiotoxicity. The pathogenesis of DOX-induced cardiomyopathy (DiCM) is yet to be elucidated. Increasing studies proved that activation of AKT prevented cardiomyocyte apoptosis and cardiac dysfunction in response to DOX insult. Our previous studies indicated that major vault protein (MVP) deficiency was accompanied by suppressed phosphorylation of AKT in metabolic diseases. This study aimed to investigate the role and underlying mechanism of MVP on cardiomyocyte apoptosis in DiCM.MethodsMice were intraperitoneally injected with DOX 5 mg/kg, once a week for 5 weeks, the total cumulative dose was 25 mg/kg. Cardiomyocyte-specific MVP overexpression was achieved using an adeno-associated virus system under the cTnT promoter after the fourth DOX injection. Cardiac function was examined by echocardiography followed by euthanasia. Tissue and serum were collected for morphology analysis and biochemical examination.ResultsHerein, we found that MVP expression was upregulated in DOX-treated murine hearts. Cardiac-specific MVP overexpression alleviated DOX-induced cardiac dysfunction, oxidative stress and fibrosis. Mechanistically, MVP overexpression activated AKT signaling and decreased cardiomyocyte apoptosis in DiCM.ConclusionsBased on these findings, we supposed that MVP was a potential therapeutic agent against DiCM.

Epidemiology and risk factors associated with avascular necrosis in patients with autoimmune diseases: a nationwide study.

Background/AimsAvascular necrosis (AVN) is a clinical condition characterized by the death of bone components due to interruption in the blood supply. This study aimed to investigate the epidemiology and determine the risk factors for AVN in patients with autoimmune diseases.MethodsWe conducted a population-based retrospective cohort analysis using claims data from the Taiwan National Health Insurance Research Database. A total of 49,636 patients with autoimmune diseases between January 1, 2005 and December 31, 2013 were included. Cox regression analysis was used to identify associated risk factors for the development of AVN.ResultsA total of 490/49,636 patients (1.0%) developed symptomatic AVN. The systemic lupus erythematosus patients had a higher risk of AVN compared to other autoimmune diseases. AVN was positively correlated with male sex (p < 0.001), alcoholism (p < 0.001), mean daily prednisolone dosage 7.51 to 30 mg (p < 0.001) and > 30 mg (p < 0.001), and total cumulative prednisolone dose 0 g to 5 g (p = 0.002). However, AVN was inversely correlated with cumulative duration of hydroxychloroquine exposure > 0.6 years (p < 0.001).ConclusionsMale sex, systemic lupus erythematosus, alcoholism, mean daily corticosteroid > 7.5 mg and a total cumulative dose of corticosteroid 0 to 5 g were independently associated with the development of AVN in autoimmune patients. While hydroxychloroquine use > 0.6 years conferred significant protection against the development of AVN. Clinicians should regularly assess patients with risk factors to enable the early diagnosis of AVN.

Breath biomarkers of total body irradiation in non-human primates

Background. Radiation exposure causes oxidative stress, eliciting production of metabolites that are exhaled in the breath as volatile organic compounds (VOCs). We evaluated breath VOCs as potential biomarkers for use in radiation biodosimetry. Methods. Five anesthetized non-human primates receive total body irradiation (TBI) of three daily fractions of 120 cGy per day for three days, resulting in a cumulative dose of 10.8 Gy. Breath samples were collected prior to irradiation and after each radiation fraction, and analyzed with gas chromatography mass spectrometry. Results. TBI elicited a prompt and statistically significant increase in the abundance of several hundred VOCs in the breath, including some that were increased more than five-fold, with100% sensitivity and 100% specificity for radiation exposure. The most significant breath VOC biomarkers of radiation mainly comprised straight-chain n-alkanes (e.g. hexane), as well as methylated alkanes (e.g. 3-methyl-pentane) and alkane derivatives (e.g. 2-butyl-1-octanol), consistent with metabolic products of oxidative stress. An unidentified breath VOC biomarker increased more than ten-fold following TBI, and rose linearly with the total cumulative dose of radiation (R 2 = 0.92). Conclusions. TBI of non-human primates elicited increased production of breath VOCs consistent with increased oxidative stress. These findings provide a rational basis for further evaluation of breath VOC biomarkers in human radiation biodosimetry.

Analysis and evaluation of the operational characteristics of a new photodynamic therapy device

One of the key aspects of photodynamic therapy is the light source that is used to irradiate the lesion to be treated. The devices used must ensure that their emission spectrum matches the absorption spectrum of the photosensitizer, so that treatment radiation is delivered only on the target area, without irradiating healthy tissue at superficial or deep levels. Irradiance values must be adequate in order to avoid thermal damage, exceed the oxygen replenishment rate and avoid long treatment times. Furthermore, the device should be user-friendly, inexpensive, and able to be adapted to different photosensitizers. We have developed an easy-to-use and highly customizable device based on LED technology. Its innovative geometric design allows radiation to be delivered to a small treatment surface, since the LEDs are arranged in three arms, the configuration of which directs their radiation on the treatment point. Different high-power color LEDs are disposed on the arms, and can be independently selected based on the most effective wavelengths for exciting the different photodynamic therapy photosensitizers. We have tested the prototype in 5 different patients (1 actinic keratose, 1 actinic cheilitis, 1 superficial basal cell carcinoma and 2 Bowen's disease) and after 1–2 sessions of total cumulative dose of 25–50 J / cm2, 100% clearance of lesions were obtained. Our device can be used by any professional in the field, whether for medical or research purposes. It facilitates the development of treatment protocols and trials with different photosensitizers.

Polarization effect of Schottky-barrier CdTe semiconductor detectors after electron irradiation

Spectrometric properties of cadmium telluride (CdTe) radiation semiconductor detectors with Schottky-barrier contacts were studied after irradiation with a high energy electron beam of 5 MeV-energy. The total cumulative dose of 2.25 kGy was delivered stepwise and the response of detectors to 241Am radioisotope source was acquired using a standard spectrometric chain at reverse bias voltages of 300 V, 400 V and 500 V. To evaluate the radiation damage, the spectral parameters of the 59.5 keV-photopeak were determined, namely the peak position, the full width at half maximum (FWHM), the peak amplitude and the net peak area. The time evolution of these parameters was followed by recording the spectra in 30-seconds (or 2-minutes) intervals after applying the reverse bias voltages. The results demonstrated significant effect of high energy electrons on the spectral characteristics even after applying the lowest dose of 0.5 kGy. The shift of the photopeak to lower energies, the increase of the FWHM and decrease of the peak height and area were confirmed. The time evolution of the observed tendencies disclosed that electron irradiation results in earlier onset of the polarization mechanism. After irradiating with the highest dose of 2.25 kGy, the polarization effect occurs practically immediately after applying the bias voltage.

Is fractionated robotic stereotactic body radiosurgery optional salvage treatment for the re-irradiation of locally recurrent nasopharyngeal carcinoma?

Recurrent nasopharyngeal carcinoma (NPC) after previous radiation therapy is a significant problem. This study was to determine the potential benefits from re-irradiation by fractionated stereotactic body radiotherapy (FSRT) on survival benefits and effects of severe late toxicities. Between 2009 and 2018, treatment outcomes were evaluated retrospectively in 26 patients with locally recurrent NPC treated using FSRT with CyberKnife. Five patients who had metastatic disease and one who had second recurrence were excluded from the study, and the remaining 20 patients were analyzed. The median age was 52 years (range, 28-80 years); re-treatment T stage was as follows: 6 (30%) - T2, 5 (25%) - T3, and 9 (45%) - T4. The median time from initial RT to recurrence was 22 months (range, 8-159 months). The median re-irradiation FSRT dose was 30 Gy in 5 fractions. The median follow-up was 44 months; the overall survival (OS), local failure-free survival, and disease progression-free survival rates at 3 years were 89%, 73%, and 53%, respectively. All patients were evaluated for response after treatment: 9 (45%) had complete, 3 (15%) had partial, and 6 (30%) had no response. Univariate analysis demonstrated that higher cumulative total radiotherapy dose, gross tumor volume, and recurrent time interval were prognostic factors for local failure-free survival. The recurrent time interval was also an independent factor for progression-free survival and OS. The incidence of temporal lobe necrosis and trismus was 10% and 20%, respectively. One patient had Grade 5 toxicity to treatment-related bleeding. Tumor dose coverage is important for treating recurrent NPC, and treatment-related mortality was vascular in nature. FSRT is a promising treatment modality for recurrent NPC.

Colistin induced acute kidney injury in critically ill children: a prospective study utilizing RIFLE criteria.

Colistin is one of the last resort antibiotic options for resistant gram-negative pathogens. Renal injury is the most common side effect of colistin. Characteristics of nephrotoxicity are well described in adults. However, this data is sparse in children. In this study we evaluated the incidence, severity, time course and risk factors of colistin nephrotoxicity in a pediatric population. In a prospective study over a 9-month period, children who received intravenous colistin for at least 48h were evaluated for renal side effect by utilizing Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria. Children receiving renal replacement therapy (RRT) or received a repeated course of colistin were excluded. Thirty-seven children were included. Median age of participants was 4.5months. Overall, 48.6% of the cases developed AKI and consisted 56% in the Risk, 33% in the Injury and 11% in the Failure categories of RIFLE criteria. AKI was reversible while colistin continued and no one required RRT. Mean ± SD time to AKI development was 10.94 ± 7.51days. Multivariate logistic regression analysis demonstrated that total cumulative dose of colistin was an independent predictor of nephrotoxicity (standardized ß = 1.024, P = 0.034). AKI is a common side effect of colistin therapy in critically ill children developing in nearly half of recipients. However, with the dosage range utilized in this study, in the majority of children, renal injury seemed to be mild to moderate in nature. Given the limited treatment options available in critically ill children with resistant gram-negative pathogens, colistin remains a marvelous therapeutic option. Further studies are required to fully elucidate the risk factors and clinical pictures of colistin-induced nephrotoxicity.

Abstract 11535: Persistent Qt Prolongation After Doxorubicin Administration at Doses Similar to Adjuvant Breast Cancer Therapy in African Green Monkeys

Introduction: Cancer patients undergoing doxorubicin (Dox)-based chemotherapy often experience cardiac repolarization abnormalities, including electrocardiography (ECG)-derived QT and corrected QT (QTc) interval prolongation, which increases the risk for life-threatening arrhythmias such as torsades de pointes. We have previously reported that African Green monkeys exhibit CMR-derived myocardial fibrosis long-term after receiving Dox at doses similar to those experienced by women treated for breast cancer. Here, we sought to determine if QT/QTc prolongation persists after treatment cessation and its association with myocardial fibrosis. Methods: Five female African Green AGMs (AGMs) aged 13±1 years received Dox (30 - 60 mg/m 2 / biweekly IV, total cumulative dose: 240 mg/m 2 ) and underwent 12-lead ECG and CMR imaging with pre- and post-contrast T1 maps from which extracellular volume (ECV) was calculated, before and 15 weeks after the final dose of Dox treatment. A blinded paired and correlation analysis was performed on ECG-derived heart rate (HR), QRS, QT, QTc interval durations and ECV. Results: After Dox, all monkeys exhibited increased QT (BL: 323.2 ± 27.4 ms vs. Post-Dox: 366.4 ± 18.7 ms, p=0.002) and QTc (BL: 440.2 ± 22.8 ms vs. Post-Dox: 500.8 ± 22.0 ms, p=0.009) intervals, without any significant changes in HR or QRS duration (p=0.92 and p=0.47 respectively). Longer QTc intervals were associated with increases in ECV ( r =0.58, p=0.05) (Figure). Conclusions: AGMs that received Dox - in a fashion similar to adjuvant anthracycline chemotherapy for breast cancer- exhibited longer QT and QTc intervals associated with myocardial fibrosis. Our study suggests this may not be solely due to transient ion channel disruption from Dox but rather from persistent changes in the electrophysiological properties of cardiomyocytes and the extracellular matrix. Future longitudinal studies are needed to determine the clinical significance of these findings.

Abstract 13174: Female Sex is Not Associated With Subsequent Heart Failure in Adult Patients Treated With Anthracyclines

Introduction and Hypothesis: Female sex has long been considered a risk factor for anthracycline-associated cardiotoxicity, based largely on data in childhood cancer survivors. However, preclinical experiments suggest that female sex hormones present in adulthood may protect against doxorubicin cardiotoxicity. We therefore hypothesized that female sex would be associated with a decreased odds of heart failure in adult patients treated with anthracyclines. Methods: We conducted a retrospective cohort study of 871 adult patients (44% women and 56% men) at our medical center with no prior history of heart failure who were treated with anthracyclines for non-hormone-dependent malignancies including lymphoma, leukemia, and sarcoma. Patients who expired during the study period were excluded. The presence or absence of heart failure within five years of initiation of anthracyclines was assessed using ICD-9/10 codes. Logistic regression models were used to assess odds ratios based on self-reported sex and other covariates, adjusting for age. Results: Baseline characteristics were similar in men and women, including age, total cumulative anthracycline dose, and prevalence of cardiovascular comorbidities such as hypertension, diabetes, and coronary artery disease. The odds of heart failure increased modestly with age (OR: 1.02; 95% CI: 1.01 to 1.03, p = 0.001). In an age-adjusted model, female sex was not associated with subsequent heart failure (OR: 1.03, 95% CI 0.72 to 1.47, p = 0.88), including after stratification by age ≤ 50 years or &gt; 50 years as a surrogate for menopausal status. Conclusions: In this retrospective cohort study, female sex was not associated with heart failure in adult patients treated with anthracyclines for non-hormone-dependent tumors. These findings diverge from prior reports suggesting an increased risk of cardiotoxicity in women. Future studies will assess the competing risks of cancer and cardiovascular disease/death in men versus women treated with anthracyclines.

Abstract 10607: Evaluating Diastolic Function by Echocardiography in a Prospective Cohort of Patients with Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL) Who Received Anthracycline-Based Chemotherapy

Introduction: Anthracyclines are a first-line chemotherapeutic agent used in the treatment of lymphoma. Myocardial injury can occur with cumulative doses of 250 to 350 mg/m 2 . Echocardiography is the imaging modality for identifying cardiac dysfunction; however, identifying diastolic changes in patients who received anthracyclines is not well represented in the literature. Variables used to identify diastolic dysfunction include lateral e’, medial e’, mitral E velocity, mitral A velocity, E/A, E/e’, and left atrial volume index (LAVI). This study aims to identify if diastolic abnormalities develop in a prospective cohort of patients with HL or NHL who received anthracycline-based chemotherapy. Methods: Lymphoma patients treated with anthracyclines from 2013 to 2020 were prospectively enrolled. Echocardiography was obtained at 3-time points: before the start of chemotherapy (T1), at 3-6 months (T2), and 9-12 months (T3). Diastolic variables were measured and analyzed based on the total cumulative dose of Doxorubicin per body surface area. Those that received greater than 250 mg/m 2 and greater than 300 mg/m 2 of Doxorubicin were compared to those that did not. Statistical analysis was done using one-way ANOVA, adjusting for age and gender. Results: 151 total patients (90 males, mean age 61 + 16 years); 21 (14%) HL, 130 (85%) NHL. 114 and 66 patients received a total cumulative dose of Doxorubicin greater than 250 mg/m 2 and 300 mg/m 2 , respectively. There was no significant association with 250 mg/m2. Lateral e’ at T3 vs. T1, was lower in those that received greater than 300 mg/ m 2 compared to those received less (0.09 vs 0.10, p &lt; 0.02) (Table 1). Conclusions: Lateral e’ decreased at 1-year follow-up in those that received higher doses of Doxorubicin. These changes in the lateral e’ could reflect early relaxation abnormalities related to anthracycline-based chemotherapy and suggest that changes in lateral e’ should be considered by itself since E/e’ was normal.

Incidence rate and factors associated with the development of secondary cancers after radioiodine therapy in differentiated thyroid cancer: a multicenter retrospective study.

The objective of this study was to estimate the incidence of secondary cancers and the factors associated with their development among patients who underwent radioiodine therapy (RIT) with differentiated thyroid cancer. We retrospectively collected medical records for patients who underwent first RIT between January 1, 2000, and December 31, 2005, from seven tertiary hospitals in South Korea after total thyroidectomy for differentiated thyroid cancer. Cancer incidence and calculated standardized rate ratio were compared with Korean cancer incidence data. The association between the development of secondary cancers and various parameters was analyzed by Cox-proportional hazard regression. A total of 3106 patients were included in this study. Mean age at the time of diagnosis of thyroid cancer was 45.7 ± 13.3 years old, and 2669 (85.9%) patients were female. The follow-up period was 11.9 ± 4.6 (range, 1.2-19.6) years. A total of 183 secondary cancers, which included 162 solid and 21 hematologic cancers, occurred in 173 patients (5.6%). There was no significant difference between solid cancer incidence in our study population who underwent RIT and the overall Korean population, but the incidence of hematologic cancers and total cancer in our study was significantly higher compared with that of the Korean population. A multivariate analysis identified independent prognostic factors for the development of secondary cancer including age at 1st RIT, male, and total cumulative dose over 200 mCi. We need to assess the risk benefit for patients who receive over 200 mCi of a total cumulative dose.

Prospective superficial EPR in-vivo dosimetry study during hypofractionated radiotherapy of breast cancer patients treated with helical tomotherapy

BackgroundIn-vivo dosimetry (IVD) is a patient specific measure of quality control and safety during radiotherapy. With regard to current reporting thresholds for significant occurrences in radiotherapy defined by German regulatory authorities, the present study examines the clinical feasibility of superficial electron paramagnetic resonance (EPR) IVD of cumulative total doses applied to breast cancer patients treated with helical intensity-modulated radiotherapy (tomotherapy).MethodsIn total, 10 female patients with left- or right-sided breast cancer were enrolled in this prospective IVD study. Each patient received a hypofractionated whole breast irradiation. A total median dose of 42.4 Gy in 16 fractions (5 fractions per week) was prescribed to the planning target volume. The treatments were completely delivered using helical tomotherapy and daily image guidance via megavoltage CT (MVCT). For each patient, three EPR dosimeters were prepared and placed at distinct locations on the patient’s skin during the delivery of all fractions. Two dosimeters were placed next to the ipsilateral and contralateral mammilla and one dosimeter was placed ventrally to the thyroid (out-of-primary-beam). The total doses delivered to the dosimeters were readout after all fractions had been administered. The measured total dose values were compared to the planned dose values derived from the treatment planning system (TPS). Daily positional variations (displacement vectors) of the ipsilateral mammilla and of the respective dosimeter were analyzed with respect to the planned positions using the daily registered MVCT image.ResultsAveraged over all patients, the mean absolute dose differences between measured and planned total dose values (± standard deviation (SD)) were: 0.49 ± 0.85 Gy for the ipsilateral dosimeter, 0.17 ± 0.49 Gy for the contralateral dosimeter and -0.12 ± 0.30 Gy for the thyroid dosimeter. The mean lengths of the ipsilateral displacement vectors (± SD) averaged over all patients and fractions were: 10 ± 7 mm for the dosimeter and 8 ± 4 mm for the mammilla.ConclusionSuperficial EPR IVD is suitable as additional safeguard for dose delivery during helical tomotherapy of breast cancer. Despite positional uncertainties in clinical routine, the observed dose deviations at the ipsilateral breast were on average small compared to national reporting thresholds for total dose deviations (i.e. 10%/4 Gy). EPR IVD may allow for the detection of critical dose errors during whole breast irradiations.

Laboratory Abnormalities in Acne Patients Treated With Oral Isotretinoin: A Retrospective Epidemiological Study.

BackgroundIsotretinoin has been used to treat moderate to severe acne. It is well known that isotretinoin can cause an elevation in liver enzymes, triglycerides, and cholesterol. Laboratory monitoring is indicated while patients are on isotretinoin, but the frequency of laboratory monitoring is very variable among physicians who prescribe it.Study objectivesThis study aimed to determine the frequency of laboratory abnormalities of triglycerides, cholesterol, and liver aminotransferases in acne patients treated with oral isotretinoin in order to assess the need for frequent laboratory monitoring while on isotretinoin and to study the association between body weight and laboratory abnormalities.MethodsA retrospective chart review has been conducted using data extracted from electronic medical records of the Department of Dermatology, Qassim University Medical City, Saudi Arabia. We included all acne patients who were treated with Isotretinoin for at least four months. Data were analyzed using the statistical program SPSS version 25 (Armonk, NY: IBM Corp.).ResultsA total of 407 patients met the inclusion criteria and were included in our study, 198 (48.6%) were female and 209 (51.4%) were males. Patients' age ranged from 10 to 51 years, with a mean age of 22.15 years. At baseline, aspartate aminotransferase (AST) was elevated in 5.4% of patients and alanine aminotransferase (ALT) was elevated in 12.7% of patients. At the last visit, AST was elevated in 3.9% of patients while ALT was elevated in 9% of patients. Triglycerides level was elevated in 12.7% of patients at the last visit compared to 6.5% of patients at baseline. Total cholesterol was elevated in 9% of patients at the last visit compared to 10.5% of patients at baseline. The increase in triglyceride levels and differences between triglycerides (TG) classifications between baseline and last visit was statistically significant (P<0.001). Higher body weight was associated with a higher incidence of elevation in ALT and triglycerides levels, and this association was statistically significant. There was no statistically significant relationship between total cumulative dose and laboratory abnormalities in ALT, AST, triglycerides, or total cholesterol.ConclusionThe findings of this study indicate that oral isotretinoin can cause an elevation in ALT, AST, total cholesterol, and triglyceride levels but the incidence of these laboratory abnormalities is low and the elevation was not associated with significant morbidity, and therefore the practice of monthly laboratory monitoring for all patients while on isotretinoin needs to be revised as there is no strong evidence for such practice. We also found that patients with higher body weight are at higher risk of laboratory abnormalities and may require more frequent laboratory monitoring. Our findings support less frequent laboratory monitoring for acne patients on isotretinoin who had normal baseline labs. Frequent laboratory monitoring in these patients carries financial and emotional implications and lacks strong evidence to support this practice.

Minimum Bladder Reference Contour to Guide Bladder Filling for Prostate Radiotherapy

The purpose of this study was to evaluate if a minimum bladder reference contour could help reduce treatment delays and imaging needed for pre-treatment setup in patients undergoing prostate stereotactic body radiation therapy (SBRT).20 patients undergoing 5-fraction SBRT to the prostate and seminal vesicles were included in this pilot study. Patients were simulated with a full bladder (1 cup, 45min prior). The simulated bladder was contoured and then a script automatically generated four possible "min reference contours as a contraction by 1, 2, 3, and 4 cm from the superior bladder border. The smallest reference contour that still met our bladder dose constraints was selected as the min_bladder to be used to guide pre-treatment setup. Radiation therapists and treating physicians were instructed to consider bladder filling sufficient if the volume on the cone-beam CT (CBCT) upon visual inspection appeared larger than the min_bladder reference even if smaller than the simulated bladder. Approved CBCTs were used to evaluate bladder and bowel dosimetry. Treatment time (first kV image to beam-off) and number of CBCTs were compared to 66 consecutive patients treated prior to introducing the min-bladder reference contour.The average simulated bladder, min_bladder, and treated bladder sizes were 398 ± 139cc, 157 ± 54cc and 300 ± 150cc, respectively. There was 1 of 100 total fractions where bladder constraints were exceeded, however the approved CBCT bladder volume was less than the min_bladder reference and the total cumulative bladder dose for this patient was within constraints. Average cumulative max bowel dose was 14.5 Gy in 5 fractions with a maximum cumulative max bowel dose 32.5 Gy in 5 fractions. Compared to our historical average treatment time of 31.5 ± 20 min/fraction, the pilot study average was 26 ± 15 min/fraction (P = 0.003). Average number of CBCTs/fraction also decreased from 1.38 ± 0.69 to 1.24 ± 0.60 (P = 0.048). Based on our annual SBRT treatment volume, we estimate that use of this reference contour will save > 150 hours and > 260 CBCTs per year in our department.Our results suggest that the reference contour accurately predicted the minimum bladder volume needed to avoid exceeding bladder constraints, did not inadvertently overexpose bowel, and significantly reduced treatment time and number of pre-treatment CBCTs. A similar reference contour is now being developed for other prostate definitive and post-op regimens at our institution.

Doxorubicin-induced delayed-onset subclinical cardiotoxicity in mice.

Subclinical cardiotoxicity at low total cumulative doxorubicin (DOX) doses can manifest into cardiomyopathy in long-term cancer survivors. However, the underlying mechanisms are poorly understood. In male B6C3F1 mice, assessment of cardiac function by echocardiography was performed at 1, 4, 10, 17, and 24 weeks after exposure to 6, 9, 12, and 24 mg/kg total cumulative DOX doses or saline (SAL) to monitor development of delayed-onset cardiotoxicity. The 6- or 9-mg/kg total cumulative doses resulted in a significant time-dependent decline in systolic function (left ventricular ejection fraction (LVEF) and fractional shortening (FS)) during the 24-week recovery although there was not a significant alteration in % LVEF or % FS at any specific time point during the recovery. A significant decline in systolic function was elicited by the cardiotoxic cumulative DOX dose (24 mg/kg) during the 4- to 24-week period after treatment compared to SAL-treated counterparts. At 24 weeks after DOX treatment, a significant dose-related decrease in the expression of genes and proteins involved in sarcoplasmic reticulum (SR) calcium homeostasis (Ryr2 and Serca2) was associated with a dose-related increase in the transcript level of Casp12 (SR-specific apoptosis) in hearts. These mice also showed enhanced apoptotic activity in hearts indicated by a significant dose-related elevation in the number of apoptotic cardiomyocytes compared to SAL-treated counterparts. These findings collectively suggest that a steady decline in SR calcium handling and apoptosis might be involved in the development of subclinical cardiotoxicity that can evolve into irreversible cardiomyopathy later in life.

Comparative Study Among Three Different Models for Induction of Acute Myocardial Infarction in Rats

Abstract Aim Laboratory study of Acute Myocardial Infarction (AMI) has become of great importance for further investigations about prevention, diagnosis and treatment of the increasing number of patients worldwide. In this study, we are seeking the best experimental AMI model by comparing three methods by which AMI can be experimentally induced in rats to illuminate the most reliable model to use in further studies. Methods and Results Experimentally, AMI can be produced by either drug induced methods or surgical methods. Here, we compared two drug induced methods (isoproterenol and doxorubicin) and a surgical model to find out which method is best simulating human AMI. 50 male sprague dowley rats were put into 5 groups, each contained 10 rats as follows. Surgical group in which the proximal left anterior descending coronary artery (LADCA) was dissected and ligated. Isoproterenol group in which Isoproterenol (300 gm/kg) was injected in ten rats subcutaneously on 2 doses a day apart. Doxorubicin group in which doxorubicin (2.5 mg/kg) was given intraperitonially every other day for total cumulative dose of 15 mg/kg. Control group where rats received only 2 ml of saline intraperitonially or subcutaneously. Sham group where rats underwent a similar surgery, but without LADAC ligation. After the induction, the biochemical parameter (serum Troponin I) at 12, 24, 36, 48 and 72 hours and histopathological changes (using hematoxylin, eosin and Mallory's trichrome stains) in all groups on days 1, 7, 14 and 21 were recorded. Data were statically analyzed, and Troponin curves were designed for each group to be correlated with that of AMI in human. After 7 days, histopathological studies of the surgical group exhibited wide areas of focal fibrosis at the apex and scattered mononuclear inflammatory cells infiltration. While the isoproterenol group showed moderate degree of inflammation with multifocal areas of fibrosis and scattered mononuclear inflammatory cells. However, the doxorubicin group showed more or less normal histology of cardiomyocytes. Biochemical studies reflected a significant difference in serum Troponin levels and peak timing among the groups. The surgical and isoproterenol groups Troponin peaked around 24 hours after the intervention, with higher levels in the surgical group. However, the doxorubicin group showed lower peaks around 36 hours post intervention. Correlations with human AMI histopathology and biochemical markers show more mimicking changes in the surgical group when compared to the other models, followed by the isoproterenol group and least similar in the doxorubicin- induced group. However, the survival rate of rats in the isoproterenol group was superior, followed by the surgical group and the doxorubicin group showed the lowest survival rates. Conclusions Surgical induction of AMI in rats achieves the high similarity to AMI in human but the low survival rates jeopardize the reliability of the model. However, isoproterenol shows sufficient levels of mimicking and higher survival indicating the highest reliability in simulation. Doxorubicin based models are the least reliable.

Antipsychotic treatment effects and structural MRI brain changes in schizophrenia.

Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia. A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest. The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms. We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.

Association of childhood growth hormone treatment with long-term cardiovascular morbidity

Importance Concerns about the cardiovascular safety of recombinant human growth hormone (rhGH) treatment in childhood have recently been raised; however, long-term studies are limited. Objective To investigate the long-term risk of overall and severe cardiovascular events in patients previously treated with rhGH in childhood and whether there is an association with treatment duration or dose. Design, Setting, and Participants This nationwide population-based cohort study included patients treated with rhGH during childhood from January 1, 1985, to December 31, 2010, in Sweden, with follow-up through December 31, 2014. Included patients were treated with rhGH owing to isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS). For each patient, 15 age-, sex-, and region-based matched control individuals were randomly selected from the general population as a comparison group. Data on cardiovascular outcomes and covariates including gestational age, birth weight, birth length, socioeconomic status, and height were obtained through linkage with several health care and population-based registers. Data were analyzed from January 1, 1985, to December 31, 2014. Exposures Treatment with rhGH during childhood and adolescence (aged 0-18 years). Main Outcomes and Measures The primary outcome was the first cardiovascular event recorded after the start of follow-up, and the secondary outcome was the first severe cardiovascular event. Results A total of 53 444 individuals (3408 patients and 50 036 controls; 67.7% men; mean [SD] age at study end, 25.1 [8.2] years) were followed up for as long as 25 years (median follow-up, 14.9 [range, 0-25] years; total, 795 125 person-years). Among 1809 recorded cardiovascular events, the crude incidence rates were 25.6 events per 10 000 person-years for patients and 22.6 events per 10 000 person-years for controls. The adjusted hazard ratio (HR) for all cardiovascular events was higher in patients compared with controls (HR, 1.69; 95% CI, 1.30-2.19), especially for women (HR, 2.05; 95% CI, 1.31-3.20) compared with men (HR, 1.55; 95% CI, 1.12-2.13). All subgroups had increased HRs (SGA, 1.97 [95% CI, 1.28-3.04]; GHD, 1.66 [95% CI, 1.21-2.26]; and ISS, 1.55 [95% CI, 1.01-2.37]). Longer duration of rhGH treatment (HR, 2.08; 95% CI, 1.35-3.20) and total cumulative dose (HR, 2.05; 95% CI, 1.18-3.55) were associated with higher risk for overall cardiovascular disease. The adjusted HR for severe cardiovascular disease was 2.27 (95% CI, 1.01-5.12). Conclusions and Relevance In this cohort study, treatment with rhGH during childhood due to GHD, SGA, or ISS was associated with increased risks of cardiovascular events in early adulthood, particularly in women; however, conclusions of causality are still limited and the absolute risk remains low.