The scientific publications of AIFM members in 2015–2019: A survey of the FutuRuS working group

PurposeWithin the Italian Association of Medical Physics and Health Physics (AIFM) working group “FutuRuS” we carried out a survey regarding the number of the peer-reviewed articles by AIFM members.MethodsWe surveyed papers published in the years 2015–2019. Data extracted from Scopus included information regarding authors, title, journal, impact factor (IF), leading or standard authorship by AIFM members, keywords, type of collaboration (monocentric/multicentric/international), area of interest [radiation oncology (RO), radiology (RAD), nuclear medicine (NM), radioprotection (RP) and professional issue (PI)] and topics.ResultsWe found 1210 papers published in peer-reviewed journals: 48%, 22%, 16%, 6%, 2 and 6% in RO, RAD, NM, RP, PI and other topics, respectively. Forty-seven percent of the papers involved monocentric teams, 31% multicentric and 22% international collaborations. Leading authorship of AIFM members was in 56% of papers, with a corresponding IF equal to 52% of the total IF (3342, IF_mean = 2.8, IF_max = 35.4). The most represented journal was Physica Medica, with 15% of papers, while a relevant fraction of IF (54%) appeared in clinically oriented journals. The number of papers increased significantly between 2015 and 2016 and remained almost constant in 2017–2019.ConclusionsThis survey led to the first quantitative assessment of the number and theme distribution of peer-reviewed scientific articles contributed by AIFM members. It constitutes a ground basis to support future AIFM strategies and promote working groups on scientific activity of medical physicists, and to build the basis for rational comparison with other countries, first of all within Europe.     

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study protocol for a phase 1 dose-escalation trial of patients with xerostomia after radiation therapy for head and neck cancer: MARSH: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction

BackgroundXerostomia, or dry mouth, is a common side effect of head and neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Adult stem cells are the ultimate source for replenishment of salivary gland tissue. Bone marrow–derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. We have undertaken studies enabling U.S. Food and Drug Administration Investigational New Drug status, demonstrating the normal phenotype, intact functionality, and pro-growth secretome of interferon-γ (IFNγ)-stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation ± chemotherapy. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow–derived, IFNγ-activated BM-MSCs for the treatment of radiation-induced xerostomia.MethodsThis single-center phase 1 dose-escalation with expansion cohort, non–placebo-controlled study will assess the safety and tolerability of BM-MSCs for the treatment of radiation-induced xerostomia in patients who had head and neck cancer. The phase 1 dose-escalation study will be a 3 + 3 design with staggered enrollment. A total of 21 to 30 subjects (9 to 18 in phase 1 study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of IFNγ-stimulated BM-MSCs to enable further studies on the efficacy of BM-MSCs. Patients’ bone marrow will be aspirated, and BM-MSCs will be expanded, stimulated with IFNγ, and injected into the submandibular gland. The RP2D will be determined by dose-limiting toxicities occurring within 1 month of BM-MSC injection. Secondary outcomes of saliva amounts and composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3-, 6-, 12-, and 24-month visits.DiscussionAutotransplantation of IFNγ-stimulated BM-MSCs in salivary glands after radiation therapy or chemoradiation therapy may provide an innovative remedy to treat xerostomia and restore quality of life. This is the first therapy for radiation-induced xerostomia that may be curative.Trial registrationWorld Health Organization International Clinical Trials Registry Platform: NCT04489732     

Patients’ view of the differences in topical creams for radiation dermatitis prevention. A pilot study of cosmetic properties

AimTo investigate the feasibility of including patients’ reports on the cosmetic properties of topical formulations for acute radiation dermatitis (ARD).BackgroundNo topical agent tested for acute radiation dermatitis (ARD) has proven to be better than any other, all achieving similar objective outcomes. No clear guidelines have therefore been established in clinics. Because the vehicle for such creams has shown to be an important factor in patient adherence to treatments in other dermatological diseases, patients’ opinions are evaluated.Material and methodsSeventy breast cancer patients referred for postoperative radiotherapy after conservative surgery were enrolled. Patients were assigned to use one of the 7 topical agents that are most-commonly used in the prevention of ARD. Patients’ reports were assessed using continuous visual analogue scales (VAS), objective signs and symptoms produced by ARD, and were rated using the RTOG and RISRAS scales.ResultsThe creams tested differed in their cosmetic properties significantly (p = 0.044). The performance of the agent, their absorption and any residue left over were also significantly different (p = 0.022, 0.014 and 0.02, respectively).ConclusionsTopical agents for preventive ARD are reported by patients to show different cosmetic properties. Cosmetic properties are important when choosing topical agents for ARD prevention. Recommending those with better cosmetic profiles would improve patient adherence to treatments.     

Systematic review and meta-analysis of the association between bridging therapy and outcomes of chimeric antigen receptor T cell therapy in patients with large B cell lymphoma

BackgroundThe existing evidence about the impact of bridging therapy (BT) on chimeric antigen receptor (CAR)-T cell therapy in patients with large B cell lymphoma (LBCL) is conflicting. Therefore, we reviewed all available evidence to examine the association between BT and CAR-T therapy outcomes by systematic review and meta-analysis approach.MethodsTwo reviewers independently searched Embase, PubMed, Web of Science, and Cochrane library to identify all records that described BT for LBCL treated with CAR-T. We then applied a fixed- or random-effects meta-analysis to estimate the pooled hazard ratios (HRs) and rate ratio (RRs) for efficacy and safety endpoints and assessed differences across various BT modalities. The Newcastle-Ottawa Scale was used to evaluate study quality.ResultsTwenty-six reports from 24 studies involving 2014 patients were included in the analysis. Pooled results showed that patients requiring BT had significantly worse 1-year overall survival rate (RR = 0.76, 95% confidence interval [CI] 0.68–0.85, P < 0.001), 1-year progression-free survival rate (RR = 0.71, 95% CI 0.60–0.85, P < 0.001), progression-free survival (HR = 1.35, 95% CI 1.07–1.69, P = 0.01), overall response rate (RR = 0.88, 95% CI 0.81–0.95, P = 0.001), complete response rate (RR = 0.78, 95% CI 0.65–0.93, P = 0.005), and grade ≥3 immune effector cell-associated neurotoxicity syndrome (RR = 1.43, 95% CI 1.10–1.87, P = 0.007), and tended to have poorer overall survival (HR = 1.42, 95% CI 0.99–2.02, P = 0.056) and grade ≥3 cytokine release syndrome (RR = 1.59, 95% CI 0.92–2.75, P = 0.096). Prolonged cytopenias were the common toxicity event associated with BT. Radiotherapy may serve as a promising BT option that can provide safe and effective disease control for patients with LBCL before CAR-T infusion. The inconsistency of patient baselines in the current study hindered further comparisons between different BT modalities. Most of the available evidence was rated as low quality because of concerns over low comparability.ConclusionBT appears to be associated with comparatively poor efficacy and safety outcomes after CAR-T infusion. However, due to the considerable heterogeneity between the BT and non-BT cohorts at disease baseline, no definitive conclusions can be made for the true impact of BT on CAR-T until further randomized studies are conducted.     

Predictors of clinical outcomes in patients with neuropsychiatric systemic lupus erythematosus

IntroductionNeuropsychiatric systemic lupus erythematosus (NPSLE), a serious organ disorder with a variety of symptoms, has diverse therapeutic outcomes because of the variability of NPSLE manifestations. A comprehensive association study of NPSLE among clinical and immunopathogenic aspects and outcomes has not been conducted.MethodsWe analyzed the laboratory data, NPSLE symptoms, and clinical outcomes at 1 yr post-treatment and the profiles of 27 cytokines, chemokines and growth factors in cerebrospinal fluid (CSF) samples using the Bio-Plex Human 27-plex panel from 28 NPSLE patients. Univariate and multivariable competing risks regression analyses were used to determine the predictive factors of clinical response. We also tried to predict the outcome of NPSLE by the 27 cytokines/chemokines/growth factors using a weighted-voting (WV) algorithm.ResultsOf the two males and 26 females (92.9%), 16 were non-responders at 1 yr post-treatment; in the final model, the independent predictors of non-responders were longer disease durations of SLE (odds ratio [OR]: 1.490, 95% confidence interval [CI]: 1.143–2.461, p = 0.0003) and patients with more than one NPSLE symptom types (OR: 15.14, 95% CI: 1.227–452.1, p = 0.0334). The pretreatment CSF interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) levels were significantly higher in the non-responders (p = 0.0207, p = 0.0054, p = 0.0242 and p = 0.0077, respectively). We identified six “minimum predictive markers:” IL-10, TNF-α, IL-6, IFN-γ, IL-4 and IL-13 by a WV algorithm that showed the highest accuracy (70.83%) and highest Matthews correlation coefficient (54.23%).ConclusionsWe have devised a numerical prediction scoring system that was able to separate the non-responders from responders. The patients with longer disease durations of SLE and those with more than one NPSLE symptom types had poorer outcomes. Our findings may indicate both the importance of making a diagnosis at an earlier phase for better therapeutic response and the usefulness of measuring multiple cytokines to predict NPSLE therapeutic outcomes.     

Evaluation of rectal dose discrepancies between planned and in vivo dosimetry using MOSkin detector and PTW 9112 semiconductor probe during 60Co HDR CT-based intracavitary cervix brachytherapy

PurposeDose to the rectum during brachytherapy treatment may differ from an approved treatment plan which can be quantified with in vivo dosimetry (IVD). This study compares the planned with in vivo doses measured with MOSkin and PTW 9112 rectal probe in patients undergoing CT based HDR cervical brachytherapy with Co-60 source.MethodsDose measurement of a standard pear-shaped plan carried out in phantom to verify the MOSkin dose measurement accuracy. With MOSkin attached to the third diode, RP3 of the PTW 9112, both detectors were inserted into patients’ rectum. The RP3 and MOSkin measured doses in 18 sessions as well as the maximum measured doses from PTW 9112, RP_max in 48 sessions were compared to the planned doses.ResultsPercentage dose differences ΔD (%) in phantom study for two MOSkin found to be 2.22 ± 0.07% and 2.5 ± 0.07%. IVD of 18 sessions resulted in ΔD(%) of −16.3% to 14.9% with MOSkin and ΔD(%) of −35.7% to −2.1% with RP3. In 48 sessions, RP_max recorded ΔD(%) of −37.1% to 11.0%. MOSkin_measured doses were higher in 44.4% (8/18) sessions, while RP3_measured were lower than planned doses in all sessions. RP_max_measured were lower in 87.5% of applications (42/47).ConclusionsThe delivered doses proven to deviate from planned doses due to unavoidable shift between imaging and treatment as measured with MOSkin and PTW 9112 detectors. The integration of MOSkin on commercial PTW 9112 surface found to be feasible for rectal dose IVD during cervical HDR ICBT.     

Modulation of blood oxylipin levels by long-chain omega-3 fatty acid supplementation in hyper- and normolipidemic men

IntroductionLong chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) such as EPA and DHA have been shown to possess beneficial health effects, and it is believed that many of their effects are mediated by their oxygenated products (oxylipins). Recently, we have shown that serum levels of several hydroxy, epoxy, and dihydroxy FAs are dependent on the individual status of the parent FAs in a cohort of normo- and hyperlipidemic subjects. So far, the effect of an increased dietary LC n-3 PUFA intake on hydroxy, epoxy, and dihydroxy FA levels has not been investigated in subjects with mild combined hyperlipidemia.Subjects and methodsIn the present study, we compared oxylipin patterns of 10 hyperlipidemic (cholesterol >200 mg/dl; triglyceride >150 mg/ml) and 10 normolipidemic men in response to twelve weeks of LC n-3 PUFA intake (1.14 g DHA and 1.56 g EPA). Levels of 44 free hydroxy, epoxy and dihydroxy FAs were analyzed in serum by LC-MS. Additionally, oxylipin levels were compared with their parent PUFA levels in erythrocyte membranes; a biomarker for the individual PUFA status.ResultsDifferences in the oxylipin pattern between normo- and hyperlipidemic subjects were minor before and after treatment. In all subjects, levels of EPA-derived oxylipins (170–4800 pM) were considerably elevated after LC n-3 PUFA intake (150–1400%), the increase of DHA-derived oxylipins (360–3900 pM) was less pronounced (30–130%). The relative change of EPA in erythrocyte membranes is strongly correlated (r≥0.5; p<0.05) with the relative change of corresponding epoxy and dihydroxy FA serum levels. The effect on arachidonic acid (AA)-derived oxylipin levels (140–27,100 pM) was inconsistent.Discussion and conclusionsThe dietary LC PUFA composition has a direct influence on the endogenous oxylipin profile, including several highly biological active EPA- and DHA-derived lipid mediators. The shift in oxylipin pattern appears to be dependent on the initial LC PUFA status particularly for EPA. The finding that also levels of other oxylipins derived from ALA, LA or AA are modified by LC n-3 PUFA intake might suggest that at least some of the effects of EPA and DHA could be mediated by a shift in the entire oxylipin profile.     

Investigating micronucleus assay applicability for prediction of normal tissue intrinsic radiosensitivity in gynecological cancer patients

BackgroundPelvic organs morbidity after irradiation of cancer patients remains a major problem although new technologies have been developed and implemented. A relatively simple and suitable method for routine clinical practice is needed for preliminary assessment of normal tissue intrinsic radiosensitivity. The micronucleus test (MNT) determines the frequency of the radiation induced micronuclei (MN) in peripheral blood lymphocytes, which could serve as an indicator of intrinsic cell radiosensitivity.AimTo investigate a possible use of the micronucleus test (MNT) for acute radiation morbidity prediction in gynecological cancer patients.Materials and methodsForty gynecological cancer patients received 50 Gy conventional external pelvic irradiation after radical surgery. A four-field “box” technique was applied with 2D planning. The control group included 10 healthy females.Acute normal tissue reactions were graded according to NCI CTCAE v.3.0. From all reaction scores, the highest score named “summarized clinical radiosensitivity” was selected for a statistical analysis.MNT was performed before and after in vitro irradiation with 1.5 Gy. The mean radiation induced frequency of micronuclei per 1000 binucleated cells (MN/1000) and lymphocytes containing micronuclei per 1000 binucleated cells (cells with MN/1000) were evaluated for both patients and controls.An arbitrary cut off value was created to pick up a radiosensitive individual: the mean value of spontaneous frequency of cells with MN/1000 ± 2SD, found in the control group.ResultsBoth mean spontaneous frequency of cells with MN/1000 and MN/1000 were registered to be significantly higher in cancer patients compared to the control group (t = 2.46, p = 0.02 and t = 2.51, p = 0.02). No statistical difference was registered when comparing radiation induced MN frequencies between those groups.Eighty percent (32) of patients developed grade 2 summarized clinical radiosensitivity, with great variations in MNT parameters. Only three patients with grade 2 “summarized clinical radiosensitivity” had values of cells with MN/1000 above the chosen radiosensitivity threshold.ConclusionThe present study was not able to confirm in vitro MNT applicability for radiosensitivity prediction in pelvic irradiation.     

Survival after recurrence of stage I–III breast,colorectal, or lung cancer

BackgroundThe experiences of patients with recurrent cancer are assumed to reflect those of patients with de novo stage IV disease; yet, little is truly known because most registries lack recurrence status. Using two databases with excellent recurrence and death information, we examined determinants of survival duration after recurrence of breast (BC), colorectal (CRC), and lung cancers (LC).MethodsRecurrence status was abstracted from the medical records of patients who participated in the Cancer Care Outcomes Research and Surveillance study and who received care at two Cancer Research Network sites—the Colorado and Northwest regions of Kaiser Permanente. The analysis included 1653 patients who developed recurrence after completing definitive therapy for stages I–III cancer. Multivariable modeling identified independent determinants of survival duration after recurrence, controlling for other factors.ResultsThrough 60 months’ average follow-up, survival after recurrence for BC, CRC, and LC were 28.4, 23.1 and 16.1 months, respectively. Several factors were independently associated with shorter survival for all three cancers, including higher initial stage (III vs. I: BC −9.9 months; CRC −6.9 months; LC −7.4 months; P ≤ 0.01). Factors associated with shorter survival for selected cancers included: distant/regional recurrence for BC and CRC; current/former smoker for LC; high grade for CRC; and <4-year time-to-recurrence for BC.ConclusionsInitial stage predicts survival duration after recurrence, whereas time-to-recurrence usually does not. The impact of biologic characteristics (e.g., grade, hormone-receptor status) on survival duration after recurrence needs further study. Predictors of survival duration after recurrence may help facilitate patient decision-making.     

Spectral optimization of iodine-enhanced CT: Quantifying the effect of tube voltage on image quality and radiation exposure determined at an anthropomorphic phantom

PurposeTo provide an experimental basis for spectral optimization of iodine-enhanced CT by a quantitative analysis of image quality and radiation dose characteristics consistently measured for a large variety of scan settings at an anthropomorphic phantom.MethodsCT imaging and thermoluminescent dosimetry were performed at an anthropomorphic whole-body phantom with iodine inserts for different tube voltages (U, 70–140 kV) and current-time products (Q, 60–300 mAs). For all U-Q combinations, the iodine contrast (C), the noise level (N) and, from these, the contrast-to-noise ratio (CNR) of reconstructed CT images were determined and parameterized as a function of U, Q or the measured absorbed dose (D). Finally, two characteristic curves were derived that give the relative increase of CNR at constant D and the relative decrease of D at constant CNR when lowering U.ResultsLowering U affects the measured CNR only slightly but markedly reduces D. For example, reducing U from 120 kV to 70 kV increases the CNR at constant D by a factor of nearly 1.8 or, alternatively, reduces D at constant CNR by a factor of nearly 5.ConclusionSpectral optimization by lowering U is an effective approach to attain the necessary CNR for a specific diagnostic task at hand while at the same time reducing radiation exposure as far as practically achievable. The characteristic curves derived in this study from extensive measurements at a reference ‘person’ can support CT users in an easy-to-use manner to select an appropriate voltage for various clinical scenarios.     

Changes in prostate cancer incidence,mortality and survival in relation to prostate specific antigen testing in New South Wales,Australia

BackgroundTo examine changes in prostate cancer incidence and mortality rates, and 5-year relative survival, in relation to changes in the rate of prostate specific antigen (PSA) screening tests and the use of radical prostatectomy (RP) in the Australian population.MethodsProstate cancer stage-specific incidence rates, 5-year relative survival and mortality rates were estimated using New South Wales Cancer Registry data. PSA screening test rates and RP/Incidence ratios were estimated from Medicare Benefits Schedule claims data. We used multiple imputation to impute stage for cases with “unknown” stage at diagnosis. Annual percentage changes (APC) in rates were estimated using Joinpoint regression.ResultsTrends in the age-standardized incidence rates for localized disease largely mirrored the trends in PSA screening test rates, with a substantial ‘spike’ in the rates occurring in 1994, followed by a second ‘spike’ in 2008, and then a significant decrease from 2008 to 2015 (APC −6.7, 95% CI −8.2, −5.1). Increasing trends in incidence rates were observed for regional stage from the early 2000s, while decreasing or stable trends were observed for distant stage since 1993. The overall RP/Incidence ratio increased from 1998 to 2003 (APC 9.6, 95% CI 3.8, 15.6), then remained relatively stable to 2015. The overall 5-year relative survival for prostate cancer increased from 58.4% (95% CI: 55.0–61.7%) in 1981–1985 to 91.3% (95% CI: 90.5–92.1%) in 2011–2015. Prostate cancer mortality rates decreased from 1990 onwards (1990–2006: APC −1.7, 95% CI −2.1, −1.2; 2006–2017: APC −3.8, 95% CI −4.4, −3.1).ConclusionsOverall, there was a decrease in the incidence rate of localized prostate cancer after 2008, an increase in survival over time and a decrease in the mortality rate since the 1990s. This seems to indicate that the more conservative use of PSA screening tests in clinical practice since 2008 has not had a negative impact on population-wide prostate cancer outcomes.     

A critical evaluation of salivary testosterone as a method for the assessment of serum testosterone

Although salivary testosterone (T) is often used in clinical studies accuracy is mostly questionable. State of the art data for men is sparse and for women absent. Our objective was to perform a critical evaluation of salivary T (Sal-T) as a method for indirect assessment of serum T using state of the art methods. Saliva was collected via ‘Salivette’ and ‘passive drooling’ methods. Sal-T and free T in serum after equilibrium dialysis were measured by LC-MS/MSResultsEvaluation of Sal-T results versus free T by equilibrium dialysis (ED-T) for men gave: ‘Salivette’ Sal-T = 0.05 + 0.88x ED-T, r = 0.43; ‘passive drooling’ Sal-T = 0.17 + 0.91x ED-T r = 0.71. In women, correlation was comparable but values are higher than free T: ‘passive drooling’ Sal-T = 0.12 + 2.32x ED-T, r = 0.70. The higher than expected T values in saliva, appear to be explained by T binding to salivary proteins. Iso-electric focusing of saliva proteins, followed by fractionation and LC–MS/MS assay of T showed marked testosterone peaks at pH 5.3 and 8.4, providing evidence for T binding in saliva to proteins such as albumin and proline rich protein (PRP).ConclusionsPassive drooling is the collection method of choice for testosterone in saliva. Sal-T is not directly comparable to serum free T due to T binding to saliva proteins, which substantially affects the low Sal-T in women but not the higher Sal-T in healthy adult men.     

Ablation index-guided 50W radiofrequency ablation for left atrial posterior wall isolation in atrial fibrillation

BackgroundAblation index (AI)-guided ablation for posterior wall isolation (PWI) using high-power, short-duration remains untested. We sought to evaluate the acute outcomes of AI-guided 50 W ablation vs. conventional ablation, and investigate the differences in relationship between contact force (CF), time and AI in both groups.MethodsConsecutive patients undergoing first-time AI-guided ablation with PWI using either 50 W or 35–40 W ablation were enrolled. Acute procedural metrics and individual lesion level ablation data were compared between groups.Results40 patients (50 W: n = 20, 35–40 W: n = 20) with atrial fibrillation were included. Total procedure time was significantly reduced with 50 W (120 vs. 143 mins, p = 0.004) and there was a trend toward decreased ablation time (22 vs. 28 mins, p = 0.052). First pass and acute success of PWI were comparable between the 50 W and 35–40 W groups (10 vs. 8 patients, p = 0.525 and 20 vs. 19 patients, p = 1.000, respectively). Individual lesion analysis of all 959 RF applications (50 W: n = 458, 35–40 W: n = 501) demonstrated that 50 W ablation led to lower ablation time per lesion (10.4 vs. 13.0s, p < 0.001), and increased AI (471 vs. 461, p < 0.001) and impedance drop (7.4 vs. 6.9ohms, p = 0.007). Excessive ablations (AI>600 for roof line; AI>500 elsewhere) were more frequently observed in the 50 W group (9.0% vs. 4.6%, p = 0.007). CF had very good discriminative capability for excessive ablation in both groups. At 50 W, limiting the CF to <10 g reduced the number of excessive ablations on the floor line and within the posterior box to 12% and 4%,respectively. Recurrence of atrial arrhythmias at 12 months were comparable between the groups.ConclusionAI-guided 50 W RF ablation reduces the ablation time of individual lesions and total procedure time without compromising first pass and acute success rates of PWI or 12-month outcomes compared to conventional powers.     

Prediction of all-cause mortality with copeptin in cardio-cerebrovascular patients: A meta-analysis of prospective studies

BackgroundMeasurement of the biomarker copeptin may help identify disease severity and risk of mortality for a various diseases. This study sought to determine the relationship between copeptin and all-cause mortality of patients with cardio-cerebrovascular disease.MethodsDatabase of Medline and Web of Science were searched for studies with data involving the baseline copeptin levels and subsequent all-cause mortality outcomes. The pooled HRs of all-cause mortality were calculated and presented with 95%CIs. Subgroup analysis and sensitivity analysis were conducted to explore the possible sources of heterogeneity.ResultsData from 14,395 participants were derived from 28 prospective studies. Higher copeptin significantly increased the risk of all-cause mortality (per unit copeptin: HR = 1.020, 95%CI = 1.004–1.036; log unit copeptin: HR = 2.884, 95%CI = 1.844–4.512; categorical copeptin: HR = 3.371, 95%CI = 2.077–5.472). Subgroup analysis indicated that the risk of all-cause death was higher in cerebrovascular patients (per unit copeptin: HR = 2.537, 95%CI = 0.956–6.731; log unit copeptin: HR = 3.419, 95%CI = 2.391–4.888) than cardiovascular patients (per unit copeptin: HR = 1.011, 95%CI = 1.002–1.020; log unit copeptin: HR = 2.009, 95%CI = 1.119–3.608).ConclusionCopeptin is associated with all-cause mortality of patients with cardiovascular and cerebrovascular disease. Our study suggests that copeptin seems to be a promising novel biomarker for prediction of mortality in cardio-cerebrovascular patients, especially for cerebrovascular patients.     

Dosimetric comparison of RapidPlan and manually optimized plans in volumetric modulated arc therapy for prostate cancer

PurposeThis study evaluated whether RapidPlan based plans (RP plans) created by a single optimization, are usable in volumetric modulated arc therapy (VMAT) for patients with prostate cancer.MethodsWe used 51 previously administered VMAT plans to train a RP model. Thirty RP plans were created by a single optimization without planner intervention during optimization. Differences between RP plans and clinical manual optimization (CMO) plans created by an experienced planner for the same patients were analyzed (Wilcoxon tests) in terms of homogeneity index (HI), conformation number (CN), D_95%, and D_2% to planning target volume (PTV), mean dose, V_50Gy, V_70Gy, V_75Gy, and V_78Gy to rectum and bladder, monitor unit (MU), and multi-leaf collimator (MLC) sequence complexity.ResultsRP and CMO values for PTV D_95%, PTV D_2%, HI, and CN were significantly similar (p < 0.05 for all). RP mean dose, V_50Gy, and V_70Gy to rectum were superior or comparable to CMO values; RP V_75Gy and V_78Gy were higher than in CMO plans (p < 0.05). RP bladder dose-volume parameter values (except V_78Gy) were lower than in CMO plans (p < 0.05). MU values were RP: 730 ± 55 MU and CMO: 580 ± 37 MU (p < 0.05); and MLC sequence complexity scores were RP: 0.25 ± 0.02 and CMO: 0.35 ± 0.03 (p < 0.05).ConclusionsRP plans created by a single optimization were clinically acceptable in VMAT for patient with prostate cancer. Our simple model could reduce optimization time, independently of planner’s skill and knowledge.     

A new quantitative LC tandem mass spectrometry assay for serum 25-hydroxy vitamin D

BackgroundThe accurate measurement of 25-hydoxy vitamin D (25OH-D) in serum has been a challenge for many years. We developed a liquid chromatography tandem mass spectrometry (LC Tandem MS) assay for the quantitative determination of 25OH-D₂ and 25OH-D₃ in serum. The new method was compared with two widely used commercially available immunoassays.MethodsSample preparation involved protein precipitation with acetonitrile containing deuterated forms of the target species as internal standards. An API 5000 mass spectrometer coupled with a photoionization source was used for quantitation. The performance of the new LC Tandem MS assay was compared with a radioimmunoassay (RIA, Diasorin) and a chemiluminescence immunoassay (ECLIA, Roche Diagnostics), analysing serum obtained from 152 individuals.ResultsUsing 100 μl of serum, the LC Tandem MS assay had a limit of quantitation of 1.3 nmol/L for both 25OH-D₂ and 25OH-D₃ with a linear response between 1.3 and 625 nmol/L and accuracy of between 95 and 124%. Intra- and inter-assay precision were ≤7% and ≤4%, respectively. Measurement of 25OH-D levels in 152 serum samples gave run averages of 71, 56 and 62 nmol/L for LC Tandem MS, ECLIA and RIA, respectively. Correlations between the various methods were: LC Tandem MS vs. RIA: r = 0.931; LC Tandem MS vs. ECLIA: r = 0.784; RIA vs. ECLIA: r = 0.787. The LC Tandem MS method had a positive proportional bias of 26% over the RIA, whereas the ECLIA showed variable differences.ConclusionThe new LC Tandem MS assay is accurate and precise at physiologically relevant 25OH-D concentrations, and compares favourably with the RIA. In contrast, the ECLIA shows variable bias with the other assays tested.     

Molecular Characteristics and Efficacy of 16D10 siRNAs in Inhibiting Root-Knot Nematode Infection in Transgenic Grape Hairy Roots

Root-knot nematodes (RKNs) infect many annual and perennial crops and are the most devastating soil-born pests in vineyards. To develop a biotech-based solution for controlling RKNs in grapes, we evaluated the efficacy of plant-derived RNA interference (RNAi) silencing of a conserved RKN effector gene, 16D10, for nematode resistance in transgenic grape hairy roots. Two hairpin-based silencing constructs, containing a stem sequence of 42 bp (pART27-42) or 271 bp (pART27-271) of the 16D10 gene, were transformed into grape hairy roots and compared for their small interfering RNA (siRNA) production and efficacy on suppression of nematode infection. Transgenic hairy root lines carrying either of the two RNAi constructs showed less susceptibility to nematode infection compared with control. Small RNA libraries from four pART27-42 and two pART27-271 hairy root lines were sequenced using an Illumina sequencing technology. The pART27-42 lines produced hundred times more 16D10-specific siRNAs than the pART27-271 lines. On average the 16D10 siRNA population had higher GC content than the 16D10 stem sequences in the RNAi constructs, supporting previous observation that plant dicer-like enzymes prefer GC-rich sequences as substrates for siRNA production. The stems of the 16D10 RNAi constructs were not equally processed into siRNAs. Several hot spots for siRNA production were found in similar positions of the hairpin stems in pART27-42 and pART27-271. Interestingly, stem sequences at the loop terminus produced more siRNAs than those at the stem base. Furthermore, the relative abundance of guide and passenger single-stranded RNAs from putative siRNA duplexes was largely correlated with their 5′ end thermodynamic strength. This study demonstrated the feasibility of using a plant-derived RNAi approach for generation of novel nematode resistance in grapes and revealed several interesting molecular characteristics of transgene siRNAs important for optimizing plant RNAi constructs.     

Photon-beam radiotherapy in pregnant patients: Can the fetal dose be limited to 10 cGy or less?

PurposeTo estimate fetal dose and its components from three-dimensional conformal radiotherapy for several malignancies presented during pregnancy.Materials and methodsFetal dose was measured from radiotherapy for Hodgkin's lymphoma and for tumors in the region of nasopharynx, breast and lung. Anthropomorphic phantoms were used to simulate an average pregnant patient at the first, second and third trimesters of gestation. Thermoluminescent dosemeters (TLD) were employed for fetal dose measurements. Phantom exposures were also performed to estimate fetal dose due to head leakage, scatter from collimators and beam modifiers and scatter generated inside the phantom (D_in). All treatments were delivered for 6 MV photon beams.ResultsRadiotherapy of Hodgkin's lymphoma resulted in a fetal dose of 5.6–57.9 cGy depending upon the gestational age and the distance between the fetal level and the field edge. The corresponding dose ranges for treatment of nasopharyngeal, breast and lung cancer was 4.0–17.1 cGy, 3.9–24.8 cGy and 5.7–74.3 cGy, respectively. The D_in at the first trimester of gestation was always smaller than 10 cGy for all examined malignancies. Pregnancy progression resulted in D_in values above or below 10 cGy depending upon the treatment site and gestational age.ConclusionThis study provides data about the fetal exposure and the contribution of D_in to the total fetal dose from conformal radiation therapy. The D_in knowledge prior to patient's irradiation enables radiation oncologists and medical physicists to decide whether fetal dose may be limited to 10 cGy or less with or without the introduction of special shielding materials.     

Low baseline vitamin D levels increase the risk of bone metastases among females with breast cancer − Hospital based cohort study

BackgroundSerum vitamin D (Vit-D) has been linked to the development of breast cancer (BC); however, their effect on pathological features and outcomes is undetermined. The purpose of this study was to examine the prognostic significance of baseline Vit-D levels and their effect on clinical outcomes.MethodsWe evaluated baseline serum Vit-D levels and baseline clinic-pathological features of female patients with non-metastatic BC between October 2018 and December 2019. A low Vit-D level was described as less than 30 nanogram per liter (ng/l). Patients were observed for a median of 24 months. To evaluate relationships between qualitative variables, the chi-square test was used. The Kaplan-Meier technique was used for survival analysis, and the log-rank test was used to compare the two survival curves. Correlation analysis was also used to examine the link between Vit-D levels and clinical outcomes.ResultsThe eligibility criteria were fulfilled by 221 patients. The median age of onset was (50.7). The median Vit-D level was (23.1 ng/l) with a range of (4–46 ng/l). Approximately half of the patients (56.5%) had Vit-D levels < 30 ng/l, with HER2 positive and triple negative (TNBC) patients having a greater proportion of low Vit-D levels (p = <0.001). Patients with low baseline Vit-D levels had a larger tumor size, more positive lymph nodes, and were diagnosed at a later stage. Following follow-up, Vit-D deficiency was associated with a significantly increased risk of bone metastases (HR 3.37, 95% CI 1.32–8.59, p = 0.006), and Vit-D levels were significantly correlated with disease-free survival (DFS) and overall survival (OS) (r = 0.850, r = 0.573, p < 0.00, p < 0.001, respectively).ConclusionsLow serum Vit-D is associated with advanced stage and adverse characteristics. It is more prevalent in HER-2 positive and TNBC patients; it increases the chance of bone metastases, and has a significant correlation with DFS and OS.     

Accounting for spatial variation of trabecular anisotropy with subject-specific finite element modeling moderately improves predictions of local subchondral bone stiffness at the proximal tibia

IntroductionPreviously, a finite element (FE) model of the proximal tibia was developed and validated against experimentally measured local subchondral stiffness. This model indicated modest predictions of stiffness (R² = 0.77, normalized root mean squared error (RMSE%) = 16.6%). Trabecular bone though was modeled with isotropic material properties despite its orthotropic anisotropy. The objective of this study was to identify the anisotropic FE modeling approach which best predicted (with largest explained variance and least amount of error) local subchondral bone stiffness at the proximal tibia.MethodsLocal stiffness was measured at the subchondral surface of 13 medial/lateral tibial compartments using in situ macro indentation testing. An FE model of each specimen was generated assuming uniform anisotropy with 14 different combinations of cortical- and tibial-specific density-modulus relationships taken from the literature. Two FE models of each specimen were also generated which accounted for the spatial variation of trabecular bone anisotropy directly from clinical CT images using grey-level structure tensor and Cowin’s fabric-elasticity equations. Stiffness was calculated using FE and compared to measured stiffness in terms of R² and RMSE%.ResultsThe uniform anisotropic FE model explained 53–74% of the measured stiffness variance, with RMSE% ranging from 12.4 to 245.3%. The models which accounted for spatial variation of trabecular bone anisotropy predicted 76–79% of the variance in stiffness with RMSE% being 11.2–11.5%.ConclusionsOf the 16 evaluated finite element models in this study, the combination of Synder and Schneider (for cortical bone) and Cowin’s fabric-elasticity equations (for trabecular bone) best predicted local subchondral bone stiffness.