Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload.

PURPOSE: To explore the use and reproducibility of magnetic resonance-derived myocardial T1 mapping in patients with iron overload. MATERIALS AND METHODS: The research received ethics committee approval and all patients provided written informed consent. This was a prospective study of 88 patients and 67 healthy volunteers. Thirty-five patients underwent repeat scanning for reproducibility. T1 mapping used the shortened modified Look-Locker inversion recovery sequence (ShMOLLI) with a second, confirmatory MOLLI sequence in the reproducibility group. T2 * was performed using a commercially available sequence. The analysis of the T2 * interstudy reproducibility data was performed by two different research groups using two different methods. RESULTS: Myocardial T1 was lower in patients than healthy volunteers (836 ± 138 msec vs. 968 ± 32 msec, P < 0.0001). Myocardial T1 correlated with T2 * (R = 0.79, P < 0.0001). No patient with low T2 * had normal T1 , but 32% (n = 28) of cases characterized by a normal T2 * had low myocardial T1 . Interstudy reproducibility of either T1 sequence was significantly better than T2 *, with the results suggesting that the use of T1 in clinical trials could decrease potential sample sizes by 7-fold. CONCLUSION: Myocardial T1 mapping is an alternative method for cardiac iron quantification. T1 mapping shows the potential for improved detection of mild iron loading. The superior reproducibility of T1 has potential implications for clinical trial design and therapeutic monitoring.

History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with ß thalassemia major.

Endocrinopathies are common complications of transfusional hemosiderosis among patients with ß thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI-R2 since 2008 and average 10-yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20 ms (P < 0.001 and P = 0.008, respectively) and increased age (P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 µg/L (P = 0.003) and >2000 µg/L (P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM.

Nurse practitioner model of care for the initiation of pre-exposure prophylaxis: A case series study.

AIM: The purpose of this study was to create and implement a nurse practitioner model of care in the initiation of a pre-exposure prophylaxis (PrEP) protocol with African American men who have sex with men (MSM). DESIGN: A case series design was used to implement the protocol for a nurse practitioner PrEP-based model of care. METHODS: The participatory, evidence-based, patient-focus process (PEPPA) framework and the American Association of Colleges of Nursing (AACN) Doctoral Essentials for Advanced Practice were aligned to guide the development, implementation, and evaluation of this advanced practice role in an urban medical clinic. RESULTS: Seven African American HIV-negative MSM who received treatment under the nurse practitioner PrEP-based model of care had increased PrEP knowledge and medication adherence and did not contract a sexually transmitted infection. CONCLUSIONS: New models of care can be created to meet the Getting to Zero HIV initiative of reducing rates of HIV infections with MSM.

Prospective study of histomorphometry, biochemical bone markers and bone densitometric response to pamidronate in ß-thalassaemia presenting with osteopenia-osteoporosis syndrome.

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic-therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1-collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre-therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre-therapy with high turnover bone disease (HTO) in TM and low-turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low-turnover disease.

A Brief Educational Pre-exposure Prophylaxis Intervention in an Infectious Disease Clinic: Protocol for a Case Series Study.

BACKGROUND: Black men who have sex with men (BMSM) remain the highest group infected with HIV despite treatment with medications known as pre-exposure prophylaxis (PrEP). PrEP in combination with safer sex practices has shown efficacy in preventing HIV infection. Despite awareness campaigns, PrEP uptake remains low among BMSM. While brief educational interventions have value in fast-paced clinical settings with limited appointment times, a brief PrEP educational intervention has not been initiated with BMSM in a fast-paced outpatient infectious disease clinic in North Carolina. OBJECTIVE: The purpose of this study was to examine the effect of initiating a brief PrEP educational intervention to reduce HIV infection rates in BMSM in a fast-paced infectious disease clinic delivered by a doctoral-prepared nurse practitioner. METHODS: This case-series study uses a brief educational intervention to develop and pilot-test a brief PrEP educational uptake intervention with BMSM. The participants met with the nurse practitioner at 3 different time points: baseline, 4 weeks later (first visit), and at the 3-month follow-up (second visit). We used a pretest-posttest design to examine the primary outcomes of PrEP knowledge, medication adherence, and sexually transmitted infection outcomes. RESULTS: Due to the COVID-19 pandemic, the recruitment process was delayed. From November 1, 2019, to August 30, 2021, a total of 7 participants consented to participate in the study. Data analysis will be completed by the end of September 2022. We will submit a manuscript for publication consideration by December 2022. CONCLUSIONS: Brief educational interventions delivered in a fast-paced infectious disease clinic have the potential to increase PrEP awareness and knowledge, medication adherence, and decreased rates of sexually transmitted diseases in BMSM. This protocol will contribute to the literature on the development of brief PrEP educational interventions and has the potential to be generalized to other populations (eg, women and adolescents). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/33093.

Profile of European radiotherapy departments contributing to the EORTC Radiation Oncology Group (ROG) in the 21st century.

PURPOSE: Since 1982, the Radiation Oncology Group of the EORTC (EORTC ROG) has pursued an extensive Quality Assurance (QA) program involving all centres actively participating in its clinical research. The first step is the evaluation of the structure and of the human, technical and organisational resources of the centres, to assess their ability to comply with the current requirements for high-tech radiotherapy (RT). MATERIALS AND METHODS: A facility questionnaire (FQ) was developed in 1989 and adapted over the years to match the evolution of RT techniques. We report on the contents of the current FQ that was completed online by 98 active EORTC ROG member institutions from 19 countries, between December 2005 and October 2007. RESULTS: Similar to the data collected previously, large variations in equipment, staffing and workload between centres remain. Currently only 15 centres still use a Cobalt unit. All centres perform 3D Conformal RT, 79% of them can perform IMRT and 54% are able to deliver stereotactic RT. An external reference dosimetry audit (ERDA) was performed in 88% of the centres for photons and in 73% for electrons, but it was recent (<2 years) in only 74% and 60%, respectively. CONCLUSION: The use of the FQ helps maintain the minimum quality requirements within the EORTC ROG network: recommendations are made on the basis of the analysis of its results. The present analysis shows that modern RT techniques are widely implemented in the clinic but also that ERDA should be performed more frequently. Repeated assessment using the FQ is warranted to document the future evolution of the EORTC ROG institutions.

Quality assurance in the EORTC 22921 trial on preoperative radiotherapy with or without chemotherapy for resectable rectal cancer: evaluation of the individual case review procedure.

The aim of this study was to assess any inconsistency with the protocol guidelines for preoperative radiotherapy for rectal cancer among radiotherapy institutions participating in the framework of a multicentre phase-III European Organization for Research and Treatment of Cancer (EORTC) clinical trial. Twelve radiotherapy departments with more than 10% of the evaluable patients recruited in the trial, were invited to participate in this individual case review. Participating institutions were asked to send five full patient records with the chemotherapy charts, surgical and pathology reports, radiation treatment charts, treatment planning calculations, computed tomography (CT) scans, portal images and follow-up charts. The sample of the 5 patients per institution was randomly selected at the EORTC Data Center. All 12 departments participated. In 21 (35%) of the cases, a three-field technique with two lateral opposed wedge fields and a posterior field was used, while in 39 (65%) of the cases a four-field pelvic box technique was used. All participants used linear accelerators with a minimum of 6 MeV photon-beam energy. In general, the patients were eligible, documentation of clinical data was fair to good and there were no systematic major protocol deviations. The actual total dose was 44.7+/-a standard deviation (S.D.) of 4.6 Gy. Some variation was found in the fraction size. All institutions complied with the protocol in specifying the reference dose at the ICRU point. The clinical target volume (CTV) drawn on the CT scan was narrow in 7 (12%) cases, but eventually the actually treated volumes in terms of planned treatment volume (PTV) were correct. In two institutions, although the CTV was drawn correctly, the fields appeared to be narrow especially in cranio-caudal direction. Variations in treated volumes and total radiation dose were encountered in the individual case review. By providing recommendations early during the course of the trial, we expect to improve the inter-institutional consistency and to promote a high quality treatment in all of the participating institutions.

Monitoring chelation therapy to achieve optimal outcome in the treatment of thalassaemia.

Effective management of iron overload in thalassaemia requires monitoring both for iron toxicity and the effects of excessive chelation. Careful monitoring together with adherence to established regimens using desferrioxamine (DFO) results in a 78% survival rate at 40 years of age at UCLH, with steadily improving survival as progressive cohorts receive chelation earlier in life. By contrast, survival is considerably below this in non-specialist centres. The prognostic significance of the measures being used in monitoring should be known so that decisions about chelation management are evidence-based. Serum ferritin measurement, although easy to perform frequently, is subject to variability and falsely high or falsely low values in relation to body iron are frequently obtained. However, there is evidence that persistently high ferritin values above 2500 microg/l have poor prognostic significance in patients treated with DFO. Liver iron predicts total body iron in a more predictable way than serum ferritin in thalassaemia. Liver iron concentrations of 15 mg/g dry weight appear to predict those patients who develop heart failure in subjects treated with DFO. The prognostic significance of this measurement or indeed other measurements of iron overload in patients treated with other chelation regimens is not known. Recent advances with MRI imaging have aroused interest in its use for monitoring patients with thalassaemia. A recent publication suggests a relationship between left ventricular ejection fraction and cardiac T2*, the value of which shortens with increasing iron concentrations in the liver and hence by inference in the heart. The prognostic value of this technique has not yet been demonstrated in prospective studies and hence changes in therapy based on this measurement alone should be considered with caution at this time. The value of monitoring to decrease morbidity from iron overload is also discussed, particularly with reference to the estimation of iron deposition in the pituitary.

Quality assurance of the 22961 EORTC trial. A phase III study of the optimal combination of hormonal adjuvant treatment by LHRH analogue and radiation therapy for the management of locally advanced prostate cancer: the dummy run.

PURPOSE: The EORTC trial 22961, opened in 1997, was designed to investigate the optimal combination of hormonal adjuvant treatment by LHRH analogue and radiation therapy for the management of locally advanced prostate cancer. A dummy run was established to assess centre compliance to the radiotherapy protocol. MATERIALS AND METHODS: Medical and anatomical data obtained from 37 CT slices (5mm thickness) of an eligible patient were sent to 19 participating centres, which were asked to complete a questionnaire according to their practice and plan a theoretical radiotherapy treatment. The Planning Target Volume 1 (PTV1) should include prostate, seminal vesicles, internal iliac lymph nodes and inferior part of common iliac lymph nodes (extended pelvic fields). Centres which usually irradiate with small pelvic fields (N0 patients), were allowed to include the prostate, seminal vesicles and internal iliac lymph nodes plus a safety margin of 2 cm. For the Planning Target Volume 2 (PTV2), a safety margin of 1.5 to 2 cm should be around the prostate and seminal vesicles. Checks included patient positioning, treatment simulation, target volume definition, treatment set-up and clinical controls during treatment. RESULTS: Eleven institutions with actual 81% of patients' accrual in the protocol have responded. All centres used a supine treatment position and positioning lasers for the set-up, while 73 and 45% of the centres performed cystograms and used rectal contrast, respectively. Among the participating centres, 45% and 55% used blocks and MLC, respectively, to treat patients. Extended pelvic fields in terms of PTV1 were used by 63% of the centres. The remaining centres treated a small PTV1 with a 10-20 mm margin around to CTV1. All centres defined PTV2 according to protocol guidelines. Doses to PTV1 and PTV2 were correctly prescribed. It was difficult to assess the treated volumes due to a lack of standardisation in DVH calculations. CONCLUSION: In general, centres participating in the dummy run adhered to the guidelines. The dummy run enhances the reliability of the conclusions of the trial.

Prostaglandin E Suppresses Hepatic Fibrosis: Section I. The In Vivo Approach; Section II. The In Vitro Approach.

Recent studies suggest that prostaglandin E may have the ability to suppress cytokine responsiveness. We examined the effects of prostaglandin E administration on several parameters of the acute and chronic hepatic injury induced by bile duct ligation. Enisoprost, a prostaglandin E(1) analog was found to suppress early hepatic and Ito cell type I collagen gene expression without diminishing the induction of the fibrogenic cytokine, transforming growth factor beta. Overall hepatic inflammation and cell proliferation were not altered, suggesting that prostaglandin E acts distal to the initial injurious event(s). During the later phases, drug administration reduced total collagen accumulation as well as type I collagen periductular infiltration associated with early nodule formation. Ito cell mitogenesis occurs during liver injury and fibrogenesis in vivo coincident with the de novo expression of Ito cell platelet-derived growth factor beta (PDGFbeta) receptor messenger RNA. PDGF-induced mitogenesis was studied in cultured rat hepatic Ito cells which resemble the myofibroblast associated with liver injury. Pretreatment with prostaglandin E markedly suppressed the PDGF response in a dose-dependent fashion. The PDGF-induced cascade was studied plus minus PGE to determine the level of regulation which induced the observed suppression. PGE caused no apparent diminution in the abundance of the surface PDGFbeta receptor nor its subsequent activation and tyrosine phosphorylation following PDGF stimulation. The cytoplasmic "secondary messengers" mitogen-activated protein kinase pp42--44 and raf kinase appeared to be comparably induced and therefore unaffected by PGE. Raf perinuclear translocation was also intact, and comparable degrees of nuclear egr, fos, and jun expression occurred. Because other studies have suggested that many of these features of the PDGF cascade may be causally and sequentially linked, the data collectively suggest that the dominant PGE mitogenic suppressive effect resides at a Raf-MAP parallel pathway or at a nuclear level distal to the induction of these early growth response genes.

Metabolism of N-acetylbenzidine and initiation of bladder cancer.

A 100-fold increased incidence of bladder cancer is observed with workers exposed to high levels of benzidine (BZ). This review evaluates the overall metabolism of BZ to determine pathways involved in initiation of carcinogenesis. Enzymatic and liver slice incubations demonstrated N-acetylation and N-glucuronidation of BZ and N-acetylbenzidine (ABZ). With rat, N,N'-diacetylbenzidine (DABZ) is the major slice metabolite. With human, ABZ is the major metabolite along with N-glucuronides. Differences between rat and human are attributed to preferential acetylation of BZ and deacetylation of DABZ, resulting in N-glucuronide formation by human liver. Glucuronidation of BZ and its analogues exhibited the following relative ranking of UDP-glucuronosyltransferase (UGT) metabolism: UGT1A9>UGT1A4>>UGT2B7>UGT1A6 approximately UGT1A1. N-Glucuronides of BZ, ABZ, and N'-hydroxy-N-acetylbenzidine (N'HA) are acid labile with the latter having a much longer t(1/2) than the former two glucuronides. O-Glucuronides are not acid labile. In urine from BZ-exposed workers, an inverse relationship between urine pH and levels of free (unconjugated) BZ and ABZ is observed. This is consistent with the presence of labile urinary N-glucuronides. Cytochrome P-450 oxidizes BZ to an inactive product (3-OHz.sbnd;BZ) and ABZ to N'HA and N-hydroxy-N-acetylbenzidine (NHA). Cytochrome P-450, PHS, and horseradish peroxidase activate ABZ to bind DNA forming N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine (dGp-ABZ). This is the major adduct detected in bladder cells from workers exposed to BZ. An inverse relationship exists between urine pH and levels of bladder cell dGp-ABZ. Bladder epithelium contains relatively high levels of prostaglandin H synthase (PHS) and low levels of cytochrome p-450, suggesting activation by PHS. Activation by PHS involves a peroxygenase oxidation of ABZ to N'HA, while horseradish peroxidase activates ABZ to a diimine monocation. Reactive nitrogen oxygen species (RNOS) offer a new pathway for metabolism and potential activation. Results suggest BZ initiation of bladder cancer is complex, involving multiple organs (i.e. liver, kidney, and bladder) and metabolic pathways (i.e. N-acetylation, N-glucuronidation, peroxidation, and RNOS).

IMRT in oral cavity cancer.

BACKGROUND: Except for early T1,2 N0 stages, the prognosis for patients with oral cavity cancer (OCC) is reported to be worse than for carcinoma in other sites of the head and neck (HNC). The aim of this work was to assess disease outcome in OCC following IMRT.Between January 2002 and January 2007, 346 HNC patients have been treated with curative intensity modulated radiation therapy (IMRT) at the Department of Radiation Oncology, University Hospital Zurich. Fifty eight of these (16%) were referred for postoperative (28) or definitive (30) radiation therapy of OCC.40 of the 58 OCC patients (69%) presented with locally advanced T3/4 or recurred lesions. Doses between 60 and 70 Gy were applied, combined with simultaneous cisplatin based chemotherapy in 78%. Outcome analyses were performed using Kaplan Meier curves.In addition, comparisons were performed between this IMRT OCC cohort and historic in-house cohorts of 33 conventionally irradiated (3DCRT) and 30 surgery only patients treated over the last 10 years. RESULTS: OCC patients treated with postoperative IMRT showed the highest local control (LC) rate of all assessed treatment sequence subgroups (92% LC at 2 years). Historic postoperative 3DCRT patients and patients treated with surgery alone reached LC rates of approximately 70-80%. Definitively irradiated patients revealed poorest LC rates with approximately 30 and 40% following 3DCRT and IMRT, respectively.T1 stage resulted in an expectedly significantly higher LC rate (95%, n = 19, p < 0.05) than T2-4 and recurred stages (LC approximately 50-60%, n = 102).Analyses according to the diagnosis revealed significantly lower LC in OCC following definitive IMRT than that in pharyngeal tumors treated with definitive IMRT in the same time period (43% vs 82% at 2 years, p < 0.0001), while the LC rate of OCC following postoperative IMRT was as high as in pharyngeal tumors treated with postoperative IMRT (>90% at 2 years). CONCLUSION: Postoperative IMRT of OCC resulted in the highest local control rate of the assessed treatment subgroups. In conclusion, generous indication for IMRT following surgical treatment is recommended in OCC cases with unfavourable features like tight surgical margin, nodal involvement, primary tumor stage >T1N0, or already recurred disease, respectively.Loco-regional outcome of OCC following definitive IMRT remained unsatisfactory, comparable to that following definitive 3DCRT.

Postoperative IMRT in head and neck cancer.

BACKGROUND: Aim of this work was to assess loco-regional disease control in head and neck cancer (HNC) patients treated with postoperative intensity modulated radiation therapy (pIMRT). For comparative purposes, risk features of our series have been analysed with respect to histopathologic adverse factors. Results were compared with an own historic conventional radiation (3DCRT) series, and with 3DCRT and pIMRT data from other centres.Between January 2002 and August 2006, 71 patients were consecutively treated with pIMRT for a squamous cell carcinoma (SCC) of the oropharynx (32), oral cavity (22), hypopharynx (7), larynx (6), paranasal sinus (3), and an unknown primary, respectively. Mean and median follow up was 19 months (2-48), and 17.6 months. 83% were treated with IMRT-chemotherapy. Mean prescribed dose was 66.3 Gy (60-70), delivered with doses per fraction of 2-2.3 Gy, respectively. RESULTS: 2-year local, nodal, and distant control rates were 95%, 91%, and 96%, disease free and overall survival 90% and 83%, respectively. The corresponding survival rates for the subgroup of patients with a follow up time >12 months (n = 43) were 98%, 95%, 98%, 93%, and 88%, respectively. Distribution according to histopathologic risk features revealed 15% and 85% patients with intermediate and high risk, respectively. All loco-regional events occurred in the high risk subgroup. CONCLUSION: Surgery followed by postoperative IMRT in patients with substantial risk for recurrence resulted in high loco-regional tumor control rates compared with large prospective 3DCRT trials.