Patient-targeted education (ePRO-E) to increase ePRO intent within an Alliance clinical trial (A221805-SI1).

BACKGROUND: The Patient Cloud ePRO app was adopted by the National Cancer Institute National Clinical Trials Network (NCTN) to facilitate capturing electronic patient-reported (ePRO) outcome data, but use has been low. The study objectives were to test whether a patient-targeted ePRO educational resource (ePRO-E) would increase ePRO intent (number of users) and improve data quality (high quality: ≥80% of the required surveys submitted) within an ongoing NCTN study. METHODS: The ePRO-E intervention, a patient-targeted educational resource (written material and 6-minute animated YouTube video), was designed to address ePRO barriers. ePRO intent and data quality were compared between 2 groups (N = 69): a historical control group and a prospectively recruited intervention group exposed to ePRO-E. Covariates included technology attitudes, age, sex, education, socioeconomic status, and comorbidity. RESULTS: Intervention group ePRO intent (78.8%) was statistically significantly higher than historical control group intent (47.1%) (P = .03). Patients choosing ePRO versus paper surveys had more positive and higher technology attitudes scores (P = .03). The odds of choosing ePRO were 4.7 times higher (95% Confidence Interval [CI] = 1.2 to 17.8) (P = .02) among intervention group patients and 5.2 times higher (95% CI = 1.3 to 21.6) (P = .02) among patients with high technology attitudes scores, after controlling for covariates. However, the 80% submission rate (percentage submitting ≥80% of required surveys) in the ePRO group (30.6%) was statistically significantly lower than in the paper group (57.9%) (P = .05). CONCLUSIONS: ePRO-E exposure increased ePRO intent. High technology attitudes scores were associated with ePRO selection. Since the ePRO survey submission rate was low, additional strategies are needed to promote high-quality data submission.

Actin-binding protein profilin1 is an important determinant of cellular phosphoinositide control.

Membrane polyphosphoinositides (PPIs) are lipid-signaling molecules that undergo metabolic turnover and influence a diverse range of cellular functions. PPIs regulate the activity and/or spatial localization of a number of actin-binding proteins (ABPs) through direct interactions; however, it is much less clear whether ABPs could also be an integral part in regulating PPI signaling. In this study, we show that ABP profilin1 (Pfn1) is an important molecular determinant of the cellular content of PI(4,5)P2 (the most abundant PPI in cells). In growth factor (EGF) stimulation setting, Pfn1 depletion does not impact PI(4,5)P2 hydrolysis but enhances plasma membrane (PM) enrichment of PPIs that are produced downstream of activated PI3-kinase, including PI(3,4,5)P3 and PI(3,4)P2, the latter consistent with increased PM recruitment of SH2-containing inositol 5' phosphatase (SHIP2) (a key enzyme for PI(3,4)P2 biosynthesis). Although Pfn1 binds to PPIs in vitro, our data suggest that Pfn1's affinity to PPIs and PM presence in actual cells, if at all, is negligible, suggesting that Pfn1 is unlikely to directly compete with SHIP2 for binding to PM PPIs. Additionally, we provide evidence for Pfn1's interaction with SHIP2 in cells and modulation of this interaction upon EGF stimulation, raising an alternative possibility of Pfn1 binding as a potential restrictive mechanism for PM recruitment of SHIP2. In conclusion, our findings challenge the dogma of Pfn1's binding to PM by PPI interaction, uncover a previously unrecognized role of Pfn1 in PI(4,5)P2 homeostasis and provide a new mechanistic avenue of how an ABP could potentially impact PI3K signaling byproducts in cells through lipid phosphatase control.

Randomized phase III trial evaluating motivational interviewing and text interventions to optimize adherence to breast cancer endocrine therapy (Alliance A191901): the GETSET protocol.

BACKGROUND: Hormone receptor-positive (HR +) breast cancer is the most common type of breast cancer in the USA but has excellent long-term outcomes in recent decades, in part due to effective oral endocrine therapy (ET). ET medications are typically prescribed for 5 to 10 years, depending on the risk of recurrence, and must be taken daily. One limiting factor to ET efficacy is nonadherence, with high-risk groups for nonadherence including younger women and Black women. METHODS: The Alliance for Clinical Trials in Oncology (Alliance) trial A191901 is an ongoing, four-arm (text message reminder (TMR), motivational interviewing (MI), TMR plus MI, or enhanced usual care) randomized clinical trial that tests the efficacy and effect of two interventions (TMR and/or MI) on improved ET adherence, patient-reported outcomes (PROs), and resource use requirements among HR + breast cancer survivors. Participants are randomized in a 1:1:1:1 ratio to the four arms. With an assumed loss to follow-up of approximately 11%, we plan to recruit 1180 participants. Randomization is stratified based on age and race to ensure balance between the arms, and we oversample younger and Black women, with each group representing 30% of the study population. Participants randomized to an intervention will actively participate in the intervention for 9 months, and all participants will be followed for adherence data and PRO endpoints, through the use of the Pillsy cap medication event monitoring system and Alliance ePRO survey app (i.e., Patient Cloud). The primary analysis will compare Pillsy-measured ET adherence among study arms at 12 months. DISCUSSION: This multisite study will not only define strategies to improve adherence to breast cancer oral therapies, but it will also potentially support strategies in large cooperative research groups that can increase delivery and tolerability of ET, involve diverse patient populations in clinical research, and engage patients effectively in interventional studies, using remote and cost-effective delivery methods. TRIAL REGISTRATION: Clinicaltrials.gov NCT04379570 . Registered on 7 May 2020.

Improving patient-centered communication in breast cancer: a study protocol for a multilevel intervention of a shared treatment deliberation system (SharES) within the NCI community oncology research program (NCORP) (Alliance A231901CD).

BACKGROUND: Advances in precision medicine have given oncologists new evaluative tools to better individualize treatments for patients with curable breast cancer. These innovations have revealed a need to improve patient understanding of novel, often complex information related to breast cancer treatment decisions. Ensuring patients have the emotional support to face consequential treatment decisions, as well as the opportunity to engage and discuss with their clinicians, is key to improving patient-centered communication and patient understanding. METHODS/DESIGN: This study will implement a multilevel intervention with patient and clinician components as a NCORP Cancer Care Delivery Research (CCDR) trial within the Alliance for Clinical Trials in Oncology Research Base (Alliance). The two interventions in this study, the Shared Decision Engagement System (SharES), include (1) two versions of an evidence-based patient-facing breast cancer treatment decision tool (iCanDecide +/- an emotional support module) and (2) a clinician-facing dashboard (Clinician Dashboard) that is reviewed by surgeons/clinicians and summarizes ongoing patient needs. The design is a near minimax, hybrid stepped wedge trial of SharES where both interventions are being evaluated in a crossed design over six 12-week time periods. The primary outcome (knowledge) and key secondary outcomes (i.e., self-efficacy and cancer worry) are assessed via patient report at 5 weeks after surgery. Secondary outcomes are also assessed at 5 weeks after surgery, as well as in a second survey 9 months after registration. We anticipate recruiting a total of 700 breast cancer patients (600 evaluable after attrition) from 25 surgical practices affiliated with Alliance. DISCUSSION: Upon study completion, we will have better understanding of the impact of a multilevel intervention on patient-centered communication in breast cancer with a specific focus on whether the intervention components improve knowledge and self-efficacy and reduce cancer worry. TRIAL REGISTRATION: ClinicalTrials.gov NCT04549571 . Registered on 16 September 2020.

Increasing socioeconomically disadvantaged patients' engagement in breast cancer surgery decision-making through a shared decision-making intervention (A231701CD): protocol for a cluster randomised clinical trial.

INTRODUCTION: Socioeconomic disparities for breast cancer surgical care exist. Although the aetiology of the observed socioeconomic disparities is likely multifactorial, patient engagement during the surgical consult is critical. Shared decision-making may reduce health disparities by addressing barriers to patient engagement in decision-making that disproportionately impact socioeconomically disadvantaged patients. In this trial, we test the impact of a decision aid on increasing socioeconomically disadvantaged patients' engagement in breast cancer surgery decision-making. METHODS AND ANALYSIS: This multisite randomised trial is conducted through 10 surgical clinics within the National Cancer Institute Community Oncology Research Program (NCORP). We plan a stepped-wedge design with clinics randomised to the time of transition from usual care to the decision aid arm. Study participants are female patients, aged ≥18 years, with newly diagnosed stage 0-III breast cancer who are planning breast surgery. Data collection includes a baseline surgeon survey, baseline patient survey, audio-recording of the surgeon-patient consultation, a follow-up patient survey and medical record data review. Interviews and focus groups are conducted with a subset of patients, surgeons and clinic stakeholders. The effectiveness of the decision aid at increasing patient engagement (primary outcome) is evaluated using generalised linear mixed-effects models. The extent to which the effect of the decision aid intervention on patient engagement is mediated through the mitigation of barriers is tested in joint linear structural equation models. Qualitative interviews explore how barriers impact engagement, especially for socioeconomically disadvantaged women. ETHICS AND DISSEMINATION: This protocol has been approved by the National Cancer Institute Central Institutional Review Board, and Certificate of Confidentiality has been obtained. We plan to disseminate the findings through journal publications and national meetings, including the NCORP network. Our findings will advance the science of medical decision-making with the potential to reduce socioeconomic health disparities. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03766009).

Dosimetric comparison of volumetric modulated arc therapy (VMAT) and high-dose-rate brachytherapy (HDR-BT) for superficial skin irradiation with significant curvature in one or more planes.

PURPOSE: This study compares the plan quality of high-dose-rate brachytherapy (HDR-BT) and volumetric modulated arc therapy (VMAT) for superficial irradiation of large areas of skin with significant curvature in one or more planes. METHODS: A total of 14 patients from two centres previously treated with either HDR-BT or VMAT were retrospectively replanned using the alternative technique. Sites included scalp and lower limbs. Identical computed tomography (CT) scans, clinical target volume (CTV) and organs at risk (OARs) and prescription were used for both techniques. Conformity, skin surface dose and OAR doses were compared. RESULTS: Conformity index was consistently better with VMAT than HDR-BT (p < 0.01). Maximum skin surface dose (D0.1cc) had a higher mean of 49.6 Gy with HDR-BT compared to 31.4 Gy for VMAT (p < 0.01). Significantly smaller volumes of healthy tissue were irradiated with VMAT than with HDR-BT. This can be seen in brain volumes receiving 10, 20 and 30 Gy EQD2 and in extremities receiving 5 and 10 Gy. When close to the volume, the lens received significantly lower doses with VMAT (p < 0.01). CONCLUSION: In this small sample, VMAT gives equal coverage with lower OAR and skin surface doses than HDR-BT for both scalp and extremities. VMAT is a useful technique for treating large, superficial volumes with significant curvature in one or more planes.

Induced Dimerization Tools to Deplete Specific Phosphatidylinositol Phosphates.

Chemical dimerization systems have been used to drive acute depletion of polyphosphoinsitides (PPIns). They do so by inducing subcellular localization of enzymes that catabolize PPIns. By using this approach, all seven PPIns can be depleted in living cells and in real time. The rapid permeation of dimerizer agents and the specific expression of recruiter proteins confer great spatial and temporal resolution with minimal cell perturbation. In this chapter, we provide detailed instructions to monitor and induce depletion of PPIns in live cells.

Site-Selective Peptide Macrocyclization.

Cyclized peptides have seen a rise in popularity in the pharmaceutical industry as drug molecules. As such, new macrocyclization methodologies have become abundant in the last several decades. However, efficient methods of cyclization without the formation of side products remain a great challenge. Herein, we review cyclization approaches that focus on site-selective chemistry. Site selectivity in macrocyclization decreases the generation of side products, leading to a greater yield of the desired peptide macrocycles. We will also take an in-depth look at the new exclusively intramolecular N-terminal site-selective CyClick strategy for the synthesis of cyclic peptides. The CyClick method uses imine formation between an aldehyde and the N terminus. The imine is then trapped by a nucleophilic attack from the second amidic nitrogen in an irreversible site-selective fashion.

Probing the subcellular distribution of phosphatidylinositol reveals a surprising lack at the plasma membrane.

The polyphosphoinositides (PPIn) are central regulatory lipids that direct membrane function in eukaryotic cells. Understanding how their synthesis is regulated is crucial to revealing these lipids' role in health and disease. PPIn are derived from the major structural lipid, phosphatidylinositol (PI). However, although the distribution of most PPIn has been characterized, the subcellular localization of PI available for PPIn synthesis is not known. Here, we used several orthogonal approaches to map the subcellular distribution of PI, including localizing exogenous fluorescent PI, as well as detecting lipid conversion products of endogenous PI after acute chemogenetic activation of PI-specific phospholipase and 4-kinase. We report that PI is broadly distributed throughout intracellular membrane compartments. However, there is a surprising lack of PI in the plasma membrane compared with the PPIn. These experiments implicate regulation of PI supply to the plasma membrane, as opposed to regulation of PPIn-kinases, as crucial to the control of PPIn synthesis and function at the PM.

PI(4,5)P2 controls plasma membrane PI4P and PS levels via ORP5/8 recruitment to ER-PM contact sites.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a critically important regulatory lipid of the plasma membrane (PM); however, little is known about how cells regulate PM PI(4,5)P2 levels. Here, we show that the phosphatidylinositol 4-phosphate (PI4P)/phosphatidylserine (PS) transfer activity of the endoplasmic reticulum (ER)-resident ORP5 and ORP8 is regulated by both PM PI4P and PI(4,5)P2 Dynamic control of ORP5/8 recruitment to the PM occurs through interactions with the N-terminal Pleckstrin homology domains and adjacent basic residues of ORP5/8 with both PI4P and PI(4,5)P2 Although ORP5 activity requires normal levels of these inositides, ORP8 is called on only when PI(4,5)P2 levels are increased. Regulation of the ORP5/8 attachment to the PM by both phosphoinositides provides a powerful means to determine the relative flux of PI4P toward the ER for PS transport and Sac1-mediated dephosphorylation and PIP 5-kinase-mediated conversion to PI(4,5)P2 Using this rheostat, cells can maintain PI(4,5)P2 levels by adjusting the availability of PI4P in the PM.

SAC1 degrades its lipid substrate PtdIns4P in the endoplasmic reticulum to maintain a steep chemical gradient with donor membranes.

Gradients of PtdIns4P between organelle membranes and the endoplasmic reticulum (ER) are thought to drive counter-transport of other lipids via non-vesicular traffic. This novel pathway requires the SAC1 phosphatase to degrade PtdIns4P in a 'cis' configuration at the ER to maintain the gradient. However, SAC1 has also been proposed to act in 'trans' at membrane contact sites, which could oppose lipid traffic. It is therefore crucial to determine which mode SAC1 uses in living cells. We report that acute inhibition of SAC1 causes accumulation of PtdIns4P in the ER, that SAC1 does not enrich at membrane contact sites, and that SAC1 has little activity in 'trans', unless a linker is added between its ER-anchored and catalytic domains. The data reveal an obligate 'cis' activity of SAC1, supporting its role in non-vesicular lipid traffic and implicating lipid traffic more broadly in inositol lipid homeostasis and function.

TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes.

Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end. TMEM55B overexpression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery. TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome-lysosome fusion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.

The dosimetric impact of air in vaginal vault brachytherapy.

PURPOSE: Vaginal vault brachytherapy is an adjuvant treatment to reduce risk of local recurrence in endometrial cancer. Axial imaging has demonstrated the presence of air gaps between the surface of a cylindrical applicator and mucosal wall. The impact of these on dosimetry and applicability of the TG-43 formalism in the presence of air has been assessed. METHODS AND MATERIALS: The planning CT scans for a retrospective sample of 82 patients were examined for the presence of air gaps. These were quantified in terms of the radial and longitudinal aspect with reference to the applicator, frequency per patient, and location along the applicator. Monte Carlo calculations and ionization chamber measurements were made in a phantom to estimate the uncertainty of the TG-43 algorithm. RESULTS: The overall incidence of air gaps was 91.4%. The most common radial size was between 2 and 3 mm (43.0%) that resulted in an average dose reduction of 14.8%. There is a strong correlation between radial dimension and TG-43 calculated dose reduction. Monte Carlo simulations and phantom measurements indicated that the inhomogeneity resulted in a maximum of 2.4% deviation from doses calculated using TG-43. CONCLUSIONS: Air gaps are common. TG-43 formalism is not significantly compromised by the presence of air. However, the presence of the air does produce a displacement of the mucosal surface away from the applicator and this causes a significant dose reduction.

Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells.

Type 2 diabetes (T2D) is characterized by insulin resistance and reduced functional ß-cell mass. Developmental differences, failure of adaptive expansion and loss of ß-cells via ß-cell death or de-differentiation have emerged as the possible causes of this reduced ß-cell mass. We hypothesized that the proliferative response to mitogens of human ß-cells from T2D donors is reduced, and that this might contribute to the development and progression of T2D. Here, we demonstrate that the proliferative response of human ß-cells from T2D donors in response to cdk6 and cyclin D3 is indeed dramatically impaired. We show that this is accompanied by increased nuclear abundance of the cell cycle inhibitor, p27(kip1). Increasing nuclear abundance of p27(kip1) by adenoviral delivery decreases the proliferative response of ß-cells from non-diabetic donors, mimicking T2D ß-cells. However, while both p27(kip1) gene silencing and downregulation by Skp2 overexpression increased similarly the proliferative response of human ß-cells, only Skp2 was capable of inducing a significant human ß-cell expansion. Skp2 was also able to double the proliferative response of T2D ß-cells. These studies define c-Myc as a central Skp2 target for the induction of cell cycle entry, expansion and regeneration of human T2D ß-cells.

Individuals with Smith-Magenis syndrome display profound neurodevelopmental behavioral deficiencies and exhibit food-related behaviors equivalent to Prader-Willi syndrome.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder associated with intellectual disability, sleep disturbances, early onset obesity and vast behavioral deficits. We used the Behavior Problems Inventory-01 to categorize the frequency and severity of behavioral abnormalities in a SMS cohort relative to individuals with intellectual disability of heterogeneous etiology. Self-injurious, stereotyped, and aggressive/destructive behavioral scores indicated that both frequency and severity were significantly higher among individuals with SMS relative to those with intellectual disability. Next, we categorized food behaviors in our SMS cohort across age using the Food Related Problems Questionnaire (FRPQ) and found that problems began to occur in SMS children as early as 5-11 years old, but children 12-18 years old and adults manifested the most severe problems. Furthermore, we evaluated the similarities of SMS adult food-related behaviors to those with intellectual disability and found that SMS adults had more severe behavioral problems. Many neurodevelopmental disorders exhibit syndromic obesity including SMS. Prader-Willi syndrome (PWS) is the most frequent neurodevelopmental disorder with syndromic obesity and has a well-established management and treatment plan. Using the FRPQ we found that SMS adults had similar scores relative to PWS adults. Both syndromes manifest weight gain early in development, and the FRPQ scores highlight specific areas in which behavioral similarities exist, including preoccupation with food, impaired satiety, and negative behavioral responses. SMS food-related behavior treatment paradigms are not as refined as PWS, suggesting that current PWS treatments for prevention of obesity may be beneficial for individuals with SMS.

Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice.

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

Early and Late G1/S Cyclins and Cdks Act Complementarily to Enhance Authentic Human ß-Cell Proliferation and Expansion.

ß-Cell regeneration is a key goal of diabetes research. Progression through the cell cycle is associated with retinoblastoma protein (pRb) inactivation via sequential phosphorylation by the "early" cyclins and cyclin-dependent kinases (cdks) (d-cyclins cdk4/6) and the "late" cyclins and cdks (cyclin A/E and cdk1/2). In ß-cells, activation of either early or late G1/S cyclins and/or cdks is an efficient approach to induce cycle entry, but it is unknown whether the combined expression of early and late cyclins and cdks might have synergistic or additive effects. Thus, we explored whether a combination of both early and late cyclins and cdks might more effectively drive human ß-cell cell cycle entry than either group alone. We also sought to determine whether authentic replication with the expansion of adult human ß-cells could be demonstrated. Late cyclins and cdks do not traffic in response to the induction of replication by early cyclins and cdks in human ß-cells but are capable of nuclear translocation when overexpressed. Early plus late cyclins and cdks, acting via pRb phosphorylation on distinct residues, complementarily induce greater proliferation in human ß-cells than either group alone. Importantly, the combination of early and late cyclins and cdks clearly increased human ß-cell numbers in vitro. These findings provide additional insight into human ß-cell expansion. They also provide a novel tool for assessing ß-cell expansion in vitro.

Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human ß-cell replication: a revised model of human ß-cell G1/S control.

Harnessing control of human ß-cell proliferation has proven frustratingly difficult. Most G1/S control molecules, generally presumed to be nuclear proteins in the human ß-cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human ß-cell proliferation and promptly translocated into the nucleus in association with proliferation. In contrast, the cell cycle inhibitors p15, p18, and p19 did not alter their location, remaining cytoplasmic. Conversely, p16, p21, and p27 increased their nuclear frequency. In contrast once again, p57 decreased its nuclear frequency. Whereas proliferating ß-cells contained nuclear cyclin D3 and cdk6, proliferation generally did not occur in ß-cells that contained nuclear cell cycle inhibitors, except p21. Dynamic cytoplasmic-nuclear trafficking of cdk6 was confirmed using green fluorescent protein-tagged cdk6 and live cell imaging. Thus, we provide novel working models describing the control of cell cycle progression in the human ß-cell. In addition to known obstacles to ß-cell proliferation, cytoplasmic-to-nuclear trafficking of G1/S molecules may represent an obstacle as well as a therapeutic opportunity for human ß-cell expansion.

Critical structure movement in cervix brachytherapy.

BACKGROUND AND PURPOSE: To investigate critical structure movement and subsequent dose received during conformal MR-guided cervix brachytherapy. MATERIALS AND METHODS: 21 patients (36 HDR fractions) undergoing brachytherapy for cervical cancer underwent a second MR immediately prior to treatment (pre-treatment MR). Bowel (including sigmoid), bladder and rectum were outlined on both planning and pre-treatment MR scans and dosimetry compared. RESULTS: No statistically significant differences were found between the volumes of the OAR doses across the two scans but there were large variations between patients with differences of up to 3.3 Gy observed. The percentage of fractions for which D2cc was within 10% of that planned was 61.1%, 41.7% and 47.2% for bladder, rectum and bowel, respectively. The average time between MR scans was found to be 4.75 h (SD±1.2; range 3.2-9.9 h), with no correlation found with critical structure movement within this range. CONCLUSIONS: OAR movement is difficult to predict though significant changes occur in individual patients. In 61% of cases in our sample the D2cc dose changed by at least 10% for at least one OAR from that planned. Pre-treatment imaging with subsequent adjustment of dosimetry will minimise the impact of organ movement on delivered dose.

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy.

Image-guided brachytherapy in cervical cancer is increasingly replacing X-ray based dose planning. In image-guided brachytherapy the geometry of the applicator is extracted from the patient 3D images and introduced into the treatment planning system; a process referred to as applicator reconstruction. Due to the steep brachytherapy dose gradients, reconstruction errors can lead to major dose deviations in target and organs at risk. Appropriate applicator commissioning and reconstruction methods must be implemented in order to minimise uncertainties and to avoid accidental errors. Applicator commissioning verifies the location of source positions in relation to the applicator by using auto-radiography and imaging. Sectional imaging can be utilised in the process, with CT imaging being the optimal modality. The results from the commissioning process can be stored as library applicators. The importance of proper commissioning is underlined by the fact that errors in library files result in systematic errors for clinical treatment plans. While the source channel is well visualised in CT images, applicator reconstruction is more challenging when using MR images. Availability of commercial dummy sources for MRI is limited, and image artifacts may occur with titanium applicators. The choice of MR sequence is essential for optimal visualisation of the applicator. Para-transverse imaging (oriented according to the applicator) with small slice thickness (< or =5 mm) is recommended or alternatively 3D MR sequences with isotropic voxel sizes. Preferably, contouring and reconstruction should be performed in the same image series in order to avoid fusion uncertainties. Clear and correct strategies for the applicator reconstruction will ensure that reconstruction uncertainties have limited impact on the delivered dose. Under well-controlled circumstances the reconstruction uncertainties are in general smaller than other brachytherapy uncertainties such as contouring and organ movement.