The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy).

BACKGROUND: Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5-year OS to 73%. We report outcomes of this strategy in UK. METHODS: Questionnaires were sent to all 20 UK pediatric oncology primary treatment centers to collect retrospective data on delivered treatment, toxicity and survival with this strategy in children aged 3-19 years with MMB. RESULTS: Between February 2009 and October 2011, 34 patients fulfilled the entry criteria of the original study. The median age was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the original series. The incidence of grade 3 or 4 hematological toxicities with IC and HDC was 83-100%. All 16 patients who achieved complete response by the end of the regimen remain in remission but only three of 18 patients with lesser responses are still alive (P < 0.0001). With a median follow-up of 45 months for survivors, the estimated 3-year OS is 56% (95% CI 38, 71). This result is outside the 95% CI of the original study results and encompasses the historical survival result of 40%. CONCLUSION: Within the limits of statistical significance, we did not replicate the improved survival results reported in the original series. The reasons include differences in patient sub-groups and protocol administration. International randomized phase III studies are needed.

Adverse Childhood Experiences in Trainees and Physicians With Professionalism Lapses: Implications for Medical Education and Remediation.

PURPOSE: Unprofessional behavior, which can include failure to engage, dishonest and/or disrespectful behavior, and poor self-awareness, can be demonstrated by medical trainees and practicing physicians. In the authors' experience, these types of behaviors are associated with exposure to adverse childhood experiences (ACEs). Given this overlap, the authors studied the percentage of ACEs among trainees and physicians referred for fitness-for-duty evaluations and patterns between the types of ACEs experienced and the reason for referral. METHOD: A final sample of 123 cases of U.S. trainees and physicians who had been referred to a Midwestern center for assessment and/or remediation of professionalism issues from 2013 to 2018 was created. Included professionalism lapses fell within 3 categories: boundary violation, disruptive behavior, or potential substance use disorder concerns. All participants completed a psychosocial developmental interview, which includes questions about ACE exposure. Overall rate of reported ACEs and types of ACEs reported were explored. RESULTS: Eighty-six (70%) participants reported at least 1 ACE, while 27 (22%) reported 4 or more. Compared with national data, these results show significantly higher occurrence rates of 1 or more ACEs and a lower occurrence rate of 0 ACEs. ACEs that predicted reasons for referral were physical or sexual abuse, feeling unwanted or unloved, witnessing abuse of their mother or stepmother, or caretaker substance use. CONCLUSIONS: In this sample, ACE exposure was associated with professionalism issues. Remediating individuals with professionalism issues and exposure to ACEs can be complicated by heightened responses to stressful stimuli, difficulties with collaboration and trust, and decreased self-efficacy. Adoption of a trauma-informed medical education approach may help those that have been impacted by trauma rebuild a sense of control and empowerment. The findings of this study may be useful predictors in identifying those at risk of problematic behavior and recidivism before a sentinel event.

Understanding and Remediating Lapses in Professionalism: Lessons From the Island of Last Resort.

BACKGROUND: The literature on unprofessional behavior is reviewed. It is well accepted that unprofessional behavior, including a lack of civility and respect, can have a negative impact on patient safety and quality of care. METHODS: We used a focused review in the context of 20 years of experience of assessing, treating, and remediating unprofessional behavior. The review highlights that unprofessional behavior can stem from a variety of sources, including health, psychological/psychiatric issues, social functioning or support, or a combination of these. The review covers the challenges in the work environment and the relationship between outcome, as experienced by the physician, and the likelihood the physician will repeat or modify his or her behavior. RESULTS: Based on the evidence provided in the review and our clinical and research experience, we offer a new framework for the assessment, treatment, and remediation of physicians with professionalism transgressions: the Environmentally Valid Learning Approach. The approach is related to and expands on Miller's Pyramid by adding bio-psycho-social functioning and professional identity to the Pyramid. It emphasizes the dynamic and environmental characteristics of professional identity. CONCLUSIONS: Effective intervention is possible. Consideration of contributory factors, addressing/treating those factors, teaching/remediating skill deficiencies, and determining elements that need to be in place to foster implementation and maintenance of the developing skills are necessary components for successful resolution. The behavior is fully remediated when a self-sustaining alternative to the unprofessional behavior is established and the desired behavior becomes a permanent part of the physician's behavioral repertoire.

Stage migration and pilot studies of reduced chemotherapy supported by positron-emission tomography findings suggest new combined strategies for stage 2 nonseminoma germ cell tumour.

OBJECTIVE: To examine the nodal (N+) vs extranodal (M+) staging in each of the International Germ Cell Consensus Classification Group (IGCCCG) subgroups in an audit of 437 patients treated in The Anglian Germ Cell Cancer Group, where chemotherapy was the primary management, as there is an increasingly earlier presentation of patients with less advanced disease who thus face potentially unnecessary treatment. PATIENTS AND METHODS: Clinicians from seven centres prospectively registered patients in a central database, and the follow-up was coordinated by one of the authors. RESULTS: Between 1982 and 2002, 436 patients (median follow-up 60 months) were registered; 63% of IGCCCG good risk (298), 42% of intermediate (62) and 8% poor risk (77) were stage II; 79% of N+M0 intermediate and poor risk cases (29) were alive, vs only 60% of M+ stage IV cases (92, P < 0.05). The trend was similar in IGCCCG good risk patients, with 92% of N+ stage II (156) alive vs only 85% (94) of stage IV M+ (not significant). The frequency of retroperitoneal lymph node dissection after chemotherapy increased from 26% (1983-1993) to 34% (1994-2002), and survival from 89% to 94%. There were no relapses in eight patients who elected to stop treatment after two courses. Four of six patients with positive findings on positron emission tomography had a durable complete response, assessed by standard uptake values, when tested at 72-96 h. CONCLUSION: Extra-lymphatic spread, although prognostically important within the IGCCCG subgroups, is only statistically significant for intermediate and poor risk combined. The observation that there might be N+ patients cured by two chemotherapy courses alone suggests that there might be opportunities to reduce the morbidity of treatment.

Ultrasound-guided core-needle biopsy of the testis for focal indeterminate intratesticular lesions.

The aim of this study was to evaluate ultrasound (US)-guided core-needle testicular biopsy. Twelve biopsies were performed in eleven patients, under US guidance using disposable 16- or 18-gauge needles, between April 2003 and October 2006. Details were entered on a database and records reviewed 9 months to 3 years after biopsy. Final diagnoses were based on histology of the biopsy, open surgical resection where performed, and interval follow-up. Biopsies were well tolerated and no complications were encountered apart from a single minor testicular haemorrhage. Benign histology was demonstrated on the core-needle samples of six patients and US follow-up was compatible with these diagnoses. Of five patients whose core-needle biopsies yielded malignancy, two patients had primary testicular tumours; both have been treated successfully with orchiectomy and chemotherapy. Three patients with haematological malignancies had successful chemotherapy without orchiectomy; one of these three underwent post-chemotherapy biopsy demonstrating resolution. There are four main clinical scenarios when core-needle testicular biopsy is performed in our institution: (1) lesions with equivocal malignant US features, (2) discrepancy between radiological and clinical findings, (3) suspected malignant process where orchiectomy is unnecessary, e.g. lymphoma, (4) atrophic testes, where it is frequently difficult to differentiate malignancy from the heterogeneous echo pattern.

Dreyfus and Dreyfus and Indicators of Behavioral Performance: A Study of Measurement Convergence.

INTRODUCTION: Assessment of efficacy of continuous professional development is an important part of continuing professional development programing as one of its goals is to increase the performance of the clinicians that serve the community. A frequently used and researched classification system for skill mastery is the Dreyfus and Dreyfus Model of Skill Acquisition. An alternative approach is the core competency framework that informs the assessment of residents and forms the foundation of the American Board of Medical Specialties Program for Maintenance of Certification. There are a number of methods of assessment of each competence. One of the most broadly employed and researched methods is a multisource assessment (360°) methodology. METHODS: Three hundred sixty-degree data were collected from 264 raters of physicians holding supervisory roles. Raters included the physicians' leaders, peers, and support/reports. The scale items were taken from an instrument developed for the assessment of interpersonal and communications skills, professionalism, and system-based practice. The Dreyfus scale was purposely built for this application. RESULTS: The Dreyfus scale was reduced to a single dimension, and raters assigned their score on that dimension as the indicator of their assessment of the physician's level of mastery. Results of a multivariate analysis of variance indicated a significant relationship between Dreyfus mastery score and competency items (P < .0001). DISCUSSION: These findings demonstrate a relationship between a measure of Dreyfus skill acquisition and measures based on the American Board of Medical Specialties/Accreditation Council for Graduate Medical Education six core competency framework. Results have implication for continuing professional development design and assessment.

Assessment of fitness for duty of underperforming physicians: The importance of using appropriate norms.

OBJECTIVE: To determine whether population-specific normative data should be employed when screening neurocognitive functioning as part of physician fitness for duty evaluations. If so, to provide such norms based on the evidence currently available. METHODS: A comparison of published data from four sources was analyzed. Data from the two physician samples were then entered into a meta-analysis to obtain full information estimates and generate provisional norms for physicians. RESULTS: Two-way analysis of variance (Study x Index) revealed a significant main effect and an interaction. Results indicate differences in mean levels of performance and standard deviation for physicians. CONCLUSIONS: Reliance on general population normative data results in under-identification of potential neuropsychological difficulties. Population specific normative data are needed to effectively evaluate practicing physicians.

Miller's Pyramid and Core Competency Assessment: A Study in Relationship Construct Validity.

INTRODUCTION: Continuous professional development relies on the link between performance and an educational process aimed at improving knowledge and skill. One of the most broadly used frameworks for assessing skills is Miller's Pyramid. This Pyramid has a series of levels of achievement beginning with knowledge (at the base) and ending with routine application in the clinical setting. METHODS: The purpose of this study was to determine the degree of convergence of two measurement methods, one based on Miller's framework, the second using the Accreditation Council for Graduate Medical Education/American Board of Medical Specialties (ACGME/ABMS) Core Competency framework. The data were gathered from the faculty of a large, Midwestern regional health care provider and hospital system. Data from 264 respondents were studied. The 360° data were from raters of physicians holding supervisory roles in the organization. The scale items were taken from an instrument that has been validated for both structure and known group prediction. RESULTS: The Miller scale was purposely built for this application. The questions were designed to describe each level of the model. The Miller scale was reduced to a single dimension. This result was then regressed on the items from the 360° item ratings. Results of a multivariate analysis of variance isolated a significant relationship between the Miller's Pyramid score and the competency items (P < 0.001). DISCUSSION: These findings demonstrate a relationship between measures based on Miller's framework and behavioral measures based on the ABMS/ACGME core competencies. Equally important is the finding that while they are related they are not identical. These findings have implications for continuous professional development programing design.

Fast imaging employing steady-state acquisition (FIESTA) MRI to investigate cerebrospinal fluid (CSF) within dural reflections of posterior fossa cranial nerves.

OBJECTIVE: There is no consensus approach to covering skull base meningeal reflections-and cerebrospinal fluid (CSF) therein-of the posterior fossa cranial nerves (CNs VII-XII) when planning radiotherapy (RT) for medulloblastoma and ependymoma. We sought to determine whether MRI and specifically fast imaging employing steady-state acquisition (FIESTA) sequences can answer this anatomical question and guide RT planning. METHODS: 96 posterior fossa FIESTA sequences were reviewed. Following exclusions, measurements were made on the following scans for each foramen respectively (left, right); internal acoustic meatus (IAM) (86, 84), jugular foramen (JF) (83, 85) and hypoglossal canal (HC) (42, 45). A protocol describes measurement procedure. Two observers measured distances for five cases and agreement was assessed. One observer measured all the remaining cases. RESULTS: IAM and JF measurement interobserver variability was compared. Mean measurement difference between observers was -0.275 mm (standard deviation 0.557). IAM and JF measurements were normally distributed. Mean IAM distance was 12.2 mm [95% confidence interval (CI) 8.8-15.6]; JF was 7.3 mm (95% CI 4.0-10.6). The HC was difficult to visualize on many images and data followed a bimodal distribution. CONCLUSION: Dural reflections of posterior fossa CNs are well demonstrated by FIESTA MRI. Measuring CSF extension into these structures is feasible and robust; mean CSF extension into IAM and JF was measured. We plan further work to assess coverage of these structures with photon and proton RT plans. Advances in knowledge: We have described CSF extension beyond the internal table of the skull into the IAM, JF and HC. Oncologists planning RT for patients with medulloblastoma and ependymoma may use these data to guide contouring.

Relationship among knowledge acquisition, motivation to change, and self-efficacy in CME participants.

INTRODUCTION: The relationship among an individual's sense of self-efficacy, motivation to change, barriers to change, and the implementation of improvement programs has been reported. This research reports the relationship among self-efficacy, motivation to change, and the acquisition of knowledge in a continuing medical education (CME) activity. METHODS: The measure of individual sense of self-efficacy was a 4-item scale. The measure of motivation was a 6-item scale following on the work of Prochaska and colleagues. The knowledge acquisition was measured in a simple post measure. The participants were enrolled in a CME activity focused on HIV.  RESULTS: The CME activities had a significant effect on knowledge. Preliminary analysis demonstrates a relationship among the self-efficacy measure, the motivation to change measure, and global intent to change. Specifically, as reported earlier, the sense of efficacy in effecting change in the practice environment is predictive of a high level of motivation to change that, in turn, is predictive of formation of intent to change practice patterns. Interestingly, there were also relationships among the self-efficacy measure, the motivation to change measure, and knowledge acquisition. Finally, as expected, there was a significant relationship between knowledge and intent to change practice.  DISCUSSION: Further inspection of the motivation to change construct suggests that it mediates the self-efficacy constructs' effect on intent as well as its effect on knowledge acquisition. This new finding suggests that the proximal construct motivation completely masks an important underlying causal relationship that appears to contribute to practice change as well as learning following CME-self-efficacy.

A method for reducing ovarian doses in whole neuro-axis irradiation for medulloblastoma.

BACKGROUND AND PURPOSE: Cranio-spinal irradiation for medulloblastoma can impair fertility in girls. The literature indicates that an ovarian dose of 4 Gy causes permanent infertility in 30% of young females and that doses of <1.5 Gy over the whole treatment are desirable. We report a modified radiotherapy technique using a non-divergent beam edge inferiorly to reduce the ovarian dose. PATIENTS AND METHODS: Eight female patients with medulloblastoma had magnetic resonance imaging (MRI) studies in the treatment position to identify the position of their ovaries relative to the radiation field. The information was transferred to the radiotherapy planning system and plans were generated using conventional spinal fields and modified fields with a half beam block at the inferior border. RESULTS: Identifying the position of the ovaries by MRI enabled the dose to be estimated for the two techniques. Using a non-divergent beam inferiorly, the mean ovarian dose was reduced in all cases by a median value of 2.45 Gy (range 0.6-19.5 Gy) and the median percentage reduction was 66.8% (range 2.6-84.6%). The position of the ovary relative to the beam edge was critical in determining the dose reduction for each case. The modified technique doubled the number of patients receiving <4 Gy to a single ovary from three to six. With this alteration, three patients also had an ovary receiving <1.5 Gy whereas all exceeded this dose with conventional treatment. CONCLUSION: We recommend using asymmetry at the inferior spinal border to achieve a non-divergent edge to the treatment field to reduce the dose to the ovary. Using MRI to localise the ovaries is important in estimating their dose and in assisting the counselling of patients and their families about future fertility.

Quantitative assessment of inter-clinician variability of target volume delineation for medulloblastoma: quality assurance for the SIOP PNET 4 trial protocol.

BACKGROUND AND PURPOSE: To assess inter-clinician variability amongst specialist paediatric radiation oncologists in delineating clinical target volumes for treating medulloblastoma as a quality assurance exercise prior to the introduction of the SIOP PNET 4 trial protocol of conformal radiotherapy to the posterior fossa and tumour bed. PATIENTS AND METHODS: Participants from 17 UK centres attended an educational meeting and then completed a clinical planning exercise to outline: (1) the whole posterior fossa and (2) the tumour bed. Quantitative analysis of the volumes, lengths, spatial positioning and axial planes for each individual was carried out and variation between individuals analysed. RESULTS: Outlining of the posterior fossa was reasonably consistent, although most variation was seen in defining the superior border of the tentorium. A major difference was the decision whether or not to include the post-surgical meningocoele in the clinical target volume (CTV). The CTV for the tumour bed was under treated by all participants due to lack of inclusion of pre-operative tumour extent. CONCLUSIONS: This exercise demonstrated several ambiguities in the draft protocol and highlighted particular areas of inter-clinician variation. Consequently the protocol was revised and improved to take account of these findings. We recommend that planning exercises, in conjunction with education and training, should be implemented before the start of any new radiotherapy trial. In the future, the use of image transfer will allow prospective peer review of target volumes before treatment commences. These measures are essential to ensure that alterations in clinical practice are achieved in a uniform way.

Relationship among practice change, motivation, and self-efficacy.

INTRODUCTION: The relationship between an individual's sense of self-efficacy, motivation to change, and the implementation of improvement programs has been reported. This research reports the relationship among self-efficacy, motivation to change, and intent to implement continuing medical education (CME) activity learnings. METHODS: The measure of individual sense of self-efficacy was a 4-item scale. The measure of motivation was a 4-item scale following on the work of Johnson, et al. The self-efficacy scale has been confirmed for structure, and together the 2 scales provide indicators of 3 underlying variables-2 self-efficacy constructs and a motivation variable. In addition, a global intent to implement measure was collected. RESULTS: Preliminary analysis demonstrates a significant relationship between a self-efficacy construct, the motivation to change construct, and global intent to change. Specifically, the sense of efficacy in effecting change in the practice environment is predictive of a high level of motivation to change, which, in turn, is predictive of formation of an intent to change practice patterns. DISCUSSION: Further inspection of the motivation to change construct suggests that it mediates the self-efficacy constructs' effect on intent. This is consistent with an earlier report on the relationship among self-efficacy, barriers to change, and stated intent. This new finding suggests that the proximal construct motivation completely masks an important underlying causal relationship that appears to contribute to practice change following CME: self-efficacy. A focus on the participants' sense of self-agency may provide a path to practice change.

Risk of premature menopause after treatment for Hodgkin's lymphoma.

BACKGROUND: Modern treatment of Hodgkin's lymphoma (HL) has transformed its prognosis but causes late effects, including premature menopause. Cohort studies of premature menopause risks after treatment have been relatively small, and knowledge about these risks is limited. METHODS: Nonsurgical menopause risk was analyzed in 2127 women treated for HL in England and Wales at ages younger than 36 years from 1960 through 2004 and followed to 2003 through 2012. Risks were estimated using Cox regression, modified Poisson regression, and competing risks. All statistical tests were two-sided. RESULTS: During follow-up, 605 patients underwent nonsurgical menopause before age 40 years. Risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation, but was not statistically significantly raised after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Menopause generally occurred sooner after ovarian radiotherapy (62.5% within five years of ≥5 Gy treatment) and BEAM (50.9% within five years) than after alkylating chemotherapy (24.2% within five years of ≥6 cycles), and after treatment at older than at younger ages. Cumulative risk of menopause by age 40 years was 81.3% after greater than or equal to 5Gy ovarian radiotherapy, 75.3% after BEAM, 49.1% after greater than or equal to 6 cycles alkylating chemotherapy, 1.4% after ABVD, and 3.0% after solely supradiaphragmatic radiotherapy. Tables of individualized risk information for patients by future period, treatment type, dose and age are provided. CONCLUSIONS: Patients treated with HL need to plan intended pregnancies using personalized information on their risk of menopause by different future time points.

Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study.

PURPOSE: To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. PATIENTS AND METHODS: Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. RESULTS: Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age ≥ 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving ≥ 40 Gy mantle radiotherapy at young ages was 48%. CONCLUSION: This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages.