Melanoma-the therapeutic considerations in the clinical practice.

The incidence of melanoma is increasing and prolonged exposure to ultraviolet (UV) radiation remains the main risk factor. Public health measures have been vital in tackling the increased incidence and prevalence of melanoma. The management of melanoma has been revolutionised with the approval of new immunotherapy treatments (anti PD-1, CTLA-4 and LAG-3 antibodies) and targeted therapies (BRAF and MEK inhibitors). With some of these therapies becoming the standard of care in the management of advanced disease, it is likely we will see their use increase in the adjuvant and neoadjuvant setting. Recently, literature has demonstrated the benefits patients could derive from the combination of immune checkpoint inhibitors (ICIs) due to the promising results on its efficacy when compared to monotherapy. However, greater clarity on its use is needed in more unique presentations such as BRAF-wild type melanoma, where the lack of driver mutations makes disease management more challenging. Surgical resection remains an integral part of the management of earlier stages of the disease with a consequent decrease in reliance on other forms of therapy such as chemotherapy and radiotherapy. Finally, we evaluated the novel emerging experimental approaches to treatment such as adoptive T cell therapy, novel oncolytic treatments and cancer vaccines. We discussed how their use could improve patients' prognosis, enhance treatment efficacy, and potentially achieve cure.

Changing estimates of leadership ability before a programme: retrospective self-assessments and response-shift bias.

BACKGROUND: Most evaluations of clinical leadership development programmes rely on self-assessments. Self-assessments are vulnerable to response-shift bias. Using retrospective then-tests may help to avoid this bias.In this study, we investigate whether post-programme then-tests (retrospective self-assessments) are more sensitive to change in clinical leadership development programme participants than traditional pre-programme pre-tests when paired with post-test self-assessments. METHODS: 17 healthcare professionals participated in an 8-month single-centre multidisciplinary leadership development programme. Participants completed prospective pre-test, retrospective then-test and traditional post-test self-assessments using the Primary Colours Questionnaire (PCQ) and Medical Leadership Competency Framework Self-Assessment Tool (MLCFQ). Pre-post pairs and then-post pairs were analysed for changes using Wilcoxon signed-rank tests and compared with a parallel multimethod evaluation organised by Kirkpatrick levels. RESULTS: A greater number of significant changes were detected using then-test pairs than pre-test pairs for both the PCQ (11 of 12 vs 4 of 12 items) and MLCFQ (7 of 7 vs 3 of 7 domains). The multimethods data showed positive outcomes at all Kirkpatrick levels. CONCLUSIONS: In ideal circumstances, both pre-test and then-test evaluations should be conducted. We cautiously suggest that if only one post-programme evaluation can be conducted, then-tests may be appropriate means of detecting change.

Evaluating the impact of the metastatic spinal cord compression coordinator in a regional cancer network: a prospective, non-randomized pilot study.

BACKGROUND: Extradural metastatic spinal cord compression (MSCC) is a debilitating and potentially irreversible complication of cancer. Delay in treatment could lead to irreversible neurological damage, adverse quality of life and a burden on health care resources. Lack of effective communication between teams has been identified as one of the reasons for delay in treatment. The MSCC coordinator (often a nurse, radiotherapy radiographer or a doctor) is responsible for coordinating the diagnosis and management of patients with MSCC. The role has been shown to streamline service, ensure timely decision-making and improved survival outcomes. However, available data are anecdotal or from limited series presented as abstracts in conferences. In this study, we assessed the impact (time to treatment) of the newly introduced role on the treatment pathway compared to similar period in the preceding year. METHODS: This was a multi-centre, prospective, pilot study carried out in Kent, UK between 1st April to 30th June 2021. Patients were considered eligible if they had magnetic resonance imaging (MRI)-confirmed cauda equina or cord compression. The data prospectively collected include: (I) time from diagnostic imaging to radiotherapy treatment; (II) number of referrals to hospital palliative care (HPC), occupational/physiotherapy (OPH) and community hospice referrals (CHP). A comparative retrospective data for (I) was collected for the same time period in the preceding year. The study outcome assessed was reduction in time from radiological diagnosis of MSCC to receiving radiotherapy. RESULTS: Fifty-eight patients in 2020 and 24 patients in 2021 were included in the dataset. The MSCC coordinator role (introduced in 2021) led to reduction in the time from imaging to treatment (P=0.045). Compared to 2020, there was a shorter mean/median time to treatment, seeing more patients being treated within 24 hours. All hospitals except East Kent Hospitals saw more patients being treated within 24 hours. 7 referrals each made to HPC, OPH and CHP respectively. CONCLUSIONS: Introduction of MSCC coordinator role led to improved time from imaging to radiotherapy treatment. The new service led to engagement with rehabilitative and palliative services. Future work should be done to assess the long-term impact of this role on utilization of support services and patient recovery.

The future of PSMA PET and WB MRI as next-generation imaging tools in prostate cancer.

Radiolabelled prostate-specific membrane antigen (PSMA)-based PET-CT has been shown in numerous studies to be superior to conventional imaging in the detection of nodal or distant metastatic lesions. 68Ga-PSMA PET-CT is now recommended by many guidelines for the detection of biochemically relapsed disease after radical local therapy. PSMA radioligands can also function as radiotheranostics, and Lu-PSMA has been shown to be a potential new line of treatment for metastatic castration-resistant prostate cancer. Whole-body (WB) MRI has been shown to have a high diagnostic performance in the detection and monitoring of metastatic bone disease. Prospective, randomized, multicentre studies comparing 68Ga-PSMA PET-CT and WB MRI for pelvic nodal and metastatic disease detection are yet to be performed. Challenges for interpretation of PSMA include tracer trapping in non-target tissues and also urinary excretion of tracers, which confounds image interpretation at the vesicoureteral junction. Additionally, studies have shown how long-term androgen deprivation therapy (ADT) affects PSMA expression and could, therefore, reduce tracer uptake and visibility of PSMA+ lesions. Furthermore, ADT of short duration might increase PSMA expression, leading to the PSMA flare phenomenon, which makes the accurate monitoring of treatment response to ADT with PSMA PET challenging. Scan duration, detection of incidentalomas and presence of metallic implants are some of the major challenges with WB MRI. Emerging data support the wider adoption of PSMA PET and WB MRI for diagnosis, staging, disease burden evaluation and response monitoring, although their relative roles in the standard-of-care management of patients are yet to be fully defined.

Microsatellite instability testing in colorectal patients with Lynch syndrome: lessons learned from a case report and how to avoid such pitfalls.

We present the case of a patient with Lynch syndrome and metastatic colorectal carcinoma (mCRC). The initial immunohistochemistry (IHC) test for deficient mismatch repair gave a false negative result. However, the same mutation has accurately been detected with IHC in other cancers with microsatellite instability (MSI). This supports the determining role of somatic missense mutations in MMR IHC. MSI-PCR testing confirmed MSI and the patient benefited from nivolumab with a complete metabolic response. We explain the rationale for immunotherapy in mCRC, current testing strategies and discuss future developments in MSI testing. We advocate for upfront testing using both IHC and MSI-PCR to direct therapy in mCRC, and a greater understanding of IHC and MSI-PCR testing pitfalls.

Bowel cancer that has spread is a serious condition that will often lead to loss of life. There is a new treatment called immunotherapy which helps extend the life of people with cancer that has spread beyond the bowel, but it does not work for everyone. Immunotherapy works best for people whose tumors have lost the ability to repair DNA. People with Lynch syndrome often have these types of tumors because they are born with an inherited predisposition for faulty DNA repair. We treated a patient with Lynch syndrome and bowel cancer, and wanted to use immunotherapy, but the test we used failed to give the right result. We think this is because the test is not very good at picking up unusual types of mutations that can occur and that using another test as well will prevent this mistake from happening to others.

Suicidal behavior in juvenile bipolar disorder and major depressive disorder patients: Systematic review and meta-analysis.

OBJECTIVE: To assess rates and lethality of suicidal behavior in studies of children and adolescents diagnosed with major depressive disorder (MDD) or bipolar disorder (BD). METHODS: This PROSPERO-registered protocol (CRD-42019159676) systematically reviewed reports on suicidal behavior among juveniles (age ≤ 18 years), and pooled data on risk (% of subjects) and rates (%/year), followed by random-effects meta-analysis and multivariable linear regression modeling. RESULTS: Included were 41 reports (1995-2020) from 15 countries involving 104,801 juveniles (102,519 diagnosed with MDD, 2282 with BD), at risk for 0.80-12.5 years. Meta-analytically pooled suicide attempter-rates averaged 7.44%/year [95%CI: 5.63-9.25] with BD and 6.27%/year [5.13-7.41] with MDD. Meta-analysis of 5 studies with both diagnostic groups found significantly greater attempt risk with BD vs. MDD (OR = 1.59 [1.24-2.05], p < 0.0001). In 6 studies, suicide rate with juvenile mood disorders averaged 125 [56.9-236]/100,000/year, similar to adult rates, >30-times greater than in the general juvenile population, and higher among older adolescents. The ratio of attempts/suicides (A/S) was 52.6 among mood-disordered juveniles, indicating greater lethality than among juveniles in the general population (A/S ≥ 250), but somewhat less than in the estimated adult general population (A/S ca. 30). CONCLUSIONS: Rates of suicide attempts in juveniles with a major mood disorder averaged 6580/100,000/year, were greater in BD versus MDD observed under the same conditions, and greater with shorter periods of observation. Lethality (fatalities per suicide attempt) was greater in juveniles diagnosed with major affective disorders than in the juvenile general population, but less than in adults.

Metastatic Anorectal Melanoma Presenting as Seizures: An Infrequent Culprit.

Anorectal malignant melanoma is a rare culprit of malignancies in the anorectal region. With a presentation that mimics the vastly more common colorectal tumours, clinical misdiagnosis and diagnostic delays often occur, contributing to a dismal prognosis. The authors report a case of metastatic anorectal malignant melanoma presenting as seizures. Though our standard diagnostic pathway for suspected anorectal malignancies was followed, and despite the patient having computerized tomography (CT) of the head earlier, this presentation nonetheless led to a prolongation of time needed to reach histological diagnosis and delay in commencing definitive treatment. It also highlights the paucity of research into the pathophysiology and management of this infrequent but aggressive disease, and the need for raising awareness about this condition to the medical community so that it is considered as a plausible differential diagnosis from the outset and diagnostic pathways adjusted accordingly.

Epidermolysis bullosa aquisita following immune-checkpoint inhibitor treatment for metastatic melanoma.

A case of epidermolysis bullosa aquisita following immunotherapy for melanoma. This adds to the repertoire of subepidermal blistering disorders documented following immune checkpoint therapy.

Evidence-based medical leadership development: a systematic review.

Health systems invest significant resources in leadership development for physicians and other health professionals. Competent leadership is considered vital for maintaining and improving quality and patient safety. We carried out this systematic review to synthesise new empirical evidence regarding medical leadership development programme factors which are associated with outcomes at the clinical and organisational levels. Using Ovid MEDLINE, we conducted a database search using both free text and Medical Subject Headings. We then conducted an extensive hand-search of references and of citations in known healthcare leadership development reviews. We applied the Medical Education Research Study Quality Indicator (MERSQI) and the Joanna Briggs Institute (JBI) Critical Appraisal Tool to determine study reliability, and synthesised results using a meta-aggregation approach. 117 studies were included in this systematic review. 28 studies met criteria for higher reliability studies. The median critical appraisal score according to the MERSQI was 8.5/18 and the median critical appraisal score according to the JBI was 3/10. There were recurring causes of low study quality scores related to study design, data analysis and reporting. There was considerable heterogeneity in intervention design and evaluation design. Programmes with internal or mixed faculty were significantly more likely to report organisational outcomes than programmes with external faculty only (p=0.049). Project work and mentoring increased the likelihood of organisational outcomes. No leadership development content area was particularly associated with organisational outcomes. In leadership development programmes in healthcare, external faculty should be used to supplement in-house faculty and not be a replacement for in-house expertise. To facilitate organisational outcomes, interventions should include project work and mentoring. Educational methods appear to be more important for organisational outcomes than specific curriculum content. Improving evaluation design will allow educators and evaluators to more effectively understand factors which are reliably associated with organisational outcomes of leadership development.

Late post-treatment radiographic changes 3 years following chemoradiation for glioma: the importance of histopathology.

Treatment-related changes can mimic brain tumor progression both clinically and radiographically. Distinguishing these two entities represents a major challenge in neuro-oncology. No single imaging modality is capable of reliably achieving such distinction. While histopathology remains the gold standard, definitive pathological criteria are also lacking which can further complicate such cases. We report a patient with high-grade glioma who, after initially presenting with histopathologically confirmed pseudoprogression 10 months following treatment, re-presented 3 years following concurrent chemoradiation with clinical and radiographic changes that were most consistent with progressive disease but for which histopathology revealed treatment effects without active glioma. This case highlights the potential late onset of treatment-related changes and underscores the importance of histopathologic assessment even years following initial therapy.