Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics.

Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including single nucleotide polymorphisms and genetic syndromes, and sporadic somatic mutations, often induced by carcinogenic exposure to UV radiation. This review outlines the currently known germline and somatic mutations implicated in the pathogenesis of BCC, including the key molecular pathways affected by these mutations, which drive oncogenesis. With advances in next generation sequencing and our understanding of the molecular genetics of BCC, established and emerging targeted therapeutics are offering new avenues for the non-surgical treatment of BCC. These agents, including Hedgehog pathway inhibitors, immune modulators, and histone deacetylase inhibitors, will also be discussed.

Phase II Open-Label, Single-Arm Trial to Investigate the Efficacy and Safety of Topical Remetinostat Gel in Patients with Basal Cell Carcinoma.

PURPOSE: The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential treatment for BCC. Here we conduct the first proof-of-principle study of a topical pan-HDAC inhibitor, remetinostat, in human BCC. PATIENTS AND METHODS: We conducted a phase II, open-label, single-arm, single-institution trial of a topical HDAC inhibitor. Participants with at least one BCC were recruited. All participants applied 1% remetinostat gel three times daily for 6 weeks, with measurements of tumor diameter conducted at baseline and week 8. Surgical excision of the remaining tumor was conducted at the end of the study and microscopic evaluation was performed. RESULTS: Thirty-three per-protocol tumors from 25 participants were included in the analysis. The overall response rate, defined as the proportion of tumors achieving more than 30% decrease in the longest diameter from baseline to week 8, was 69.7% [90% confidence interval (CI), 54%-82.5%]. On pathologic examination, 54.8% of tumors demonstrated complete resolution. Pharmacodynamic analysis demonstrated similar levels of acetylated histone H3 in skin tissue before and after treatment, however, phosphorylation was increased. No systemic adverse events were reported. CONCLUSIONS: The HDAC inhibitor remetinostat is a well-tolerated and effective topical treatment for reducing BCC disease burden in a clinically significant manner. This provides in-human validation of HDAC inhibitors as a therapy for BCC.

"Is this the GVHD?" A qualitative exploration of quality of life issues in individuals with graft-versus-host disease following allogeneic stem cell transplant and their experiences of a specialist multidisciplinary bone marrow transplant service.

BACKGROUND: Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogeneic stem cell transplantation. These patients face unique challenges due to the complexity of GVHD which can affect multiple organ systems, and the toxicity of treatments. Despite the known impact on quality of life (QOL), qualitative data within the bone marrow transplantation (BMT) literature is rare, and there has been no qualitative work exploring patient experience of specialist healthcare provision for GVHD in the United Kingdom. METHODS: We conducted a primary explorative qualitative study of the experience of QOL issues and multidisciplinary care in patients with chronic GVHD following allogeneic stem cell transplantation. Eight patients were identified using convenience sampling from specialist BMT outpatient clinics. Following consent, patients were interviewed individually via telephone. Transcripts of interviews were analyzed using an inductive thematic approach. RESULTS: Mean participant age was 61-years-old (range 45-68), with a mean time post-transplant of 3 years at time of interview (range 3 months-15 years). Five key QOL themes were identified: (1) 'Restricted as to what I can do'; (2) Troubling symptoms-'you can sort of get GVHD anywhere'; (3) Confusion/uncertainty over GVHD symptoms-'Is this the GVHD?'; (4) Unpredictable course and uncertainty about the future; and (5) Adapting to the sick role. In addition, four themes related to experience of service provision were identified: (1) personal care and close relationship with BMT nurses; (2) efficiency versus long waits-'On the case straight away'; (3) information provision-'went into it with a bit of a rosy view'; and (4) the role of support groups. CONCLUSIONS: These qualitative data reflect the heterogeneity of experiences of the GVHD patient population, reflecting the need for a flexible and nuanced approach to patient care with emphasis on comprehensive information provision. We have identified the key role that BMT specialist nurses within the multidisciplinary team play in supporting patients. We advocate future research should focus on ways to meet the complex needs of this patient group and ensure that the personal care and close relationships are not lost in service redesigns embracing remote consultations.

Systematic Review of Patient-Reported Outcome Measures in Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation. These patients face a unique challenge due to the complexity of GVHD and the toxicity of treatments received. GVHD has significant impact on quality of life (QOL), but this is not routinely evaluated formally. Despite the availability of patient-reported outcome measures (PROMs) to assess QOL, there is currently no consensus regarding the optimal PROMs that should be used to evaluate the impact of GVHD. We undertook a systematic review to determine the current evidence for the use of PROMs in assessment of QOL, symptom burden, and disease severity of patients with GVHD. A comprehensive systematic review based on the COSMIN guidelines was conducted to identify studies using PROMs (including those for QOL and symptom burden) in acute and chronic GVHD (cGVHD) patients. The following databases were searched: OVID Medline, AMED, CINAHL, Embase, PROQOLID, ProQuest, PsychINFO, and Social Sciences Citation Index from inception to May 2018. Hand searches updated the search to December 2018. Articles were screened by 2 independent reviewers, with discrepancies resolved by a third independent reviewer. Included articles were critically appraised using the COSMIN Risk of Bias tool, and relevant data on measurement properties for the included PROMs were extracted from within the target population. A total of 4545 articles were identified, and 64 articles reporting on 27 PROMs were included in this review. PROMs were separated into 5 groups; generic patient-reported measures (n = 7), cancer-specific measures (n = 4), bone marrow transplant-specific measures (n = 2), cGVHD-specific measures (n = 4), and dimension-specific measures (n = 10). Three PROMs (Human Activity Profile, Lee Symptom Scale, National Institutes of Health Eleven Point Scale) had evidence to support strong reliability (including internal consistency), responsiveness, and aspects of validity within the cGVHD population. Only 5 included PROMs were used in patients with acute GVHD. This review summarizes the current evidence regarding the use of 27 included PROMs in the context of GVHD. The choice of the most optimal PROM depends on the clinical or research context of use. Future research should comprehensively validate these tools in the GVHD population, including the testing and possible development of a PROM for use in acute GVHD, which remains a current critical gap in the existing literature.