Establishing Consensus for Mohs Micrographic Surgical Techniques in the Treatment of Melanoma in Situ for Future Clinical Trials: A Modified Delphi Study.

BACKGROUND: Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials. METHODS: A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale. RESULTS: Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood's lamp, dermatoscope, and negative tissue controls was established in Round 2. CONCLUSIONS: This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.

Topical Treatment of Cutaneous Squamous Cell Carcinoma in Situ and the Impact of Clinical Risk Factors and Positive Histologic Margins at the Time of Diagnosis.

BACKGROUND: Limited data exist for the efficacy of topical 5-fluorouracil (5-FU) and imiquimod for cutaneous squamous cell carcinoma (cSCC) in situ (cSCCis) with positive histologic margins at the time of diagnosis. OBJECTIVE: Identify the efficacy of topical 5-FU and imiquimod in the treatment of cSCCis with positive histologic margins at the time of diagnosis in relation to clinical risk factors. MATERIALS AND METHODS: Pathology records were screened at a single institution from 2014 to 2021 for cSCCis with positive histologic margins. Patients were included if they were treated with curative intent with topical 5-FU or imiquimod. Recurrences were evaluated in relation to multiple clinical risk factors. RESULTS: Of 215 patients treated with 5-FU or imiquimod after biopsy-proven cSCCis, 19 patients had recurrent cSCCis and 1 patient had upstaging to invasive cSCC. Recurrence was more likely in larger lesions at the time of initial biopsy ( p = .033) and in patients treated with topical imiquimod compared with topical 5-FU ( p < .01). CONCLUSION: Topical 5-FU is an appropriate therapy for cSCCis in the correct clinical scenario. Extra consideration should be taken for use of 5-FU in larger diameter cSCCis lesions. Although limited by sample size, our study does not support the use of imiquimod for cSCCis.

Clinical Impact and Accuracy of Shave Biopsy for Initial Diagnosis of Cutaneous Melanoma.

INTRODUCTION: Effective treatment of malignant melanomas is dependent upon accurate histopathological staging of preoperative biopsy specimens. While narrow excision is the gold standard for melanoma diagnosis, superficial shave biopsies have become the preferred method by dermatologists but may transect the lesion and result in inaccurate Breslow thickness assessment. This is a retrospective cohort study evaluating an initial method of biopsy for diagnosis of cutaneous melanoma and indication for reoperation based on inaccurate initial T-staging. METHODS: We retrospectively analyzed consecutive patients referred to the Medical College of Wisconsin, a tertiary cancer center, with a diagnosis of primary cutaneous melanoma. Adult patients seen between 2015 and 2018 were included. Fisher's exact test was used to assess the association between method of initial biopsy and need for unplanned reoperation. RESULTS: Three hundred twenty three patients with cutaneous melanoma from the head and neck (H&N, n = 101, 31%), trunk (n = 90, 15%), upper extremity (n = 84, 26%), and lower extremity (n = 48, 28%) were analyzed. Median Breslow thickness was 0.54 mm (interquartile range = 0.65). Shave biopsy was the method of initial biopsy in 244 (76%), excision in 23 (7%), and punch biopsy in 56 (17%). Thirty nine (33%) shave biopsies had a positive deep margin, as did seven (23%) punch biopsies and 0 excisional biopsies. Residual melanoma at definitive excision was found in 131 (42.5%) of all surgical specimens: 95 (40.6%) shave biopsy patients, 32 (60.4%) punch biopsy patients, and four (19.0%) excision biopsy patients. Recommendations for excision margin or sentinel lymph node biopsy changed in 15 (6%) shave biopsy patients and five (9%) punch biopsy patients. CONCLUSIONS: Shave biopsy is the most frequent method of diagnosis of cutaneous melanoma in the modern era. While shave and punch biopsies may underestimate true T-stage, there was no difference in need for reoperation due to T-upstaging based on initial biopsy type, supporting current diagnostic practices. Partial biopsies can thus be used to guide appropriate treatment and definitive wide local excision when adjusting for understaging.

Xanthomatous Dermal Changes in a Patient With Locally Advanced Basal Cell Carcinoma Treated Using Vismodegib.

ABSTRACT: Basal cell carcinoma (BCC) is the most commonly diagnosed cutaneous cancer in the United States with more than 2.5 million treated annually. Genetic studies have revealed that approximately 90% of BCCs have a mutation in the hedgehog-signaling pathway. Patients with BCC usually have an excellent prognosis with surgical modalities, however, patients with locally advanced BCC may potentially experience significant cosmetic or functional impairment, with only surgical intervention. Vismodegib is a hedgehog pathway inhibitor that has been successful in treating patients with locally advanced BCC. We report a patient with BCC with a good response to vismodegib and a novel xanthomatous change in the excision specimen.

Evaluating the Utility of Routine Imaging in Squamous Cell Carcinoma of the Nail Unit.

BACKGROUND: Squamous cell carcinoma (SCC) is the most common malignant tumor of the nail unit. No guidelines currently exist regarding the role of imaging in this specific location. OBJECTIVE: To investigate the utility of routine imaging in SCC of the nail apparatus. METHODS: A multi-institutional retrospective review of patients treated for nail unit SCC was performed. Data were collected on patient characteristics, tumor qualities, treatment, and radiographic imaging. A change in treatment was defined as more aggressive treatment (amputation) rather than local excision or Mohs micrographic surgery (MMS). RESULTS: One hundred seven patients with nail unit SCC were identified. Approximately 44/107 (41.1%) of patients were imaged and 63/107 (58.9%) were not. Mohs micrographic surgery was the most common primary treatment (66.4%). Mohs micrographic surgery was more commonly performed in nonimaged patients, and amputation was more commonly performed in imaged patients (p < .001). Bony changes were identified in 13/44 (29.5%) of imaged patients. In 8/44 (18.2%), imaging findings caused a change in treatment. In 99/107 (92.5%) of the cohort, imaging was either not performed or did not change management. CONCLUSION: In select cases, imaging may help guide patient management. Sufficient evidence does not yet exist to support routine imaging for patients with nail unit SCC.

Circulating Tumor Cells as Potential Biomarkers in Bladder Cancer.

PURPOSE: We explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing. MATERIALS AND METHODS: A total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFlux™ System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing. RESULTS: Median circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low-fewer than 10, medium-11 to 30 and high-greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch® showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity. CONCLUSIONS: This study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells.

Impact of warm versus cold ischemia on renal function following partial nephrectomy.

INTRODUCTION: We evaluated renal function following partial nephrectomy with cold ischemia (CI) versus warm ischemia (WI). METHODS: Data were collected from 1,396 patients at six institutions who underwent partial nephrectomy for a renal mass with normal contralateral kidney to evaluate percent change in glomerular filtration rate (GFR) at 3-18 months. A multivariate linear regression model tested the association of percent change GFR with clinical, operative, and pathologic factors. RESULTS: A total of 874 patients (63 %) underwent PN with CI and 522 (37 %) with WI. All patients undergoing laparoscopic and robotic-assisted partial nephrectomy (n = 443) had WI, whereas 92 % of open partial nephrectomy patients (n = 953) had CI. The CI group had a lower mean baseline GFR (72 vs. 80 ml/min/1.73 m(2)), longer median ischemia time (33 vs. 29 min), and larger mean tumor size (3.2 vs. 2.9 cm) with more advanced pathologic stage (T1b-T3: 25 vs. 16 %) (all p values <0.001). Patients with CI and WI demonstrated 12.3 and 10.1 % reductions in renal function from baseline, respectively (p = 0.067). Increasing age, female gender, and increasing tumor size were associated with reduction in renal function (all p values <0.001). Neither renal hypothermia nor operative technique independently predicted reduced renal function. Sensitivity analyses limited to ischemia time >30 min, baseline estimated glomerular filtration rate <60 ml/min/1.73 m(2), or tumors >4 cm did not significantly alter the findings. CONCLUSIONS: Increasing age, female gender, and larger tumor size independently predict a decrease in renal function following partial nephrectomy with a normal contralateral kidney. Within the limitations of a non-randomized comparison, including lack of parenchymal preservation percentage, neither surgical approach (open or laparoscopic) nor presence of hypothermia appears to be associated with long-term renal function.

The Severe Skin Cancer Consequences of Extended Tanning Bed Use, A Case Report.

INTRODUCTION: Tanning bed use has been directly correlated with increased risk of melanoma and non-melanoma skin cancers with greater duration and frequency of use. Despite this, complete bans for minors accessing indoor tanning devices are active in less than half of the states in the United States. CASE PRESENTATION: A 65-year-old female presented to our Mohs surgery clinic with a history of left temporal T2a melanoma, multiple untreated advanced keratinocyte carcinomas, and innumerable smaller untreated keratinocyte carcinomas on her legs, arms, and back after more than 40 years of weekly tanning bed use. DISCUSSION: Reports from the literature indicate that first exposure under age 35 to tanning devices increases the risk for melanoma and non-melanoma skin cancers. Several programs currently focus on prevention, education, and legislative change surrounding this topic. CONCLUSIONS: Highlighting such severe cases may provide an effective form of education for the public regarding the potential disease burden that results from indoor tanning.

A systematic review and meta-analysis of depression and apathy frequency in adult-onset Huntington's disease.

Depression and apathy are associated with decreased functional capacity in Huntington's disease (HD) but frequency of depression and apathy in HD is largely unknown. Systematic literature searching was conducted across 21 databases until 30 June 2021. Inclusion criteria was limited to clinician-rated assessments of depression and apathy and adult-onset HD. Inverse-variance heterogeneity meta-analyses were conducted exploring depression and apathy frequency within individuals from families affected by HD, and within individuals with confirmed HD gene-positive status. Screening identified 289 articles for full-text review; nine remained for meta-analysis. Depression frequency in the lifetime in adults affected by or at-risk for HD was 38%, I2 = 99%. Apathy frequency in the lifetime in adults affected by or at-risk for HD was 40%, I2 = 96%. The robustness of the findings improved when limiting the analysis to gene-positive individuals only where apathy was found to be slightly more common than depression, 48% and 43% respectively. Future studies may consider reporting results from juvenile-onset HD and adult-onset HD cohorts separately to further explore phenotypic profiles.

SNP chromosome microarray genotyping for detection of uniparental disomy in the clinical diagnostic laboratory.

Single nucleotide polymorphism (SNP) chromosome microarray is well established for investigation of children with intellectual deficit/development delay and prenatal diagnosis of fetal malformation but has also emerged for uniparental disomy (UPD) genotyping. Despite published guidelines on clinical indications for testing there are no laboratory guidelines published for performing SNP microarray UPD genotyping. We evaluated SNP microarray UPD genotyping using Illumina beadchips on family trios/duos within a clinical cohort (n=98) and then explored our findings in a post-study audit (n=123). UPD occurred in 18.6% and 19.5% cases, respectively, with chromosome 15 most frequent (62.5% and 25.0%). UPD was predominantly maternal in origin (87.5% and 79.2%), highest in suspected genomic imprinting disorder cases (56.3% and 41.7%) but absent amongst children of translocation carriers. We assessed regions of homozygosity among UPD cases. The smallest interstitial and terminal regions were 2.5 Mb and 9.3 Mb, respectively. We found regions of homozygosity confounded genotyping in a consanguineous case with UPD15 and another with segmental UPD due to non-informative probes. In a unique case with chromosome 15q UPD mosaicism, we established the detection limit of mosaicism as ∼5%. From the benefits and pitfalls identified in this study, we propose a testing model and recommendations for UPD genotyping by SNP microarray.

Balance on the Brain: a randomised controlled trial evaluating the effect of a multimodal exercise programme on physical performance, falls, quality of life and cognition for people with mild cognitive impairment-study protocol.

INTRODUCTION: Exercise and physical activity have been shown to improve cognition for people living with mild cognitive impairment (MCI). There is strong evidence for the benefits of aerobic exercise and medium evidence for participating in regular strength training for people with MCI. However, people living with MCI fall two times as often as those without cognitive impairment and the evidence is currently unknown as to whether balance training for people with MCI is beneficial, as has been demonstrated for older people without cognitive impairment. The aim of this study is to determine whether a balance-focused multimodal exercise intervention improves balance and reduces falls for people with MCI, compared with a control group receiving usual care. METHODS AND ANALYSIS: This single blind randomised controlled trial (Balance on the Brain) will be offered to 396 people with MCI living in the community. The multimodal exercise intervention consists of two balance programmes and a walking programme to be delivered by physiotherapists over a 6-month intervention period. All participants will be followed up over 12 months (for the intervention group, this involves 6-month intervention and 6-month maintenance). The primary outcomes are (1) balance performance and (2) rate of falls. Physical performance, levels of physical activity and sedentary behaviour, quality of life and cognition are secondary outcomes. A health economic analysis will be undertaken to evaluate the cost-effectiveness of the intervention compared with usual care. ETHICS AND DISSEMINATION: Ethics approval has been received from the South Metropolitan Health Service Human Research Ethics Committee (HREC), Curtin University HREC and the Western Australia Department of Health HREC; and approval has been received to obtain data for health costings from Services Australia. The results will be disseminated through peer-review publications, conference presentations and online platforms. TRIAL REGISTRATION NUMBER: ACTRN12620001037998; Australian New Zealand Clinical Trials Registry (ANZCTR).

Chronic kidney disease before and after partial nephrectomy.

PURPOSE: We performed a multi-institutional retrospective cohort study to evaluate baseline renal function of patients who underwent partial nephrectomy for renal tumors, and determined rates of progression to higher stages of chronic kidney disease. MATERIALS AND METHODS: The Modification of Diet in Renal Disease study equation was used to estimate glomerular filtration rate. Preoperative and postoperative serum creatinine values were obtained from patients who underwent partial nephrectomy at 6 institutions with a normal contralateral kidney, and had baseline chronic kidney disease stage I (estimated glomerular filtration rate greater than 90 ml/minute/1.73 m(2)), II (estimated glomerular filtration rate 60 to 89 ml/minute/1.73 m(2)) or III (estimated glomerular filtration rate 30 to 59 ml/minute/1.73 m(2)). The end point was change in chronic kidney disease stage at long-term followup (3 to 18 months). Multivariate logistic and Cox regression models tested the association of newly acquired chronic kidney disease stage III or greater with pertinent demographic, tumor and surgical factors. RESULTS: For 1,228 patients with followup creatinine data at least 3 months after partial nephrectomy median baseline glomerular filtration rate was 74 ml/minute/1.73 m(2). At baseline 19%, 59% and 22% of patients had chronic kidney disease stage I, II and III, respectively. At long-term followup for patients with baseline chronic kidney disease stage I or II median postoperative glomerular filtration rate was 67 ml/minute/1.73 m(2) with 29% having progression to chronic kidney disease stage III or greater. Increasing age, female gender, increasing tumor size, clamping of the renal artery and vein, and lower preoperative estimated glomerular filtration rate were independently associated with newly acquired chronic kidney disease stage III or greater. The presence of comorbid conditions such as coronary artery disease, diabetes mellitus or hypertension did not independently predict an increased risk of higher chronic kidney disease stage. CONCLUSIONS: Chronic kidney disease stage III or greater will develop postoperatively in approximately a third of patients with an estimated glomerular filtration rate greater than 60 ml/minute/1.73 m(2), and this progression is associated with definable demographic, tumor and surgical factors.

Chronic Kidney Disease Epidemiology Collaboration versus Modification of Diet in Renal Disease equations for renal function evaluation in patients undergoing partial nephrectomy.

PURPOSE: A novel equation, the Chronic Kidney Disease Epidemiology Collaboration, has been proposed to replace the Modification of Diet in Renal Disease for estimated glomerular filtration rate due to higher accuracy, particularly in the setting of normal renal function. We compared these equations in patients with 2 functioning kidneys undergoing partial nephrectomy. MATERIALS AND METHODS: We assembled a cohort of 1,158 patients from 5 institutions who underwent partial nephrectomy between 1991 and 2009. Only subjects with 2 functioning kidneys were included in the study. The end points were baseline estimated glomerular filtration rate, last followup estimated glomerular filtration rate (3 to 18 months), absolute and percent change estimated glomerular filtration rate ([absolute change/baseline] × 100%), and proportion of newly developed chronic kidney disease stage III. The agreement between the equations was evaluated using Bland-Altman plots and the McNemar test for paired observations. RESULTS: Mean baseline estimated glomerular filtration rate derived from the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations were 73 and 77 ml/minute/1.73 m(2), respectively, and following surgery were 63 and 67 ml/minute/1.73 m(2), respectively. Mean percent change estimated glomerular filtration rate was -12% for both equations (p = 0.2). The proportion of patients with newly developed chronic kidney disease stage III following surgery was 32% and 25%, according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations, respectively (p = 0.001). CONCLUSIONS: For patients with 2 functioning kidneys undergoing partial nephrectomy the Chronic Kidney Disease Epidemiology Collaboration equation provides slightly higher glomerular filtration rate estimates compared to the Modification of Diet in Renal Disease equation, with 7% fewer patients categorized as having chronic kidney disease stage III or worse.

Improving Effective Preventative Care Within an Urban Working Population.

OBJECTIVE: To assess whether standardized screening and service navigation improve access to primary care in low wage workers. METHODS: Four rapid plan-do-study-act cycles were conducted over an 8-week period. Each cycle consisted of four core interventions. Data were collected every 2 to 3 days, then analyzed on run charts and aggregate data tables. RESULTS: Effective care was achieved by increasing the percentage of patients with a primary care provider from 52% to 79%. Patients' perception of health increased from 3.6 to 4.4 and team communication and support score increased from 3.9 to 4.2 on a 5-point Likert scale. CONCLUSIONS: Patient engagement and a standardized referral process aids in the establishment of routine, effective care. Application of "smart phrases" in electronic health records provides sustainability for use in other occupational medicine practices.

No association between common genetic variation in FOXP2 and language impairment in schizophrenia.

The FOXP2 gene is hypothesised to be involved in schizophrenia by affecting speech and language development. Associations between common single nucleotide polymorphisms (SNPs) in FOXP2 and language have been inconsistent. We tested five previously associated SNPs for association with language in the Western Australian Family Study of Schizophrenia (n = 709, including n = 333 with schizophrenia/spectrum disorder) and found no significant associations. When we included all common FOXP2 variants, one SNP (rs2189008) was nominally associated with language. This is the most comprehensive analysis to date and indicates that common variants in FOXP2 do not play a major role in speech and language development in a clinical family sample.