Incidence and Survival Outcomes of Dermatofibrosarcoma Protuberans From 2000 to 2020: A Population-Based Retrospective Cohort Analysis.

BACKGROUND: Recent changes in the incidence and survival of dermatofibrosarcoma protuberans (DFSP) have not been described. OBJECTIVE: To characterize the incidence and survival of DFSP. MATERIALS AND METHODS: A retrospective cohort study of patients with DFSP from 2000 to 2020 in the Surveillance, Epidemiology, and End Results database was performed. Cox and Fine-Gray regression models were used to assess overall and DFSP-specific survival. RESULTS: The incidence of DFSP has not changed from 2000 to 2020 with 4.6 cases/million person-years, with higher rates in dark-skinned and middle-age individuals. Factors associated with overall mortality in DFSP patients include advanced age ( p < .0001), male sex (hazard ratio [HR] 1.8, p < .0001), larger tumors (HR 1.002 per millimeter, p < .001), lower household income (HR 1.8, p = .0002), and lower extremity location (HR 1.7, p = .008). Mohs surgery is associated with improved overall survival (HR 0.4, p = .02). Large tumor size (6.0+ cm, HR 6.7, p = .01) and advanced age (age 80+ years, HR 21.3, p = .003) were associated with worse DFSP-specific mortality. CONCLUSION: Dermatofibrosarcoma protuberans incidence has remained constant from 2000 to 2020. Increasing age and tumor size, decreased income, male sex, and lower extremity location are associated with worsened survival. Mohs surgery is associated with improved overall survival. Increased age and tumor size are associated with worsened DFSP-specific mortality.

The impact of the COVID-19 pandemic in 2020 on the diagnosis, treatment, and outcomes of invasive cutaneous melanoma: A retrospective national cohort study.

BACKGROUND: Prior multiinstitutional studies demonstrate that patients diagnosed with melanoma during the Coronavirus Disease 2019 (COVID-19) pandemic presented with more advanced melanomas. OBJECTIVES: To further characterize patients diagnosed with melanoma during the COVID-19 pandemic. METHODS: Retrospective population-based cohort study of the Surveillance, Epidemiology, and End-Results (SEER) registry of patients diagnosed with cutaneous melanoma from 2018-2020. RESULTS: Patients diagnosed with melanoma in 2020 were more likely to have increased Breslow depth, more ulceration, nodular tumors, and more advanced stage at diagnosis despite less treatment delays. Patients tended to be from wealthier, more urban areas. Primary surgical treatment was more likely to be with Mohs surgery. Diagnosis in the year 2020 was not correlated with overall or disease specific survival. LIMITATIONS: This is a retrospective cohort review and limited by short follow-up times, which could affect survival outcomes. There was a 15.5% drop in melanoma diagnosis in 2020 compared to prior years, which could relate to delayed presentation. CONCLUSIONS AND RELEVANCE: Patients diagnosed with melanoma in 2020 tended to have thicker, more ulcerated, and more advanced tumors, but this was not associated with survival. Further studies are needed to characterize outcomes for patients diagnosed with melanoma during the COVID-19 pandemic.

Delays in the surgical treatment of melanoma are associated with worsened overall and melanoma-specific mortality: A population-based analysis.

BACKGROUND: The effect of treatment delays on melanoma outcomes remains unclear. OBJECTIVE: To assess the impact of surgical treatment delays on melanoma-specific mortality (MSM) and overall mortality (OM). METHODS: Patients with stage I to III cutaneous melanoma were identified through the Surveillance, Epidemiology, and End Results database (N = 108,689). Included cases had time from diagnosis to definitive surgery and follow-up time. Cox proportional hazards and Fine-Gray competing risks analyses were used to assess the impact of treatment delays on mortality. RESULTS: Across all stages, treatment delays of 3 to 5 months were associated with worse MSM and any delay beyond 1 month was associated with worse OM. In a subgroup analysis of patients with stage I disease, delays of 3 to 5 months were associated with worse MSM and any delay beyond 1 month was associated with worse OM. In patients with stage II disease, worse MSM was found with delays of 6+ months and worse OM was seen with delays of 3 to 5 months. No significant effect of treatment delays was noted in stage III disease. LIMITATIONS: The Surveillance, Epidemiology, and End Results database does not collect comprehensive data on adjuvant treatments, disease recurrence, or treatment failure. CONCLUSION: Timely treatment of melanoma may be associated with improved OM and MSM.

Implications of Satellitosis or In-transit Metastasis in Cutaneous Squamous Cell Carcinoma: A Prognostic Omission in Cancer Staging Systems.

IMPORTANCE: Unlike Merkel cell carcinoma and melanoma, satellitosis or in-transit metastasis (S-ITM) is not incorporated into the current cutaneous squamous cell carcinoma (CSCC) staging systems. It is important to determine if the clinical outcomes of S-ITM are relevant to prognosis for patients with CSCC. OBJECTIVES: To evaluate the association of S-ITM with clinical outcomes in patients with CSCC and to determine its prognostic implications. DESIGN, SETTINGS, AND PARTICIPANTS: A dual-institution (Cleveland Clinic and Brigham and Women's Hospital) database was queried for patients who were treated for CSCC in 2010 to 2020. Patients who were node-negative and had S-ITM-the presence of dermal lesions between the primary tumor and first-echelon lymphatic nodal basins at any point in the disease course-were identified. Subcohorts of patients with T3N0 tumors, T4N0 tumors (bone invasive), N1 to 3, and M1 disease were identified for comparison. The American Joint Committee on Cancer staging system was used to define cancer stages. Data were analyzed from January 15 to March 31, 2021. MAIN OUTCOMES AND MEASURES: Pairwise comparison of CSCC recurrence and disease-specific survival in patients with and without S-ITM was performed using Cox proportional hazard modeling. Kaplan-Meier and Fine-Gray competing risk methods were used to estimate disease-specific survival and CSCC recurrence, respectively. RESULTS: In a total of 518 patients with CSCC, S-ITM was present in 72 (13.9 %) patients (median age [range], 73.9 [31.6-95.8] years; 59 [82%] men; 69 [96%] White non-Hispanic individuals; 25 [35%] patients with immunosuppression) who were node-negative. The subcohorts were composed of 341 patients with T3N0 cancer, 36 with T4N0, 70 with N1 to 3, and 19 with M1 disease. Pairwise comparisons between disease levels using Cox proportional hazard model demonstrated lower cumulative incidence of CSCC recurrence rates in the T3N0 (HR, 0.21; 95% CI, 0.14-0.30; P < .001) and T4N0 (HR, 0.36; 95% CI, 0.19-0.68; P = .001) cohorts compared with the S-ITM cohort. No significant difference was observed between patients who were node-positive and those with S-ITM (HR, 0.74; 95% CI, 0.48-1.14; P = .16). The 5-year disease-specific survival rates were 76% for T3N0, 64% for T4N0, 41% for S-ITM, and 39% for N1 to 3. Compared with the S-ITM cohort, DSS was significantly higher in the T3N0 (HR, 0.23; 95% CI, 0.15-0.35; P < .0001) and T4N0 (HR, 0.37; 95% CI, 0.19-0.76; P = .01) cohorts, and not significantly different in the node-positive (HR, 0.77; 95% CI, 0.84-3.93; P = .30) and metastatic cohorts (HR, 1.81; 95% CI, 0.84-3.93; P = .13). CONCLUSIONS AND RELEVANCE: This multi-institutional cohort study found that patients with CSCC and S-ITM appear to have clinical outcomes comparable to those of patients who are node-positive, and an increased risk of recurrence and worse survival compared with patients who have T3 and T4 disease. These outcomes are similar to those observed for Merkel cell carcinoma and melanoma. Given that S-ITM may be a powerful prognostic factor, it should be incorporated into clinical staging systems.

Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis.

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene Chi3l1, is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of Chi3l1/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, Chi3l1 deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, Chi3l1 deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that Chi3l1 may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, Chi3l1 knockdown increased phagocytosis of zymosan particles and of ß-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of Chi3l1 is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal Chi3l1 expression, whereas deletion of the negative clock regulators PER1/PER2 increased Chi3l1 expression. Basal Chi3l1 mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of Chi3l1 was gated by the clock. Our findings reveal Chi3l1/YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory Chi3l1 induction.

Rethinking the 10-pack-year rule for favorable human papillomavirus-associated oropharynx carcinoma: A multi-institution analysis.

BACKGROUND: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved. METHODS: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation). RESULTS: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%. CONCLUSIONS: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.

Mohs Surgery for SEER Registry-Captured Melanoma In Situ and Rare Cutaneous Tumors: Comparing National Utilization Patterns Before and After Implementation of the Affordable Care Act (2010) and Appropriate Use Criteria (2012).

BACKGROUND: The Affordable Care Act (ACA) and the appropriate use criteria (AUC) for Mohs micrographic surgery (MMS) had the potential to increase utilization rates of MMS for indicated skin cancers, but it is unknown whether this has occurred. OBJECTIVE: To determine whether rates of MMS utilization for head and neck melanoma in situ (MIS) and rare cutaneous tumors (RCTs) increased after the implementation of the ACA and AUC publication. MATERIALS AND METHODS: Retrospective review using data from the SEER database. Melanoma in situ and RCT tumor cases from before and after the ACA and AUC publication were compared. RESULTS: Twenty-four thousand six hundred seventy-eight cases were analyzed. Mohs micrographic surgery utilization for MIS decreased from 13.9% before the ACA to 12.3% after the ACA (odds ratio 0.87; p = .012). There was no significant change in MMS utilization for MIS after publication of the AUC. There was also no significant change in MMS utilization for treatment of RCT after the ACA or AUC publication. Stratification of patients into age groups younger or older than 65 years did not change utilization rates. CONCLUSION: Rates of MMS for treatment of MIS and RCT have not increased since the advent of the ACA or AUC. This finding highlights the need for continued efforts to improve access to MMS and to increase education of its utility in treating skin cancer.

Outcomes in intermediate-risk squamous cell carcinomas treated with Mohs micrographic surgery compared with wide local excision.

BACKGROUND: Brigham and Women's Hospital stage T2a squamous cell carcinomas, demonstrating a single high-risk feature, have a low risk of metastasis and death but an increased risk of local recurrence. Little evidence exists for the best treatment modality and associated outcomes in T2a squamous cell carcinoma. OBJECTIVE: We aimed to compare outcomes for T2a squamous cell carcinoma treated by Mohs micrographic surgery compared with wide local excision with permanent sections. METHODS: Retrospective review of an institutional review board-approved single-institution registry of T2a squamous cell carcinoma. RESULTS: Three hundred sixty-six primary T2a tumors were identified, including 240 squamous cell carcinomas (65.6%) treated with Mohs micrographic surgery and 126 (34.4%) treated with wide local excision. A total of 32.5% of patients were immunosuppressed and mean oncologic follow-up was 2.8 years. Local recurrence was significantly more likely after wide local excision (4.0%) than after Mohs micrographic surgery (1.2%) (P = .03). Multiple logistic regression demonstrated immunocompromised state (odds ratio [OR] 5.1; 95% confidence interval [CI] 1.1-23.3; P = .03) and wide local excision (OR 4.8; 95% CI 1.1-21.6; P = .04) associated with local recurrence; and wide local excision (OR 7.8; 95% CI 2.4-25.4; P < .001), high-risk head and neck location (OR 8.3; 95% CI 1.8-38.7; P = .004), and poor histologic differentiation (OR 4.7; 95% CI 1.4-15.4; P = .03) associated with poor outcomes (overall recurrence or disease-specific death). CONCLUSION: Mohs micrographic surgery provides improved outcomes in Brigham and Women's Hospital T2a squamous cell carcinoma.

Patient-reported allergies predict postoperative outcomes and psychosomatic markers after spine surgery.

BACKGROUND CONTEXT: Prior studies have shown that patient-reported allergies can be prognostic of poorer postoperative outcomes. PURPOSE: The objective of this study was to investigate the correlation between self-reported allergies and outcomes after cervical or lumbar spine surgery. STUDY DESIGN/SETTING: This is a retrospective cohort study at a single tertiary care institution. PATIENT SAMPLE: The patient sample included all patients undergoing cervical or lumbar spine surgery from 2009 to 2014. OUTCOME MEASURES: The primary outcome measure was change in the EuroQol-5 Dimensions (EQ-5D) after surgery. Secondary outcomes included changes in the Pain Disability Questionnaire (PDQ) and in the Patient Health Questionnaire-9 (PHQ-9), achievement of the minimal clinically important difference (MCID) in these measures, and cost of admission. METHODS: Before and after surgery, EQ-5D, PDQ, and PHQ-9 were recorded for patients with available data. Paired Student t tests were used to compare changes in these measures after surgery. Multivariable linear and logistic regressions were used to assess the relationship between the log transformation of the total number of allergies and outcomes. RESULTS: A total of 592 cervical patients and 4,465 lumbar patients were included. The median number of reported allergies was two. The EQ-5D index increased from 0.539 to 0.703 for cervical patients and from 0.530 to 0.676 for lumbar patients (p<.01 for both). Patients experienced significant pain improvement by the PDQ (80.1-58.2 for cervical patients and 79.4-58.1 for lumbar patients, p<.01). Using multivariable logistic regression, the log transformation of the number of allergies predicted significantly higher odds of achieving the PDQ MCID (odds ratio [OR]=2.09, 95% confidence interval [CI] 1.05-4.15, p=.02, for cervical patients; OR=1.30, 95% CI 1.03-1.68, p=.03, for lumbar patients). However, this relationship was not durable for patients with follow-up exceeding 1 year. The log transformation of the number of allergies for lumbar patients predicted a significantly increased cost of admission (ß=$3,597, p<.01) and trended toward significance among cervical patients (ß=$1,842, p=.10). CONCLUSIONS: Patient-reported allergies correlate with subjective improvement in pain and disability after spine surgery and may serve as a marker of postoperative outcomes. The relationship between allergies and PDQ improvement may be secondary to the short-term expectation-actuality discrepancy, as this relationship was not durable beyond 1 year.

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1.

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease.

Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy.

OBJECTIVE: The nicotinamide-nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule-associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy. Nmnat1 targeted to the cytoplasm (cytNmnat1) is neuroprotective in a mouse model of neonatal hypoxia-ischemia, but the effect of cytNmnat1 on tauopathy remains unknown. METHODS: We examined the impact of overexpression of cytNmnat1 on tau pathology, neurodegeneration, and brain functional connectivity in the P301S mouse model of chronic tauopathy. RESULTS: Overexpression of cytNmnat1 preserved cortical neuron functional connectivity in P301S mice in vivo. However, whereas Nmnat1 overexpression decreased the accumulation of detergent-insoluble tau aggregates in the cerebral cortex, it exerted no effect on immunohistochemical evidence of pathologic tau phosphorylation and misfolding, hippocampal atrophy, or inflammatory markers in P301S mice. INTERPRETATION: Our results demonstrate that cytNmnat1 partially preserves neuronal function and decreases biochemically insoluble tau in a mouse model of chronic tauopathy without preventing tau phosphorylation, formation of soluble aggregates, or tau-induced inflammation and atrophy. Nmnat1 might thus represent a therapeutic target for tauopathies.

Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease.

Disturbances in the sleep-wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep-wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep-wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep-wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.