Aberrant DNA methylation is an epigenetic hallmark of melanoma, known to play important roles in melanoma formation and progression. Recent advances in genome-wide methylation methods have provided ...the means to identify differentially methylated genes, methylation signatures, and potential biomarkers. However, despite considerable effort and advances in cataloging methylation changes in melanoma, many questions remain unanswered. The aim of this review is to summarize recent developments, emerging trends, and important unresolved questions in the field of aberrant DNA methylation in melanoma. In addition to reviewing recent developments, we carefully synthesize the findings in an effort to provide a framework for understanding the current state and direction of the field. To facilitate clarity, we divided the review into DNA methylation changes in melanoma, biomarker opportunities, and therapeutic developments. We hope this review contributes to accelerating the utilization of the diagnostic, prognostic, and therapeutic potential of DNA methylation for the benefit of melanoma patients.
Background Long-term survival after R0 resection for non-small cell lung cancer (NSCLC) is less than 50%. The majority of mortality after resection is related to tumor recurrence. The purpose of this ...study was to identify independent perioperative and pathologic variables that are associated with NSCLC recurrence after complete surgical resection. Methods A retrospective examination was performed of a prospectively maintained database of patients who underwent resection for NSCLC from July 1999 to August 2008 at a single institution. Clinicopathologic variables were evaluated for their influence on time to recurrence. Cox's proportional regression hazard model examined the association of recurrence in NSCLC. Results A total of 1,143 patients met inclusion criteria and had complete follow-up information. Of these patients, 378 (33.1%) had recurrence of the primary cancer. Median follow-up was 24 months (range, 3–134 months). Preoperative tumor maximum standardized uptake value (SUVmax ) greater than 5 was associated with increased risk of recurrence (hazard ratio HR, 1.81; p = 0.01). Preoperative radiation was independently associated with recurrence (HR, 1.98; p = 0.05) as well as the presence of pathologic stage II and stage III disease (stage II: HR, 2.53; p = 0.05; stage III: HR, 6.49; p = 0.006). Subgroup analysis found that sublobar resection was also associated with locoregional recurrence after resection (HR, 4.17; p = 0.02) and lymphovascular invasion of distant recurrence (HR, 4.21; p = 0.002). Conclusions In the largest series reported to date on postresectional recurrence of NSCLC, SUVmax greater than 5, increasing pathologic stage, and the administration of preoperative radiation were independently associated with NSCLC recurrence after resection. Sublobar resection was independently associated with locoregional recurrence, and lymphovascular invasion was associated with distant recurrence.
DNA methyltransferase DNMT3B is frequently overexpressed in tumor cells and plays important roles during the formation and progression of several cancer types. However, the specific signaling ...pathways controlled by DNMT3B in cancers, including melanoma, are poorly understood. Here, we report that DNMT3B plays a pro-tumorigenic role in human melanoma and that DNMT3B loss dramatically suppresses melanoma formation in the Braf/Pten mouse melanoma model. Loss of DNMT3B results in hypomethylation of the miR-196b promoter and increased miR-196b expression, which directly targets the mTORC2 component Rictor. Loss of RICTOR in turn prevents mTORC2 activation, which is critical for melanoma formation and growth. These findings establish Dnmt3b as a regulator of melanoma formation through its effect on mTORC2 signaling. Based on these results, DNMT3B is a potential therapeutic target in melanoma.
Display omitted
•Loss of Dnmt3b suppresses melanoma formation in vivo•Dnmt3b regulates the protein level of mTORC2 component Rictor•Dnmt3b modulates Rictor levels via miR-196b promoter methylation•miR-196 methylation is associated with reduced survival in melanoma
DNMT3B is frequently overexpressed in melanoma, but it remains unclear how DNMT3B modulates melanoma growth. Micevic et al. report that loss of DNMT3B in a mouse model of melanoma delays tumor formation by altering mTORC2 signaling in melanoma cells. Their results suggest DNMT3B as a therapeutic target in melanoma.
Long INterspersed Element-1 (LINE-1 or L1) is the only autonomously active, transposable element in the human genome. L1 sequences comprise approximately 17 % of the human genome, but only the ...evolutionarily recent, human-specific subfamily is retrotransposition competent. The L1 promoter has a bidirectional orientation containing a sense promoter that drives the transcription of two proteins required for retrotransposition and an antisense promoter. The L1 antisense promoter can drive transcription of chimeric transcripts: 5' L1 antisense sequences spliced to the exons of neighboring genes.
The impact of L1 antisense promoter activity on cellular transcriptomes is poorly understood. To investigate this, we analyzed GenBank ESTs for messenger RNAs that initiate in the L1 antisense promoter. We identified 988 putative L1 antisense chimeric transcripts, 911 of which have not been previously reported. These appear to be alternative genic transcripts, sense-oriented with respect to gene and initiating near, but typically downstream of, the gene transcriptional start site. In multiple cell lines, L1 antisense promoters display enrichment for YY1 transcription factor and histone modifications associated with active promoters. Global run-on sequencing data support the activity of the L1 antisense promoter. We independently detected 124 L1 antisense chimeric transcripts using long read Pacific Biosciences RNA-seq data. Furthermore, we validated four chimeric transcripts by quantitative RT-PCR and Sanger sequencing and demonstrated that they are readily detectable in many normal human tissues.
We present a comprehensive characterization of human L1 antisense promoter-driven transcripts and provide substantial evidence that they are transcribed in a variety of human cell-types. Our findings reveal a new wide-reaching aspect of L1 biology by identifying antisense transcripts affecting as many as 4 % of all human genes.
Post-inflammatory hypopigmentation is a common acquired pigmentary disorder that is more prominent in skin of color, leading to great cosmetic and psychosocial implications. Often, a diagnosis with a ...pigmentary disorder can negatively impact an individual's health-related quality of life and may result in stigma. Although most cases of post-inflammatory hypopigmentation resolve spontaneously over time, a systematic diagnostic approach can help with identifying the underlying etiology and informing treatment strategies. It can be due to cutaneous inflammation, sequelae of inflammatory or infectious dermatoses, or dermatologic procedures. Therefore, a thorough understanding of the epidemiology, patient history, physical exam findings, and clinical features of post-inflammatory hypopigmentation phenomenon can explain the primary cause to providers and allow for patient education. It is also important to understand the various therapeutic approaches available and the efficacy of these options, which will inform providers to choose the appropriate therapy for patients. Although algorithms exist for classifying acquired disorders of hypopigmentation, there are no established algorithms for the diagnosis and treatment of post-inflammatory hypopigmentation, which warrants further exploration and discourse.
BackgroundImmune checkpoint inhibitors (ICI) generate T-cell mediated anti-tumor responses that are effective across numerous malignancies, but their use is frequently complicated by immune-related ...adverse events (irAEs). irAEs may lead to treatment delays, need for immunosuppression, morbidity, and even mortality.1–3Checkpoint inhibitor pneumonitis (CIP) is the most common cause of fatality related to anti-programmed cell death receptor/ligand 1 (PD-1/PD-L1) agents, and can be difficult to diagnose.3 We aimed to characterize the real-world incidence and management of CIP, as well as its impact on clinical course and healthcare utilization, in a large cohort of ICI patients using a multi-institutional database.MethodsPropensity score-matched cohorts of 14,461 lung cancer patients who did or did not receive PD-1/PD-L1 inhibitors between 2014 to 2021 were identified from TriNetX Dataworks, a database of health records and claims data from over 40 institutions. Incidence of pneumonia/pneumonitis was estimated using billing codes. A subgroup of 158 patients was selected by the most specific code group and confirmed to have features consistent with suspected CIP, permitting analysis of management practices and outcomes. To describe differences in healthcare utilization and survival, a second propensity score-matched cohort was generated for the subgroup.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors in lung cancer at 1 year after ICI initiation was 6.88% (95% CI 6.01–7.75%). Median time to onset of drug-induced pneumonitis in the subgroup was 4.4 months (IQR 2.1–7.8 months). Of 158 patients, 21 (13.3%) underwent bronchoscopy within 30 days after diagnosis. Prednisone (130/158, 82.3%), methylprednisolone (80/158, 50.6%), and antibiotics (135/158, 85.4%) were frequently prescribed. ICI was discontinued in 69.5% of patients within 90 days of drug-induced pneumonitis. Within the first year of PD-1/PD-L1 therapy, patients with pneumonitis had more hospitalizations (83.5% vs 49.4%, RR 1.69, p<0.0001) and ICU requirements than controls (28.5% vs 8.9%, RR 3.21, p<0.0001). Landmark analysis at 6 months demonstrated that CIP associated with reduced overall survival, with a mortality HR of 1.43 (95% CI 1.03–1.97, p=0.03).ConclusionsTo our knowledge, this is the largest study of CIP to date. Importantly, the study found that the incidence of PD-1/PD-L1-induced pneumonitis, 6.88%, is higher than clinical trial estimates (2–5%), but lower than reported in uncontrolled real-world studies (17–19%).4–8 CIP had significant negative impacts on therapy continuation, healthcare utilization, and overall survival in lung cancer. This work demonstrates proof of concept that studies of irAE incidences and patient outcomes are feasible using large claims and electronic health record databases.ReferencesBrahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology 2018;36(17):1714–1768. doi:10.1200/JCO.2017.77.6385.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer 2017;5(1):95. doi:10.1186/s40425-017-0300-z.Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncology 2018;4(12):1721–1728. doi:10.1001/jamaoncol.2018.3923.Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer a systematic review and meta-analysis. JAMA Oncology 2016;2(12):1607–1616. doi:10.1001/jamaoncol.2016.2453.Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. Journal of Clinical Oncology 2017;35(7):709–717. doi:10.1200/JCO.2016.68.2005.Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. European Respiratory Journal 2017;50(2). doi:10.1183/13993003.00050-2017.Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. Journal of Thoracic Oncology 2018;13(12):1930–1939. doi:10.1016/j.jtho.2018.08.2035.Cathcart-Rake EJ, Sangaralingham LR, Henk HJ, Shah ND, Riaz I bin, Mansfield AS. A population-based study of immunotherapy-related toxicities in lung cancer. Clinical Lung Cancer 2020;21(5):421–427.e2. doi:10.1016/j.cllc.2020.04.003Ethics ApprovalAs described on TriNetX's website (https://trinetx.com/trinetx-publication-guidelines/), all data available on the network is de-identified and in-line with HIPAA Privacy Rule standards.
BackgroundImmune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as ...checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts.MethodsA combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1–7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71).ConclusionsIn a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.
BackgroundIt is unclear whether treatment with immune checkpoint inhibitors (ICIs) is a risk factor for contracting COVID-19. We investigated whether patients prescribed ICIs were more or less likely ...to contract COVID-19 than matched controls in a collaboration between a large academic healthcare system and the Massachusetts Department of Health.MethodsWe performed a retrospective study of 1,577 cancer patients prescribed ICI and 26,241 matched controls. We included all patients infused with an ICI in the Mass General Brigham (MGB) network between 7/1/19 and 2/29/20 and generated an exact match of control patients from the MGB database on age, sex, and Charlson comorbidity index. For both groups, we cross referenced COVID-19 infection data through June 19, 2020 from the Massachusetts Department of Public Health using date of birth, last name, and first four letters of the first name. We calculated odds ratios (OR) for COVID-19 diagnosis using a multivariate logistic regression adjusting for age, sex, race, CCI, zip code income, and local infection rate.ResultsTwenty-one patients (1.3%) prescribed ICIs and 527 controls (2.0%) were identified as COVID positive in the Massachusetts department of health database. When controlling for local infection rate, age, sex, race, CCI, and zip code income, there were no significant differences in COVID infection between ICI recipients and matched controls (OR: 0.7, 95% CI: 0.45 – 1.09, p=0.1; table 1).Abstract 826 Table 1Multivariable logistic regression for patients treated with ICI with Odds Ratios for defining ‘event’ to be COVID-19 positivityConclusionsIn our experience, patients who were prescribed ICI were not more likely to contract COVID-19 than matched controls, which may assist in decision-making around continuation of therapy during the pandemic. More research needs to be conducted to determine potential behavioral and testing factors that may affect COVID-19 diagnosis.
Mucormycosis is a rare and aggressive fungal infection, most often caused by species of the Mucor, Rhizomucor, Rhizopus, Absidia, and Cunninghamella genera. The condition most commonly affects ...patients with uncontrolled diabetes, HIV/AIDS, malignancy, and those receiving long-term immunosuppressive therapy. We report the case of a 39-year-old male with biopsy-proven cutaneous mucormycosis of the left axilla 4 months after an orthotopic heart transplant for congenital tricuspid atresia.
PDF
