Establishment and molecular characterization of HCB-541, a novel and aggressive human cutaneous squamous cell carcinoma cell line.

Cutaneous squamous cell carcinoma (cSCC) is a common type of skin cancer that can result in significant morbidity, although it is usually well-managed and rarely metastasizes. However, the lack of commercially available cSCC cell lines hinders our understanding of this disease. This study aims to establish and characterize a new metastatic cSCC cell line derived from a Brazilian patient. A tumor biopsy was taken from a metastatic cSCC patient, immortalized, and named HCB-541 after several passages. The cytokeratin expression profile, karyotypic alterations, mutational analysis, mRNA and protein differential expression, tumorigenic capacity in xenograft models, and drug sensitivity were analyzed. The HCB-541 cell line showed a doubling time between 20 and 30 h and high tumorigenic capacity in the xenograft mouse model. The HCB-541 cell line showed hypodiploid and hypotetraploidy populations. We found pathogenic mutations in TP53 p.(Arg248Leu), HRAS (Gln61His) and TERT promoter (C228T) and high-level microsatellite instability (MSI-H) in both tumor and cell line. We observed 37 cancer-related genes differentially expressed when compared with HACAT control cells. The HCB-541 cells exhibited high phosphorylated levels of EGFR, AXL, Tie, FGFR, and ROR2, and high sensitivity to cisplatin, carboplatin, and EGFR inhibitors. Our study successfully established HCB-541, a new cSCC cell line that could be useful as a valuable biological model for understanding the biology and therapy of metastatic skin cancer.

Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure.

Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival. TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.

Acute symptomatic complications among patients with advanced cancer admitted to acute palliative care units: A prospective observational study.

BACKGROUND: Limited information is available on the symptomatic complications that occur in the last days of life. AIM: We documented the frequency, clinical course, and survival for 25 symptomatic complications among patients admitted to acute palliative care units. DESIGN: Prospective longitudinal observational study. MEASUREMENTS: Their attending physician completed a daily structured assessment of symptomatic complications from admission to discharge or death. SETTING/PARTICIPANTS: We enrolled consecutive advanced cancer patients admitted to acute palliative care units at MD Anderson Cancer Center, USA, and Barretos Cancer Hospital, Brazil. RESULTS: A total of 352 patients were enrolled (MD Anderson Cancer Center = 151, Barretos Cancer Hospital = 201). Delirium, pneumonia, and bowel obstruction were the most common complications, occurring in 43%, 20%, and 16% of patients on admission, and 70%, 46%, and 35% during the entire acute palliative care unit stay, respectively. Symptomatic improvement for delirium (36/246, 15%), pneumonia (52/161, 32%), and bowel obstruction (41/124, 33%) was low. Survival analysis revealed that delirium (p < 0.001), pneumonia (p = 0.003), peritonitis (p = 0.03), metabolic acidosis (p < 0.001), and upper gastrointestinal bleed (p = 0.03) were associated with worse survival. Greater number of symptomatic complications on admission was also associated with poorer survival (p < 0.001). CONCLUSION: Symptomatic complications were common in cancer patients admitted to acute palliative care units, often do not resolve completely, and were associated with a poor prognosis despite active medical management.

Clinical signs of impending death in cancer patients.

BACKGROUND: The physical signs of impending death have not been well characterized in cancer patients. A better understanding of these signs may improve the ability of clinicians to diagnose impending death. We examined the frequency and onset of 10 bedside physical signs and their diagnostic performance for impending death. METHODS: We systematically documented 10 physical signs every 12 hours from admission to death or discharge in 357 consecutive patients with advanced cancer admitted to two acute palliative care units. We examined the frequency and median onset of each sign from death backward and calculated their likelihood ratios (LRs) associated with death within 3 days. RESULTS: In total, 203 of 357 patients (52 of 151 in the U.S., 151 of 206 in Brazil) died. Decreased level of consciousness, Palliative Performance Scale ≤20%, and dysphagia of liquids appeared at high frequency and >3 days before death and had low specificity (<90%) and positive LR (<5) for impending death. In contrast, apnea periods, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, pulselessness of radial artery, respiration with mandibular movement, and decreased urine output occurred mostly in the last 3 days of life and at lower frequency. Five of these signs had high specificity (>95%) and positive LRs for death within 3 days, including pulselessness of radial artery (positive LR: 15.6; 95% confidence interval [CI]: 13.7-17.4), respiration with mandibular movement (positive LR: 10; 95% CI: 9.1-10.9), decreased urine output (positive LR: 15.2; 95% CI: 13.4-17.1), Cheyne-Stokes breathing (positive LR: 12.4; 95% CI: 10.8-13.9), and death rattle (positive LR: 9; 95% CI: 8.1-9.8). CONCLUSION: We identified highly specific physical signs associated with death within 3 days among cancer patients.

Longitudinal temporal and probabilistic prediction of survival in a cohort of patients with advanced cancer.

CONTEXT: Survival prognostication is important during the end of life. The accuracy of clinician prediction of survival (CPS) over time has not been well characterized. OBJECTIVES: The aims of the study were to examine changes in prognostication accuracy during the last 14 days of life in a cohort of patients with advanced cancer admitted to two acute palliative care units and to compare the accuracy between the temporal and probabilistic approaches. METHODS: Physicians and nurses prognosticated survival daily for cancer patients in two hospitals until death/discharge using two prognostic approaches: temporal and probabilistic. We assessed accuracy for each method daily during the last 14 days of life comparing accuracy at Day -14 (baseline) with accuracy at each time point using a test of proportions. RESULTS: A total of 6718 temporal and 6621 probabilistic estimations were provided by physicians and nurses for 311 patients, respectively. Median (interquartile range) survival was 8 days (4-20 days). Temporal CPS had low accuracy (10%-40%) and did not change over time. In contrast, probabilistic CPS was significantly more accurate (P < .05 at each time point) but decreased close to death. CONCLUSION: Probabilistic CPS was consistently more accurate than temporal CPS over the last 14 days of life; however, its accuracy decreased as patients approached death. Our findings suggest that better tools to predict impending death are necessary.