Genotype prediction of 336,463 samples from public expression data.

Tens of thousands of RNA-sequencing experiments comprising hundreds of thousands of individual samples have now been performed. These data represent a broad range of experimental conditions, sequencing technologies, and hypotheses under study. The Recount project has aggregated and uniformly processed hundreds of thousands of publicly available RNA-seq samples. Most of these samples only include RNA expression measurements; genotype data for these same samples would enable a wide range of analyses including variant prioritization, eQTL analysis, and studies of allele specific expression. Here, we developed a statistical model based on the existing reference and alternative read counts from the RNA-seq experiments available through Recount3 to predict genotypes at autosomal biallelic loci in coding regions. We demonstrate the accuracy of our model using large-scale studies that measured both gene expression and genotype genome-wide. We show that our predictive model is highly accurate with 99.5% overall accuracy, 99.6% major allele accuracy, and 90.4% minor allele accuracy. Our model is robust to tissue and study effects, provided the coverage is high enough. We applied this model to genotype all the samples in Recount 3 and provide the largest ready-to-use expression repository containing genotype information. We illustrate that the predicted genotype from RNA-seq data is sufficient to unravel the underlying population structure of samples in Recount3 using Principal Component Analysis.

FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA.

Analysis of DNA methylation in cell-free DNA reveals clinically relevant biomarkers but requires specialized protocols such as whole-genome bisulfite sequencing. Meanwhile, millions of cell-free DNA samples are being profiled by whole-genome sequencing. Here, we develop FinaleMe, a non-homogeneous Hidden Markov Model, to predict DNA methylation of cell-free DNA and, therefore, tissues-of-origin, directly from plasma whole-genome sequencing. We validate the performance with 80 pairs of deep and shallow-coverage whole-genome sequencing and whole-genome bisulfite sequencing data.

FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA.

Analysis of DNA methylation in cell-free DNA (cfDNA) reveals clinically relevant biomarkers but requires specialized protocols and sufficient input material that limits its applicability. Millions of cfDNA samples have been profiled by genomic sequencing. To maximize the gene regulation information from the existing dataset, we developed FinaleMe, a non-homogeneous Hidden Markov Model (HMM), to predict DNA methylation of cfDNA and, therefore, tissues-of-origin directly from plasma whole-genome sequencing (WGS). We validated the performance with 80 pairs of deep and shallow-coverage WGS and whole-genome bisulfite sequencing (WGBS) data.

The Influence of Using Novel Predictive Technologies on Judgments of Stigma, Empathy, and Compassion among Healthcare Professionals.

BACKGROUND: Our objective was to evaluate whether the description of a machine learning (ML) app or brain imaging technology to predict the onset of schizophrenia or alcohol use disorder (AUD) influences healthcare professionals' judgments of stigma, empathy, and compassion. METHODS: We randomized healthcare professionals (N = 310) to one vignette about a person whose clinician seeks to predict schizophrenia or an AUD, using a ML app, brain imaging, or a psychosocial assessment. Participants used scales to measure their judgments of stigma, empathy, and compassion. RESULTS: Participants randomized to the ML vignette endorsed less anger and more fear relative to the psychosocial vignette, and the brain imaging vignette elicited higher pity ratings. The brain imaging and ML vignettes evoked lower personal responsibility judgments compared to the psychosocial vignette. Physicians and nurses reported less empathy than clinical psychologists. CONCLUSIONS: The use of predictive technologies may reinforce essentialist views about mental health and substance use that may increase specific aspects of stigma and reduce others.

Oral Sedation Anesthesia Protocol for In-Office Oculoplastic Surgery.

PURPOSE: To present an oral anesthesia protocol for in-office oculoplastic surgery and to compare safety outcomes and patient and physician experiences to ambulatory surgery center (ASC)-based surgery with intravenous sedation or general anesthesia. METHODS: A prospective study was performed on consecutive patients undergoing surgery at an oculofacial plastic surgery practice. Surgery was performed in an in-office setting using our standardized oral sedation protocol or at an ASC with intravenous sedation or general anesthesia. Preoperative and postoperative surveys were conducted by patients and physicians to compare surgical experience, safety, and efficacy of our oral sedation protocol for in-office surgery in the ASC setting. RESULTS: Two hundred and fifty-three patients (167 in-office and 86 at ASC) underwent surgery between March and November 2022. There was no significant difference in how patients or physicians rated their experience between the 2 locations. A significantly higher proportion of ASC patients would have rather had surgery in-office (34.9% vs. 19.2%; p = 0.006). A significantly higher number of physicians in the office setting would have rather performed surgery at the ASC than the reverse (12.7% vs. 2.3%, respectfully; p = 0.007). There were no safety complications reported in either setting. CONCLUSIONS: Within our patient cohort, the presented oral sedation protocol provided safe and effective anesthesia for in-office oculoplastic surgery that is comparable to an ASC.

Psychedelics to Relieve Psychological Suffering Associated with a Life-Threatening Diagnosis: Time for a Canadian Policy Discussion.

In Canada, the conversation to enable access to therapeutic psychedelics is under way. With recent federal initiatives, Canadians can request access to psychedelic-assisted therapies (PATs) to alleviate enduring and intolerable psychological suffering (EIPS) associated with life-threatening conditions on a case-by-case basis. The resurgence of past research concerning the therapeutic potential of PATs, promising preliminary results from contemporary clinical trials, public and media interest and the recognition of traditional Indigenous use of psychedelics have facilitated a change in the popular narrative around these stigmatized substances. A lack of access to PATs for treating EIPS, especially at end of life, is a public policy problem worth addressing.

Does witness type affect the chance of receiving bystander CPR in out-of-hospital cardiac arrest?

OBJECTIVES: The relationship between the bystander witness type and receipt of bystander CPR (BCPR) is not well understood. Herein we compared BCPR administration between family and non-family witnessed out-of-hospital cardiac arrest (OHCA). BACKGROUND: In many communities, interventions in the past decade have contributed to an increased receipt of BCPR, for example in Singapore from 15% to 60%. However, BCPR rates have plateaued despite sustained and ongoing community-based interventions, which may be related to gaps in education or training for various witness types. The purpose of this study was to investigate the association between witness type and BCPR administration. METHODS: Singapore data from 2010-2020 was extracted from the Pan-Asian Resuscitation Outcomes Study (PAROS) network registry (n = 25,024). All adult, layperson witnessed, non-traumatic OHCAs were included in this study. RESULTS: Of 10,016 eligible OHCA cases, 6,895 were family witnessed and 3,121 were non-family witnessed. After adjustment for potential confounders, BCPR administration was less likely for non-family witnessed OHCA (OR 0.83, 95% CI 0.75, 0.93). After location stratification, non-family witnessed OHCAs were less likely to receive BCPR in residential settings (OR 0.75, 95% CI 0.66, 0.85). In non-residential settings, there was no statistically significant association between witness type and BCPR administration (OR 1.11, 95% CI 0.88, 1.39). Details regarding witness type and bystander CPR were limited. CONCLUSION: This study found differences in BCPR administration between family and non-family witnessed OHCA cases. Elucidation of witness characteristics may be useful to determine populations that would benefit most from CPR education and training.

Extrascleral extension of choroidal melanoma after iodine-125 brachytherapy treatment: a case series.

BACKGROUND/OBJECTIVES: The purpose of this study is to report cases of choroidal melanoma that developed extrascleral tumour recurrence after treatment with iodine-125 brachytherapy. SUBJECTS/METHODS: In this single-institution retrospective observational case series, all instances of biopsy-confirmed orbital melanoma after known intraocular melanoma were reviewed. Tumour characteristics, clinical course, time to recurrence, cytogenetics of initial tumour and recurrence, and presence of intraocular recurrence were documented. RESULTS: Five cases of orbital melanoma following treatment with plaque radiotherapy are described. Tumour staging was Ia (1), IIa (2), and IIb (2). The primary lesion in four of the five appeared to have undergone complete regression for an average of 2 years, with the orbital melanoma developing after this interval. Recurrence of the intraocular tumour was seen in conjunction with an extrascleral component in two cases. Four cases ultimately underwent enucleation or exenteration; three had evidence of direct extension of tumour through the sclera. Four cases in this series had molecular characteristics associated with high metastatic risk (three patients with monosomy 3, one with BAP1 mutation). CONCLUSIONS: High-risk tumour biology may predispose to late appearance of extrascleral melanoma despite optimal treatment and adequate control of the intraocular tumour. Extended follow-up with detailed orbital examination and imaging is recommended for this population.

Biopsychosocial Markers of Body Image Concerns in Patients with Head and Neck Cancer: A Prospective Longitudinal Study.

(1) Background: Patients and survivors of head and neck cancer (HNC) are at a high risk of developing body image concerns. Despite the prevalence of body image concerns in patients with HNC, there is a lack of longitudinal research exploring the wide array of its associated determinants. The current longitudinal study examined the determinants and longitudinal course of body image dissatisfaction in patients with HNC. (2) Methods: Patients participated in Structured Clinical Interviews and self-administered questionnaires at four time-points: (T1) upon cancer diagnosis, (T2) at 3 months post-diagnosis, (T3) at 6 months post-diagnosis, and (T4) at 12 months post-diagnosis. They also underwent a disfigurement rating on an objective scale. (3) Results: Two hundred and twenty-four patients participated in our study. Fourteen percent to twenty-eight percent of patients reported at least moderate body image concerns across time points, with the lowest rates at baseline and the highest at 3 months (T1). It was found that patients more predisposed to developing higher levels of body image concerns presented physical markers (i.e., advanced cancer stage, lower physical functioning, higher disfigurement), psychosocial markers (i.e., higher depression, higher anxiety, and higher levels of coping with denial), and health disparities (i.e., younger age, female sex, French language, and marital status, with divorced and widowers most affected). (4) Conclusions: The findings of this study highlight the multifaceted nature of body image concerns in patients with HNC and its biopsychosocial determinants. Clinicians should pay specific attention to these biopsychosocial markers in their clinics to predict high levels of body image concerns and tailor communication/refer for support accordingly.

Body Image Concerns in Patients With Head and Neck Cancer: A Longitudinal Study.

Objective: Head and neck cancer (HNC) treatments are known to significantly affect functionality and appearance, leading to an increased risk for body image disturbances. Yet, few longitudinal studies exist to examine body image in these patients. Based on a conceptual model, the current study aimed to determine, in patients newly diagnosed with HNC: (1) the prevalence, level, and course of body image concerns; (2) correlates of upon cancer diagnosis (pre-treatment) body image concerns; (3) predictors of immediate post-treatment body image concerns; and (4) association between body image concerns and levels of anxiety, depression, suicidal ideation, support (i.e., satisfaction with support from physician, social/family wellbeing, and unmet support needs), and alcohol and drug misuse. Methods: Two hundred and twenty-three (participation rate = 72%), newly diagnosed with a primary HNC were assessed using structured clinical interviews and psychometric measures at three, and 6 months after diagnosis. Primary outcome was 3-month, as it was most salient to body image disturbance. Multiple linear regression analyses were conducted on the potential body image predictors, based on the model. Results: Sixty-eight percent of patients with HNC (n = 148 of 218) presented some level of body image concerns. Body image concerns at baseline (i.e., upon cancer diagnosis, pre-treatment) and post-treatment were significantly related and significantly increased from pre- to post-treatment. Immediately post-treatment (i.e., at 3 month follow-up), 89% (n = 132 of 148) presented some level of body image concerns. Correlates of body image concerns in patients with HNC at baseline included: physical symptom burden, difficulties with communication and eating, coping with the cancer diagnosis using denial, suicidal ideation, and having had a past anxiety diagnosis. When controlling for sociodemographic and medical variables, body image concerns in patients with HNC in the immediate post-treatment were predicted by: baseline body image, physical symptom burden, and neuroticism. Conclusion: This longitudinal study helps identify patients more susceptible to experience body image disturbance following head and neck cancer. Clinicians ought to pay special attention to body image concerns upon cancer diagnosis, physical symptom burden, and neuroticism, and may want to target these factors in future preventive interventions.

Liquid biopsy detection of genomic alterations in pediatric brain tumors from cell-free DNA in peripheral blood, CSF, and urine.

BACKGROUND: The ability to identify genetic alterations in cancers is essential for precision medicine; however, surgical approaches to obtain brain tumor tissue are invasive. Profiling circulating tumor DNA (ctDNA) in liquid biopsies has emerged as a promising approach to avoid invasive procedures. Here, we systematically evaluated the feasibility of profiling pediatric brain tumors using ctDNA obtained from plasma, cerebrospinal fluid (CSF), and urine. METHODS: We prospectively collected 564 specimens (257 blood, 240 urine, and 67 CSF samples) from 258 patients across all histopathologies. We performed ultra-low-pass whole-genome sequencing (ULP-WGS) to assess copy number variations and estimate tumor fraction and developed a pediatric CNS tumor hybrid capture panel for deep sequencing of specific mutations and fusions. RESULTS: ULP-WGS detected copy number alterations in 9/46 (20%) CSF, 3/230 (1.3%) plasma, and 0/153 urine samples. Sequencing detected alterations in 3/10 (30%) CSF, 2/74 (2.7%) plasma, and 0/2 urine samples. The only positive results were in high-grade tumors. However, most samples had insufficient somatic mutations (median 1, range 0-39) discoverable by the sequencing panel to provide sufficient power to detect tumor fractions of greater than 0.1%. CONCLUSIONS: Children with brain tumors harbor very low levels of ctDNA in blood, CSF, and urine, with CSF having the most DNA detectable. Molecular profiling is feasible in a small subset of high-grade tumors. The level of clonal aberrations per genome is low in most of the tumors, posing a challenge for detection using whole-genome or even targeted sequencing methods. Substantial challenges therefore remain to genetically characterize pediatric brain tumors from liquid biopsies.

Sutureless Transconjunctival Insertion of Eyelid Weights: A Novel Technique.

PURPOSE: To describe a novel surgical technique for implanting eyelid weights via a sutureless transconjunctival approach. In comparison to the traditional supratarsal crease approach, this technique does not involve any external incisions or suture placement. The procedure can reduce surgical time and complications associated with the traditional external approach. METHODS: This case series includes 13 patients who underwent eyelid weight placement via the transconjunctival approach for paralytic lagophthalmos secondary to facial nerve paralysis (12 patients had unilateral paralysis and 1 patient had bilateral) with a total of 14 eyelid weights placed. The procedures were performed at an outpatient office-based surgical center. All procedures were performed or supervised by the same surgeon. Patients were followed for an average 6-month postoperative period for postoperative complications. RESULTS: The sutureless transconjunctival approach to eyelid weight insertion was successful in achieving the desired functional and aesthetic outcomes. Patients undergoing this technique avoided the discomfort of postoperative suture removal. All patients achieved comparable outcomes postoperatively. There were no complications reported across the 13 patients throughout the 6-month postoperative period. CONCLUSIONS: This case series demonstrates that the transconjunctival approach for metal eyelid weight insertion is practical, relatively easy to perform, and associated with functional outcomes that are comparable to those achieved with the traditional approach, however, without external incision or placement of sutures.

Natural history of inflammatory and non-inflammatory dry eye in thyroid eye disease.

PURPOSE: The purpose is to understand the natural history and physical findings in thyroid eye disease (TED) patients with severe dry eye symptoms (DES). METHODS: Prospective cohort study, studying DES in TED patients over two years. Baseline data included clinical activity score (CAS), time since disease onset, punctate epithelial erosions (PEE), lagophthalmos, superior limbic keratoconjunctivitis (SLK), and marginal reflex distance 1 (MRD1). Ocular Surface Disease Index (OSDI) was utilized to measure symptomatology and scores > 33 (severe) were the primary outcome measure. Multivariate logistic regression was performed on two groups (<9 months, >9 months) to assess if variables change in early versus late disease. RESULTS: 88 met the inclusion criteria. 80.7% (n = 71) were female. There were 42 patients in the group with onset of symptoms under nine months and 46 patients over nine months. Mean CAS score was greater under nine months (2.45) than over nine months (1.29) (p < .05).In the multivariate logistic regression for the group presenting with symptoms under nine months, CAS was the only significant predictor of severe OSDI. Every increase in CAS of one yielded a 2.0x increased risk of severe OSDI. For the patients over nine months from onset, PEE was the significant predictor of severe OSDI. PEE was associated with a 5.9x increased risk of severe OSDI. CONCLUSIONS: Severe DES correlate with inflammatory features within the first nine months. Afterward, presence of PEE became more important. DES in TED tends to be a manifestation of orbital inflammation early in disease and exposure later.

Periphlebitis of the Superior Ophthalmic Vein.

Isolated orbital periphlebitis in the context of nonspecific orbital inflammation is rare. This case series describes 3 patients with periphlebitis of the superior ophthalmic vein, 2 of which were confirmed with pathology. All 3 cases had a history of Graves hyperthyroidism. Superior ophthalmic vein periphlebitis is a rare form of orbital inflammation presenting with proptosis and motility restriction yet few inflammatory signs. It may be associated with autoimmune hyperthyroidism and represent a rare feature of thyroid eye disease, or perhaps could be an overlap syndrome between thyroid eye disease and nonspecific orbital inflammation. Treatment response is variable and may require a prolonged course of steroids or other immunosuppressive medications.

What is in a Name? It is Time to Retire the Term "Asian Blepharoplasty".

PURPOSE: This perspective explores the term "Asian blepharoplasty" and its socioemotional meaning to some patients. METHODS: N/A. RESULTS: Words have power. The term "Asian blepharoplasty" makes some patients uncomfortable. To our knowledge, it is the only medical descriptor that uses race. CONCLUSIONS: The use of the term "Asian Blepharoplasty" may unwittingly make patients uncomfortable and pathologize Asian features. Therefore, we suggest replacing the term "Asian Blepharoplasty" with "Double Eyelid Surgery." For the subset of procedures which do not include the creation of an eyelid crease, "Blepharoplasty" is appropriate.

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

PURPOSE: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing. EXPERIMENTAL DESIGN: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples. RESULTS: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% (n = 13/16) in newly diagnosed MBC, 23% (n = 7/30) at postoperative and 19% (n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months). CONCLUSIONS: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.

Conversational avoidance during existential interviews with patients with progressive illness.

We examined patterns of avoidance when existential emotional topics were raised during conversations with patients with pulmonary arterial hypertension (PAH), an incurable life-limiting disease. 30 adult outpatients with PAH were recruited for a 20 to 60-minute interview about their illness experience. Qualitative content analysis was used to identify avoidance strategies that patients employed. Participants averaged 58 years in age (SD = 18), 77% were female, and mean length of illness was 6.3 years (SD = 5.3). We found four avoidance strategies: (1) Reversal, when individuals would begin discussing a negative concern and then backtrack to more positive sentiments; (2) Diversion for when patients would sidetrack the conversation to a different and less uncomfortable topic; (3) Diminishment for when a concern is raised and then made to seem unimportant; and (4) Obstruction, when patients refuse to discuss a concern further. Exploration of existential concerns can elicit distress but may be necessary to promote adaptation to progressive illness and to the foreseeable challenges that may affect the sense of life meaning and value. By recognizing when existential concerns may be present but not adequately discussed, clinicians may be better able to assist patients to cope and prepare for the future.

Estimating the Impact of Carbon Dioxide Absorbent Performance Differences on Absorbent Cost During Low-Flow Anesthesia.

BACKGROUND: Reducing fresh gas flow when using a circle anesthesia circuit is the most effective strategy for reducing both inhaled anesthetic vapor cost and waste. As fresh gas flow is reduced, the amount of exhaled gas rebreathed increases, but the utilization of carbon dioxide absorbent increases as well. Reducing fresh gas flow may not make economic sense if the increased cost of absorbent utilization exceeds the reduced cost of anesthetic vapor. The primary objective of this study was to determine the minimum fresh gas flow at which absorbent costs do not exceed vapor savings. Another objective is to provide a qualitative insight into the factors that influence absorbent performance as fresh gas flow is reduced. METHODS: A mathematical model was developed to compare the vapor savings with the cost of carbon dioxide absorbent as a function of fresh gas flow. Parameters of the model include patient size, unit cost of vapor and carbon dioxide absorbent, and absorbent capacity and efficiency. Boundaries for fresh gas flow were based on oxygen consumption or a closed-circuit condition at the low end and minute ventilation to approximate an open-circuit condition at the high end. Carbon dioxide production was estimated from oxygen consumption assuming a respiratory quotient of 0.8. RESULTS: For desflurane, the cost of carbon dioxide absorbent did not exceed vapor savings until fresh gas flow was almost equal to closed-circuit conditions. For sevoflurane, as fresh gas flow is reduced, absorbent costs increase more slowly than vapor costs decrease so that total costs are still minimized for a closed circuit. Due to the low cost of isoflurane, even with the most effective absorbent, the rate of absorbent costs increase more rapidly than vapor savings as fresh gas flow is reduced, so that an open circuit is least expensive. The total cost of vapor and absorbent is still lowest for isoflurane when compared with the other agents. CONCLUSIONS: The relative costs of anesthetic vapor and carbon dioxide absorbent as fresh gas flow is reduced are dependent on choice of anesthetic vapor and performance of the carbon dioxide absorbent. Absorbent performance is determined by the product selected and strategy for replacement. Clinicians can maximize the performance of absorbents by replacing them based on the appearance of inspired carbon dioxide rather than the indicator. Even though absorbent costs exceed vapor savings as fresh gas flow is reduced, isoflurane is still the lowest cost choice for the environmentally sound practice of closed-circuit anesthesia.

Emotion And Symptom-focused Engagement (EASE): a randomized phase II trial of an integrated psychological and palliative care intervention for patients with acute leukemia.

PURPOSE: We designed a novel, manualized intervention called Emotion And Symptom-focused Engagement (EASE) for acute leukemia (AL) and report here on a phase II randomized controlled trial (RCT) to assess its feasibility and preliminary efficacy. METHODS: Patients were recruited within 1 month of hospital admission and randomized to EASE plus usual care (UC) or UC alone. EASE includes (1) EASE-psy, a tailored psychotherapy delivered over 8 weeks, and (2) EASE-phys, weekly physical symptom screening over 8 weeks to trigger early palliative care. The primary outcome was traumatic stress symptoms; secondary outcomes included physical symptom burden and quality of life. Assessments were conducted at baseline and at 4, 8, and 12 weeks. Between-group differences were evaluated using multilevel modeling. RESULTS: Forty-two patients were randomized to EASE (n = 22) or UC (n = 20), with 76% retention at 12 weeks. Predefined feasibility outcomes were met: 86% (19/22) of EASE participants completed ≥ 50% of EASE-psy sessions (goal ≥ 64%); 100% received Edmonton Symptom Assessment System (ESAS, modified for AL) screenings, 64% (14/22) of whom completed ≥ 50% of planned screenings (goal ≥50%); and 100% with scores ≥ 4/10 on any physical ESAS-AL item had ≥ 1 meeting with the EASE-phys team (goal 100%). Significant treatment-group differences favoring EASE were observed in traumatic stress symptoms at 4 and 12 weeks, and pain intensity and interference at 12 weeks (all p < .05). CONCLUSIONS: EASE is feasible in patients newly diagnosed with AL and shows promise of effectiveness. These results warrant a larger RCT to provide evidence for its more routine use as a standard of care.

Death talk and relief of death-related distress in patients with advanced cancer.

OBJECTIVES: The circumstances of advanced cancer heighten the need for affected individuals to communicate mortality-related concerns, although there may be obstacles to such communication. Managing Cancer and Living Meaningfully(CALM) is a supportive-expressive therapy designed to address such barriers and to facilitate communication of mortality-related concerns in patients and caregivers facing advanced disease. This study explores death-related distress in patients with advanced cancer and the perceived influence of CALM therapy on overcoming barriers to communication of this distress. METHODS: Semistructured interviews were conducted with a subset of patients with advanced cancer (n=17) participating in a CALM phase III trial at a large urban regional cancer centre. Interviews were transcribed, and qualitative data were analysed using thematic analysis. RESULTS: Death-related distress was experienced in terms of three key themes: diffuse and overwhelming fear, fear of uncertainty and fear of suffering. The perceived barriers to communicating such distress were as follows: reluctance of loved ones to discuss mortality-related issues and the participants´ own reluctance to discuss death-related concerns to protect their loved ones or themselves from distress. CALM therapists were perceived to facilitate discussions on dying and death in sessions and to support patients´ communication of death-related distress with healthcare providers and loved ones. CONCLUSIONS: Patients with advanced cancer perceive barriers to effective communication of death distress to be related to their own reluctance, as well as reluctance of their loved ones to address such fears. CALM therapy may help patients with advanced cancer to overcome obstacles to communication and to alleviate death-related distress. TRIAL REGISTRATION NUMBER: NCT01506492.