Complete response to donor lymphocyte infusion for primary hemophagocytic lymphohistiocytosis relapse after allogeneic hematopoietic cell transplantation.

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory disorder characterized by dysregulation of inflammatory cells and cytokine signalling. Although first-line treatment consisting of immunosuppressive therapy and allogeneic hematopoietic cell transplantation (HCT) is often curative, it remains unknown whether any effective therapies exist for disease relapse/progression after HCT. Here we present a case of a 29-year-old male with primary HLH that relapsed after HCT and subsequently achieved durable long disease-free survival following a donor-lymphocyte infusion (DLI). To our knowledge, this represents the first case demonstrating the efficacy of DLI for relapsed primary HLH.

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.

Nodal Metastases in Stage 3 Head and Neck Melanoma: Patterns of Metastases and Patterns of Failure.

OBJECTIVE: Stage 3 patients with clinically positive nodal metastasis are treated with therapeutic neck dissection and adjuvant systemic therapy. The aim of our study was to examined the predictability of pre-operative CT as a nodal drainage assessment tool. METHODS: Retrospective review of all patients with clinically positive head and neck cutaneous melanoma between 2010 and 2019. Clinical disease was diagnosed as radiological suspicious, biopsy-proven node. A pre-operative CT evaluation for nodal metastasis was compared to pathology report. RESULTS: A total of 53 patients were included. Forty patients (75.5%) were males with a mean age of 59 (SD 15.52). The majority of patients (26.4%) had an unknown primary site. The most common sites for primary were the cheek in eight patients (15.1%) followed by forehead (9.4%) and lateral neck (9.4%). Preoperative CT predicted nodal disease in 84.6% of cases. The primary region that mainly failed from the previously described clinical prediction was the upper anterior neck with 83.3% parotid involvement. A total of 10 patients (18.9%) were diagnosis with non-clinical nodes on pathology with a median non-clinical node of 1 (range 1-2). Of them, 9 (90%) were in the same clinical levels detected by CT. Pre-operative CT was associated with a neck level accuracy of 98.1%. CONCLUSION: Stage 3 head and neck melanoma with clinically positive nodal metastasis that are eligible for an adjuvant systemic treatment, may benefit from a highly selective neck dissection according to their pre-operative imaging studies. This should be further evaluated in a large-scale clinical trial. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:4292-4297, 2024.

Prevalence and Risk Factors for Moral Distress in Pediatric Oncology Health Care Professionals.

PURPOSE: Moral distress (MoD) is prevalent among health care professionals (HCPs) in oncology and is associated with burnout. The objectives of this study were to quantify MoD among pediatric oncology healthcare professionals (HCPs) at a Canadian quaternary care hospital, identify root causes, and evaluate change over time. METHODS: Eligible pediatric oncology HCPs were identified, and consenting participants completed the Measure of Moral Distress-Healthcare Professionals (MMD-HP) and MoD Thermometer (MDT) at baseline, followed by biweekly MDTs over 12 weeks. RESULTS: A total of 139 HCPs participated. The mean MMD-HP score was 123 ± 57.0, range 9-288. Demographic risk factors identified for elevated MMD-HP scores were female sex (female 127.1 and male 83.6, P = .01) and nursing role (nurse 136.3 and most responsible physician 85.3, P = .02). Higher MMD-HP scores were found in HCPs who were currently considering resigning because of MoD compared with those who were not (169.9 v 115.4, P < .001). Situations involving administration of treatment to children with poor prognosis cancers that was perceived to be overly aggressive were ranked as the greatest environmental contributor to MoD. Baseline and mean MDT scores over time strongly correlated with MMD-HP scores (P < .0001 and P = .0003, respectively), with mean MDT scores showing no significant fluctuation over the 12-week period. CONCLUSION: MoD was common among pediatric oncology HCPs. Risk factors for elevated levels of MoD included both demographic and environmental factors. Implementation of systems to improve team communication and decision making, especially in the care of patients with poor prognosis cancers, may affect HCP MoD.

The Role of Adjuvant Radiotherapy for the Treatment of Resected High-Risk Stage III Cutaneous Melanoma in the Era of Modern Systemic Therapies.

Modern adjuvant systemic therapies (STs) have revolutionized the management of stage III melanoma. Currently, the role of adjuvant radiotherapy (RT) remains unclear. In this single-center retrospective study, patients with clinically detectable stage III melanoma with high-risk features for lymph node basin (LNB) recurrence and whose tumors were fully resected with complete lymphadenectomy (CLD) between 2010 and 2019 were assessed. We determined the cumulative incidence (CIF) of LNB recurrence and any disease recurrence or progression using competing risk analysis. A total of 108 patients were identified; the median age was 59 years (24-92), and 74 (69%) were men. A total of 51 (42%) received adjuvant RT, 22 (20%) received adjuvant ST, and 35 (32%) received no adjuvant therapy. The advent of ST changed clinical practice, with a significant increase in the use of adjuvant ST and a decrease in the use of RT when comparing practice patterns before and after 2015 (p < 0.001). The 3-year CIF of LNB recurrence was similar in patients treated with adjuvant RT (6.3%) and adjuvant ST (9.8%). The 3-year CIF of any disease recurrence or progression was lower in patients receiving adjuvant ST (24%) compared to those receiving adjuvant RT (52%) or no adjuvant therapy (55%, p = 0.06). Three-year overall survival (OS) was not significantly different in patients treated with ST compared to those not treated with any ST (p = 0.118). Despite ST replacing RT as the dominant adjuvant treatment modality, this change in practice has not resulted in increased LNB recurrence for patients at high risk of LNB recurrence following CLD.

Clinical interpretation of serum hepcidin-25 in inflammation and renal dysfunction.

Introduction: Hepcidin is a hormone that regulates systemic iron homeostasis. Serum hepcidin levels are under the influence of various stimuli, particularly inflammation and renal dysfunction. The measurement of hepcidin in circulation is a potentially useful clinical tool in the diagnosis, monitoring and treatment of iron metabolism disorder, although clinical interpretation of hepcidin level remains difficult. We evaluated he diagnostic potential and limitations of hepcidin-25 by investigating its relationship with iron and hematological indices, inflammation, and renal dysfunction. Methods: This retrospective study included 220 adult patients not requiring dialysis. Variations of biologically active hepcidin-25 were examined using a mass spectrometry-based assay in various inflammatory and renal states. The log[hepcidin]:log[ferritin] ratio was calculated as an hepcidin index. Results: In 220 adult patients not requiring dialysis, variation in hepcidin-25 level was significantly larger once CRP exceeded 10 mg/l (p < 0.001). Inflammation was not a determinant of hepcidin-25 in the setting of renal dysfunction. Hepcidin-25 median (7.37 nM) and variance were significantly higher (p < 0.001), once estimated glomerular filtration rate (eGFR) dropped below 30 ml/min/1.73 m2. The log[hepcidin]:log[ferritin] index normalized hepcidin levels. Patients with iron deficiency have a notably lower index when compared to controls (-0.66 vs 0.3). Conclusion: Severe renal dysfunction (eGFR < 30) affected hepcidin-25 expression and clearance to variable degree between individuals. Although, hepcidin-25 testing is not warranted in patients with infection, inflammatory autoimmune conditions (CRP > 10 mg/l) and/or severe renal dysfunction (eGFR < 30), the hepcidin index may serve as a potential biomarker for iron deficiency in complex cases.

Longitudinal Assessment of Health Utility Scores, Symptoms and Toxicities in Patients with Small Cell Lung Cancer Using Real World Data.

INTRODUCTION: Recent advances in small cell lung cancer (SCLC) treatments necessitate a better understanding of real-world health utility scores (HUS) in patients treated under current standards to facilitate robust pharmaco-economic assessments. METHODS: In this single institution cohort observational study, HUS were evaluated in patients with SCLC through EQ-5D questionnaires at outpatient visits (encounters). In addition, patients completed questionnaires relating to treatment toxicities and cancer symptoms. Clinical and pathological variables were abstracted from electronic medical records and disease status at each patient visit was documented. The impact of these variables on HUS were explored. RESULTS: There were 282 clinical encounters (12% newly diagnosed; 37% stable on treatment; 22% progressing on treatment; 29% stable off therapy/other) in 111 SCLC patients (58% male; 64% extensive stage (ES) SCLC). At the first encounter 29% of patients had an ECOG performance status (PS) ≥ 2. ES-SCLC, bone metastases, female sex, progressive disease and/or PS were each significantly associated with decreased HUS in multivariable analyses. Patients clinically stable on first line therapy had generally steady HUS longitudinally, with differences in HUS between limited disease (LD) and ES patients emerging as treatment progressed. Decreased HUS were associated with increased severity of the majority of measured symptoms (fatigue/tiredness, loss of appetite, pain, drowsiness, shortness of breath, anxiety, depression, and overall well-being; each p<0.001), supporting the value of EQ-5D-derived HUS in assessing health utility. CONCLUSION: Our HUS values in chemotherapy-treated SCLC are clinically relevant and are associated with specific clinico-demographic, symptom and toxicity factors.

Characterization and outcomes of patients enrolled to multiple phase I cancer trials.

PURPOSE: Some patients who participate in early phase cancer trials enroll to more than one trial. Whether these patients have different characteristics or outcomes than patients who enroll to a single phase I trial is unknown. METHODS: The study included all patients who participated in the solid tumor drug development program of the Princess Margaret Cancer Centre, a specialized academic cancer center, from July 2014 to January 2017. Patients sequentially enrolled to multiple phase I trials were compared to those enrolled in a single trial according to demographics, clinical characteristics, reported toxicities and prognosis. RESULTS: The study cohort included 328 patients, including 61 (19%) enrolled to multiple phase I trials and 267 (81%) enrolled to a single phase I trial. Demographics, comorbidities, performance status, cancer site and time between initial diagnosis and initial enrollment to the phase I program were comparable between both groups. Patients enrolled to multiple phase I trials received more previous non-trial treatment lines (median 3 versus 2, p < 0.001) and had a higher average response rate on phase I trials (18% versus 10%, p = 0.03). Toxicity data, including number of any adverse events (AEs), grade 3/4 AEs, serious AEs and dose-limiting toxicities were comparable between both groups. Time to disease progression and time to last documented follow-up were also comparable between both groups. CONCLUSIONS: Patients enrolled to multiple phase I trials and those enrolled to a single trial had similar toxicity and prognostic profiles. These patients do not introduce bias into early-phase cancer trials results.

Cancer Patient-Reported Preferences and Knowledge for Liquid Biopsies and Blood Biomarkers at a Comprehensive Cancer Center.

BACKGROUND: Blood-based biomarkers (liquid biopsy) are increasingly used in precision oncology. Yet, little is known about cancer patients' perspectives in clinical practice. We explored patients' depth of preferences for liquid vs tissue biopsies and knowledge regarding the role of blood biomarkers on their cancer. METHODS: Three interviewer-administered trade-off scenarios and a 54-item self-administered questionnaire were completed by cancer outpatients across all disease sites at the Princess Margaret Cancer Centre. RESULTS: Of 413 patients, 54% were female; median age was 61 (range 18-101) years. In trade-off scenario preference testing, 90% (n=372) preferred liquid over tissue biopsy at baseline; when wait times for their preferred test were increased from 2 weeks, patients tolerated an additional mean of 1.8 weeks (SD 2.1) for liquid biopsy before switching to tissue biopsy (with wait time 2 weeks). Patients also tolerated a 6.2% decrease (SD 8.8) in the chance that their preferred test would conclusively determine optimal treatment before switching from the baseline of 80%. 216 patients (58%) preferred liquid biopsy even with no chance of adverse events from tissue biopsy. Patients' knowledge of blood-based biomarkers related to their cancer was low (mean 23%); however, the majority viewed development of blood biomarkers as important. CONCLUSION: Patients had limited understanding of cancer-specific blood-based biomarkers, but 90% preferred liquid over tissue biopsies to assess biomarkers. There was little tolerance to wait longer for results, or for decreased test-conclusiveness. Developing accurate, low-risk tests for cancer diagnosis and management for blood biomarkers is therefore desirable to patients.