Citations

Abstract BACKGROUND One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell communications, particularly ligand–receptor pairs, allows for the inference of significant intercellular communications based on the expression of corresponding genes. Consequently, we hypothesised that the most influential cell-cell interactions within the tumour immune microenvironment (TME) of MYC-driven MB could unveil prevalent immune-suppressive interactions and potential vulnerabilities for therapeutic exploration. METHODS/RESULTS Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. CONCLUSIONS Essential cellular interactions and therapeutic vulnerabilities have been identified in the tumour-microenvironment of MYC-driven primary-recurrent MB.

Objective: To investigate fecal incontinence and defecatory, urinary, and sexual functional outcomes after transanal total mesorectal excision (taTME). Background: Proctectomy for rectal cancer may result in alterations in defecatory, urinary, and sexual function that persist beyond 12 months. The recent multicenter phase II taTME trial demonstrated the safety of taTME in patients with stage I to III tumors. Methods: Prospectively registered self-reported questionnaires were collected from 100 taTME patients. Fecal continence [Fecal Incontinence Quality of Life (FIQL), Wexner], defecatory function [Colorectal Functional Outcome (COREFO)], urinary function (International Prostate Symptom Score), and sexual function (Female Sexual Function Index-female, International Index of Erectile Function-male) were assessed preoperatively (PQ), 3 to 4 months postileostomy closure (FQ1), and 12 to 18 months post-taTME [postoperative questionnaire 2 (FQ2)]. Results: Among 83 patients who responded at all 3 time points, FIQL, Wexner, and COREFO significantly worsened postileostomy closure. Between FQ1 and FQ2, FIQL lifestyle and coping, Wexner, and COREFO incontinence, social impact, frequency, and need for medication significantly improved, while FIQL depression and embarrassment did not change. International Prostate Symptom Score did not change relative to preoperative scores. For females, Female Sexual Function Index declined for desire, orgasm, and satisfaction between PQ and FQ1, and did not improve between FQ1 and FQ2. In males, International Index of Erectile Function declined with no change between FQ1 and FQ2. Conclusions: Although taTME resulted in initial decline in defecatory function and fecal continence, most functional domains improved by 12 months after ileostomy closure, without returning to preoperative status. Urinary function was preserved while sexual function declined without improvement by 18 months post-taTME. Our results address patient expectations and inform shared decision-making regarding taTME.

Abstract Objective Emotional distress has been correlated with greater healthcare utilization and economic costs in cancer; however, the prospective relationship between positive distress screens and future healthcare utilization is less clear. Taken together, there is a critical need to synthesize studies examining the prospective relationship between emotional distress and future healthcare use to inform distress management protocols and motivate institutional resource allocation to distress management. The aim of the systematic review is to explore the relationship between emotional distress, measured via validated emotional distress questionnaires, and subsequent healthcare utilization in patients diagnosed with cancer. Methods A systematic search of seven databases was conducted on 29 March 2022 and updated 3 August 2023. Eligibility criteria were: (1) peer‐reviewed, (2) quantitative or mixed methods, (3) adults (≥18 years) diagnosed with cancer, (4) cancer distress questionnaire(s) completed prior to healthcare utilization, and (5) written in English. Exclusion criteria included: (1) non‐emotional aspects of distress (i.e., spiritual or physical distress), (2) healthcare utilization characterized via economic or monetary variables, and (3) caregiver or non‐cancer populations. Results Nineteen peer‐reviewed articles were included in the review. There was significant heterogeneity in emotional distress instruments and type of healthcare utilization used. Most studies examining general distress or anxiety found that increased distress was predictive of greater future healthcare utilization. Conclusion The results suggest that individuals with higher levels of general distress and anxiety are at increased risk for future healthcare utilization.

Introduction: Subcutaneous emphysema is characterized by the accumulation of air beneath the dermal layers of the skin. We present a case of extensive subcutaneous emphysema of the neck, face and arms in a patient who was two days post operative from laser assisted dilation of subglottic stenosis.Materials and Methods: We present a case of subcutaneous emphysema in a patient who presented to the emergency department. As this is a case report, no additional materials or specific methods were required.Case Presentation: A 71-year-old man with history of tracheal stenosis status post laser assisted subglottic dilation presented to the emergency department two days post-operatively for progressively worsening swelling of the face, neck and arms. Physical exam was notable for crepitus of the face, neck and arms. Oropharyngeal exam showed no edema to the posterior oropharynx or tongue. Breathing was non-labored without stridor. Imaging revealed extensive subcutaneous emphysema without any obvious source. The otolaryngology (ENT) service evaluated the patient and admitted him to their service. Initially he was managed conservatively via observation and supportive care however, on day two of hospitalization his respiratory status worsened. He required intubation and tracheal stent placement. The tracheal defect was never found on exploration in the operating room, suggesting the defect was sub-centimeter in size. He was extubated on hospital day four and discharged with a plan to have the tracheal stent in place for three months. Conclusion: Subcutaneous emphysema secondary to a tracheobronchial tree defect is a known complication of laser dilatation of subglottic stenosis. Most cases resolve spontaneously and can be managed conservatively. However, patients require close airway monitoring as some may require emergent airway management. Clinicians should be aware of this complication and subsequent management.

ImportancePostoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.ObjectiveTo evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins.Design, Setting, and ParticipantsThe American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023.Main Outcomes and MeasuresMain outcomes were risk factors for local recurrence.ResultsA total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group.Conclusions and RelevanceIn this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Abstract RTOG 9402 demonstrated procarbazine (P), lomustine (CCNU/C), and vincristine (V), collectively PCV, added to radiation therapy significantly improved survival for patients with newly diagnosed anaplastic oligodendroglial tumors. The improvement was most pronounced in 1p19q codeleted cases, and to a lesser extent, IDH-mutant cases, with no survival benefit in cases with neither biomarker. Analogous results were observed in other phase III trials. However, vincristine (V) can cause substantial toxicity and requires intravenous administration, both negatively affecting quality of life, with debatable contribution to PCV efficacy. As a randomized trial comparing PCV to PC is unlikely to be conducted, we explored correlations between survival and V-dosing in patients randomized to PCV in RTOG 9402. We performed post-hoc analyses of all evaluable participants (n = 143) randomized to PCV on RTOG 9402, supplemented by restricting the analyses to the chemosensitive molecular subsets (IDH-mutant and/or 1p/19q codeleted, n = 118). Total V dose by quartile (Q) was calculated. Survival from six months post-randomization was compared among V dose groups, adjusting for age, extent of resection (EOR), and Karnofsky Performances Status (KPS) in a Cox proportional hazards model. Higher V dose received correlated with longer survival in multivariate analyses (n = 134, median-Q3 vs. < Q1, HR 0.40 (0.22, 0.73), p = 0.003; ≥Q3 vs. < Q1, HR 0.39 (0.22, 0.72), p = 0.002). Excluding chemoresistant cases (IDH wild-type/not codeleted), survival was also significantly longer in evaluable participants receiving the highest doses of vincristine (≥Q3 vs. < Q1 HR 0.42 (0.21,0.81), p = 0.01). In this post-hoc analysis, higher overall V-dose received correlated with longer survival in evaluable patients with anaplastic oligodendroglial tumors receiving PCV chemotherapy in RTOG 9402. Of note, as vincristine dosing was not assigned by randomization, confounding due to differences in patient characteristics among V dose groups cannot be ruled out. Caution should be exercised when considering discarding V from the PCV regimen.

Abstract Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Abstract Introduction The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer‐related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6 ‐guided opioid prescribing for patients with cancer and reported pilot outcome data. Methods Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation‐effectiveness clinical trial and randomized to CYP2D6 ‐genotype‐guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient‐reported pain and symptom scores at baseline and up to 8 weeks, were assessed. Results Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3–37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6 ‐genotype‐guided recommendations to change therapy ( n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow‐up questionnaires ( n = 48), there was no difference in change in mean composite pain score (−1.01 ± 2.1 vs. −0.41 ± 2.5; p = 0.19) or symptom severity at last follow‐up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm ( n = 26) and genotype‐guided arm ( n = 22), respectively. Conclusion Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype‐guided recommendations was low, impacting assessment of pain‐related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.