Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

A Phase II Study Evaluating the Effect of Intensity Modulated Postmastectomy Radiation Therapy on Implant Failure Rates in Breast Cancer Patients With Immediate, 2-Stage Implant Reconstruction With an MRI Imaging Correlative Substudy.

PURPOSE: Postmastectomy radiation therapy is a mainstay in the adjuvant treatment of node-positive breast cancer, but it poses risks for women with breast reconstruction. Multibeam intensity-modulated radiation therapy improves dose conformality and homogeneity, potentially reducing complications in breast cancer patients with implant-based reconstruction. To investigate this hypothesis, we conducted a single-arm phase 2 clinical trial of breast cancer patients who underwent mastectomy/axillary dissection and prosthesis-based reconstruction. METHODS AND MATERIALS: The primary endpoint was the rate of implant failure (IF) within 24 months of permanent implant placement, which would be considered an improvement over historical controls if below 16%. IF was defined as removal leading to a flat chest wall or replacement with another reconstruction. Patients were analyzed in 2 cohorts. Cohort 1 (RT-PI) received radiation therapy to the permanent implant. Cohort 2 (RT-TE) received radiation therapy to the TE. IF rates, adverse events, and quality of life were analyzed. Follow-up/postradiation therapy assessments were compared with the baseline/preradiation therapy assessments at 3 to 10 weeks after exchange surgery. A subgroup underwent serial magnetic resonance imaging (MRI) sessions to explore the association between MRI-detected changes and capsular contracture, a known adverse effect of radiation therapy. RESULTS: Between June 2014 and March 2017, 119 women were enrolled. Cohort 1 included 45 patients, and cohort 2 had 74 patients. Among 100 evaluable participants, 25 experienced IF during the study period. IF occurred in 8/42 (19%) and 17/58 (29%) in cohorts 1 and 2, respectively. Among the IFs, the majority were due to capsular contracture (13), infection (7), exposure (3), and other reasons (2). Morphologic shape features observed in longitudinal MRI images were associated with the development of Baker grade 3 to 4 contractures. CONCLUSIONS: The rate of IF in reconstructed breast cancer patients treated with intensity-modulated radiation therapy was similar to, but not improved over, that observed with conventional, 3-dimensional-conformal methods. MRI features show promise for predicting capsular contracture but require validation in larger studies.

Digitally Enabled Transitional Care Management in Oncology.

PURPOSE: Improving care transitions for patients with cancer discharged from the hospital is considered an important component of quality care. Digital monitoring has the potential to better the delivery of transitional care through improved patient-provider communication and enhanced symptom management. However, remote patient monitoring (RPM) interventions have not been widely implemented for oncology patients after discharge, an innovative setting in which to apply this technology. METHODS: We implemented a RPM intervention which identifies medical oncology patients at discharge, monitors their symptoms for 10 days, and intervenes as necessary to manage symptoms. We evaluated the feasibility (>50% patient engagement with symptom assessment), appropriateness (symptom alerts), and acceptability (net promoter score >0.7) of the intervention and the initial effect on acute care visits and return on investment. RESULTS: During the study period, January 1, 2021, to December 31, 2022, we evaluated 2,257 medical oncology discharges representing 1,857 unique patients. We found that 65.9% of patients discharged (N = 1,489) completed at least one symptom assessment postdischarge and of them, 45.5% (n = 678) generated a severe symptom alert that we helped to manage. Patients expressed high satisfaction with the intervention with a net promoter score of 84%. In preliminary analysis of patients with GI malignancies (n = 449), we found a nonsignificant decrease in 30-day readmissions for the intervention cohort (n = 269) by 5.8% as compared with the control (n = 180; from 33.3% to 27.5%; P = .22). CONCLUSION: Digital transitional care management was feasible and demonstrated that patients transitioning from the hospital to home have a substantial symptom burden. The intervention was associated with high patient satisfaction but will require further refinement and evaluation to increase its impact on 30-day readmission.

Proposal of Novel Binary Grading Systems for Cervical Squamous Cell Carcinoma.

We compared grading systems and examined associations with tumor stroma and survival in patients with cervical squamous cell carcinoma. Available tumor slides were collected from 10 international institutions. Broders tumor grade, Jesinghaus grade (informed by the pattern of tumor invasion), Silva pattern, and tumor stroma were retrospectively analyzed; associations with overall survival (OS), progression-free survival (PFS), and presence of lymph node metastases were examined. Binary grading systems incorporating tumor stromal changes into Broders and Jesinghaus grading systems were developed. Of 670 cases, 586 were reviewed for original Broders tumor grade, 587 for consensus Broders grade, 587 for Jesinghaus grade, 584 for Silva pattern, and 556 for tumor stroma. Reproducibility among grading systems was poor (κ = 0.365, original Broders/consensus Broders; κ = 0.215, consensus Broders/Jesinghaus). Median follow-up was 5.7 years (range, 0-27.8). PFS rates were 93%, 79%, and 71%, and OS rates were 98%, 86%, and 79% at 1, 5, and 10 years, respectively. On univariable analysis, original Broders ( P < 0.001), consensus Broders ( P < 0.034), and Jesinghaus ( P < 0.013) grades were significant for OS; original Broders grade was significant for PFS ( P = 0.038). Predictive accuracy for OS and PFS were 0.559 and 0.542 (original Broders), 0.542 and 0.525 (consensus Broders), 0.554 and 0.541 (Jesinghaus grade), and 0.512 and 0.515 (Silva pattern), respectively. Broders and Jesinghaus binary tumor grades were significant on univariable analysis for OS and PFS, and predictive value was improved. Jesinghaus tumor grade ( P < 0.001) and both binary systems (Broders, P = 0.007; Jesinghaus, P < 0.001) were associated with the presence of lymph node metastases. Histologic grade has poor reproducibility and limited predictive accuracy for squamous cell carcinoma. The proposed binary grading system offers improved predictive accuracy for survival and the presence of lymph none metastases.

Agreement between youth and caregiver report of pain and functioning in pediatric sickle cell disease: PedsQL sickle cell disease module.

ABSTRACT: Pain is a primary symptom of sickle cell disease (SCD) and is often severe and chronic. To treat SCD-related pain, proper assessment of SCD pain among youth, including the degree of concordance or agreement between youth and caregiver reports of pain, is essential but has not yet been adequately evaluated. In this study, 525 youth with SCD and their parents were evaluated as part of the Sickle Cell Clinical Research and Intervention Program (SCCRIP) to examine pain rating concordance and predictors of concordance. Youth and parents completed the Pediatric Quality of Life Inventory Sickle Cell Disease module (PedsQL-SCD) to measure pain, pain interference, and pain-related constructs. Disease, clinical, and demographic variables were obtained from the SCCRIP database. Intraclass correlations demonstrated moderate-to-poor consistency between youth and caregiver reports of pain and pain interference (ICCs range from 0.17 to 0.54). Analysis of covariance and regression models found that patient age, frequency of hospitalizations and emergency department (ED) visits, economic hardship, and fetal hemoglobin levels were significantly associated with varying pain-rating agreement levels among parent proxy and child self-report pain. Concordance of pain assessments among youth with SCD and their caregivers using the PedsQL-SCD Module was moderate at best, corroborating prior research. Youth factors predicting discordance among pain-related factors included increased ED visits, older age, and female sex. Collectively, these results bolster the use of integrated pain assessments to reduce parent-child discrepancies, thereby improving the adequacy of SCD-related pain assessment and treatment.

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. METHODS: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. FINDINGS: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. INTERPRETATION: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. FUNDING: National Cancer Institute.

Invasive Squamous Cell Carcinoma of the Cervix: A Review of Morphological Appearances Encountered in Human Papillomavirus-associated and Papillomavirus-independent Tumors and Precursor Lesions.

Cervical cancer is the fourth most common cancer among women globally. Historically, human papillomavirus (HPV) infection was considered necessary for the development of both precursor and invasive epithelial tumors of the cervix; however, studies in the last decade have shown that a significant proportion of cervical carcinomas are HPV-independent (HPVI). The 2020 World Health Organization (WHO) Classification of Female Genital Tumors separates both squamous cell carcinomas (SCCs) and endocervical adenocarcinomas (ECAs) by HPV status into HPV-associated (HPVA) and HPVI tumors. The classification further indicates that, in contrast to endocervical adenocarcinomas, HPVI and HPVA SCCs cannot be distinguished by morphological criteria alone and suggests that HPV testing or correlates thereof are required for correct classification. Moreover, while HPVA SCC precursor lesions (ie, high-grade squamous intraepithelial lesion) are well known and characterized, precursors to HPVI SCCs have only been described recently in a small number of cases. We studied 670 cases of SCCs from the International Squamous Cell Carcinoma Project (ISCCP) to analyze the reproducibility of recognition of invasive SCC growth patterns, presence of lymphovascular space invasion, tumor grade, and associations with patient outcomes. Consistent with previous studies, we found histologic growth patterns and tumor types had limited prognostic implications. In addition, we describe the wide morphologic spectrum of HPVA and HPVI SCCs and their precursor lesions, including tumor growth patterns, particular and peculiar morphologic features that can lead to differential diagnoses, and the role of ancillary studies in the diagnosis of these tumors.

Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial.

PURPOSE: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm. METHODS AND MATERIALS: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival. RESULTS: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004). CONCLUSIONS: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy.

Modeling Tumor Growth Using Partly Conditional Survival Models: A Case Study in Colorectal Cancer.

PURPOSE: There are multiple approaches to modeling the relationship between longitudinal tumor measurements obtained from serial imaging and overall survival. Many require strong assumptions that are untestable and debatable. We illustrate how to apply a novel, more flexible approach, the partly conditional (PC) survival model, using images acquired during a phase III, randomized clinical trial in colorectal cancer as an example. METHODS: PC survival approaches were used to model longitudinal volumetric computed tomography data of 1,025 patients in the completed VELOUR trial, which evaluated adding aflibercept to infusional fluorouracil, leucovorin, and irinotecan for treating metastatic colorectal cancer. PC survival modeling is a semiparametric approach to estimating associations of longitudinal measurements with time-to-event outcomes. Overall survival was our outcome. Covariates included baseline tumor burden, change in tumor burden from baseline to each follow-up time, and treatment. Both unstratified and time-stratified models were investigated. RESULTS: Without making assumptions about the distribution of the tumor growth process, we characterized associations between the change in tumor burden and survival. This change was significantly associated with survival (hazard ratio [HR], 1.04; 95% CI, 1.02 to 1.05; P < .001), suggesting that aflibercept works at least in part by altering the tumor growth trajectory. We also found baseline tumor size prognostic for survival even when accounting for the change in tumor burden over time (HR, 1.02; 95% CI, 1.01 to 1.02; P < .001). CONCLUSION: The PC modeling approach offers flexible characterization of associations between longitudinal covariates, such as serially assessed tumor burden, and survival time. It can be applied to a variety of data of this nature and used as clinical trials are ongoing to incorporate new disease assessment information as it is accumulated, as indicated by an example from colorectal cancer.

Exploring the Relationship Between Health-Illness Transition Experiences and Distress Among Patients With Pancreatic Cancer.

OBJECTIVES: To explore the correlation between health-illness transition (HIT) experiences and distress among patients with pancreatic cancer. SAMPLE & SETTING: 55 patients with a diagnosis of pancreatic cancer receiving chemotherapy at a tertiary cancer center in New York. METHODS & VARIABLES: A prospective correlational study was performed to explore the frequency, extent, and management of HITs. HITs were evaluated using the Measurement of Transitions in Cancer Scale, and distress was measured with the National Comprehensive Cancer Network Distress Thermometer. RESULTS: All patients experienced at least one HIT. The extent of HITs decreased over time. Patients reported that they managed HITs moderately well. There was a significant correlation between unmanaged HITs and distress. As distress increased, the extent of the physical and emotional HITs increased and management worsened. IMPLICATIONS FOR NURSING: HITs are ubiquitous among patients diagnosed with pancreatic cancer. Associated distress inhibits management. Nurses are well suited to assess for potential HITs and to support self-management of HITs.

Incidence and Clinicopathologic Characteristics of Human Papillomavirus-independent Invasive Squamous Cell Carcinomas of the Cervix: A Morphologic, Immunohistochemical, and Human Papilloma-Virologic Study of 670 Cases.

We aimed to determine the frequency of human papillomavirus-independent (HPVI) cervical squamous cell carcinoma (SCC) and to describe clinicopathologic characteristics. Among 670 patients with surgically treated SCCs in an established multi-institutional cohort, 447 had available tissue. Tissue microarrays were constructed and studied by in situ hybridization (ISH) for high-risk and low-risk human papillomavirus (HPV) mRNA and immunohistochemistry for p16 and p53. Tumors were HPVI if negative by HPV ISH and they failed to show diffuse p16 positivity by immunohistochemistry, and human papillomavirus-associated (HPVA) if positive by HPV ISH. Ten HPVI SCCs and 435 HPVA SCCs were identified; 2 cases were equivocal and excluded from analysis. The overall rate of HPVI SCC was low (2%) but was higher among older patients (7% in patients above 60 y of age and 17% in patients above 70 y of age). Compared with HPVA, patients with HPVI SCC were significantly older (median age, 72 vs. 49, P <0.001) and diagnosed at a higher stage (40% vs. 18% with stage III/IV disease, P =0.055). p53 expression was varied; 2 cases (20%) had null expression and 8 (80%) had wild-type expression. HPVI SCCs were heterogenous, with keratinizing, nonkeratinizing, and warty morphologies observed. Several cases had a precursor lesion reminiscent of differentiated vulvar intraepithelial neoplasia, with prominent basal atypia and hypereosinophilia or a basaloid-like morphology. Two patients (20%) had distant recurrences within 12 months, and 3 (30%) died of disease during follow-up. HPVI SCCs are rare tumors that are more common among older patients with higher stage disease and have important clinical and histologic differences from HPVA SCCs.

Utility of routine pulmonary function test after autologous hematopoietic cell transplantation in lymphoma.

This study aims to evaluate the predictive value of routine pulmonary function testing (PFT) at the 12-month mark post-autologous hematopoietic cell transplant (AHCT) in identifying clinically significant lung disease in lymphoma survivors. In 247 patients, 173 (70%) received BEAM (carmustine, etoposide, cytarabine, melphalan), and 49 (20%) received TBC (thiotepa, busulfan, cyclophosphamide) conditioning regimens. Abnormal baseline PFT was noted in 149 patients (60%). Thirty-four patients had a significant decline (reduction of >/= 20% in DLCO or FEV1 or FVC) in post-AHCT PFT, with the highest incidence in the CNS lymphoma group (39%). The incidence of clinically significant lung disease post-transplant was low at 2% and there was no association between abnormal pre- and 1-year post-transplant PFTs with the development of clinical lung disease. While this study illustrates the impact of treatment regimens on PFT changes, it did not demonstrate a predictive value of scheduled PFTs in identifying clinically significant post-AHCT lung disease.

Extensive versus focal lymphovascular invasion in squamous cell carcinoma of the cervix: A comprehensive international, multicenter, retrospective clinicopathologic study.

OBJECTIVE: We evaluated clinicopathologic parameters of patients with cervical squamous cell carcinoma (SCC) who were treated with initial surgical management and assessed their relation to survival outcomes. Specifically, we evaluated the relation between extent of lymphovascular invasion (LVI) and survival outcomes. METHODS: All available tumor slides from patients with initially surgically treated cervical SCC were collected from 10 institutions and retrospectively analyzed. Standard clinicopathological parameters, tumor stroma, and extent of LVI were assessed (focal: <5 spaces, extensive: ≥5 spaces). PFS and OS were evaluated using Kaplan-Meier methodology. Univariable and multivariable Cox proportional hazards models were created to determine prognostic survival-related risk factors. RESULTS: A total of 670 tumor samples were included in the analysis. Median age at diagnosis was 47 years (IQR: 38-60), 457 patients (72%) had a 2018 International Federation of Gynecology and Obstetrics (FIGO) stage I tumor, and 155 tumors (28%) were flat and/or ulcerated. There were 303 nonkeratinizing tumors (51%), 237 keratinizing tumors (40%), and 356 histologic grade 2 tumors (61%). Quantifiable LVI was present in 321 cases (51%; 23% focal and 33% extensive). On multivariable analysis for PFS, extensive and focal LVI had worse outcomes compared to negative LVI (HR: 2.38 [95% CI: 1.26-4.47] and HR: 1.54 [95% CI: 0.76-3.11], respectively; P = 0.02). The difference did not reach statistical significance for OS. CONCLUSION: Presence of LVI is a prognostic marker for patients with cervical SCC. Quantification (extensive vs. focal vs. negative) of LVI may be an important biomarker for oncologic outcome.

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma.

Fludarabine is one of the most common agents given for lymphodepletion before CD19 chimeric antigen receptor T cells, but its optimal therapeutic intensity is unknown. Using data from a multicenter consortium, we estimated fludarabine exposure (area under the curve [AUC]) using a population pharmacokinetic (PK) model in 199 adult patients with aggressive B-cell non-Hodgkin lymphomas who received commercial axicabtagene ciloleucel (Axi-cel). We evaluated the association of estimated fludarabine AUC with key outcomes, aiming to find an AUC that optimized efficacy and tolerability. We identified low (<18 mg × hour/L [mgh/L]), optimal (18-20 mgh/L), and high (>20 mgh/L) AUC groups for analyses; the 6-month cumulative incidences of relapse/progression of disease (relapse/POD) by AUC groups were 54% (45%-62%), 28% (15%-44%), and 30% (14%-47%), respectively; and the 1-year progression-free survival (PFS) rates were 39% (31%-48%), 66% (52%-84%), and 46% (30%-70%) and the overall survival (OS) rates were 58% (50%-67%), 77% (64%-92%), and 66% (50%-87%), respectively. In multivariable analyses compared with low AUC, an optimal AUC was associated with the highest PFS (hazard ratio [HR], 0.52; 0.3-0.91; P = .02) and lowest risk of relapse/POD (HR, 0.46; 0.25-0.84; P = .01) without an increased risk of any-grade cytokine release syndrome (HR, 1.1; 0.7-1.6; P = .8) or and immune effector cell-associated neurotoxicity syndrome (ICANS) (HR, 1.36; 0.83-2.3; P = .2). A high AUC was associated with the greatest risk of any-grade ICANS (HR, 1.9; 1.1-3.2; P = .02). Although the main cause of death in all groups was relapse/POD, nonrelapse-related deaths, including 3 deaths from ICANS, were more frequent in the high AUC group. These findings suggest that PK-directed fludarabine dosing to achieve an optimal AUC may result in improved outcomes for patients receiving axi-cel.

Adolescent and Young Adult Understanding of Their Childhood Cancer Predisposition Diagnosis: A Qualitative Study.

We characterized germline genetic test result understanding in adolescents and young adults (AYAs) (n = 21) with cancer 1-3.9 years post-disclosure using semistructured qualitative interviews. Most AYAs articulated their cancer risk; however, 5 did not remember results and a subset demonstrated misperceptions regarding risk or confusion regarding their medical care. These findings highlight variability in AYA understanding warranting further inquiry.

Ethnic diversity in treatment response for colorectal cancer: proof of concept for radiomics-driven enrichment trials.

BACKGROUND: Several barriers hamper recruitment of diverse patient populations in multicenter clinical trials which determine efficacy of new systemic cancer therapies. PURPOSE: We assessed if quantitative analysis of computed tomography (CT) scans of metastatic colorectal cancer (mCRC) patients using imaging features that predict overall survival (OS) can unravel the association between ethnicity and efficacy. METHODS: We retrospectively analyzed CT images from 1584 mCRC patients in two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466) collected from August 2006 to March 2013. Primary and secondary endpoints compared RECIST1.1 response at month-2 and delta tumor volume at month-2, respectively. An ancillary study compared imaging phenotype using a peer-reviewed radiomics-signature combining 3 imaging features to predict OS landmarked from month-2. Analysis was stratified by ethnicity. RESULTS: In total, 1584 patients were included (mean age, 60.25 ± 10.57 years; 969 men). Ethnicity was as follows: African (n = 50, 3.2%), Asian (n = 66, 4.2%), Caucasian (n = 1413, 89.2%), Latino (n = 27, 1.7%), Other (n = 28, 1.8%). Overall baseline tumor volume demonstrated Africans and Caucasians had more advanced disease (p < 0.001). Ethnicity was associated with treatment response. Response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. Overall delta tumor volume at month-2 demonstrated that Latino patients more likely experienced response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023). CONCLUSION: This study highlights how clinical trials that inadequately represent minority groups may impact associated translational work. In appropriately powered studies, radiomics features may allow us to unravel associations between ethnicity and treatment efficacy, better elucidate mechanisms of resistance, and promote diversity in trials through predictive enrichment. CLINICAL RELEVANCE STATEMENT: Radiomics could promote clinical trial diversity through predictive enrichment, hence benefit to historically underrepresented racial/ethnic groups that may respond variably to treatment due to socioeconomic factors and built environment, collectively referred to as social determinants of health. KEY POINTS: •Findings indicate ethnicity was associated with treatment response across all 3 endpoints. First, response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. •Second, the overall delta tumor volume at month-2 demonstrated that Latino patients were more likely to experience response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023).

Association between busulfan exposure and survival in patients undergoing a CD34+ selected stem cell transplantation.

Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS.

Locoregional Control Benefit of a Tumor Bed Boost for Ductal Carcinoma In Situ.

Purpose: Radiation therapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces invasive and in situ recurrences. Whereas landmark studies suggest that a tumor bed boost improves local control for invasive breast cancer, the benefit in DCIS remains less certain. We evaluated outcomes of patients with DCIS treated with or without a boost. Methods and Materials: The study cohort comprised patients with DCIS who underwent BCS at our institution from 2004 to 2018. Clinicopathologic features, treatment parameters, and outcomes were ascertained from medical records. Patient and tumor characteristics were evaluated relative to outcomes using univariable and multivariable Cox models. Recurrence-free survival (RFS) estimates were generated using the Kaplan-Meier method. Results: We identified 1675 patients who underwent BCS for DCIS (median age, 56 years; interquartile range, 49-64 years). Boost RT was used in 1146 cases (68%) and hormone therapy in 536 (32%). At a median follow-up of 4.2 years (interquartile range, 1.4-7.0 years), we observed 61 locoregional recurrence events (56 local, 5 regional) and 21 deaths. Univariable logistic regression demonstrated that boost RT was more common among younger patients (P < .001) with positive or close margins (P < .001) and with larger tumors (P < .001) of higher grade (P = .025). The 10-year RFS rate was 88.8% among those receiving a boost and 84.3% among those without a boost (P = .3), and neither univariable nor multivariable analyses revealed an association between boost RT and locoregional recurrence. Conclusions: Among patients with DCIS who underwent BCS, use of a tumor bed boost was not associated with locoregional recurrence or RFS. Despite a preponderance of adverse features among the boost cohort, outcomes were similar to those of patients not receiving a boost, suggesting that a boost may mitigate risk of recurrence among patients with high-risk features. Ongoing studies will elucidate the extent to which a tumor bed boost influences disease control rates.