Value of Dynamic Contrast-Enhanced MRI for Grade Group Prediction in Prostate Cancer: A Radiomics Pilot Study.

RATIONALE AND OBJECTIVES: To determine the role of dynamic contrast-enhanced (DCE) MRI-radiomics in predicting the International Society of Urological Pathology Grade Group (ISUP-GG) in therapy-naïve prostate cancer (PCa) patients. MATERIALS AND METHODS: In this ethics review board-approved retrospective study on two prospective clinical trials between 2017 and 2020, 73 men with suspected/confirmed PCa were included. All participants underwent multiparametric MRI. On MRI, dominant lesions (per PI-RADS) were identified. DCE-MRI radiomic features were extracted from the segmented volumes following the image biomarker standardisation initiative (IBSI) guidelines through 14 time points. Histopathology evaluation on the cognitive-fusion targeted biopsies was set as the reference standard. Univariate regression was done to evaluate potential predictors across all calculated features. Random forest imputation was used for multivariate modelling. RESULTS: 73 index lesions were reviewed. Histopathology revealed 28, 16, 13 and 16 lesions with ISUP-GG-Negative/1/2, ISUP-GG-3, ISUP-GG-4 and ISUP-GG-5, respectively. From the extracted features, total lesion enhancement (TLE), minimum enhancement intensity and Grey-Level Run Length Matrix (GLRLM) were the most significantly different parameters among ISUP-GGs (Neg/1/2 vs 3/4 vs 5). 16 features with significant cross-sectional associations with ISUP-GGs entered the multivariate analysis. The final DCE partitioning model used only four features (lesion sphericity, TLE, GLRLM and Grey-Level Zone Length Matrix). For the binarized diagnosis (ISUP-GG≤2 vs ISUP-GG>2), the accuracy reached 81%. CONCLUSION: DCE-MRI radiomics might be used as a non-invasive tool for aiding pathological grade group prediction in therapy-naïve PCa patients, potentially adding complementary information to PI-RADS for supporting tailored diagnostic pathways and treatment planning.

Predictive [18F]-FDG PET/CT-Based Radiogenomics Modelling of Driver Gene Mutations in Non-small Cell Lung Cancer.

RATIONALE AND OBJECTIVES: To investigate whether [18F]-FDG PET/CT-derived radiomics may correlate with driver gene mutations in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: In this IRB-approved retrospective study, 203 patients with surgically treated NSCLC who underwent subsequent genomic analysis of the primary tumour at our institution between December 2004 and January 2014 were identified. Of those, 128 patients (mean age 62.4 ± 10.8 years; range: 35-84) received preoperative [18F]-FDG PET/CT as part of their initial staging and thus were included in the study. PET and CT image segmentation and feature extraction were performed semi-automatically with an open-source software platform (LIFEx, Version 6.30, lifexsoft.org). Molecular profiles using different next-generation sequencing (NGS) panels were collected from a web-based resource (cBioPortal.ca for Cancer genomics). Two statistical models were then built to evaluate the predictive ability of [18F]-FDG PET/CT-derived radiomics features for driver gene mutations in NSCLC. RESULTS: More than half (68/128, 53%) of all tumour samples harboured three or more gene mutations. Overall, 55% of tumour samples demonstrated a mutation in TP53, 26% of samples had alterations in KRAS and 17% in EGFR. Extensive statistical analysis resulted in moderate to good predictive ability. The highest Youden Index for TP53 was achieved using combined PET/CT features (0.70), for KRAS using PET features only (0.57) and for EGFR using CT features only (0.60). CONCLUSION: Our study demonstrated a moderate to good correlation between radiomics features and driver gene mutations in NSCLC, indicating increased predictive ability of genomic profiles using combined [18F]-FDG PET/CT-derived radiomics features.

A phase 2 study of a longitudinal multidimensional rehabilitation program for allogeneic blood and marrow transplantation patients.

ABSTRACT: Allogeneic blood and marrow transplantation (alloBMT) is a curative treatment for blood cancers associated with various treatment-related adverse events and morbidities for which rehabilitation programs are currently limited. A phase 2 randomized controlled trial (RCT) was conducted to assess the feasibility, acceptability, and impact of CaRE-4-alloBMT, a longitudinal, multidimensional cancer rehabilitation program for patients undergoing alloBMT. The primary outcomes included the feasibility and acceptability of the intervention and the methods. Feasibility was assessed through recruitment, retention, and adherence rates. Acceptability was assessed through qualitative interviews. Secondary clinical outcomes were collected through questionnaires and physiological assessments at 4 time points. A total of 80 participants were recruited and randomized. Recruitment (72%) and retention (70%) rates, along with qualitative findings, support the feasibility of the intervention. Adherence was suboptimal, most notably educational module completion (22.7%). Treatment effect sizes of 0.70 (95% confidence interval [CI], 0.20-1.21; 30-second sit-to-stand test) and 0.46 (95% CI, -0.17 to 1.09; 36-Item Short Form Survey) were observed in favor of the intervention. The results appear promising; however, the findings are limited by missing data owing to attrition. Modifications will be required to refine the program and inform a phase 3 RCT. This trial was registered at www.ClinicalTrials.gov as #NCT04966156.

A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Glial fibrillary acidic protein, neurofilament light, matrix metalloprotease 3 and fatty acid binding protein 4 as non-invasive brain tumor biomarkers.

BACKGROUND: Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival. METHODS: Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays. RESULTS: High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas. CONCLUSIONS: GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas.

Clinical Utility of Tumor Next-Generation Sequencing Panel Testing to Inform Treatment Decisions for Patients With Advanced Solid Tumors in a Tertiary Care Center.

PURPOSE: There is limited information about the clinical utility of targeted next-generation sequencing (NGS) panel testing to inform decision making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is a prospective study that enrolled more than 4,500 patients with solid tumor for NGS panel testing. We performed a retrospective survey of medical oncologists to evaluate the impact of NGS testing on treatment decisions. METHODS: Patients and treating oncologists were identified at the Princess Margaret Cancer Center between 2016 and 2021. Tumor-only sequencing was performed using a gene panel of either 555 or 161 cancer genes. Oncologists were asked to review testing results and complete a survey indicating whether NGS testing affected treatment decisions. The primary outcome of this study was rate of treatment change on the basis of mutation results. Patient, test, and physician factors were evaluated for association with treatment changes using univariate analyses and a mixed-effects model. RESULTS: Of the 582 surveys sent, 394 (67.7%) were completed. We found that 188 (47.7%) patients had testing results classified as actionable by the oncologist and 62 (15.7%) patients were matched to treatment, of whom 37 (60%) were enrolled in a clinical trial, 13 (21%) received an approved drug, four (6%) were prescribed off-label therapy, and eight (13%) avoided ineffective treatment. Patient, test, and physician characteristics were not significantly associated with treatment change. There was no difference in overall survival between patients who received matched treatment versus those who did not (P = .55, median survival not reached). CONCLUSION: OCTANE testing led to a change in drug treatment in 15.7% of patients, supporting the clinical utility of NGS panel testing for patients with advanced solid tumors.

The [18F]F-FDG PET/CT Radiomics Classifier of Histologic Subtypes and Anatomical Disease Origins across Various Malignancies: A Proof-of-Principle Study.

We aimed to investigate whether [18F]F-FDG-PET/CT-derived radiomics can classify histologic subtypes and determine the anatomical origin of various malignancies. In this IRB-approved retrospective study, 391 patients (age = 66.7 ± 11.2) with pulmonary (n = 142), gastroesophageal (n = 128) and head and neck (n = 121) malignancies were included. Image segmentation and feature extraction were performed semi-automatically. Two models (all possible subset regression [APS] and recursive partitioning) were employed to predict histology (squamous cell carcinoma [SCC; n = 219] vs. adenocarcinoma [AC; n = 172]), the anatomical origin, and histology plus anatomical origin. The recursive partitioning algorithm outperformed APS to determine histology (sensitivity 0.90 vs. 0.73; specificity 0.77 vs. 0.65). The recursive partitioning algorithm also revealed good predictive ability regarding anatomical origin. Particularly, pulmonary malignancies were identified with high accuracy (sensitivity 0.93; specificity 0.98). Finally, a model for the synchronous prediction of histology and anatomical disease origin resulted in high accuracy in determining gastroesophageal AC (sensitivity 0.88; specificity 0.92), pulmonary AC (sensitivity 0.89; specificity 0.88) and head and neck SCC (sensitivity 0.91; specificity 0.92). Adding PET-features was associated with marginal incremental value for both the prediction of histology and origin in the APS model. Overall, our study demonstrated a good predictive ability to determine patients' histology and anatomical origin using [18F]F-FDG-PET/CT-derived radiomics features, mainly from CT.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

Multiplex Proteomics in the Identification of Potential Biomarkers of Very Severe Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease in Allogeneic Hematopoietic Cell Transplant Patients Treated with Defibrotide.

INTRODUCTION: Despite well-established clinical criteria for diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) following allogeneic hematopoietic cell transplantation (HCT), there is a lack of established diagnostic protein biomarkers. METHODS: Prospective samples were collected from patients with very severe SOS/VOD at diagnosis and days +3, +7, +14, and +30 post-initiation of defibrotide. Samples from age-matched controls with no VOD were collected at days +14, +30, +60, +90, and +180 following allogeneic HCT. Serum samples were analyzed for 2,925 protein levels by antibody-based proximity extension assay (PEA). Mean differences in the log-transformed abundance values were compared using t tests in a volcano plot. RESULTS: Five patients with very severe SOS/VOD and 5 control patients were compared. Ten proteins were identified that showed a statistically significant and log-transformed 3-fold increase in concentration. They were CALCA, CCL20, GPR37, IGFBP4, IL1RL1, SLC39A14, SPINK4, FABP3, MYL3, and CHCHD10. Four different proteins, namely, CD83, leukocyte associated immunoglobulin-like receptor 2 (LAIR2), CD7, and HEM6 showed a significant decrease with defibrotide treatment. SOS/VOD resolved in 80% (n = 4) of patients, while 1 patient deceased due to SOS/VOD. CONCLUSION: PEA technology identified 10 proteins that were significantly elevated in patients with very severe SOS/VOD. Prospective studies in a larger cohort using this technology may be able to conclusively identify diagnostic protein biomarkers for SOS/VOD.

Virtual Cancer Care Beyond the COVID-19 Pandemic: Patient and Staff Perspectives and Recommendations.

PURPOSE: COVID-19 catalyzed rapid implementation of virtual cancer care (VC); however, work is needed to inform long-term adoption. We evaluated patient and staff experiences with VC at a large urban, tertiary cancer center to inform recommendations for postpandemic sustainment. METHODS: All physicians who had provided VC during the pandemic and all patients who had a valid e-mail address on file and at least one visit to the Princess Margaret Cancer Centre in Toronto, Canada, in the preceding year were invited to complete a survey. Interviews and focus groups with patients and staff across the cancer center were analyzed using qualitative descriptive analysis and triangulated with survey findings. RESULTS: Response rates for patients and physicians were 15% (2,343 of 15,169) and 41% (100 of 246), respectively. A greater proportion of patients than physicians were satisfied with VC (80.1 v 53.4%; P < .01). In addition, fewer patients than physicians felt that virtual visits were worse than those conducted in person (28.0 v 43.4%; P < .01) and that telephone and video visits negatively affected the human interaction that they valued (59.8% v 82.0%; P < .01). Major barriers to VC for patients were respect for care preferences and personal boundaries, accessibility, and equitable access. For staff, major barriers included a lack of role clarity, dedicated resources (space and technology), integration of nursing and allied health, support (administrative, clinical, and technical), and guidance on appropriateness of use. CONCLUSION: Patient and staff perceptions and barriers to virtual care are different. Moving forward, we need to pay attention to both staff and patient experiences with virtual care since this will have major implications for long-term adoption into clinical practice.

Efficacy of the Rehabilitation Planning Consult for Survivors of Head and Neck Cancer: A Phase 2 Randomized Controlled Trial.

PURPOSE: Survivors of head and neck cancer may have significant lasting impairments and poor access to rehabilitation. To address this, our group developed and evaluated a rehabilitation planning consult (RPC). The RPC is conducted through an initial consultation and a single follow-up session with a rehabilitation professional. During the initial consultation, rehabilitation needs are determined and the survivor sets individualized goals and plans. They then implement their plans independently and are facilitated to evaluate and modify plans as necessary during the follow-up session. METHODS AND MATERIALS: We used a waitlist control design to compare the proportion of participants attaining a minimally importantly different change in quality of life (QOL) on the Short Form 36 Physical Health Summary Score from baseline to 3 months after study enrollment, between patients randomized to receive (n = 77) or wait 14 ± 3 weeks to receive (n = 76) the RPC. Additional outcomes included goal attainment indicators measured using the Brief Rehabilitation Assessment for Survivors of Head and Neck Cancer (BRASH). RESULTS: Of 153 participants recruited, 95 (62%) completed the intervention; 57 were in the immediate (RPC) group and 38 were in the waiting list control (WLC) group. No significant between-group differences were seen in the proportion of patients achieving a minimally important improvement (2.5 units) on the Physical Health Summary Score from baseline to 3 months after recruitment. No between-group differences were seen on any secondary QOL indicators. Among the 67 (RPC n = 42, WLC n = 22) participants who set individualized rehabilitation goals, BRASH scores on goal performance and satisfaction with goal performance were significantly better in the RPC group. CONCLUSIONS: Our results suggest that the RPC may provide benefit in patients' individualized domains of choice among those who set goals, without affecting overall QOL. Future work could refine the subset of patients who benefit and explore the optimal timing and intensity of the intervention.

IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies.

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

Impact of 18F-DCFPyL PET/MRI in Selecting Men With Low-/Intermediate-Risk Prostate Cancer for Focal Ablative Therapies.

PURPOSE: To compare the diagnostic performance of multiparametric (mp) MRI to 18F-DCFPyL PET/MRI for detecting clinically significant (cs) prostate cancer (PCa) in men with low-/intermediate-risk PCa being considered for focal ablative therapy (FT), using 2 interpretation schemes, and to assess the rate of exclusion from FT for each modality. METHODS: This prospective study evaluated men with low- or intermediate-risk PCa, potential candidates for FT based on initial biopsy as per institutional protocol, who underwent 18F-DCFPyL PET/MRI. Each modality (mpMRI, PET/MRI using PROMISE classification [PET/MRI PROMISE], and PET/MRI considering any focal lesion on PET as positive [PETFL/MRI]) was assessed independently. All suspicious lesions underwent PET/MRI-ultrasound fusion biopsies. Diagnostic performances were calculated and compared using the exact binomial test on paired proportions. RESULTS: Thirty-four men (median age, 64 years; interquartile range, 60-70 years) were included. Overall, 40 of 67 lesions (60%) identified on mpMRI and/or PET/MRI were malignant, and 34 of 40 lesions (85%) were csPCa (≥6 mm ISUP [International Society of Urological Pathology Grade Group] GG1 or ISUP-GG ≥2). On lesion-level analysis, for detecting csPCa, sensitivity appeared higher for PETFL/MRI than mpMRI and PET/MRI PROMISE (97% vs 76% and 79%, respectively [P = 0.02 and 0.03]), whereas specificity was lower (30% vs 85% and 88%, respectively [P < 0.001]). The calculated overall accuracy rates for PETFL/MRI, mpMRI, and PET/MRI PROMISE were 64%, 81%, and 84%, respectively. PETFL/MRI, mpMRI, and PET/MRI PROMISE excluded 10 of 34 (29%), 7 of 34 (21%), and 6 of 34 (18%) men from FT, respectively. CONCLUSIONS: 18F-DCFPyL PET/MRI excluded nearly 30% of patients with low-/intermediate-risk PCa from FT, with a potential role in decreasing selection failure. Compared with mpMRI, PET/MRI had a higher sensitivity for detecting csPCa in men who were candidates for FT.ClinicalTrials.gov identifier NCT03149861.

Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.

PURPOSE: Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma. PATIENTS AND METHODS: Patients were randomized to receive durvalumab 1,500 mg IV every 4 weeks with either olaparib 300 mg twice a day orally (Arm A) or cediranib 20 mg every day orally 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiologic assessments and stool collections were performed. Primary endpoints were safety and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic, and microbiome parameters. RESULTS: Among 30 heavily pretreated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On Arm A, 1 patient achieved partial response (PR) with increase in CD8 T cells and macrophages in the TME during treatment, while 4 had stable disease (SD) ≥ 6 months. No patients on Arm B achieved PR or SD ≥ 6 months. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival. CONCLUSIONS: Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma. Baseline M1-macrophage and B-cell activity may identify patients with leiomyosarcoma with favorable outcomes on immunotherapy and should be further evaluated.

The association of cancer-related fatigue on the social, vocational and healthcare-related dimensions of cancer survivorship.

BACKGROUND: Cancer-related fatigue (CRF) is well documented in cancer survivors, but little is known about the personal and societal impact of CRF. This study aimed to examine the impact of CRF in relation to social and vocational functioning and health care utilization in a large sample of post-treatment cancer survivors. METHODS: We conducted a cross-sectional descriptive study of early stage breast and colorectal cancer survivors (n = 454) who were within 5 years from treatment completion. Social difficulties (SDI-21), work status, absenteeism and presenteeism (WHO-HPQ) and healthcare utilization (HSUQ) were compared in those with (CFR +) and without (CRF -) clinically significant fatigue (FACT-F ≤ 34). RESULTS: A total of 32% met the cut-off criteria for CRF (≤ 34). Participants with CRF + had significantly higher scores on the SDI-21 across all domains and 55% of CRF + vs. 11% in CRF - was above the SDI cut-off (> 10) for significant social difficulties. Participants with CRF + were 2.74 times more likely to be unemployed or on leave (95% CI 1.62, 4.61, p < 0.001). In the subgroup of participants who were currently working (n = 249), those with CRF + reported working on average 27.4 fewer hours in the previous 4 weeks compared to CRF - (p = 0.05), and absolute presenteeism was on average 13% lower in the CRF + group (95% CI 8.0, 18.2, p < 0.001). Finally, individuals with CRF + reported significantly more physician (p < 0.001), other health care professional (p = 0.03) and psychosocial visits (p = 0.002) in the past month. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: CRF is associated with substantial disruption in social and work role functioning in the early transitional phase of cancer survivorship. Better management of persistent CRF and funding for the implementation of existing guidelines and recommended evidence-based interventions are urgently needed.

Validation of the Integrated Prediction Model algorithm for outcome of cytoreduction in advanced ovarian cancer.

BACKGROUND: We previously developed the Integrated Prediction Model using a 4-step algorithm of unresectable stage IVB, patient factors, surgical resectability, and surgical complexity to predict outcome of <1 cm cytoreduction in advanced epithelial ovarian cancer, and triaged patients to neoadjuvant chemotherapy or primary cytoreductive surgery. OBJECTIVE: To validate the Integrated Prediction Model on a retrospective cohort of patients. METHODS: A retrospective cohort study of 107 patients with advanced ovarian cancer treated between January 2017 and September 2018 was carried out. The above mentioned 4-step algorithm determined cut-off points using the Youden Index. This validation study reports sensitivity, specificity, negative and positive predictive value on an external cohort. RESULTS: Among 107 patients, 61 had primary surgery and 46 had neoadjuvant chemotherapy. Compared with primary surgery, patients treated with neoadjuvant chemotherapy were significantly older (63.5 vs 61, p=0.037), more likely to have stage IV disease (52% vs 18%, p<0.001), Eastern Cooperative Oncology Group (ECOG) score >1 (30% vs 11%, 0.045), lower pre-operative albumin (37 vs 40, p<0.001), and higher CA-125 (970 vs 227.5, p<0.001). They also had higher patient factors (2 vs 0, p=0.013), surgical resectability (4 vs 1, p<0.001), and anticipated surgical complexity (8 vs 5, p<0.001). There was no significant difference in outcome of cytoreduction (<1 cm residual disease: 85% for primary surgery vs 87% interval surgery, p=0.12)In this validation cohort, triaging patients with patient factors ≤2, surgical resectability score ≤5, and surgical complexity score ≤9 to primary surgery had a sensitivity of 91% for optimal cytoreduction <1 cm and a specificity of 81%. The positive predictive value, negative predictive value, and accuracy were 83%, 90%, and 86%, respectively. Application of the Integrated Prediction Model would have prevented five patients from receiving suboptimal cytoreduction and triaged them to neoadjuvant chemotherapy. CONCLUSIONS: We validated the proposal that a triage algorithm integrating patient factors, surgical complexity, and surgical resectability in advanced ovarian cancer had high sensitivity and specificity to predict optimal cytoreduction <1 cm.

Discovery of novel glioma serum biomarkers by proximity extension assay.

BACKGROUND: Gliomas are among the most malignant tumors, with a very poor prognosis. Early diagnosis is highly desirable since it can help implement more effective treatments for smaller tumors, which have not yet extensively metastasized. Improving early diagnosis may facilitate access of patients to clinical trials and prepare them for the future availability of new disease-modifying treatments. METHODS: We analyzed retrospective samples collected at diagnosis (before therapy initiation), with PEA (Olink Proteomics), quantifying about 3000 proteins. We utilized 30 plasmas from gliomas (20 glioblastomas, 5 anaplastic astrocytomas, 5 anaplastic oligodendrogliomas) and 20 meningiomas (as controls). We then analyzed the data to identify proteins which either alone, or in combination, could discriminate gliomas from meningiomas, or correlate with clinical and molecular alterations. RESULTS: We identified 8 plasma proteins which were increased in gliomas vs. meningiomas (GFAP, NEFL, EDDM3B, PROK1, MMP3, CTRL, GP2, SPINT3) and 4 proteins which were decreased in gliomas vs. meningiomas (FABP4, ALDH3A1, IL-12B and OXT). Partition algorithms and logistic regression algorithms with two biomarkers (GFAP and FABP4) achieved sensitivity of 83% and 93% at 100% and 90% specificity, respectively. The strongest single marker was GFAP with an area under the ROC curve (AUC) of 0.86. The AUC for the GFAP-FABP4 combination was 0.98. CONCLUSION: PEA is a powerful new proteomic technology for biomarker discovery. GFAP and a handful of other plasma biomarkers may be useful for early glioma detection and probably, prognosis. STATEMENT: Detecting gliomas as early as possible is highly desirable since it can significantly improve the chances of effective treatments. Reliable glioma biomarkers can timely inform glioma patients about the efficacy of their prescribed treatment. Our results reveal some novel putative glioma markers that may prove valuable, when used alone or in combination, towards improved clinical care of gliomas. In order to better appreciate the potential usefulness of these markers, their performance needs to be further validated in a larger cohort of samples.

The role of [18F]-DCFPyL PET/MRI radiomics for pathological grade group prediction in prostate cancer.

PURPOSE: To evaluate the diagnostic accuracy of [18F]-DCFPyL PET/MRI radiomics for the prediction of pathological grade group in prostate cancer (PCa) in therapy-naïve patients. METHODS: Patients with confirmed or suspected PCa, who underwent [18F]-DCFPyL PET/MRI (n = 105), were included in this retrospective analysis of two prospective clinical trials. Radiomic features were extracted from the segmented volumes following the image biomarker standardization initiative (IBSI) guidelines. Histopathology obtained from systematic and targeted biopsies of the PET/MRI-detected lesions was the reference standard. Histopathology patterns were dichotomized as ISUP GG 1-2 vs. ISUP GG ≥ 3 categories. Different single-modality models were defined for feature extraction, including PET- and MRI-derived radiomic features. The clinical model included age, PSA, and lesions' PROMISE classification. Single models, as well as different combinations of them, were generated to calculate their performances. A cross-validation approach was used to evaluate the internal validity of the models. RESULTS: All radiomic models outperformed the clinical models. The best model for grade group prediction was the combination of PET + ADC + T2w radiomic features, showing sensitivity, specificity, accuracy, and AUC of 0.85, 0.83, 0.84, and 0.85, respectively. The MRI-derived (ADC + T2w) features showed sensitivity, specificity, accuracy, and AUC of 0.88, 0.78, 0.83, and 0.84, respectively. PET-derived features showed 0.83, 0.68, 0.76, and 0.79, respectively. The baseline clinical model showed 0.73, 0.44, 0.60, and 0.58, respectively. The addition of the clinical model to the best radiomic model did not improve the diagnostic performance. The performances of MRI and PET/MRI radiomic models as per the cross-validation scheme yielded an accuracy of 0.80 (AUC = 0.79), whereas clinical models presented an accuracy of 0.60 (AUC = 0.60). CONCLUSION: The combined [18F]-DCFPyL PET/MRI radiomic model was the best-performing model and outperformed the clinical model for pathological grade group prediction, indicating a complementary value of the hybrid PET/MRI model for non-invasive risk stratification of PCa. Further prospective studies are required to confirm the reproducibility and clinical utility of this approach.

Longitudinal efficacy and toxicity of SARS-CoV-2 vaccination in cancer patients treated with immunotherapy.

Despite more than 2 years having elapsed since the onset of SARS-CoV-2 pandemic, a level of hesitation around increased SARS-CoV-2 vaccine toxicity in cancer patients receiving immunotherapy (IO) remains. This hesitation stems from the idea that IO agents could elicit an overwhelming immune stimulation post vaccination and therefore increase the risk of vaccine-related toxicity. The aim of our study was to explore serological responses to SARS-CoV-2 vaccination in patients treated with IO and describe the level of immune stimulation using parameters such as blood cytokines, autoantibody levels and immune related adverse events (irAEs) post vaccination. Fifty-one evaluable patients were enrolled in this longitudinal study. Absolute levels and neutralization potential of anti-SARS-CoV-2 antibodies were not significantly different in the IO group compared to non-IO. Chemotherapy adversely affected seroconversion when compared to IO and/or targeted treatment. Following vaccination, the prevalence of grade ≥2 irAEs in patients treated with IO was not higher than the usual reported IO toxicity. We report, for the first time, that anti-SARS-CoV-2 vaccination, elicited the generation of five autoantibodies. The significantly increased autoantibodies were IgM autoantibodies against beta-2 glycoprotein (p = 0.02), myeloperoxidase (p = 0.03), nucleosome (p = 0.041), SPLUNC2 (p < 0.001) and IgG autoantibody against Myosin Heavy Chain 6 (MYH6) (p < 0.001). Overall, comprehensive analysis of a small cohort showed that co-administration of SARS-CoV-2 vaccine and IO is not associated with increased irAEs. Nevertheless, the detection of autoantibodies post anti-SARS-CoV-2 vaccination warrants further investigation (NCT03702309).

CT Radiomics and Whole Genome Sequencing in Patients with Pancreatic Ductal Adenocarcinoma: Predictive Radiogenomics Modeling.

We investigate whether computed tomography (CT) derived radiomics may correlate with driver gene mutations in patients with pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, 47 patients (mean age 64 ± 11 years; range: 42-86 years) with PDAC, who were treated surgically and who underwent preoperative CT imaging at our institution were included in the study. Image segmentation and feature extraction was performed semi-automatically with a commonly used open-source software platform. Genomic data from whole genome sequencing (WGS) were collected from our institution's web-based resource. Two statistical models were then built, in order to evaluate the predictive ability of CT-derived radiomics feature for driver gene mutations in PDAC. 30/47 of all tumor samples harbored 2 or more gene mutations. Overall, 81% of tumor samples demonstrated mutations in KRAS, 68% of samples had alterations in TP53, 26% in SMAD4 and 19% in CDKN2A. Extended statistical analysis revealed acceptable predictive ability for KRAS and TP53 (Youden Index 0.56 and 0.67, respectively) and mild to acceptable predictive signal for SMAD4 and CDKN2A (Youden Index 0.5, respectively). Our study establishes acceptable correlation of radiomics features and driver gene mutations in PDAC, indicating an acceptable prognostication of genomic profiles using CT-derived radiomics. A larger and more homogenous cohort may further enhance the predictive ability.