Whole-Body Positron Emission Tomography with 18F-Fluorodeoxyglucose/Magnetic Resonance Imaging as a Screening Tool for the Detection of Malignant Transformation in Individuals with Neurofibromatosis Type 1.

Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1.

Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Ro-CHOP phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT01796002) established that romidepsin (Ro) plus cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) did not yield an increased efficacy compared with CHOP alone as first-line treatment of peripheral T-cell lymphoma. We report the planned final analysis 5 years after the last patient enrolled. With a median follow-up of 6 years, median progression-free survival (PFS) was 12.0 months compared with 10.2 months (hazard ratio [HR], 0.79 [95% CI, 0.62 to 1.005]; P = .054), while median overall survival was 62.2 months (35.7-86.6 months) and 43.8 months (30.1-70.2 months; HR, 0.88 [95% CI, 0.68 to 1.14]; P = .324) in the Ro-CHOP and CHOP arms, respectively. In an exploratory analysis, the median PFS in the centrally reviewed follicular helper T-cell lymphoma subgroup was significantly longer in the Ro-CHOP arm (19.5 v 10.6 months, HR, 0.703 [95% CI, 0.502 to 0.985]; P = .039). Second-line treatments were given to 251 patients with a median PFS2 and OS2 after relapse or progression of 3.3 months and 11.5 months, respectively. Within the limits of highly heterogeneous second-line treatments, no specific regimen seemed to provide superior disease control. However, a potential benefit was observed with brentuximab vedotin in association with chemotherapy even after excluding anaplastic large-cell lymphoma subtype or after adjusting for histology and international prognostic index in a multivariate model (HR for PFS, 0.431 [95% CI, 0.238 to 0.779]; P = .005).

Prognostic Value of 18F-FDG PET Radiomics Features at Baseline in PET-Guided Consolidation Strategy in Diffuse Large B-Cell Lymphoma: A Machine-Learning Analysis from the GAINED Study.

The results of the GA in Newly Diagnosed Diffuse Large B-Cell Lymphoma (GAINED) study demonstrated the success of an 18F-FDG PET-driven approach to allow early identification-for intensification therapy-of diffuse large B-cell lymphoma patients with a high risk of relapse. Besides, some works have reported the prognostic value of baseline PET radiomics features (RFs). This work investigated the added value of such biomarkers on survival of patients involved in the GAINED protocol. Methods: Conventional PET features and RFs were computed from 18F-FDG PET at baseline and extracted using different volume definitions (patient level, largest lesion, and hottest lesion). Clinical features and the consolidation treatment information were also considered in the model. Two machine-learning pipelines were trained with 80% of patients and tested on the remaining 20%. The training was repeated 100 times to highlight the test set variability. For the 2-y progression-free survival (PFS) outcome, the pipeline included a data augmentation and an elastic net logistic regression model. Results for different feature groups were compared using the mean area under the curve (AUC). For the survival outcome, the pipeline included a Cox univariate model to select the features. Then, the model included a split between high- and low-risk patients using the median of a regression score based on the coefficients of a penalized Cox multivariate approach. The log-rank test P values over the 100 loops were compared with a Wilcoxon signed-ranked test. Results: In total, 545 patients were included for the 2-y PFS classification and 561 for survival analysis. Clinical features alone, consolidation features alone, conventional PET features, and RFs extracted at patient level achieved an AUC of, respectively, 0.65 ± 0.07, 0.64 ± 0.06, 0.60 ± 0.07, and 0.62 ± 0.07 (0.62 ± 0.07 for the largest lesion and 0.54 ± 0.07 for the hottest). Combining clinical features with the consolidation features led to the best AUC (0.72 ± 0.06). Adding conventional PET features or RFs did not improve the results. For survival, the log-rank P values of the model involving clinical and consolidation features together were significantly smaller than all combined-feature groups (P < 0.007). Conclusion: The results showed that a concatenation of multimodal features coupled with a simple machine-learning model does not seem to improve the results in terms of 2-y PFS classification and PFS prediction for patient treated according to the GAINED protocol.

Validation of the ΔSUVmax for Interim PET Interpretation in Diffuse Large B-Cell Lymphoma on the Basis of the GAINED Clinical Trial.

The GAINED phase 3 trial (ClinicalTrials.gov identifier: NCT01659099) evaluated a PET-driven consolidative strategy in patients with diffuse large B-cell lymphoma. In this post hoc analysis, we aimed to compare the prognostic value of the per-protocol PET interpretation criteria (Menton 2011 consensus) with the change in the SUVmax (ΔSUVmax) alone. Methods: Real-time central review of 18F-FDG PET/CT was performed in 581 patients after 2 cycles (PET2) and 4 cycles (PET4) of immunochemotherapy using the Menton 2011 criteria, combining the ΔSUVmax (cutoffs of 66% and 70% at PET2 and PET4, respectively) and the Deauville scale. In "special cases," when the baseline SUVmax was less than 10.0 or the interim residual tumor SUVmax was greater than 5.0, the Menton 2011 experts' consensus agreed that the ΔSUVmax may not be reliable and that the Deauville score is preferable. Prognostic values of Menton 2011 and ΔSUVmax were evaluated by Kaplan-Meier analyses in terms of progression-free survival (PFS). Results: Seventeen percent of patients at PET2 (100/581) and 8% at PET4 (49/581) had PET-negative results by ΔSUVmax but were considered to have PET-positive results according to Menton 2011 with residual SUVmax of greater than 5.0. For the population with PET2-positive results, 2-y PFS was 70% (range, 58%-80%) with ΔSUVmax alone, whereas the outcome tended to be better for those who were considered to have PET-positive results by Menton 2011, 81% (range, 72%-87%). Conversely, all 10 patients with baseline SUVmax of less than 10.0 had PET2-positive results by ΔSUVmax but were considered to have PET2-negative results by Menton 2011. These patients had the same 2-y PFS as patients with PET2-negative/PET4-negative results, indicating that the ΔSUVmax yielded false-positive results in this situation. Conclusion: We recommend the use of the ΔSUVmax alone rather than the Menton 2011 criteria for assessing the interim metabolic response in patients with diffuse large B-cell lymphoma, except when the baseline SUVmax is less than 10.0.

Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial.

Axicabtagene ciloleucel (axi-cel) demonstrated superior efficacy compared to standard of care as second-line therapy in patients with high-risk relapsed/refractory (R/R) large B cell lymphoma (LBCL) considered eligible for autologous stem cell transplantation (ASCT); however, in clinical practice, roughly half of patients with R/R LBCL are deemed unsuitable candidates for ASCT. The efficacy of axi-cel remains to be ascertained in transplant-ineligible patients. ALYCANTE, an open-label, phase 2 study, evaluated axi-cel as a second-line therapy in 62 patients with R/R LBCL who were considered ineligible for ASCT. The primary end point was investigator-assessed complete metabolic response at 3 months from the axi-cel infusion. Key secondary end points included progression-free survival, overall survival and safety. The study met its primary end point with a complete metabolic response of 71.0% (95% confidence interval, 58.1-81.8%) at 3 months. With a median follow-up of 12.0 months (range, 2.1-17.9), median progression-free survival was 11.8 months (95% confidence interval, 8.4-not reached) and overall survival was not reached. There was no unexpected toxicity. Grade 3-4 cytokine release syndrome and neurologic events occurred in 8.1% and 14.5% of patients, respectively. These results support axi-cel as second-line therapy in patients with R/R LBCL ineligible for ASCT. ClinicalTrials.gov Identifier: NCT04531046 .

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Epithelioid glioblastoma diagnosed 70 years after craniofacial radiotherapy.

The authors report a rare case of most likely radiation-induced glioma (RIG) with epithelioid features and the presence of molecular features consistent with RIG. This occurred 70 years after craniofacial brachytherapy. Such a late development of radiation-induced glioblastoma (RIGBM) and the advanced age of presentation for an epithelioid glioblastoma are both unique in the literature. Despite not receiving the full course of adjuvant chemotherapy after surgery and radiotherapy, the patient displayed no signs of recurrence during a 5-year follow-up. RIGBM should be further studied to reveal potential unique clinical and molecular characteristics, as well as to better predict survival and treatment response.

Deep Learning on Bone Scintigraphy to Detect Abnormal Cardiac Uptake at Risk of Cardiac Amyloidosis.

BACKGROUND: Cardiac uptake on technetium-99m whole-body scintigraphy (WBS) is almost pathognomonic of transthyretin cardiac amyloidosis. The rare false positives are often related to light-chain cardiac amyloidosis. However, this scintigraphic feature remains largely unknown, leading to misdiagnosis despite characteristic images. A retrospective review of all WBSs in a hospital database to detect those with cardiac uptake may allow the identification of undiagnosed patients. OBJECTIVES: The authors sought to develop and validate a deep learning-based model that automatically detects significant cardiac uptake (Perugini grade ≥2) on WBS from large hospital databases in order to retrieve patients at risk of cardiac amyloidosis. METHODS: The model is based on a convolutional neural network with image-level labels. The performance evaluation was performed with C-statistics using a 5-fold cross-validation scheme stratified so that the proportion of positive and negative WBSs remained constant across folds and using an external validation data set. RESULTS: The training data set consisted of 3,048 images: 281 positives (Perugini grade ≥2) and 2,767 negatives. The external validation data set consisted of 1,633 images: 102 positives and 1,531 negatives. The performance of the 5-fold cross-validation and external validation was as follows: 98.9% (± 1.0) and 96.1% for sensitivity, 99.5% (± 0.4) and 99.5% for specificity, and 0.999 (SD = 0.000) and 0.999 for the area under the curve of the receiver-operating characteristic curves. Sex, age <90 years, body mass index, injection-acquisition delay, radionuclides, and the indication of WBS only slightly affected performances. CONCLUSIONS: The authors' detection model is effective at identifying patients with cardiac uptake Perugini grade ≥2 on WBS and may help in the diagnosis of patients with cardiac amyloidosis.

Baseline circulating tumour DNA and total metabolic tumour volume as early outcome predictors in aggressive large B-cell lymphoma. A real-world 112-patient cohort.

Approximately 20%-50% of patients with large B-cell lymphoma (LBCL) experience poor outcomes. We aimed to evaluate the combined prognostic value of circulating tumour DNA (ctDNA) and total metabolic tumour volume (TMTV) in LBCL. This observational single-centre study included 112 newly diagnosed LBCL patients, receiving R-CHOP/R-CHOP-like chemotherapies. CtDNA load was calculated following next-generation sequencing of cell-free DNA (cfDNA) using a targeted 40-gene lymphopanel. TMTV was measured using a fully automated artificial intelligence-based method for lymphoma lesion segmentation. CtDNA was detected in cfDNA samples from 95 patients with a median concentration of 3.15 log haploid genome equivalents per mL. TMTV measurements were available for 102 patients. The median TMTV was 501 mL. High ctDNA load (>3.57 log hGE/mL) or high TMTV (>200 mL) were associated with shorter 1-year PFS (44% vs. 83%, p < 0.001 and 64% vs. 97%, p = 0.002, respectively). When combined, three prognostic groups were identified. The shortest PFS was observed when both TMTV and ctDNA load were high (p < 0.001). Even with a short follow up, combining ctDNA load with TMTV improved the risk stratification of patients with aggressive LBCL. In the near future, very high-risk patients could benefit from CAR T-cell therapy or bispecific antibodies as first-line treatments.

Amylo-AFFECT-QOL, a self-reported questionnaire to assess health-related quality of life and to determine the prognosis in cardiac amyloidosis.

Background and aims: Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA. Methods: A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire. Results: Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p-value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01). Conclusion: Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA.

Baseline 18F-FDG Metabolic Tumor Volume Predicts Response to Rituximab Induction in Post-transplant Lymphoproliferative Disorders: A Multi-institutional Retrospective Study.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of immunosuppression. Sequential treatment is commonly proposed, combining induction with rituximab (R-induction) followed by either continuation of treatment or addition of chemotherapy depending on response. Response to R-induction, often assessed by CT scan, is a major predictor of overall survival (OS). The aim of the study was to analyze predictive factors of R-induction response, including total metabolic tumor volume (TMTV), and investigate the role of 18F-FDG PET/CT in response assessment. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. Only patients treated by R-induction with a baseline 18F-FDG PET/CT were included. Response to R-induction was assessed by 18F-FDG PET/CT. The optimal threshold of TMTV for rituximab response was determined using receiver operating characteristic curves. Univariate and multivariate analyses were conducted to identify predictive factors of response. A total of 67 patients were included. Survival characteristics were similar to those previously reported: the complete response rate to R-induction was 30%, the 3-year OS estimate was 66%, and the treatment-related mortality was 4%. The optimal threshold for TMTV to predict R-induction response was 135 cm3. The response rate to R-induction was 38% in the 21 patients with TMTV ≥ 135 cm3 and 72% in the 46 patients with TMTV < 135 cm3. TMTV was a significant predictor of response, both at univariate and multivariate analyses (odd ratios = 3.71, P = 0.022). Baseline TMTV is predictive of response to R-induction. Early assessment of patient response is feasible with 18F-FDG PET/CT.

Real-Life Evaluation of an Algorithm for the Diagnosis of Cardiac Amyloidosis.

OBJECTIVE: To evaluate the real-life use of a modified Gillmore algorithm with a "one-stop-shop" approach, bone scintigraphy (BS), a monoclonal gammopathy test (GT), a salivary gland biopsy (SGB), and genetic testing performed at the same time for the diagnosis of cardiac amyloidosis at the French National Reference Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France). METHODS: This retrospective cohort study included a total of 1222 patients with suspected amyloidosis who underwent BS and GT between June 2008 and May 2019. RESULTS: Of 1222 patients, 349 had no cardiac uptake on BS and negative GT (BS-/GT-), 276 were BS-/GT positive (GT+), 420 patients were BS+/GT-, and 177 were BS+/GT+. Our one-stop-shop check-up enabled us to diagnose 892 (72.9%) patients; 330 (27.0%) patients required additional examinations, such as mass spectrometry and/or a cardiac biopsy. This subset notably included 112 patients with amyloid light chain amyloidosis. More than 64% of the patients with transthyretin amyloidosis or another type of amyloidosis were diagnosed during the one-stop shop visit. Sensitivity and specificity of BS for transthyretin amyloidosis diagnosis was 99% and 96%, respectively. For amyloid light chain diagnosis, sensitivity and specificity were 100% and 76%, respectively, for GT and 54% and 100%, respectively, for SGB. Of 910 transthyretin genetic tests, 205 (17%) detected mutations. CONCLUSION: The results of our real-life cohort study confirmed the ability of a one-stop-shop approach with a modified Gillmore algorithm to diagnose cardiac amyloidosis and the interest of simultaneous testing for earlier diagnosis. The SGB has diagnostic value because it is easy, quick, and less invasive than a cardiac biopsy.

Rituximab or rituximab plus chlorambucil for translocation (11;18)-negative gastric mucosa-associated lymphoid tissue lymphoma: a monocentric non-randomized observational study.

To assess the effectiveness and safety of rituximab alone or in combination with chlorambucil for the treatment of translocation (11;18)-negative gastric MALT lymphoma, we included 71 patients in a retrospective case-control study, 54 treated with rituximab alone and 17 with combination therapy. There was no difference between the groups in complete remission or overall response rates at weeks 25 and 52. After a median follow-up period of 5.8 years (range, 3.3 - 9.7 years), the 5-year progression-free survival probabilities were 60% and 88% in patients treated with rituximab monotherapy and combination therapy, respectively (p = .05). Adverse events were reported in 13 (18%) patients and were more frequent in the combination therapy group (p < .001). Combination therapy may be a preferable choice in patients with gastric MALT lymphoma irrespective of t(11;18) status. Further studies should assess benefit of stopping chlorambucil in early good-responder patients.

Describing mode of death in three major cardiac amyloidosis subtypes to improve management and survival.

BACKGROUND: The three main cardiac amyloidosis (CA) types have different progression and prognosis. Little is known about the mode of death (MOD) which is commonly attributed to cardiovascular causes in CA. Improving MOD's knowledge could allow to adapt patient care. OBJECTIVE: This retrospective study describes the MOD that occurred during long-term follow-up in CA patients in light-chain (AL), transthyretin hereditary (ATTRv) or wild-type (ATTRwt). MATERIAL AND METHODS: Patients referred to and cared for, at the French referral centre for CA, Henri Mondor Hospital, Créteil between 2010 and 2016 were included. Clinical information surrounding patient deaths were investigated and centrally evaluated by two blinded clinical committees which classified MOD as cardiovascular, non-cardiovascular or unknown and sub-classified it depending on its subtype. RESULTS: From the 566 patients included, 187 had AL, 206 ATTRv and 173 ATTRwt. During the 864 patient-year follow-up, 160 (28%) deaths occurred, with median survival time of 17.3 months (interquartile range 5.1-35.4). The most frequent MOD was cardiovascular (64%) of which worsening heart failure occurred most frequently and for which, 69% were of AL subtype, 79% ATTRv and 76% ATTRwt. Sudden death also occurred more frequently in AL subtype accounting for 29% of AL deaths. Non-cardiovascular MOD occurred in 26% of patients overall. Among these, infection was the most common non-cardiovascular MOD in any type of CA (80%). CONCLUSIONS: Mortality is high during natural course of CA and differs between subtypes. The main MOD were worsening heart failure, sudden death and infection, opening room to optimise management.