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B Discussion: b MRD analysis and PET scan are independent and complementary prognostic tools in FL: a MRD positivity in the two years after immuno-chemotherapy is predictive of POD24 and dismal PFS independently from the EoI PET result. This means that patients scoring PET- at EoI but showing a persistent or reappearing MRD+ signal during the following 24 months had a dismal PFS, superimposable to that of PET+ patients (Figure 1C). B Introduction: b In follicular lymphoma (FL), FDG-PET is routinely employed to evaluate response at the end of induction (EoI), while minimal residual disease (MRD) analysis is highly reliable in predicting relapse over the entire disease history. [Extracted from the article]

Abstract: Introduction: The high‐throughput era remarkably changed molecular laboratory practice. Actually, the increasing number of processed samples requires to reduce the risk of operator biases, by automating or simplifying as much as possible both the analytical and the pre‐analytical phases. Minimal residual disease (MRD) studies in hematology often require a simultaneous processing of many bone marrow and peripheral blood samples from patients enrolled in prospective, multicenter, clinical trials, monitored at several planned time points. Methods: In this study, we demonstrate that red blood cell lysis (RBL) pre‐analytical procedure can replace the time‐consuming Ficoll stratification as cell recovering step. Here, we show a MRD comparison study using both total white blood cells and mononuclear cells recovered by the 2 procedures from 46 follicular lymphoma (FL), 15 multiple myeloma (MM), and 11 mantle cell lymphoma (MCL) patients enrolled in prospective clinical trials. Results: The experiments were performed in the 4 laboratories of the Fondazione Italiana Linfomi (FIL) MRD Network and showed superimposable results, in terms of good correlation (R = 0.87) of the MRD data obtained by recovering blood cells by the 2 approaches. Conclusion: Based on these results, the FIL MRD Network suggests to optimize the pre‐analytical phases introducing RBL approach for cell recovery in the clinical trials including MRD analysis. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of Competing Interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

The aim of this paper was to assess the cost-effectiveness of pembrolizumab in first-line for microsatellite-instability-high or mismatch-repair-deficient metastatic colorectal cancer. We have considered the pivotal phase III randomized controlled trial of pembrolizumab in first-line for microsatellite-instability-high mismatch-repair-deficient metastatic colorectal cancer. The last available update of each trial was considered as the original source. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival). The costs of drugs are at the Pharmacy of the Mater Salutis Hospital of Legnago (VR, Italy) and are expressed in euros (€). Three hundred and seven patients were considered in the pivotal phase III randomized controlled trial. Pembrolizumab obtained a cost per month progression-free survival gained ranged from 6471 € towards mFOLFOX (5-FU, oxaliplatin and leucovorin) plus cetuximab to 7886 € towards mFOLFOX. To sum up, combining pharmacological costs of drugs with the measure of efficacy represented by progression-free survival, at the actual prize pembrolizumab cannot be considered cost-effectiveness for first-line treatment for microsatellite-instability-high mismatch-repair-deficient metastatic colorectal cancer. A reduction in pharmacological costs is mandatory.

The introduction of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of women with epithelial ovarian cancers (EOC) has radically changed the treatment in maintenance setting after responding to first- and second-line chemotherapy. The aim of this paper was to assess the pharmacological costs of PARP inhibitors (olaparib, niraparib, rucaparib and veliparib) in maintenance treatment after responding to first-line chemotherapy in EOC. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival (PFS)). We have considered the pivotal phase III randomized controlled trials (RCTs). Three different populations were considered: the overall population, patients with germline BRCA mutation (gBRCA) and homologous recombination deficiency (HRD) patients non-gBRCA mutation. Three thousand four hundred and twenty patients and 1209 patients were considered in maintenance treatment after responding to first- and second-line chemotherapy in EOC, respectively. At the actual price, the treatment with PARP inhibitors is not cost-effective in maintenance treatment after responding to first-line and second-line chemotherapy in EOC. A reduction in pharmacological costs is mandatory.

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood [PB] and bone marrow [BM]), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression [TTP] hazard ratio [HR], 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/)., (© 2022 by The American Society of Hematology.)

The introduction of targeted agents (lenvatinib) and immune-based therapies (atezolizumab in combination with bevacizumab) for first-line advanced hepatocellular carcinoma provided new therapeutic options. The aim of this paper was to assess the cost-effectiveness of lenvatinib and the combination of atezolizumab plus bevacizumab in first-line for advanced hepatocellular carcinoma. Pivotal phase III randomized controlled trials were considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression free survival). One thousand four hundred and fifty five patients were included. The lowest cost for month of progression free survival-gain was associated with lenvatinib, with 139.24 € per month progression free survival-gained. Combining pharmacological costs of drugs with the measure of efficacy represented by progression free survival, lenvatinib is a cost-effective treatment in first-line for advanced hepatocellular carcinoma.

Recently, the introduction of encorafenib in combination with cetuximab was considered as a practice changing in BRAFV600-mutated metastatic colorectal cancer. The aim of this paper was to assess the cost-effectiveness of encorafenib plus cetuximab in the second-line treatment of BRAFV600-mutated metastatic colorectal cancer. BEACON CRC Trail was considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (overall survival). Four hundred forty-one patients were included. Differences in costs between the two arms (encorafenib plus cetuximab vs FOLFIRI plus cetuximab) was 59 501 €, with a cost of 17 500 € per month of overall survival-gain. Combining pharmacological costs of drugs with the measure of efficacy represented by overall survival, at the actual prize encorafenib cannot be considered cost-effectiveness for second-line treatment of BRAFV600-mutated metastatic colorectal cancer.

Minimal residual disease (MRD) monitoring by PCR methods is a strong and standardized predictor of clinical outcome in mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, about 20% of MCL and 40% of FL patients lack a reliable molecular marker, being thus not eligible for MRD studies. Recently, targeted locus amplification (TLA), a next-generation sequencing (NGS) method based on the physical proximity of DNA sequences for target selection, identified novel gene rearrangements in leukemia. The aim of this study was to test TLA in MCL and FL diagnostic samples lacking a classical, PCR-detectable, t(11; 14) MTC (BCL1/IGH), or t(14; 18) major breakpoint region and minor cluster region (BCL2/IGH) rearrangements. Overall, TLA was performed on 20 MCL bone marrow (BM) or peripheral blood (PB) primary samples and on 20 FL BM, identifying a novel BCL1 or BCL2/IGH breakpoint in 16 MCL and 8 FL patients (80% and 40%, respectively). These new breakpoints (named BCL1-TLA and BCL2-TLA) were validated by ASO primers design and compared as MRD markers to classical IGH rearrangements in eight MCL: overall, MRD results by BCL1-TLA were superimposable (R Pearson = 0.76) to the standardized IGH-based approach. Moreover, MRD by BCL2-TLA reached good sensitivity levels also in FL and was predictive of a primary refractory case. In conclusion, this study offers the proof of principle that TLA is a promising and reliable NGS-based technology for the identification of novel molecular markers, suitable for further MRD analysis in previously not traceable MCL and FL patients., (© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Objectives: To report preliminary data on feasibility and patient-reported outcomes following PSMA-PET/CT guided SBRT by means of 1.5 T MRI-Linac., Methods and Materials: Between October 2019 and April 2020, twenty consecutive castration sensitive oligorecurrent prostate cancer patients were enrolled in an ethical committee approved prospective observational study (Protocol n. XXXX) and treated with PSMA-PET/CT guided SBRT by means of 1.5 T MRI-Linac (Unity, Elekta AB, Stockholm, Sweden). The mean delivered dose was 35 Gy in 5 fractions. Clinicians reported toxicity was prospectively collected according to Common Terminology Criteria for Adverse Events v5.0. Quality of life (QoL) assessment was performed using EORTC-QLQ C30 questionnaires administered at baseline, end of treatment and at first follow-up., Results: Twenty-five lesions in 20 castration sensitive oligorecurrent patients were treated: the most commonly treated anatomic sites were nodal (n = 16) and pelvic bone (n = 9). Median PSA-value preMRI guided SBRT was 1.16 ng/mL (range, 0.27-8.9), whereas median PSA value at first follow-up after SBRT was 0.44 ng/mL (range, 0.06-8.15). At first follow-up, for 16 patients showing detectable PSA, PSMA-PET/CT was performed detecting, respectively, in 6 cases partial response and in 10 cases complete response. In the remaining cases, PSA-value was undetectable after SBRT. Radiotherapy treatment was safe and well tolerated according to the PROMs. No acute G2 or higher toxicities were recorded., Conclusions: The current series represent the largest one exploring the feasibility and patient-reported outcomes following PSMA-PET/CT guided SBRT by means of 1.5 T MRI-Linac. The preliminary findings here reported are encouraging in terms of effectiveness and tolerability.

The present analysis was conducted to assess the pharmacological costs of atezolizumab as first-line treatment in triple negative metastatic breast cancer (mBC). Pivotal phase III randomized controlled trial (RCT) was considered. Nine hundred and two patients were included. Differences in costs between the 2 arms (atezolizumab plus nabpaclitaxel versus placebo plus nab-paclitaxel) was 17 398 €, with a cost of 7564 €per month of OS-gain in the overall population and 2485 €per month of OS-gain in PD-L1-positive (≥1) population. Combining pharmacological costs of drugs with the measure of efficacy represented by the OS, atezolizumab could be considered cost-effective in first-line treatment for triple-negative mBC only in PD-L1-positive population, but a reduction of costs is mandatory.

Pancreatic ductal adenocarcinoma (PDAC) is highly refractory to systemic treatment, including radiotherapy (RT) either as alone or in combination with chemotherapy. Magnetic resonance (MR)-guided RT is a novel treatment technique which conjugates the high MR imaging contrast resolution to the possibility of re-adapting treatment plan to daily anatomical variations. Magnetic field (MF) might exert a biological effect that could be exploited to enhance radiation effect. The aim of the present study was to lay the preclinical basis of the MF effect by exploring how it modifies the response to radiation in organoid cultures established from PDAC. The short-term effect of radiation, alone or in combination with MF, was evaluated in patient-derived organoids (PDOs) and monolayer cell cultures. Cell viability, apoptotic cell death, and organoid size following exposure to the treatment were evaluated. PDOs demonstrated limited sensitivity at clinically relevant doses of radiation. The combination of radiation and MF demonstrated superior efficacy than monotherapy in almost all the PDOs tested. PDOs treated with combination of radiation and MF were significantly smaller in size and some showed increased cell death as compared to the monotherapy with radiation. Long-time exposure to 1.5T MF can increase the therapeutic efficacy of radiation in PDAC organoids.

Minimal residual disease (MRD) assessment is of high clinical relevance in patients with mantle cell lymphoma (MCL). In mature B-cell malignancies, the presence of somatic hypermutations (SHM) in Variable-Diversity-Joining Heavy chain (VDJH) rearrangements leads to frequent mismatches between primers, probes, and the target, thus impairing tumor cells quantification. Alternative targets, such as immunoglobulin kappa-deleting-element (IGK-Kde) rearrangements, might be suitable for MRD detection. We aimed at evaluating the applicability of IGK-Kde rearrangements for MRD quantification in MCL patients by real-time quantitative polymerase chain reaction (RQ-PCR)/digital-droplet-PCR (ddPCR). IGK screening was performed on bone marrow samples from two cohorts: the first from Turin (22 patients enrolled in the FIL-MCL0208 trial, NCT02354313) and the second from Rome (15 patients). IGK-Kde rearrangements were found in 76% (28/37) of cases, representing the sole molecular marker in 73% (8/11) of IGH-BCL1/IGH negative cases. MRD RQ-PCR monitoring was possible in 57% (16/28) of cases, showing a 100% concordance with the conventional targets. However, the frequent background amplification affected the sensitivity of the assay, that was lower in MCL compared to acute lymphoblastic leukemia and in line with multiple myeloma published results. ddPCR had a good concordance with RQ-PCR and it might help to identify false positive/negative results. From a clinical perspective, we suggest that IGK-Kde can be a candidate target for MRD monitoring and deserves a validation of its predictive value in prospective MCL series., (© 2020 John Wiley & Sons Ltd.)

Background: The assessment of organ motion is a crucial feature for prostate stereotactic body radiotherapy (SBRT). Rectal spacer may represent a helpful device in order to outdistance rectal wall from clinical target, but its impact on organ motion is still a matter of debate. MRI-Linac is a new frontier in radiation oncology as it allows a superior visualization of the real-time anatomy of the patient and the current highest level of adaptive radiotherapy., Methods: We present data regarding a total of 100 fractions in 20 patients who underwent MRI-guided prostate SBRT for low-to-intermediate risk prostate cancer with or without spacer. Translational and rotational shifts were computed on the pre- and post-treatment MRI acquisitions referring to the delivery position for antero-posterior, latero-lateral and cranio-caudal direction, and assessed using the Mann-Whitney U-Test., Results: All patients were treated with a five sessions schedule (35 Gy/5fx) using MRI-Linac for a median fraction treatment time of 50 min (range, 46-65). In the entire study sample, median rotational displacement was 0.1° in cranio-caudal, - 0.002° in latero-lateral and 0.01° in antero-posterior direction; median translational shift was 0.11 mm in cranio-caudal, - 0.24 mm in latero-lateral and - 0.22 mm in antero-posterior. A significant difference between spacer and no-spacer patients in terms of rotational shifts in the antero-posterior direction (p = 0.033) was observed; also for translational shifts a positive trend was detected in antero-posterior direction (p = 0.07), although with no statistical significance. We observed statistically significant differences in the pre-treatment planning phase in favor of the spacer cohort for several rectum dose constraints: rectum V32Gy < 5% (p = 0.001), V28 Gy < 10% (p = 0.001) and V18Gy < 35% (p = 0.039). Also for bladder V35 Gy < 1 cc, the use of spacer provided a dosimetric advantage compared to the no-spacer subpopulation (p = 0.04). Furthermore, PTV V33.2Gy > 95% was higher in the spacer cohort compared to the no-spacer one (p = 0.036)., Conclusion: In our experience, the application of rectal hydrogel spacer for prostate SBRT resulted in a significant impact on rotational antero-posterior shifts contributing to limit prostate intra-fraction motion. Further studies with larger sample size and longer follow-up are required to confirm this ideally favorable effect and to assess any potential impact on clinical outcomes.

Minimal residual disease (MRD) has been increasingly investigated in mantle cell lymphoma (MCL), including for individual therapeutic stratification and pre-emptive treatment in clinical trials. Although patient/allele specific real-time quantitative polymerase chain reaction (qPCR) of IGH or BCL1-IGH clonal markers is the gold-standard method, its reliance on a standard curve for relative quantification limits quantification of low-level positivity within the 1E-4 to 1E-5 range; over half of positive MRD samples after treatment fall below the quantitative range (BQR) of the standard curve. Droplet digital PCR (ddPCR), in contrast, allows absolute quantification, including for samples with no baseline determination of tumor infiltration by multicolor flow cytometry (MFC), avoiding the need for a reference standard curve. Using updated, optimized, ddPCR criteria we compared it with qPCR in 416 MRD samples (and with MFC in 63), with over-representation (61%) of BQR results by qPCR, from a total of 166 patients from four prospective MCL clinical trials. ddPCR, qPCR and MFC gave comparable results in MRD samples with at least 0.01% (1E-4) positivity. ddPCR was preferable to qPCR since it provided more robust quantification at positivity between 1E-4 and 1E-5. Amongst 240 BQR samples with duplicate or triplicate analysis, 39% were positive by ddPCR, 49% negative and only 12% remained positive below quantifiable ddPCR limits. The prognostic relevance of ddPCR is currently under assessment in the context of prospective trials within the European MCL Network., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

A prospective trial conducted in the period 2000-2005 showed no survival advantage for high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (CHOP-R) as first-line therapy in 134 high-risk follicular lymphoma patients aged <60 years. The study has been updated at the 13-year median follow up. As of February 2017, 88 (66%) patients were alive, with overall survival of 66.4% at 13 years, without a significant difference between R-HDS (64.5%) and CHOP-R (68.5%). To date, 46 patients have died, mainly because of disease progression (47.8% of all deaths), secondary malignancies (3 solid tumor, 9 myelodysplasia/acute leukemia; 26.1% of all deaths), and other toxicities (21.7% of all deaths). Complete remission was documented in 98 (73.1%) patients and associated with overall survival, with 13-year estimates of 77.0% and 36.8% for complete remission versus no-complete remission, respectively. Molecular remission was documented in 39 (65%) out of 60 evaluable patients and associated with improved survival. In multivariate analysis, complete remission achievement had the strongest effect on survival ( P <0.001), along with younger age ( P =0.002) and female sex ( P =0.013). Overall, 50 patients (37.3%) survived with no disease recurrence (18 CHOP-R, 32 R-HDS). This follow up is the longest reported on follicular lymphoma treated upfront with rituximab-chemotherapy and demonstrates an unprecedented improvement in survival compared to the pre-rituximab era, regardless of the use of intensified or conventional treatment. Complete remission was the most important factor for prolonged survival and a high proportion of patients had prolonged survival in their first remission, raising the issue of curability in follicular lymphoma. (Registered at clinicaltrials.gov identifier: 00435955)., (Copyright© 2019 Ferrata Storti Foundation.)