A targeted gene signature stratifying mediastinal gray zone lymphoma into classical HL-like or PMBL-like subtypes.

Not available.

Prognostic value of lesion dissemination in doxorubicin, bleomycin, vinblastine, and dacarbazine-treated, interimPET-negative classical Hodgkin Lymphoma patients: A radio-genomic study.

We evaluated the prognostic role of the largest distance between two lesions (Dmax), defined by positron emission tomography (PET) in a retrospective cohort of newly diagnosed classical Hodgkin Lymphoma (cHL) patients. We also explored the molecular bases underlying Dmax through a gene expression analysis of diagnostic biopsies. We included patients diagnosed with cHL from 2007 to 2020, initially treated with ABVD, with available baseline PET for review, and with at least two FDG avid lesions. Patients with available RNA from diagnostic biopsy were eligible for gene expression analysis. Dmax was deduced from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) and its effect on progression free survival (PFS) was evaluated. Gene expression profiles were correlated with Dmax and analyzed using CIBERSORTx algorithm to perform deconvolution. The study was conducted on 155 eligible cHL patients. Using its median value of 20 cm, Dmax was the only variable independently associated with PFS (HR = 2.70, 95% CI 1.1-6.63, pValue = 0.03) in multivariate analysis of PFS for all patients and for those with early complete metabolic response (iPET-). Among patients with iPET-low Dmax was associated with a 4-year PFS of 90% (95% CI 82.0-98.9) significantly better compared to high Dmax (4-year PFS 72.4%, 95% CI 61.9-84.6). From the analysis of gene expression profiles differences in Dmax were mostly associated with variations in the expression of microenvironmental components. In conclusion our results support tumor dissemination measured through Dmax as novel prognostic factor for cHL patients treated with ABVD.

NR1H3 (LXRα) is associated with pro-inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b-cell lymphoma.

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared with NR1H3low cases and a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes.

A Comparative Assessment of Quality of Life in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation Through an Outpatient and Inpatient Model.

Outpatient autologous stem cell transplantation (ASCT) has proven to be feasible in terms of physical morbidity and mortality outcomes, but little data exist on the impact of this procedure on quality of life (QoL). The purpose of this prospective, observational, longitudinal cohort study was to compare the effects of inpatient (n = 76) and outpatient (n = 64) modes of care on QoL in patients with multiple myeloma who underwent ASCT. Patients were treated according to their preference for the inpatient or outpatient model. QoL was assessed using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) at baseline (7 days before ASCT; T1) and at days +7 (T2) and +30 (T3) after ASCT. Overall, inpatients achieved higher mean values at each time point (86.05 ± 15.54 at T1, 89.23 ± 19.19 at T2, and 87.96 ± 13.6 at T3) compared with outpatients (85.62 ± 14.51 at T1, 87.42 ± 23.41 at T2, and 83.98 ± 20.2 at T3), although the differences did not reach statistical significance. Inpatients showed higher mean scores than outpatients in physical well-being (7.67 ± 5.7, 15.44 ± 6.34, and 12.96 ± 6.03, respectively, versus 5.89 ± 4.33, 13.92 ± 7.05, and 8.84 ± 6.33, respectively; P < .05). Mean scores on social/family well-being were significantly higher in the outpatient group compared with the inpatient group (22.93 ± 13.29, 21.14 ± 5.31, and 21.64 ± 4.58, respectively, versus 20.59 ± 3.79, 19.52 ± 5.12, and 20.01 ± 3.97, respectively; P = .003). There were no significant between-group differences with respect to functional well-being and emotional status. Among adults at a single institution undergoing ASCT for MM, the use of outpatient care compared with standard transplantation care did not result in improved QoL during transplantation. Further research is needed for replication and to assess longer-term outcomes and implications.

Everolimus restrains the paracrine pro-osteoclast activity of breast cancer cells.

BACKGROUND: Breast cancer (BC) cells secrete soluble factors that accelerate osteoclast (OC) differentiation, leading to the formation of osteolytic bone metastases. In the BOLERO-2 trial, BC patients with bone involvement who received Everolimus had a delayed tumor progression in the skeleton as a result of direct OC suppression through the inhibition of mTOR, in addition to the general suppressor effect on the cancer cells. Here, we explored the effect of Everolimus, as mTOR inhibitor, on the pro-OC paracrine activity of BC cells. METHODS: Both MDA-MB-231 and MCF-7 BC cell lines were incubated with sub-lethal amounts of Everolimus, and their conditioned supernatants were assessed for their capacity to differentiate OCs from PBMC from healthy donors, as well as to interfere with their bone resorbing activity shown on calcium phosphate slices. We also measured the mRNA levels of major pro-OC factors in Everolimus-treated BC cells and their secreted levels by ELISA, and evaluated by immunoblotting the phosphorylation of transcription factors enrolled by pathways cooperating with the mTOR inhibition. Finally, the in vivo pro-OC activity of these cells was assessed in SCID mice after intra-tibial injections. RESULTS: We found that Everolimus significantly inhibited the differentiation of OCs and their in vitro bone-resorbing activity, and also found decreases of both mRNA and secreted pro-OC factors such as M-CSF, IL-6, and IL-1ß, whose lower ELISA levels paralleled the defective phosphorylation of NFkB pathway effectors. Moreover, when intra-tibially injected in SCID mice, Everolimus-treated BC cells produced smaller bone metastases than the untreated cells. CONCLUSIONS: mTOR inhibition in BC cells leads to a suppression of their paracrine pro-OC activity by interfering with the NFkB pathway; this effect may also account for the delayed progression of bone metastatic disease observed in the BOLERO-2 trial.

SurvIAE: Survival prediction with Interpretable Autoencoders from Diffuse Large B-Cells Lymphoma gene expression data.

BACKGROUND: In Diffuse Large B-Cell Lymphoma (DLBCL), several methodologies are emerging to derive novel biomarkers to be incorporated in the risk assessment. We realized a pipeline that relies on autoencoders (AE) and Explainable Artificial Intelligence (XAI) to stratify prognosis and derive a gene-based signature. METHODS: AE was exploited to learn an unsupervised representation of the gene expression (GE) from three publicly available datasets, each with its own technology. Multi-layer perceptron (MLP) was used to classify prognosis from latent representation. GE data were preprocessed as normalized, scaled, and standardized. Four different AE architectures (Large, Medium, Small and Extra Small) were compared to find the most suitable for GE data. The joint AE-MLP classified patients on six different outcomes: overall survival at 12, 36, 60 months and progression-free survival (PFS) at 12, 36, 60 months. XAI techniques were used to derive a gene-based signature aimed at refining the Revised International Prognostic Index (R-IPI) risk, which was validated in a fourth independent publicly available dataset. We named our tool SurvIAE: Survival prediction with Interpretable AE. RESULTS: From the latent space of AEs, we observed that scaled and standardized data reduced the batch effect. SurvIAE models outperformed R-IPI with Matthews Correlation Coefficient up to 0.42 vs. 0.18 for the validation-set (PFS36) and to 0.30 vs. 0.19 for the test-set (PFS60). We selected the SurvIAE-Small-PFS36 as the best model and, from its gene signature, we stratified patients in three risk groups: R-IPI Poor patients with High levels of GAB1, R-IPI Poor patients with Low levels of GAB1 or R-IPI Good/Very Good patients with Low levels of GPR132, and R-IPI Good/Very Good patients with High levels of GPR132. CONCLUSIONS: SurvIAE showed the potential to derive a gene signature with translational purpose in DLBCL. The pipeline was made publicly available and can be reused for other pathologies.

Fertility preservation in lymphoma patients treated with immunochemotherapy regimens with or without radiotherapy: results of a retrospective multicenter Italian study (Ferty care).

This is a retrospective, multicentric study, aimed to describe the real-life application of fertility preservation methods during treatment in female lymphoma patients, aged 18-40 years old, diagnosed between Oct 1st/2010 and May 31st/2018. Among 414 women included, median age was 28 years old, histologies were: HL 74%, PMBCL 13%, DLBCL 10%, others 3%. First line treatments were: ABVD in 295 (71%), R-CHOP like in 102 (25%), higher intensity regimens in 17 (4%) cases. Fertility preservation strategies were: GnRHa in 315 (78%), Oral Contraceptive in 41 (10%), oocytes and ovarian tissue cryopreservation in 55 and 42 patients, respectively. After therapy, we observed a restored regular period in 293 (70%) and premature ovarian failure (POF) in 33 (8%), Furthermore we recorded 43 pregnancies, all spontaneous with 5 years median follow-up. Median age at diagnosis and number of lines of treatment correlate with higher rate of amenorrhea, risk of POF and menopause (p < 0.001).

Immature dendritic cells in multiple myeloma are prone to osteoclast-like differentiation through interleukin-17A stimulation.

Interleukin 17A (IL17A), a cytokine involved in allergy, inflammation and osteoclastogenesis, was investigated in multiple myeloma (MM) to assess its role in the osteoclast (OC)-like activity of marrow immature dendritic cells (iDCs). Comparing nine MM patients with control subjects affected by monoclonal gammopathy of undetermined significance, we found high IL17A expression in the marrow plasma of MM patients in parallel with its deposits within the stromal matrix. Increased expression of the IL17A receptor (IL17RA) was also found in primary myeloma iDCs, which underwent OC-like transdifferentiation after IL17A stimulation. To assess the role of IL17A, we measured the activity of the IL17/IL17RA pathway in IL17A-transdifferentiated iDCs and the expression of functional OC genes by Western blotting and real-time polymerase chain reaction. These cells showed increased RNA transcription of genes enrolled in the maturation of OCs, while NFATC1 and FOS were induced by IL17A, independently of NFKB1 phosphorylation. Moreover, the concurrent phosphorylation of the Lip isoform of CEBPB and the down-regulation of MAFB supported the activation of IL17RA pathway in OC-like transdifferentiated iDCs that was apparently unrelated to TNFRSF11A signalling. These data emphasize the involvement of iDCs in MM hyperactive osteoclastogenesis and suggest that their bone resorption activity is also regulated, at least in vitro, by IL17RA.

ARGO 2.0: a Hybrid NLP/ML Framework for Diagnosis Standardization.

A relevant problem in medicine is the standardization of the diagnosis associated with a clinical case. Although diagnosis formulation is an intrinsically subjective and uncertain process, its standardization may take benefit from digital solutions automating the routines at the basis of such a decision. In this work, we propose ARGO 2.0: a framework for the development of decision support systems for diagnosis formulation. The framework can read free-text reports and store their clinically relevant information as personalized electronic Case Report Forms. A hybrid strategy, exploiting the synergy of Natural Language Processing and Machine Learning techniques, is used to automatically suggest a diagnosis in a standardized fashion. ARGO 2.0 has been designed to be template-independent and easily tailored to specific medical fields. We here demonstrate its feasibility in hemo lympho-pathology, by detailing its implementation, object of an ongoing validation campaign in a standing medical institute. ARGO 2.0 achieved an average Accuracy of 95.07%, an average precision of 94.85%, an average Recall of 96.31% and a F-Score of 95.32% onto the test set, outperforming both its embedded components, based on Natural Language Processing and Machine Learning.