Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms.

JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.

Outcome of 421 adult patients with Philadelphia-negative acute lymphoblastic leukemia treated under an intensive program inspired by the GIMEMA LAL1913 clinical trial: a Campus ALL study.

The introduction of pediatric-inspired regimens in adult Philadelphia-negative acute lymphoblastic leukemia (Ph-ALL) has significantly improved patients' prognosis. Within the Campus ALL network we analyzed the outcome of adult Ph-ALL patients treated according to the GIMEMA LAL1913 protocol outside the clinical trial, to compare the real-life data with the study results. We included 421 consecutive patients, with a median age of 42 years. The complete remission (CR) rate after the first course of chemotherapy was 94% and a measurable residual disease (MRD) negativity after the third course was achieved in 72% of patients. The 3-year overall survival (OS) and disease-free survival (DFS) were 67% and 57%, respectively. In a multivariate analysis, MRD positivity negatively influenced DFS. In a time-dependent analysis including only very high risk (VHR) and MRD positive cases, transplanted (HSCT) patients had a significantly better DFS than non-HSCT ones (P=0.0017). During induction, grade ≥2 pegaspargase-related hepato-toxicity was observed in 25% of patients (vs 12% in the GIMEMA LAL1913 trial, P=0.0003). In this large real-life cohort of Ph-ALL, we confirmed the very high CR rate and a superimposable OS and DFS compared to the GIMEMA LAL1913 clinical trial: CR rate after C1 94% vs 85%, P=0.0004; 3-year OS 67% vs 67%, P=0.94; 3-year DFS 57% vs 63%, P=0.17. HSCT confirms its important role in VHR and MRD-positive patients. The rate of pegaspargase-related toxicity was significantly higher in the real-life setting, emphasizing the importance of dose adjustment in the presence of risk factors to avoid excessive toxicity.

Targeting exhausted cytotoxic T cells through CTLA-4 inhibition promotes elimination of neoplastic cells in human myelofibrosis xenografts.

Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.

Identification and validation of diagnostic cut-offs of the ELISpot assay for the diagnosis of invasive aspergillosis in high-risk patients.

OBJECTIVE: We investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies. METHODS: We prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10. RESULTS: In the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases. CONCLUSIONS: ELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk.

Severe acute respiratory syndrome coronavirus 2 infection in patients with hematological malignancies in the Omicron era: Respiratory failure, need for mechanical ventilation and mortality in seronegative and seropositive patients.

Background: Patients with hematological malignancies (HM) have a high risk of severe coronavirus disease 2019 (COVID-19), also in the Omicron period. Material and methods: Retrospective single-center study including HM patients with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) infection from January 2022 to March 2023. Study outcomes were respiratory failure (RF), mechanical ventilation (MV), and COVID-related mortality, comparing patients according to SARS-CoV2 serology. Results: Note that, 112 patients were included: 39% had negative SARS-CoV2 serology. Seronegative were older (71.5 vs. 65.0 years, p = 0.04), had more often a lymphoid neoplasm (88.6% vs. 69.1%, p = 0.02), underwent anti-CD20 therapy (50.0% vs. 30.9% p = 0.04) and had more frequently a severe disease (23.0% vs. 3.0%, p = 0.02) than seropositive.Kaplan-Meier showed a higher risk for seronegative patients for RF (p = 0.014), MV (p = 0.044), and COVID-related mortality (p = 0.021). Negative SARS-CoV2 serostatus resulted in a risk factor for RF (hazards ratio [HR] 2.19, 95% confidence interval [CI] 1.03-4.67, p = 0.04), MV (HR 3.37, 95% CI 1.06-10.68, p = 0.04), and COVID-related mortality (HR 4.26, 95% CI 1.09-16.71, p = 0.04). Conclusions: : HM patients with negative SARS-CoV2 serology, despite vaccinations and previous infections, have worse clinical outcomes compared to seropositive patients in the Omicron era. The use of serology for SARS-CoV2 diagnosis could be an easy tool to identify patients prone to developing complications.

Early palliative care perceptions by patients with cancer and primary caregivers: metaphorical language.

OBJECTIVE: This article reports on the results of an analysis of metaphorical language used by patients diagnosed with advanced cancer and their caregivers receiving early palliative care (EPC). METHODS: Data were collected through a pen-and-paper questionnaire on respondents' perceptions of the disease, its treatment and their idea of death, before and after receiving EPC. The data were analysed by identifying all metaphorical uses of language, following the 'metaphor identification procedure' proposed by the Praggjelaz Group. RESULTS: Metaphors were used from a variety of semantic fields. EPC was described using spiritual terms, to indicate that this approach was instrumental in 'restoring life', 'producing hope' and making patients feel 'accompanied'. The most recurrent metaphors were those referring to light and salvation; spatial metaphors were used to describe the treatment and the hospital as a 'safe haven' and 'an oasis of peace'. Patients and caregivers were overall consistent in the aforementioned ways of referring to illness and treatment; caregivers were more likely than patients to use war metaphors, although their use overall was rare. CONCLUSIONS: Our results suggest that EPC is perceived positively by patients and their caregivers and provide insights regarding the manner in which EPC could be presented to patients, caregivers and the public.

Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial.

ABSTRACT: We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes than those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) with IC (3+7) in older fit patients with AML. HRQoL was a secondary end point, and it was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in conjunction with its elderly module (EORTC QLQ-ELD14). The following scales were a priori selected for defining the primary end point: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm; 76% (95% confidence interval [CI], 69-82) vs 88% (95% CI, 82-93); odds ratio, 0.43 (95% CI, 0.24-0.76; P = .003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and after allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, whereas this was the case for those in the 3+7 arm, in 4 of 5 primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC may be preferable to current standard IC (3+7) in fit older patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT02172872.

Positive Psychological Well-Being in Early Palliative Care: A Narrative Review of the Roles of Hope, Gratitude, and Death Acceptance.

In the advanced cancer setting, low psychological functioning is a common symptom and its deleterious impact on health outcomes is well established. Yet, the beneficial role of positive psychological well-being (PPWB) on several clinical conditions has been demonstrated. Early palliative care (EPC) is a recent value-based model consisting of the early integration of palliative care into standard care for solid tumors and hematologic malignancies. While the late palliative care primary offers short-term interventions, predominantly pharmacological in nature and limited to physical symptom reduction, EPC has the potential to act over a longer term, enabling specific interventions aimed at promoting PPWB. This narrative review examines nine English studies retrieved from MEDLINE/PubMed, published up to October 2023, focusing on EPC and three dimensions of PPWB: hope, gratitude, and death acceptance. These dimensions consistently emerge in our clinical experience within the EPC setting for advanced cancer patients and appear to contribute to its clinical efficacy. The choice of a narrative review reflects the novelty of the topic, the limited existing research, and the need to incorporate a variety of methodological approaches for a comprehensive exploration.

Financial Toxicity and Health-Related Quality of Life Profile of Patients With Hematologic Malignancies Treated in a Universal Health Care System.

PURPOSE: We investigated the association of financial toxicity (FT) with the health-related quality of life (HRQoL) profile of patients with hematologic malignancies treated in a universal health care system. METHODS: We did a secondary analysis of six multicenter studies enrolling patients with hematologic malignancies. FT was evaluated using the financial difficulties item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Multivariable linear regression models were used to assess the mean differences in HRQoL scores between patients with or without FT, while adjusting for key potential confounding factors. We also examined the prevalence of clinically important problems and symptoms by the experience of FT, using established thresholds for the EORTC QLQ-C30. Multivariable binary logistic regression analysis was performed to explore the risk factors associated with FT. RESULTS: Overall, 1,847 patients were analyzed, of whom 441 (23.9%) reported FT. We observed statistically and clinically relevant worse scores for patients with FT compared with those without FT for all the EORTC QLQ-C30 scales. The three largest clinically relevant mean differences between patients with and without FT were observed in pain (∆ = 19.6 [95% CI, 15.7 to 23.5]; P < .001), social functioning (∆ = -18.9 [95% CI, -22.5 to -15.2]; P < .001), and role functioning (Δ = -17.7 [95% CI, -22.1 to -13.3]; P < .001). Patients with FT tended to report a higher prevalence of clinically important problems and symptoms across all EORTC QLQ-C30 scales. In the univariable and multivariable analyses, the presence of FT was associated with the presence of comorbidities, an Eastern Cooperative Oncology Group performance status ≥1, and not receiving a salary. CONCLUSION: Patients with hematologic malignancies treated in the setting of a universal health care system who experience FT have a worse HRQoL profile compared with those without FT.

Cytokine storm and severe hepatitis in pregnancy due to herpes simplex virus 2.

CASE PRESENTATION: A pregnant woman developed hepatitis due to a herpes simplex virus 2 primary infection with a severe systemic inflammatory response. Treatment with acyclovir and human immunoglobulin was given and both mother and baby survived. PURPOSE: We provide the first description of the inflammatory response associated with herpetic hepatitis in pregnancy.

10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes. METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants. FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group. INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics. FUNDING: Janssen Pharmaceuticals.

Vancomycin resistant enterococcus risk factors for hospital colonization in hematological patients: a matched case-control study.

BACKGROUND: Vancomycin-resistant enterococcus (VRE) was the fastest growing pathogen in Europe in 2022 (+ 21%) but its clinical relevance is still unclear. We aim to identify risk factors for acquired VRE rectal colonization in hematological patients and evaluate the clinical impact of VRE colonization on subsequent infection, and 30- and 90-day overall mortality rates, compared to a matched control group. METHODS: A retrospective, single center, case-control matched study (ratio 1:1) was conducted in a hematological department from January 2017 to December 2020. Case patients with nosocomial isolation of VRE from rectal swab screening (≥ 48 h) were matched to controls by age, sex, ethnicity, and hematologic disease. Univariate and multivariate logistic regression compared risk factors for colonization. RESULTS: A total of 83 cases were matched with 83 controls. Risk factors for VRE colonization were febrile neutropenia, bone marrow transplant, central venous catheter, bedsores, reduced mobility, altered bowel habits, cachexia, previous hospitalization and antibiotic treatments before and during hospitalization. VRE bacteraemia and Clostridioides difficile infection (CDI) occurred more frequently among cases without any impact on 30 and 90-days overall mortality. Vancomycin administration and altered bowel habits were the only independent risk factors for VRE colonization at multivariate analysis (OR: 3.53 and 3.1; respectively). CONCLUSIONS: Antimicrobial stewardship strategies to reduce inappropriate Gram-positive coverage in hematological patients is urgently required, as independent risk factors for VRE nosocomial colonization identified in this study include any use of vancomycin and altered bowel habits. VRE colonization and infection did not influence 30- and 90-day mortality. There was a strong correlation between CDI and VRE, which deserves further investigation to target new therapeutic approaches.

Caregiver's quality of life in advanced cancer: validation of the construct in a real-life setting of early palliative care.

Introduction: Early palliative care (EPC) improves the quality of life (QoL) of advanced cancer patients and their caregivers. The increasingly widespread use of this care model requires the development of measures supporting its interventions. Although the construct of patient's QoL has been extensively investigated and several QoL measures have been further validated, there is a paucity of data concerning the QoL of the caregiver. In 2018, McDonald and colleagues addressed this issue by interviewing 23 primary caregivers of advanced cancer patients who participated in an EPC randomized clinical trial to understand their perspective on the QoL construct. The Authors identified six major dimensions associated with the construct of caregiver's QoL. The present retrospective study aimed to validate these dimensions on a larger sample and in a real-life EPC setting. Methods: Previously collected reports from 137 primary caregivers of advanced cancer patients on EPC answering questions about their experience with this care model were qualitatively analyzed through a deductive, thematic approach to identify and confirm the six dimensions constituting the construct of interest based on McDonald's and colleagues' results. Results: The six dimensions ("living in the patient's world", "burden of illness and caregiving", "assuming the caregiver role", "renegotiating relationships", "confronting mortality", and "maintaining resilience") were consistently found in the reports from primary caregivers in a real-life EPC setting, confirming to be significant themes associated to their QoL. Conclusion: A definite and recurrent construct of primary caregiver's QoL as described by McDonald and colleagues was also found in a larger sample and in a real-life EPC setting. Thus it may lay the groundwork for the development of a dedicated questionnaire.

Words hurt: common and distinct neural substrates underlying nociceptive and semantic pain.

Introduction: Recent studies have shown that processing semantic pain, such as words associated with physical pain, modulates pain perception and enhances activity in regions of the pain matrix. A direct comparison between activations due to noxious stimulation and processing of words conveying physical pain may clarify whether and to what extent the neural substrates of nociceptive pain are shared by semantic pain. Pain is triggered also by experiences of social exclusion, rejection or loss of significant others (the so-called social pain), therefore words expressing social pain may modulate pain perception similarly to what happens with words associated with physical pain. This event-related fMRI study aims to compare the brain activity related to perceiving nociceptive pain and that emerging from processing semantic pain, i.e., words related to either physical or social pain, in order to identify common and distinct neural substrates. Methods: Thirty-four healthy women underwent two fMRI sessions each. In the Semantic session, participants were presented with positive words, negative pain-unrelated words, physical pain-related words, and social pain-related words. In the Nociceptive session, participants received cutaneous mechanical stimulations that could be either painful or not. During both sessions, participants were asked to rate the unpleasantness of each stimulus. Linguistic stimuli were also rated in terms of valence, arousal, pain relatedness, and pain intensity, immediately after the Semantic session. Results: In the Nociceptive session, the 'nociceptive stimuli' vs. 'non-nociceptive stimuli' contrast revealed extensive activations in SI, SII, insula, cingulate cortex, thalamus, and dorsolateral prefrontal cortex. In the Semantic session, words associated with social pain, compared to negative pain-unrelated words, showed increased activity in most of the same areas, whereas words associated with physical pain, compared to negative pain-unrelated words, only activated the left supramarginal gyrus and partly the postcentral gyrus. Discussion: Our results confirm that semantic pain partly shares the neural substrates of nociceptive pain. Specifically, social pain-related words activate a wide network of regions, mostly overlapping with those pertaining to the affective-motivational aspects of nociception, whereas physical pain-related words overlap with a small cluster including regions related to the sensory-discriminative aspects of nociception. However, most regions of overlap are differentially activated in different conditions.