Autoimmune Diseases and Plasma Cells Dyscrasias: Pathogenetic, Molecular and Prognostic Correlations.

Multiple myeloma and monoclonal gammopathy of undetermined significance are plasma cell dyscrasias characterized by monoclonal proliferation of pathological plasma cells with uncontrolled production of immunoglobulins. Autoimmune pathologies are conditions in which T and B lymphocytes develop a tendency to activate towards self-antigens in the absence of exogenous triggers. The aim of our review is to show the possible correlations between the two pathological aspects. Molecular studies have shown how different cytokines that either cause inflammation or control the immune system play a part in the growth of immunotolerance conditions that make it easier for the development of neoplastic malignancies. Uncontrolled immune activation resulting in chronic inflammation is also known to be at the basis of the evolution toward neoplastic pathologies, as well as multiple myeloma. Another point is the impact that myeloma-specific therapies have on the course of concomitant autoimmune diseases. Indeed, cases have been observed of patients suffering from multiple myeloma treated with daratumumab and bortezomib who also benefited from their autoimmune condition or patients under treatment with immunomodulators in which there has been an arising or worsening of autoimmunity conditions. The role of bone marrow transplantation in the course of concomitant autoimmune diseases remains under analysis.

Trends in HCAHPS Survey Scores, 2008-2019: A Quality Improvement Perspective.

BACKGROUND: HCAHPS' 2008 initial public reporting, 2012 inclusion in the Hospital Value-Based Purchasing Program (HVBP), and 2015 inclusion in Hospital Star Ratings were intended to improve patient experiences. OBJECTIVES: Characterize pre-COVID-19 (2008-2019) trends in hospital consumer assessment of healthcare providers and systems (HCAHPS) scores. RESEARCH DESIGN: Describe HCAHPS score trends overall, by phase: (1) initial public reporting period (2008-2013), (2) first 2 years of HVBP (2013-2015), and (3) initial HCAHPS Star Ratings reporting (2015-2019); and by hospital characteristics (HCAHPS decile, ownership, size, teaching affiliation, and urban/rural). SUBJECTS: A total of 3909 HCAHPS-participating US hospitals. MEASURES: HCAHPS summary score (HCAHPS-SS) and 9 measures. RESULTS: The mean 2007-2019 HCAHPS-SS improvement in most-positive-category ("top-box") responses was +5.2 percentage points/pp across all hospitals (where differences of 5pp, 3pp, and 1pp are "large," "medium," and "small"). Improvement rate was largest in phase 1 (+0.8/pp/year vs. +0.2pp/year and +0.1pp/year for phases 2 and 3, respectively). Improvement was largest for Overall Rating of Hospital (+8.5pp), Discharge Information (+7.3pp), and Nurse Communication (+6.5pp), smallest for Doctor Communication (+0.8pp). Some measures improved notably through phases 2 and 3 (Nurse Communication, Staff Responsiveness, Overall Rating of Hospital), but others slowed or reversed in Phase 3 (Communication about Medicines, Quietness). Bottom-decile hospitals improved more than other hospitals for all measures. CONCLUSIONS: All HCAHPS measures improved rapidly 2008-2013, especially among low-performing (bottom-decile) hospitals, narrowing the range of performance and improving scores overall. This initial improvement may reflect widespread, general quality improvement (QI) efforts in lower-performing hospitals. Subsequent slower improvement following the introduction of HVBP and Star Ratings may have reflected targeted, resource-intensive QI in higher-performing hospitals.

Optimizing abemaciclib-induced diarrhea management in patients with breast cancer: a pragmatic 2-group study using a postbiotic microbiota stabilizer.

BACKGROUND: Abemaciclib-induced diarrhea is a relevant concern in clinical practice. Postbiotics have emerged as a promising option for managing it. MATERIALS AND METHODS: We conducted a retrospective-prospective, 2-group, observational study to assess the impact of the postbiotic PostbiotiX-Restore, derived by Lactobacillus paracasei CNCM I-5220, on abemaciclib-induced diarrhea in patients with hormone receptor-positive HER2-negative breast cancer. The prospective population (Postbio group) received postbiotic during the first cycle of abemaciclib, while the retrospective one received standard care (Standard group). Diarrhea grading was defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. RESULTS: During the first cycle, diarrhea occurred in 78.9% of patients in the Standard cohort and 97.1% in the Postbio one, with most cases being G1-G2. Severe (G3) diarrhea was significantly less frequent in the Postbio group (0%) compared to the Standard one (7.9%; P = .029). Over the entire study period, while the grading difference was not statistically significant, G3 events were less frequent in the Postbio population (5.9%) than the Standard one (15.4%). Moreover, Postbio patients required fewer dose reductions due to diarrhea compared to the Standard group (P = .002). Notably, in the Postbio population, G1 and G2 events had short median durations (3 and 1 days, respectively) and, for the 2 patients experiencing G3 events during the second abemaciclib cycle (off postbiotic), diarrhea lasted only 1 day. CONCLUSIONS: Our study demonstrates the effect of PostbiotiX-Restore in mitigating abemaciclib-induced diarrhea, resulting in reduced severity, fewer dose reductions, and shorter duration. Further exploration and validation in larger cohorts are needed.

Allogeneic transplantation after immunotherapy for relapsed/refractory non-Hodgkin lymphoma: a comparison with a historical cohort.

BACKGROUND AIMS: New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody-drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. METHODS: We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. RESULTS: The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. CONCLUSIONS: Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy.

Potential New Therapies "ROS-Based" in CLL: An Innovative Paradigm in the Induction of Tumor Cell Apoptosis.

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm.

Response to first-line pembrolizumab in metastatic KRAS-mutated non-small-cell lung cancer.

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab.

Refining patient selection for next-generation immunotherapeutic early-phase clinical trials with a novel and externally validated prognostic nomogram.

Introduction: Identifying which patient may benefit from immunotherapeutic early-phase clinical trials is an unmet need in drug development. Among several proposed prognostic scores, none has been validated in patients receiving immunomodulating agents (IMAs)-based combinations. Patients and methods: We retrospectively collected data of 208 patients enrolled in early-phase clinical trials investigating IMAs at our Institution, correlating clinical and blood-based variables with overall survival (OS). A retrospective cohort of 50 patients treated with IMAs at Imperial College (Hammersmith Hospital, London, UK) was used for validation. Results: A total of 173 subjects were selected for analyses. Most frequent cancers included non-small cell lung cancer (26%), hepatocellular carcinoma (21.5%) and glioblastoma (13%). Multivariate analysis (MVA) revealed 3 factors to be independently associated with OS: line of treatment (second and third vs subsequent, HR 0.61, 95% CI 0.40-0.93, p 0.02), serum albumin as continuous variable (HR 0.57, 95% CI 0.36-0.91, p 0.02) and number of metastatic sites (<3 vs ≥3, HR 0.68, 95% CI 0.48-0.98, p 0.04). After splitting albumin value at the median (3.84 g/dL), a score system was capable of stratifying patients in 3 groups with significantly different OS (p<0.0001). Relationship with OS reproduced in the external cohort (p=0.008). Then, from these factors we built a nomogram. Conclusions: Prior treatment, serum albumin and number of metastatic sites are readily available prognostic traits in patients with advanced malignancies participating into immunotherapy early-phase trials. Combination of these factors can optimize patient selection at study enrollment, maximizing therapeutic intent.

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy.

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.

Interventions and Hospital Characteristics Associated With Patient Experience: An Update of the Evidence.

Patient experience is a key hospital quality measure. We review and characterize the literature on interventions, care and management processes, and structural characteristics associated with better inpatient experiences as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. Prior reviews identified several promising interventions. We update these previous efforts by including more recent peer-reviewed literature and expanding the review's scope to include observational studies of HCAHPS measures with process measures and structural characteristics. We used PubMed to identify U.S. English-language peer-reviewed articles published in 2017 to 2020 and focused on hospital patient experience. The two HCAHPS domains for which we found the fewest potential quality improvement interventions were Communication with Doctors and Quietness. We identified several modifiable processes that could be rigorously evaluated in the future, including electronic health record patient engagement functionality, care management processes, and nurse-to-patient ratios. We describe implications for future policy, practice, and research.

Survey Protocols, Response Rates, and Representation of Underserved Patients: A Randomized Clinical Trial.

Importance: Surveys often underrepresent certain patients, such as underserved patients. Methods that improve their response rates (RRs) would help patient surveys better represent their experiences and assess equity and equity-targeted quality improvement efforts. Objective: To estimate the effect of adding an initial web mode to existing Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey protocols and extending the fielding period on RR and representativeness of underserved patient groups. Design, Setting, and Participants: This randomized clinical trial included 36 001 patients discharged from 46 US hospitals from May through December 2021. Data analysis was performed from May 2022 to September 2023. Exposures: Patients were randomized to 1 of 6 survey protocols: 3 standard HCAHPS protocols (mail only, phone only, mail-phone) plus 3 web-enhanced protocols (web-mail, web-phone, web-mail-phone). Main Outcomes and Measures: RR and number of respondents per 100 survey attempts (yield) were calculated and compared for each of the 6 survey protocols, overall, and by patient age, service line, sex, and race and ethnicity. Results: A total of 34 335 patients (median age range, 55-59 years; 59.3% female individuals and 40.7% male individuals) were eligible and included in the study. Of the respondents, 6.9% were Asian American or Native Hawaiian or Other Pacific Islander, 0.7% were American Indian or Alaska Native, 11.5% were Black, 17.4% were Hispanic, 61.0% were White, and 2.6% were multiracial. Of the 6 protocols, RRs were highest in web-mail-phone (36.5%), intermediate for the 3 two-mode survey protocols (mail-phone, web-mail, web-phone, 30.3%-31.1%), and lowest for the 2 single-mode protocols (mail only, phone only, 22.1%-24.3%). Web-mail-phone resulted in the highest yield for 3 racial and ethnic groups (Black, Hispanic, and White patients) and second highest for another (multiracial patients). Otherwise, the highest or second highest yield was almost always a 2-mode protocol. Mail only was the lowest-yield protocol for Black, Hispanic, and multiracial patients and phone-only was the lowest-yield protocol for White patients; these 2 protocols tied for lowest-yield for Asian American or Native Hawaiian or Other Pacific Islander patients. Gains from multimode approaches were often 2 to 3 times as large for Asian American or Native Hawaiian or Other Pacific Islander, Black, Hispanic, and multiracial patients as for White patients. Web-mail-phone had the highest RR for 6 of 8 age groups and 4 of 5 combinations of service line and sex. Conclusions and Relevance: In this randomized clinical trial, web-first multimode survey protocols significantly improved the RR and representativeness of patient surveys. The best-performing protocol based on RR and representativeness was web-mail-phone. Web-phone performed well for young and diverse patient populations, and web-mail for older and less diverse patient populations. The US Centers for Medicare & Medicaid Services will allow hospitals to use the web-mail, web-phone, and web-mail-phone protocols for HCAHPS administration beginning in 2025.

The hidden scabies: a rare case of atypical Norwegian scabies, case report and literature review.

BACKGROUND: Norwegian scabies is a rare dermatological manifestation that usually affects the most fragile populations, such as elderly and immunocompromised patients, and its diagnosis is quite complex, due to its low prevalence in the general population and because of a broad spectrum manifestation. CASE PRESENTATION: Here we describe a rare case of Norwegian scabies that was previously misdiagnosed in a sixteen year old patient affected by Down syndrome and we conducted a non-systematic literature review about this topic. Lesions were atypical, pruritic and associated with periodic desquamation of the palms and soles and after a series of specialist evaluations, she finally underwent topical treatment with complete remission. CONCLUSION: It is therefore crucial to take in consideration the relation between Down syndrome and community acquired crusted scabies, to enable preventative measures, early detection, and proper treatment.

Outcome of High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Hodgkin Lymphoma after Different Numbers of Salvage Regimens.

The introduction of novel drugs (PD-1 inhibitors and/or brentuximab vedotin) into salvage regimens has improved the response rate and the outcome of patients with relapsed/refractory Hodgkin lymphoma. However, the impact of new drugs on the outcome has not been adequately investigated so far. We retrospectively analyzed 42 consecutive patients treated at our institution with high-dose chemotherapy/autologous stem cell transplantation after either one standard chemotherapy represented by BEGEV (n = 28) or >1 salvage therapy (ST) comprising novel drugs (n = 14). With a median follow-up of 24 months, the 2-year cumulative incidence of relapse was similar between the two cohorts: 26% for 1 ST and 18% for >1 ST (p = 0.822). Consistently, overall survival and progression-free survival did not differ among the two groups: 3-year overall survival was 91% and 89% (p = 0.731), respectively, and 3-year progression-free survival was 74% and 83% (p = 0.822) for only one and more than one salvage regimens, respectively. Of note, the post-transplant side effects and engraftment rates were similar between the 1 ST and >1 ST cohorts. In conclusion, consolidation with high-dose chemotherapy/autologous stem cell transplantation is a safe and curative option, even for patients achieving disease response after more than one rescue line of therapy.

Prognostic value of mitotic count in leiomyosarcoma: A comprehensive monocentric retrospective study.

BACKGROUND: Leiomyosarcomas (LMSs) include heterogeneous entities with different clinical courses not entirely predicted by known prognostic factors. In particular, the value of mitotic count as independent prognostic factor in LMS has been poorly investigated. METHODS: We retrospectively analyzed all patients with a diagnosis of LMS who accessed to our Institution from June 1999 to May 2022 for which mitotic count was numerically expressed within the pathology report. Univariate and multivariate analyses were conducted to explore the prognostic value of mitotic count along with other clinical and histological variables. RESULTS: We identified 121 eligible patients, with a median follow-up of 91.03 months (range 0.62-275.2 months). Median progression-free survival (mPFS) was 16.7 months, and median overall survival (mOS) was 105.6 months. In univariate analysis, mitotic count showed a significant impact on PFS and OS, with an hazard ratio per mitotic unit of 1.03 (1.01-1.04, p < 0.001) and 1.03 (1.01-1.04, p = 0.007), respectively. Similar results were found for locally advanced and metastatic patients, separately. Other significant prognostic factors for PFS were stage at diagnosis, performance status, tumor size and Ki-67, while differentiation, necrosis, grade, stage at diagnosis, tumor size, performance status and age at diagnosis were identified for OS. In multivariate analysis, the only significant factors were mitotic count and the presence of metastases at diagnosis for PFS, whereas the same two factors plus age at diagnosis were identified for OS. CONCLUSION: Mitotic count represented the most important histological prognostic factor for OS and PFS in localized and metastatic LMS.

Do Hospital Characteristics Predict Racial-and-Ethnic Disparities in Patient Experience? National Results From the HCAHPS Survey.

OBJECTIVE: Assess whether hospital characteristics associated with better patient experiences overall are also associated with smaller racial-and-ethnic disparities in inpatient experience. BACKGROUND: Hospitals that are smaller, non-profit, and serve high proportions of White patients tend to be high-performing overall, but it is not known whether these hospitals also have smaller racial-and-ethnic disparities in care. RESEARCH DESIGN: We used linear mixed-effect regression models to predict a summary measure that averaged eight Hospital CAHPS (HCAHPS) measures (Nurse Communication, Doctor Communication, Staff Responsiveness, Communication about Medicines, Discharge Information, Care Coordination, Hospital Cleanliness, and Quietness) from patient race-and-ethnicity, hospital characteristics (size, ownership, racial-and-ethnic patient-mix), and interactions of race-and-ethnicity with hospital characteristics. SUBJECTS: Inpatients discharged from 4,365 hospitals in 2021 who completed an HCAHPS survey ( N =2,288,862). RESULTS: While hospitals serving larger proportions of Black and Hispanic patients scored lower on all measures, racial-and-ethnic disparities were generally smaller for Black and Hispanic patients who received care from hospitals serving higher proportions of patients in their racial-and-ethnic group. Experiences overall were better in smaller and non-profit hospitals, but racial-and-ethnic differences were slightly larger. CONCLUSIONS: Large, for-profit hospitals and hospitals serving higher proportions of Black and Hispanic patients tend to be lower performing overall but have smaller disparities in patient experience. High-performing hospitals might look at low-performing hospitals for how to provide less disparate care whereas low-performing hospitals may look to high-performing hospitals for how to improve patient experience overall.

Changes in Patient Experiences of Hospital Care During the COVID-19 Pandemic.

Importance: It is important to assess how the COVID-19 pandemic was adversely associated with patients' care experiences. Objective: To describe differences in 2020 to 2021 patient experiences from what would have been expected from prepandemic (2018-2019) trends and assess correlates of changes across hospitals. Design, Setting, and Participants: This cohort study compared 2020 to 2021 data with 2018 to 2019 data from 3 900 887 HCAHPS respondents discharged from 3381 HCAHPS-participating US hospitals. The data were analyzed from 2022 to 2023. Main Outcomes and Measures: The primary outcome was an HCAHPS summary score (HCAHPS-SS), which averaged 10 HCAHPS measures. The primary analysis estimated whether HCAHPS scores from patients discharged from 2020 to 2021 differed from scores that would be expected based on quarterly and linear trends from 2018 to 2019 discharges. Secondary analyses stratified hospitals by prepandemic overall star ratings and staffing levels. Results: Of the 3 900 887 HCAHPS 2020 to 2021 respondents, 59% were age 65 years or older, and 35% (11%) were in the surgical (maternity) service lines. Compared with trends expected based on prepandemic (2018-2019) data, HCAHPS-SS was 1.2 percentage points (pp) lower for quarter (Q) 2/2020 discharges and -1.9 to -2.0 pp for Q3/2020 to Q1/2021, which then declined to -3.6 pp by Q4/2021. The most affected measures (Q4/2021) were staff responsiveness (-5.6 pp) and cleanliness (-4.9 pp); the least affected were discharge information (-1.6 pp) and quietness (-1.8 pp). Overall rating and hospital recommendation measures initially exhibited smaller-than-average decreases, but then fell as much as the more specific experience measures by Q2/2021. Quietness did not decline until Q2/2021. The HCAHPS-SS fell most for hospitals with the lowest prepandemic staffing levels; hospitals with bottom-quartile staffing showed the largest decrements, whereas top-quartile hospitals showed smaller decrements in most quarters. Hospitals with better overall prepandemic quality showed consistently smaller HCAHPS-SS drops, with effects for 5-star hospitals about 25% smaller than for 1-star and 2-star hospitals. Conclusions and Relevance: The results of this cohort study of HCAHPS-participating hospitals found that patient experience scores declined during 2020 to 2021. By Q4/2021, the HCAHPS-SS was 3.6 pp lower than would have been expected, a medium effect size. The most affected measures (staff responsiveness and cleanliness) showed large effect sizes, possibly reflecting high illness-associated hospital workforce absenteeism. Hospitals that were lower performing and less staffed prepandemic may have been less resilient to reduced staff availability and other pandemic-associated challenges. However, by Q4/2021, even prepandemic high-performing hospitals had similar declines.

Multidisciplinary management of adolescents and young adults (AYA) sarcoma: A successful effort of an adult high-volume cancer center.

INTRODUCTION: The aim of this retrospective study was to investigate the clinicopathological characteristics of AYA sarcomas and their clinical outcomes at a high-volume single center. METHODS: Demographic, clinicopathological data on the diagnosis, treatment and follow-up of all sarcoma patients aged 16-39 years (ys) observed at our Institute between January 2010 and December 2021 were retrospectively collected, including diagnostic (TTD) and treatment delay(TTT), clinical outcomes (OS and PFS), and late-treatment effects. RESULTS: We identified 228 AYA patients, median age 30 years, 29% ≤ 25 years, 57% males, 88% soft tissue sarcomas (STS), and 12% bone sarcomas (BS). Among STSs, 13% were small round cell tumors (SRCT), 52% intermediate-high-grade, 24% low-grade STSs. Among BS, 32% were high-grade. Median TTD and TTT were 120 (0-8255) and 7 days (0-83), respectively. Surgery was performed in 83%, radiotherapy in 29%, and systemic therapy in 27%. Median follow-up was 72.9 months(1.6-145), 5-year and 10-year OS were 78.5% and 62%, respectively. Kaplan-Meyer analysis showed a significantly better 5-year OS and PFS for patients with >92 days of TTD (OS 85.7% vs. 66.7%, p = 0.001, PFS 50.2% vs. 24.9%, p = 0.009). According to age (≤25 years vs. > 25 years), 5-year OS was 69.8% versus 82.2%, respectively (p = 0.047). CONCLUSION: Our analysis confirmed previous data on sarcoma AYA patients followed in a referral center. Unexpectedly, diagnostic delay was not associated with poor OS and PFS. Patients <25 years showed a poorer prognosis due to the higher incidence of SRCT.

Impact of Preemptive Use of Tocilizumab on Chimeric Antigen Receptor T Cell Outcomes in Non-Hodgkin Lymphoma.

Despite the impressive results of chimeric antigen receptor (CAR) T cell treatment for lymphomas, adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections are major issues that can lead to intensive care unit (ICU) admission and death. Current guidelines recommend tocilizumab for treating patients with CRS grade (G) ≥2; however, the optimal timing of intervention has yet to be determined. Our institution adopted the preemptive use of tocilizumab in cases of persistent G1 CRS, defined as fever (≥38 °C) for >24 hours. This preemptive tocilizumab treatment aimed to reduce evolution to severe (G≥3) CRS, ICU admission, or death. We report on 48 prospectively collected consecutive patients with non-Hodgkin lymphoma treated with autologous CD19-targeted CAR T cells. In total, 39 patients (81%) developed CRS. CRS started as G1 in 28 patients, as G2 in patients, and as G3 in 1 patient. Tocilizumab was administered in 34 patients, including 23 patients who received "preemptive" tocilizumab and 11 patients who received tocilizumab for G2 or G3 CRS from the onset of symptoms. CRS resolved without worsening severity in 19 patients out of 23 (83%) who received preemptive tocilizumab; 4 patients (17%) progressed from G1 to G2 for the development of hypotension and quickly responded to the introduction of steroids. No patients treated with a preemptive approach developed G3 or G4 CRS. Ten out of 48 patients (21%) were diagnosed with ICANS, including 5 patients with G3 or G4. Six infectious events occurred. The overall ICU admission rate was 19%. ICANS management was the most relevant reason for ICU admission (7 patients), and no patient required ICU to manage CRS. No deaths from CAR-T toxicity were observed. Our data indicate that preemptive tocilizumab use is feasible and useful in reducing severe CRS and CRS-related ICU admission, with no impact on neurotoxicity or infection rate. Therefore, early use of tocilizumab can be considered, especially for patients at high risk of CRS.

Liquid Biopsy of Cerebrospinal Fluid Enables Selective Profiling of Glioma Molecular Subtypes at First Clinical Presentation.

PURPOSE: Current glioma diagnostic guidelines call for molecular profiling to stratify patients into prognostic and treatment subgroups. In case the tumor tissue is inaccessible, cerebrospinal fluid (CSF) has been proposed as a reliable tumor DNA source for liquid biopsy. We prospectively investigated the use of CSF for molecular characterization of newly diagnosed gliomas. EXPERIMENTAL DESIGN: We recruited two cohorts of newly diagnosed patients with glioma, one (n = 45) providing CSF collected in proximity of the tumor, the other (n = 39) CSF collected by lumbar puncture (LP). Both cohorts provided tumor tissues by surgery concomitant with CSF sampling. DNA samples retrieved from CSF and matched tumors were systematically characterized and compared by comprehensive (NGS, next-generation sequencing) or targeted (ddPCR, droplet digital PCR) methodologies. Conventional and molecular diagnosis outcomes were compared. RESULTS: We report that tumor DNA is abundant in CSF close to the tumor, but scanty and mostly below NGS sensitivity threshold in CSF from LP. Indeed, tumor DNA is mostly released by cells invading liquoral spaces, generating a gradient that attenuates by departing from the tumor. Nevertheless, in >60% of LP CSF samples, tumor DNA is sufficient to assess a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC protocol) and MGMT methylation that, combined with imaging, enable tissue-agnostic identification of main glioma molecular subtypes. CONCLUSIONS: This study shows potentialities and limitations of CSF liquid biopsy in achieving molecular characterization of gliomas at first clinical presentation and proposes a protocol to maximize diagnostic information retrievable from CSF DNA.

Why Do So Many People with Type 2 Diabetes Who Take Insulin Have Lipohypertrophy? Fate or Educational Deficiencies?

INTRODUCTION: Cutaneous lipohypertrophy (LH) is a thickened, "rubbery" lesion in the subcutaneous tissue following multiple injections performed at the same site, i.e., an incorrect injection technique. It is widespread, averaging 47% of insulin patients worldwide, and has severe direct and indirect consequences. Direct consequences consist mainly of poor metabolic control and frequent hypoglycemic events (HYPOs), and indirect ones of markedly increased healthcare costs related to hospital access due to acute events and long-term disease complications. This observation also holds for Italy, despite the National Health System organization expecting every patient with diabetes to undergo a series of visits by different care team members, each performing a specific treatment/education task. Indeed, the recent literature points to poor awareness of LH relevance and metabolic consequences among doctors from general and diabetic hospital wards, with educational deficiencies on correct injection practice in nurses too. The aim was to establish if, to what extent, and by whom they had received training on correct insulin injection techniques, and how many initially received notions had persisted over time. METHODS: We investigated the possible causes of such a failure from the point of view of 1160 insulin-requiring subjects with type 2 diabetes (T2DM), reporting for the first time to specialized diabetic structures through a validated questionnaire and, in the same patients, we searched for LH by inspection/palpation according to international guidelines, further confirmed by ultrasound scans. We then analyzed differences in education and injecting behavior between subjects classified as LH+ or LH- depending on the presence or absence of LH lesions. RESULTS: We documented significant educational gaps, with 50% of patients failing to refer to healthcare professionals and relying on their peers with diabetes, thought to be more experienced in 15% of the cases. Seventy-five percent of LH- patients received education from healthcare providers, while 90% of LH+ learned from another patient or could not remember how they knew, and 68% of LH+ versus 52% of LH- (p < 0.01) patients had failed to receive training on injection techniques by healthcare providers. All of this enabled the most disabling features of diabetes from the very beginning of the disease history. CONCLUSIONS: This study documents, from the patients' point of view, that educational gaps are significant and that, even in initially trained subjects, education on correct injection techniques has a fleeting effect if not regularly recalled. Therefore, to rehabilitate LH+ patients as soon as possible and prevent LH- patients from inadvertently slipping into the other group, there is an urgent need to educate doctors and nurses repeatedly on the importance of correctly injecting insulin to improve patients' knowledge and skills.