Intranasal administration of Escherichia coli Nissle expressing the spike protein of SARS-CoV-2 induces long-term immunization and prevents spike protein-mediated lung injury in mice.

While current anti-Spike protein (SP) vaccines have been pivotal in managing the pandemic, their limitations in delivery, storage, and the inability to provide mucosal immunization (preventing infections) highlight the ongoing necessity for research and innovation. To tackle these constraints, our research group developed a bacterial-based vaccine using a non-pathogenic E. coli Nissle 1917 (EcN) strain genetically modified to express the SARS-CoV-2 spike protein on its surface (EcN-pAIDA1-SP). We intranasally delivered the EcN-pAIDA1-SP in two doses and checked specific IgG/IgA production as well as the key immune mediators involved in the process. Moreover, following the initial and booster vaccine doses, we exposed both immunized and non-immunized mice to intranasal delivery of SARS-CoV-2 SP to assess the effectiveness of EcN-pAIDA1-SP in protecting lung tissue from the inflammation damage. We observed detectable levels of anti-SARS-CoV-2 spike IgG in serum samples and IgA in bronchoalveolar lavage fluid two weeks after the initial treatment, with peak concentrations in the respective samples on the 35th day. Moreover, immunoglobulins displayed a progressively enhanced avidity index, suggesting a selective binding to the spike protein. Finally, the pre-immunized group displayed a decrease in proinflammatory markers (TLR4, NLRP3, ILs) following SP challenge, compared to the non-immunized groups, along with better preservation of tissue morphology. Our probiotic-based technology provides an effective immunobiotic tool to protect individuals against disease and control infection spread.

MYC rearrangements in HIV-associated large B-cell lymphomas: EUROMYC, a European retrospective study.

ABSTRACT: Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.

Long-Term Follow-Up of the Response-Adapted Intergroup EORTC/LYSA/FIL H10 Trial for Localized Hodgkin Lymphoma.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Early positron emission tomography (ePET) Response-Adapted Treatment in localized Hodgkin Lymphoma H10 Trial demonstrated that in ePET-negative patients, the risk of relapse increased when involved-node radiotherapy (INRT) was omitted and that in ePET-positive patients, switching from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) significantly improved 5-year progression-free survival (PFS). Here, we report the final results of a preplanned analysis at a 10-year follow-up. In the favorable (F) ePET-negative group, the 10-year PFS rates were 98.8% versus 85.4% (hazard ratio [HR], 13.2; 95% CI, 3.1 to 55.8; P value for noninferiority = .9735; difference test P < .0001) in favor of ABVD + INRT; in the unfavorable (U) ePET-negative group, the 10-year PFS rates were 91.4% and 86.5% (HR, 1.52; 95% CI, 0.84 to 2.75; P value for noninferiority = .8577; difference test P = .1628). In ePET-positive patients, the difference in terms of PFS between standard ABVD and intensified BEACOPPesc was no longer statistically significant (HR, 0.67; 95% CI, 0.37 to 1.20; P = .1777). In conclusion, the present long-term analysis confirms that in ePET-negative patients, the omission of INRT is associated with lower 10-year PFS. Instead, in ePET-positive patients, no significant difference between standard and experimental arms emerged although intensification with BEACOPPesc was safe, with no increase in late adverse events, namely, second malignancies.

Threads of memory: Reviving the ornament of a dead child at the Neolithic village of Ba`ja (Jordan).

In 2018, a well-constructed cist-type grave was discovered at Ba`ja, a Neolithic village (7,400-6,800 BCE) in Southern Jordan. Underneath multiple grave layers, an 8-year-old child was buried in a fetal position. Over 2,500 beads were found on the chest and neck, along with a double perforated stone pendant and a delicately engraved mother-of-pearl ring discovered among the concentration of beads. The first was found behind the neck, and the second on the chest. The meticulous documentation of the bead distribution indicated that the assemblage was a composite ornament that had gradually collapsed, partly due to the burying position. Our aim was to challenge time degradation and to reimagine the initial composition in order to best explore the significance of this symbolic category of material culture, not as mere group of beads, but as an ornamental creation with further aesthetic, artisanal and socioeconomic implications. The reconstruction results exceeded our expectations as it revealed an imposing multi-row necklace of complex structure and attractive design. Through multiple lines of evidence, we suggest that the necklace was created at Ba`ja, although significant parts of beads were made from exotic shells and stones, including fossil amber, an unprecedented material never attested before for this period. The retrieval of such an ornament from life and its attribution to a young dead child highlights the significant social status of this individual. Beyond the symbolic functions related to identity, the necklace is believed to have played a key role in performing the inhumation rituals, understood as a public event gathering families, relatives, and people from other villages. In this sense, the necklace is not seen as belonging completely to the realm of death but rather to the world of the living, materializing a collective memory and shared moments of emotions and social cohesion.

Close-range photogrammetry reveals morphometric changes on replicative ground stones.

The pursuit of a quantitative approach to functional analysis of stone tools is an ongoing endeavour for traceologists. Technological advancements in 3D imaging techniques, such as photogrammetry/3D scanners, CT scanning, 3D digital microscopy, confocal microscopy, AFM and FEG-SEM and micro-topographical scanning, have greatly facilitated the detailed capturing of the geometry and surface texture at multiple levels of observation, from the object-scale to the nano-scale. However, while such technological innovations have predominantly focused on flaked assemblages, ground stone tools have only recently begun to receive due attention, and a standardised protocol for their study is yet to be established. In order to comprehend the function(s) of these tools, analytical techniques that enable a 3D visualisation of the entire item and the wear affecting the used surfaces have proven to be of great support. To this end, an analytical procedure was developed and tested on slabs and pebbles in order to replicate the use-wear traces observed on Upper Palaeolithic tools. The purpose was to assemble a site-specific reference collection tailored on the artefacts from the cultural level III of the Brînzeni I cave in north-west Moldova. Experimental replicas were used to treat different plant organs during controlled sequential experiments. The present article reports on the analysis based on photogrammetric data acquired during two stages of replicative usage. We tested multiple acquisition setups and elaborations to assess the geometry modification and the surface depletion. By exploring various acquisition strategies, a critical evaluation of potential sources of bias in data collection and subsequent elaboration were performed, and the methodology was accordingly adjusted thereby enhancing the reliability and reproducibility of the results. This study highlights the importance of carefully considering the acquisition strategy in archaeological related research to ensure accurate analyses and to validate robust interpretation.

Analysis of Heart Rate, Perception of Physical Effort and Performance of Individuals with Down Syndrome Submitted to a Protocol of Virtual Games for Home-Based Telerehabilitation.

Down syndrome (DS) is a genetic condition associated with impairments in several body systems, which may negatively influence the habit of practicing physical activities (PAs), increasing sedentary habits and the risk of comorbidities. Additionally, difficulty in accessing services, financial limitations and lack of interest may interfere with the practice of PAs. Considering the necessity of developing effective treatment alternatives, to increase the possibility of access and the interest of participants, we conducted a study using telerehabilitation with a virtual task to promote PA and analyze the motor performance of DS individuals. Our protocol consisted of 11 sessions of the virtual game called MoveHero. A total of 34 individuals with DS and 34 individuals with typical development participated in the study. Heart rate (HR) and rating of perceived effort (RPE) were collected at rest and during the game. Our results show that virtual reality presents a great possibility to promote PA and a way out of a sedentary lifestyle for DS individuals, considering the enhancement in HR and RPE found during the protocol for both groups. Moreover, our results show positive outcomes regarding motor performance, with significant improvement in the task with practice, demonstrating that individuals with DS are able to improve their motor proficiency with adequate stimuli in the virtual environment.

Long-term follow-up of rituximab plus bendamustine and cytarabine in older patients with newly diagnosed MCL.

The combination of rituximab, bendamustine, and low-dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from Fondazione Italiana Linfomi (RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with a complete remission rate of 91% and 2-year progression-free survival (PFS) of 81% (95% confidence interval [CI], 68-89). Here, we report the long-term survival outcomes, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (range, 57-107 months), the median overall survival (OS) and PFS were not reached. The 7-year PFS and OS rates were 55% (95% CI, 41-67), and 63% (95% CI, 49-74), respectively. Patients who responded (n = 53) had a 7-year PFS of 59% (95% CI, 44-71), with no relapse or progression registered after the sixth year. In the multivariate analysis, blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (P = .04). Patients with an end of treatment negative MRD had better, but not significant, outcomes for both PFS and OS than patients with MRD-positive (P = 0.148 and P = 0.162, respectively). There was no signal of late toxicity or an increase in secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in older patients with MCL. Survival outcomes compare favorably with those of other immunochemotherapy regimens (with or without maintenance), including combinations of BTK inhibitors upfront. This study was registered with EudraCT as 2011-005739-23 and at www.clinicaltrials.gov as #NCT01662050.

Role of Rituximab Addition to First-line Chemotherapy Regimens in Nodular Lymphocyte-predominant Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity whose neoplastic cells retain a B-cell phenotype with expression of CD20. Radiotherapy is recommended for favorable stage IA disease while for other stages guidelines suggest therapeutic strategies similar to those used for classic HL. The role of rituximab, although quite widespread, is not completely elucidated. We retrospectively analyzed baseline characteristics of 308 consecutive patients with NLPHL diagnosed in 19 Italian centers from 2000 to 2018. With a median follow-up of 8.4 years (interquartile range: 4.5-12.4) for treated patients, median overall survival (OS) was not reached and estimated 5-year OS was 97.8% and 5-year progression-free survival (PFS) was 84.5%. Five-year cumulative incidence of histological transformation was 1.4%, 95% confidence interval (CI), 0.5%-3.8%. After adjusting for lymphocyte count, splenic involvement, bulky disease and B symptoms (fever, drenching night sweats, unintentional loss >10% of body weight within the preceding 6 months), patients with stage II or more showed superior PFS with immunochemotherapy in comparison to chemotherapy alone (hazard ratio = 0.4, 95% CI, 0.2-0.8; P = 0.015). Our data suggest an advantage of the use of rituximab combined with chemotherapy ± radiotherapy in the treatment of stage II-III-IV NLPHL.

Five decades of breeding populations census for 12 species of colonial waterbirds in northwestern Italy.

Colonial waterbirds, a major biodiversity element occurring in the core of ultra-anthropized Europe, are ideal indicators of the wellness of inland wetlands. Nonetheless, there is a critical knowledge gap in their trend and population status. We present an uninterrupted 47 years-long dataset of the breeding populations of 12 species of colonial waterbirds (Ardeidae, Phalacrocoracidae, Plataleidae, Threskiornitidae) throughout a 58,000 km2 agricultural region in the higher Po basin (NW Italy). A trained team of collaborators censused with standardized field techniques the number of nests of each species at 419 colonies in the 1972-2018 period, summing up a total of 236,316 records. Data cleaning and standardization were performed for each census year, ensuring robust and consistent data. This dataset is among the largest ever collected for a guild of European vertebrates. It has already been used to describe the factors influencing population trends, and still offers opportunities to explore a wide range of key ecological processes such as biological invasions, global change consequences and biodiversity impact of agricultural practices.

The role of volume and intensity on the association between physical activity and mental health among adolescents: a cross-sectional study.

OBJECTIVE: To analyze the association between volume and intensity of physical activity and mental health among adolescents. METHODS: Cross-sectional study with 604 Brazilian adolescents. Data were assessed using a self-report questionnaire. The outcomes were suicidal ideation, suspicion of common mental disorders, and negative self-perception of mental health. The independent variables were leisure physical activity at low and moderate-to-vigorous intensities. Volume was analyzed in two ways: any volume (presence vs absence), and volume classified according to amount in minutes of weekly physical activity: inactive (0), low active (1-419), and high active (≥420). Poisson regression was performed to estimate prevalence ratios. RESULTS: Any volume of moderate-to-vigorous physical activity was significantly associated with a lower prevalence ratio of all outcomes (PR 0.67 to 0.77). Compared to inactive adolescents, those who were classified as low active for moderate-to-vigorous intensity, presented a lower likelihood of having suicidal ideation, suspicion of common mental disorders, and negative self-perception of mental health (PR 0.70 to 0.76). Furthermore, high active adolescents in moderate-to-vigorous physical activity presented lower suicidal ideation and negative self-perception of mental health (PR 0.62 and 0.57). CONCLUSIONS: The promotion of moderate-to-vigorous intensity physical activity at any volume can benefit the mental health of adolescents, however, no association was evidenced for low intensity physical activity.

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the Fondazione Italiana Linfomi MCL0208 trial.

In the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P < .05) and 85% vs 60% (P < .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P = .62). Moreover, the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL.

Current Treatment Options and the Role of Functional Status Assessment in Classical Hodgkin Lymphoma in Older Adults: A Review.

Along with the fact that classical Hodgkin lymphoma (cHL) in older adults is frequently considered biologically different from cHL in younger patients, its most distinctive feature is its dismal clinical outcome due to the decreased effectiveness and greater toxicity of therapies. Although strategies to mitigate specific toxicities (e.g., cardiological and pulmonary) have obtained some results, in general, reduced-intensity schemes, proposed as an alternative to ABVD, have proved to be less effective. The addition of brentuximab vedotin (BV) to AVD, especially in a sequential scheme, has demonstrated good efficacy. However, the problem of toxicity persists even with this new therapeutic combination, with comorbidities remaining an important prognostic factor. The adequate stratification of functional status is necessary to distinguish between those patients who will benefit from full treatment and those who will benefit from alternative strategies. A simplified geriatric assessment based on the determination of ADL (activity of daily living), IADL (instrumental ADL), and CIRS-G (Cumulative Illness Rating Scale-Geriatric) scores is an easy-to-use tool that permits adequate patient stratification. Other factors of considerable impact on functional status such as sarcopenia and immunosenescence are currently being studied. A fitness-based treatment choice would also be very useful for relapsed or refractory patients, a more frequent and challenging situation than that is found in young cHL patients.

Oral Immunization with Escherichia coli Nissle 1917 Expressing SARS-CoV-2 Spike Protein Induces Mucosal and Systemic Antibody Responses in Mice.

As of October 2022, the COVID-19 pandemic continues to pose a major public health conundrum, with increased rates of symptomatic infections in vaccinated individuals. An ideal vaccine candidate for the prevention of outbreaks should be rapidly scalable, easy to administer, and able to elicit a potent mucosal immunity. Towards this aim, we proposed an engineered Escherichia coli (E. coli) Nissle 1917 (EcN) strain with SARS-CoV-2 spike protein (SP)-coding plasmid, which was able to expose SP on its cellular surface by a hybridization with the adhesin involved in diffuse adherence 1 (AIDA1). In this study, we presented the effectiveness of a 16-week intragastrically administered, engineered EcN in producing specific systemic and mucosal immunoglobulins against SARS-CoV-2 SP in mice. We observed a time-dependent increase in anti-SARS-CoV-2 SP IgG antibodies in the sera at week 4, with a titre that more than doubled by week 12 and a stable circulating titre by week 16 (+309% and +325% vs. control; both p < 0.001). A parallel rise in mucosal IgA antibody titre in stools, measured via intestinal and bronchoalveolar lavage fluids of the treated mice, reached a plateau by week 12 and until the end of the immunization protocol (+300, +47, and +150%, at week 16; all p < 0.001 vs. controls). If confirmed in animal models of infection, our data indicated that the engineered EcN may be a potential candidate as an oral vaccine against COVID-19. It is safe, inexpensive, and, most importantly, able to stimulate the production of both systemic and mucosal anti-SARS-CoV-2 spike-protein antibodies.

High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review.

Background: Chimeric antigen receptor (CAR) T-cell therapy represents the most advanced immunotherapy against relapsed/refractory B cell malignancies. While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are distinctive, known CAR T-cell acute adverse events, hematological toxicity has been increasingly reported. Cytopenia following CAR T-cell treatment is attributed in most cases to lymphodepletion regimens, bridging chemotherapy, or radiotherapy. However, when cytopenia becomes prolonged, the development of myelodysplastic syndrome (MDS) should be considered. Case presentation: We report a case of high risk (HR)-MDS following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma. Eight months after CAR T-cell infusion, the blood count showed progressive, worsening cytopenia and the bone marrow biopsy revealed multilineage dysplasia without excess of blasts associated with chromosome 7 deletion and RUNX1 mutation. Next generation sequencing analysis, retrospectively performed on stored samples, showed a germ line CSF3R mutation, CEBPA clonal hematopoiesis, but no RUNX1 lesion. Conclusion: We describe a case of HR-MDS, with deletion of chromosome 7 and acquisition of RUNX1 mutation, developing after CAR T-cell therapy in a patient with clonal hematopoiesis (CH). Previous chemotherapy favored MDS onset; however, we could not exclude the fact that the impairment of immunosurveillance related to either lymphodepletion or CAR T-cell infusion may play a role in MDS development. Thus, we designed a multicenter prospective study (ClonHema-CAR-T-Study) to investigate if cytopenia after CAR T-cell treatment may be due to underling CH as well as the presence of secondary myeloid malignancies.

Bilateral Transfer of Performance between Real and Non-Immersive Virtual Environments in Post-Stroke Individuals: A Cross-Sectional Study.

(1) Background: Post-stroke presents motor function deficits, and one interesting possibility for practicing skills is the concept of bilateral transfer. Additionally, there is evidence that the use of virtual reality is beneficial in improving upper limb function. We aimed to evaluate the transfer of motor performance of post-stroke and control groups in two different environments (real and virtual), as well as bilateral transfer, by changing the practice between paretic and non-paretic upper limbs. (2) Methods: We used a coincident timing task with a virtual (Kinect) or a real device (touch screen) in post-stroke and control groups; both groups practiced with bilateral transference. (3) Results: Were included 136 participants, 82 post-stroke and 54 controls. The control group presented better performance during most parts of the protocol; however, it was more evident when compared with the post-stroke paretic upper limb. We found bilateral transference mainly in Practice 2, with the paretic upper limb using the real interface method (touch screen), but only after Practice 1 with the virtual interface (Kinect), using the non-paretic upper limb. (4) Conclusions: The task with the greatest motor and cognitive demand (virtual-Kinect) provided transfer into the real interface, and bilateral transfer was observed in individuals post-stroke. However, this is more strongly observed when the virtual task was performed using the non-paretic upper limb first.

Romidepsin-CHOEP followed by high-dose chemotherapy and stem-cell transplantation in untreated Peripheral T-Cell Lymphoma: results of the PTCL13 phase Ib/II study.

The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18-65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0-56.7), and the 18-month overall survival was 73.1% (95%CI:61.6-81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients.

A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma.

Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti-CD38 antibody) in combination with cemiplimab (Cemi, anti-programmed death-1 [PD-1] receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de-escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti-PD-1/programmed death-ligand 1 [PD-L1] naïve), and objective response rate in Cohorts A2 (cHL anti-PD-1/PD-L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti-PD-1/PD-L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations.

Diamond-based sensors for in vitro cellular radiobiology: Simultaneous detection of cell exocytic activity and ionizing radiation.

The investigation of secondary effects induced by ionizing radiation represents a new and ever-growing research field in radiobiology. This new paradigm cannot be investigated only using standard instrumentation and methodologies, but rather requires novel technologies to achieve significant progress. In this framework, we developed diamond-based sensors that allow simultaneous real-time measurements with a high spatial resolution of the secretory activity of a network of cells cultured on the device, as well as of the dose at which they are exposed during irradiation experiments. The devices were functionally characterized by testing both the above-mentioned detection schemes, namely: amperometric measurements of neurotransmitter release from excitable cells (such as dopamine or adrenaline) and dosimetric evaluation using different ionizing particles (alpha particle and X-ray photons). Finally, the sensors were employed to investigate the effects induced by X-rays on the exocytotic activity of PC12 neuroendocrine cells by monitoring the modulation of the dopamine release in real-time.

Diffuse large B-cell lymphoma in octogenarians aged 85 and older can benefit from treatment with curative intent: a report on 129 patients prospectively registered in the Elderly Project of the Fondazione Italiana Linfomi (FIL).

Octogenarian patients with diffuse large B-cell lymphoma are managed mainly with palliation, but recent improvement in their overall condition makes potentially curative treatment a possibility. Studies have shown that half of selected octogenarians may be cured using reduced-dose anthracycline chemoimmunotherapy. However, patients aged >85 (late octogenarians [LO]) were underrepresented, and selection criteria were poorly defined. We analyzed the clinical characteristics and outcomes of LO enrolled in the FIL Elderly Project in terms of the treatment received (palliative vs. curative) and of their simplified geriatric assessment (sGA), then compared them with early octogenarians (EO) aged 80- 84 and with those aged 65-79 classified as UNFIT or FRAIL according to sGA enrolled in the same study. Of the 1,163 patients, 370 were >80 and 129 LO. Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs. 23%; P=0.001) and had worse 2-year overall survival (OS) (48% vs. 63%; P=0.001) and 2-year progression-free survival (PFS) (43% vs. 56%; P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P<0.001), without any difference between full or reduced doses. Rituximab within palliation improved outcome (2-yr OS with or without rituximab 42% vs. 22%; P=0.008). Elderly Prognostic Index (EPI) performed better than sGA in identifying different risk categories, and high-risk EPI retained an independent unfavorable effect on OS and PFS, together with treatment without anthracycline. In conclusion, late octogenarians can benefit from a curative approach with reduced-dose anthracycline and from rituximab within palliation. EPI may help in patient selection more than sGA can.

The role of volume and intensity on the association between physical activity and mental health among adolescents: a cross-sectional study / O papel do volume e da intensidade na associação entre atividade física e saúde mental em adolescentes: um estudo transversal

Abstract Objective: To analyze the association between volume and intensity of physical activity and mental health among adolescents. Methods: Cross-sectional study with 604 Brazilian adolescents. Data were assessed using a self-report questionnaire. The outcomes were suicidal ideation, suspicion of common mental disorders, and negative self-perception of mental health. The independent variables were leisure physical activity at low and moderate-to-vigorous intensities. Volume was analyzed in two ways: any volume (presence vs absence), and volume classified according to amount in minutes of weekly physical activity: inactive (0), low active (1-419), and high active (≥420). Poisson regression was performed to estimate prevalence ratios. Results: Any volume of moderate-to-vigorous physical activity was significantly associated with a lower prevalence ratio of all outcomes (PR 0.67 to 0.77). Compared to inactive adolescents, those who were classified as low active for moderate-to-vigorous intensity, presented a lower likelihood of having suicidal ideation, suspicion of common mental disorders, and negative self-perception of mental health (PR 0.70 to 0.76). Furthermore, high active adolescents in moderate-to-vigorous physical activity presented lower suicidal ideation and negative self-perception of mental health (PR 0.62 and 0.57). Conclusions: The promotion of moderate-to-vigorous intensity physical activity at any volume can benefit the mental health of adolescents, however, no association was evidenced for low intensity physical activity.

Resumo Objetivo: Analisar a associação entre o volume e intensidade da atividade física e a saúde mental de adolescentes. Métodos: Estudo transversal que envolveu 604 adolescentes brasileiros. Os dados foram coletados por meio de um questionário autorrelatado. Os desfechos foram ideação suicida, suspeita de transtornos mentais comuns e autopercepção negativa de saúde mental. A variável independente foi a atividade física em tempo livre nas intensidades leve e moderada a vigorosa. O volume foi analisado de duas formas: qualquer volume (presença vs. ausência); e de acordo com a quantidade de atividade física semanal em minutos — inativos (0), pouco ativos (1-419) e altamente ativos (≥420). A regressão de Poisson foi realizada para estimar as razões de prevalência (RP). Resultados: Qualquer volume de atividade física de intensidade moderada a vigorosa foi significativamente associado à menor razão de prevalência de todos os desfechos (RP 0,67 a 0,77). Comparados aos adolescentes inativos, aqueles que foram classificados como pouco ativos na intensidade moderada a vigorosa apresentaram menor probabilidade de ter ideação suicida, suspeita de transtornos mentais comuns e autopercepção negativa de saúde mental (RP 0,70 a 0,76). Da mesma forma, adolescentes altamente ativos na intensidade moderada a vigorosa apresentaram menor ideação suicida e autopercepção negativa de saúde mental (RP 0,62 e 0,57). Conclusões: A promoção de atividade física moderada a vigorosa em qualquer volume pode beneficiar a saúde mental de adolescentes, no entanto nenhuma associação foi evidenciada para a atividade física na intensidade leve.