Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

B-cell lymphoma and lymphoproliferative diseases represent a heterogeneous and complex group of neoplasms that are accompanied by a broad range of immune regulatory disorder phenotypes. Clinical features of autoimmunity, hyperinflammation, immunodeficiency and infection can variously dominate, depending on the immune pathway most involved. Immunological imbalance can play a role in lymphomagenesis, also supporting the progression of the disease, while on the other hand, lymphoma acts on the immune system to weaken immunosurveillance and facilitate immunoevasion. Therefore, the modulation of immunity can have a profound effect on disease progression or resolution, which makes the immune system a critical target for new therapies. In the current therapeutic scenario enriched by chemo-free regimens, it is important to establish the effect of various drugs on the disease, as well as on the restoration of immune functions. In fact, treatment of B-cell lymphoma with passive immunotherapy that targets tumor cells or targets the tumor microenvironment, together with adoptive immunotherapy, is becoming more frequent. The aim of this review is to report relevant data on the evolution of the immune system during and after treatment with targeted therapy of B-cell lymphomas

Host-related factors and cancer: Malnutrition and non-Hodgkin lymphoma

Assessment of host-related factors is a crucial aspect in the comprehensive management of cancer patients. A distinct nutritional disturbance linked to cancer has been recognized to be associated with negative outcomes. However, compared to solid tumors, only a limited number of studies have looked specifically at nutritional issues in the field of lymphoma. The aim of this review is to integrate the current knowledge on interactions between malnutrition and lymphoma and address most relevant and pertinent questions. We first provide a literature review on the mutual biological relationship between malnutrition and lymphoma. Next, we explore the overlap between malnutrition, sarcopenia, cachexia and frailty in lymphoma studies. In addition, we summarize the clinical assessment scales used to measure malnutrition in lymphoma subjects. Furthermore, we address the problem of nutritional interventions aimed at patients who are candidates for treatment for lymphoma. Malnutrition can arise as a consequence of lymphoma disease and can in turn promote lymphomagenesis, negatively affect the response to therapy and favor adverse event to treatment. There is increasing evidence that malnutrition, sarcopenia and cachexia in lymphoma are intimately inter-related and are a hallmark of frailty. A variety of different tools are recorded with the apparent ability to describe nutritional status and to impact prognosis in lymphoma patients. Finally, a network of prognostic host- and disease-related factors is proposed where malnutrition can interact with each other in complex ways

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Atezolizumab; Isatuximab; Solid tumorsAtezolizumab; Isatuximab; Tumores sólidosAtezolizumab; Isatuximab; Tumors sòlidsBackground The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.This work was sponsored by Sanofi (no grant number)

Solanum nigrum Fruit Extract Modulates Immune System Activity of Mealworm Beetle, Tenebrio molitor L

: Here, we report the first evidence concerning the modulation of insect immune system activity after applying Solanum nigrum fruit extract (EXT). We focused on two main issues: (1) is EXT cytotoxic for Tenebrio molitor haemocytes? and (2) how EXT affects the basic immune mechanisms of T. molitor. The results indicate cytotoxic action of 0.01 and 0.1% EXT on beetle haemocytes. Both the injection of EXT and incubating haemocytes with the EXT solution on microscopic slides significantly increased the number of apoptotic cells. However, 24 h after injection of 0.1% EXT cytotoxic effect of the tested extract probably was masked by the increased number of circulating haemocytes. Application of 0.01 and 0.1% EXT led to impairment of the activity of basic immune mechanisms such as phenoloxidase activity and the lysozyme-like antimicrobial activity of T. molitor haemolymph. Moreover, the EXT elicited significant changes in the expression level of selected immune genes. However, some of the immunomodulatory effects of EXT were different in beetles with and without an activated immune system. The obtained results are an essential step toward a complete understanding of the EXT mode of action on the T. molitor physiology and its potential usage in pest control

Influence of oscillating positive expiratory pressure and the forced expiratory technique on sputum cell counts and quantity of induced sputum in patients with asthma or chronic obstructive pulmonary disease

OBJECTIVE: To evaluate whether respiratory therapy techniques influence the number of cells within and quantity of induced sputum in patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: Randomized clinical trial, in which patients with asthma or COPD under intervention (n = 16 and 10, respectively) were compared with control groups (n = 16 and 10). Patients in the asthma/intervention (A/I) and COPD/intervention (C/I) groups were submitted to oscillating positive expiratory pressure maneuvers for 5 min, followed by 10 forced expiratory technique sequences. These patients were also submitted to an induced sputum protocol with inhaled hypertonic saline (3%, 4% or 5%; A/I group) or inhaled isotonic saline (C/I group). The asthma/control (A/C) and COPD/control (C/C) groups were submitted only to the standard induced sputum protocol. RESULTS: The final mean weight of the sputum samples was significantly greater in the A/I group than in the A/C group (2,767.25 ± 998.08 mg vs. 1,689.17 ± 1,189.96 mg; p = 0.03). The mean/median total cell counts (×10(6)/mL) were higher in the A/I and C/I groups than in the A/C and C/C groups (4.06/0.95 and 0.63/0.39, p = 0.05, vs. 5.08/1.77 and 0.64/0.40, p = 0.02). There were no statistically significant differences among the groups in terms of cell viability. CONCLUSIONS: The use of respiratory therapy techniques can increase sputum sample weight in asthma patients, as well as increasing total cell counts in patients with asthma or COPD.OBJETIVO: Avaliar se técnicas fisioterápicas interferem no número de células e na quantidade do escarro obtido por coleta induzida, em pacientes com asma e doença pulmonar obstrutiva crônica (DPOC). MÉTODOS: Ensaio clínico prospectivo e randomizado, no qual os pacientes com asma ou DPOC sob intervenção (n = 16 e 10, respectivamente) foram comparados com grupos controle (n = 16 e 10). Pacientes dos grupos asma/intervenção (A/I) e DPOC/intervenção (D/I) foram submetidos a manobras de pressão expiratória positiva oscilante por 5 min, seguidas de 10 repetições da técnica de expiração forçada. Além disso, esses pacientes foram submetidos a um protocolo de indução de escarro com a inalação de solução salina hipertônica (3%, 4% e 5%), no caso dos A/I, e de solução salina isotônica, no caso dos D/I. Os grupos asma/controle(A/C) e DPOC/controle (D/C) foram somente submetidos ao protocolo padrão de indução de escarro. RESULTADOS: Houve aumento significante do peso média final de escarro no grupo A/I vs. grupo A/C (2.767,25 ± 998,08 mg e 1.689,17 ± 1.189,96 mg, respectivamente; p = 0,03). O número absoluto de células (×10(6)/mL) foi maior nos grupos A/I e D/I do que nos grupos A/C e D/C (média/mediana, 4,06/0,95 e 0,63/0,39, respectivamente; p = 0,05; e 5,08/1,77 e 0,64/0,40; p = 0,02). A viabilidade celular não apresentou diferença estatisticamente significante entre os grupos. CONCLUSÕES: O uso de técnicas respiratórias pode aumentar o peso do escarro em pacientes com asma, assim como aumentar o número absoluto de células em pacientes com asma ou DOPC.Universidade Regional IntegradaUniversidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

The reduced content of estrogen and progesterone receptors in varicocele sperm may be indicative of the clinical surgery in the testicular varicocele

The enigma of testicular varicocele has always attracted the researcher’s attention as attested by the consistent literature, although conflicting data are reported (1). The detrimental role of varicocele in fertility is supported by the presence of an higher frequency of affected men in the infertile population (2). Varicocele influences male fertility in a variety of ways: spermatogenesis, semen quality and gamete biology. However, the mechanism/s by which the pathology impairs sperm production and activity, are not known yet. In spite of active interest, our knowledge about sperm molecular anatomy is very limited. Instead, it is important to fully elucidate the molecular sperm architecture, in order to clarify clinical cases of idiopathic infertility since not all the apparently normal sperm are able to fertilize. The presence of steroid/steroid receptor systems was demonstrated in human sperm, suggesting that both systemic and local steroids through sperm receptors, may influence male fertility. From our data, it emerged that varicocele causes a damage in the gamete at molecular level which includes a significant reduction of estrogen and progesterone receptors, opening a new chapter in the already multifaceted physiopathology of the disease. By the time of ovulation, estradiol and progesterone are almost everywhere in the egg microenvironment affecting ability of sperm to fertilize the oocyte. Therefore, the reduced responsiveness to these hormones as we observed in varicocele sperm, impedes their goal. Altogether, these studies constrain the need of further researches on the molecular anatomy of human male gamete both in healthy and in pathological conditions related the male genital apparatus, considering the high couple infertility linked to the male. The translation of these new researches in the clinic surgery of testicular varicocele needs to be taken into account since the reduction of steroid receptors in sperm implies a decline in the acquisition of fertilizing ability

Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient’s selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated.In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed

Early clinical experience with volumetric modulated arc therapy in head and neck cancer patients

<p>Abstract</p> <p>Background</p> <p>To report about early clinical experience in radiation treatment of head and neck cancer of different sites and histology by volumetric modulated arcs with the RapidArc technology.</p> <p>Methods</p> <p>During 2009, 45 patients were treated at Istituto Clinico Humanitas with RapidArc (28 males and 17 females, median age 65 years). Of these, 78% received concomitant chemotherapy. Thirty-six patients were treated as exclusive curative intent (group A), three as postoperative curative intent (group B) and six with sinonasal tumours (group C). Dose prescription was at Planning Target Volumes (PTV) with simultaneous integrated boost: 54.45Gy and 69.96Gy in 33 fractions (group A); 54.45Gy and 66Gy in 33 fractions (group B) and 55Gy in 25 fractions (group C).</p> <p>Results</p> <p>Concerning planning optimization strategies and constraints, as per PTV coverage, for all groups, D_98%> 95% and V_95%> 99%. As regards organs at risk, all planning objectives were respected, and this was correlated with observed acute toxicity rates. Only 28% of patients experienced G3 mucositis, 14% G3 dermitis 44% had G2 dysphagia. Nobody required feeding tubes to be placed during treatment. Acute toxicity is also related to chemotherapy. Two patients interrupted the course of radiotherapy because of a quick worsening of general clinical condition.</p> <p>Conclusions</p> <p>These preliminary results stated that volumetric modulated arc therapy in locally advanced head and neck cancers is feasible and effective, with acceptable toxicities.</p

Large volume unresectable locally advanced non-small cell lung cancer: acute toxicity and initial outcome results with rapid arc

<p>Abstract</p> <p>Background</p> <p>To report acute toxicity, initial outcome results and planning therapeutic parameters in radiation treatment of advanced lung cancer (stage III) with volumetric modulated arcs using RapidArc (RA).</p> <p>Methods</p> <p>Twenty-four consecutive patients were treated with RA. All showed locally advanced non-small cell lung cancer with stage IIIA-IIIB and with large volumes (GTV:299 ± 175 cm³, PTV:818 ± 206 cm³). Dose prescription was 66Gy in 33 fractions to mean PTV. Delivery was performed with two partial arcs with a 6 MV photon beam.</p> <p>Results</p> <p>From a dosimetric point of view, RA allowed us to respect most planning objectives on target volumes and organs at risk. In particular: for GTV D_1%= 105.6 ± 1.7%, D_99%= 96.7 ± 1.8%, D_5%-D_95%= 6.3 ± 1.4%; contra-lateral lung mean dose resulted in 13.7 ± 3.9Gy, for spinal cord D_1%= 39.5 ± 4.0Gy, for heart V_45Gy= 9.0 ± 7.0Gy, for esophagus D_1%= 67.4 ± 2.2Gy. Delivery time was 133 ± 7s. At three months partial remission > 50% was observed in 56% of patients. Acute toxicities at 3 months showed 91% with grade 1 and 9% with grade 2 esophageal toxicity; 18% presented grade 1 and 9% with grade 2 pneumonia; no grade 3 acute toxicity was observed. The short follow-up does not allow assessment of local control and progression free survival.</p> <p>Conclusions</p> <p>RA proved to be a safe and advantageous treatment modality for NSCLC with large volumes. Long term observation of patients is needed to assess outcome and late toxicity.</p