Immune-Related Pneumonitis Was Decreased by Addition of Chemotherapy with PD-1/L1 Inhibitors: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials (RCTs)

Purpose: Immune-related pneumonitis (IRP) has attracted extensive attention, owing to its increased mortality rate. Conventional chemotherapy (C) has been considered as an immunosuppressive agent and may thus reduce IRP’s risk when used in combination with PD-1/L1 inhibitors. This study aimed to assess the risk of IRP with PD-1/L1 inhibitors plus chemotherapy (I+C) versus PD-1/L1 inhibitors alone (I) in solid cancer treatment. Method: Multiple databases were searched for RCTs before January 2021. This NMA was performed among I+C, I, and C to investigate IRP’s risk. Subgroup analysis was carried out on the basis of different PD-1/L1 inhibitors and cancer types. Results: Thirty-one RCTs (19,624 patients) were included. The I+C group exhibited a lower risk of IRP in any grade (RR, 0.60; 95% CI, 0.38–0.95) and in grade 3–5 (RR, 0.42; 95% CI, 0.21–0.92) as opposed to the I group. The risk of any grade IRP with PD-1 plus chemotherapy was lower than that with PD-1 monotherapy (RR, 0.50; 95% CI, 0.28–0.89), although grade 3–5 IRP was similar. There was no statistically meaningful difference in the risk of any grade IRP between PD-L1 plus chemotherapy and PD-L1 inhibitors monotherapy (RR, 0.95; 95% CI, 0.43–2.09) or grade 3–5 IRP (RR, 0.71;95% CI, 0.24–2.07). In addition, compared with the I group, the I+C group was correlated with a decreased risk in IRP regardless of cancer type, while a substantial difference was only observed in NSCLC patients for grade 3–5 IRP (RR, 0.39; 95% CI, 0.15–0.98). Conclusion: In comparison to PD-1/L1 inhibitor treatment alone, combining chemotherapy with PD-1/L1 inhibitors might reduce the risk of IRP in the general population. Furthermore, PD-1 inhibitors in combination with chemotherapy were correlated with a decreased risk of IRP compared to PD-1 inhibitor treatment alone. In contrast to the I group, the I+C group exhibited a lower risk of IRP, especially for NSCLC patients.

Multilayer microfluidic platform for the study of luminal, transmural, and interstitial flow

Efficient delivery of oxygen and nutrients to tissues requires an intricate balance of blood, lymphatic, and interstitial fluid pressures, and gradients in fluid pressure drive the flow of blood, lymph, and interstitial fluid through tissues. While specific fluid mechanical stimuli, such as wall shear stress, have been shown to modulate cellular signaling pathways along with gene and protein expression patterns, an understanding of the key signals imparted by flowing fluid and how these signals are integrated across multiple cells and cell types in native tissues is incomplete due to limitations with current assays. Here, we introduce a multi-layer microfluidic platform (MLTI-Flow) that enables the culture of engineered blood and lymphatic microvessels and independent control of blood, lymphatic, and interstitial fluid pressures. Using optical microscopy methods to measure fluid velocity for applied input pressures, we demonstrate varying rates of interstitial fluid flow as a function of blood, lymphatic, and interstitial pressure, consistent with computational fluid dynamics models. The resulting microfluidic and computational platforms will provide for analysis of key fluid mechanical parameters and cellular mechanisms that contribute to diseases in which fluid imbalances play a role in progression, including lymphedema and solid cancer.

OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients

Background Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. Methods Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. Discussion The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. Trial registration Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.

proportion and risk factors of fatal outcomes among severely and critically ill COVID-19 patients: A hospital experience, Baghdad, Iraq 2021

Background: Severe forms of Coronavirus disease 2019 (COVID‐19) were found among 6 - 10% of all COVID-19 patients. Acute respiratory distress syndrome ARDS is non-cardiogenic pulmonary edema manifested by the rapid development of shortness of breath, tachypnea, and hypoxemia. Patients’ outcomes after critical care for COVID-19 have not been adequately documented in this low-resource environment, despite advocacy for prevention and response measures in low- and middle-income countries. Objectives: To highlight the rate of severe illness among COVID-19 patients and its associated factors in Al-Imam Ali Hospital, Baghdad-Iraq 2021. Patients and Methods: A descriptive cross-sectional study on cases with severe and critical COVID-19 illness (with ARDS) admitted to the isolation ward in Al-Imam Ali Hospital from 23 March to 23 May, 2021. All COVID-19 patients admitted in a severe or critical state were included. A data collection form was filled by the researcher. The P value of < 0.05 was used to determine statistical significance. Ethical Approval was obtained. Results: A total of 504 severely ill COVID-19 patients were included in this study. There were 71 (14.1%) patients below 45 years of age. Males formed 40.9% of patients while that of females was 59.1%. Fever was the presenting symptom in 381 (75.6%) patients, 197 (39.1%) patients had anosmia, and 192 (38.1%) had ageusia. There were 358 (71.0%) survivors while 146 (29.0%) died. Patients aged 65 years or more had more possible risk for death than those below 65 years (OR=1.14, 95% CI =0.6-2.2). Female gender appeared to be protective compared to male gender (OR=0.52, 95% CI =0.35-0.77). Ex-smokers had a higher risk than non-smoker and current smokers (OR for ex-smoker=4.38, 95% CI 2.6-7.5), and (OR for current smoker=1.7, 95% CI 0.98-3). Renal disease was found to be a risk factor leading to death (OR=2.9; 95% CI=1.73-5.1). Diabetes Mellitus, respiratory diseases, and solid cancer showed a high risk for death, [OR=2.3, 95% CI=1.4-4; OR=1.7; 95% CI=1.1-2.9, OR=8, 95% CI=3.3-19 respectively]. Patients with three comorbidities had a higher mortality risk, OR=1.6, 95% CI=1.3-2. Conclusion: This study concluded that mortality of severely and critically ill COVID-19 patients was 29%, and males and older patients were risk factors for death. In addition to; ex-smoker, alcoholic, and patients with baseline comorbidities appeared to be risk factors for mortality. Finally; laboratory tests and Pao2/Fio2 ratio can be used to predict the outcome.

Live attenuated bacterium limits cancer resistance to CAR-T therapy by remodeling the tumor microenvironment

The tumor microenvironment (TME) is characterized by the activation of immune checkpoints, which limit the ability of immune cells to attack the growing cancer. To overcome immune suppression in the clinic, antigen-expressing viruses and bacteria have been developed to induce antitumor immunity. However, the safety and targeting specificity are the main concerns of using bacteria in clinical practice as antitumor agents. In our previous studies, we have developed an attenuated bacterial strain (Brucella melitensis 16M ∆vjbR, henceforth Bm∆vjbR) for clinical use, which is safe in all tested animal models and has been removed from the select agent list by the Centers for Disease Control and Prevention. In this study, we demonstrated that Bm∆vjbR homed to tumor tissue and improved the TME in a murine model of solid cancer. In addition, live Bm∆vjbR promoted proinflammatory M1 polarization of tumor macrophages and increased the number and activity of CD8+ T cells in the tumor. In a murine colon adenocarcinoma model, when combined with adoptive transfer of tumor-specific carcinoembryonic antigen chimeric antigen receptor CD8+ T cells, tumor cell growth and proliferation was almost completely abrogated, and host survival was 100%. Taken together, these findings demonstrate that the live attenuated bacterial treatment can defeat cancer resistance to chimeric antigen receptor T-cell therapy by remodeling the TME to promote macrophage and T cell-mediated antitumor immunity.

An Overview of the International Literature on Health-Related Quality of Life, Mental Health and Psychosocial Issues in People with Cancer

Background: Cancer is one of the most important leading causes of death worldwide. Early detection, screening and diagnosis have been demonstrated to significantly improve patients’ survival rates and increase awareness of the benefit of prompt therapies and healthy lifestyles. In this context, Health-related Quality of Life (HRQoL) and several psychosocial difficulties are of relevance as prognostic factors for the trajectory of the diseases of people living with cancer. Methods: This Special Issue aims to present a set of systematic reviews and research studies focusing on several psychosocial aspects in people suffering from hematologic and solid cancer. Results: Three systematic reviews regard HRQoL, the quality of patient-physician communication, depression and other stress-related difficulties, respectively. One review pointed out the difficulties in diagnosing depression in the elderly with solid cancer; another one regards the risk of cancer in severe mental illnesses, such as schizophrenia, bipolar disorders, and severe depressive disorders. One additional review regards HRQoL in people with cancer in the present era of COVID-19 pandemic. Furthermore, some research studies pointed out the usefulness of a validated instrument to assess satisfaction with care in the oncology field, as well as of the self-reinforcing feedback loop to improve fatigue, insomnia and depression in people with cancer. Other two research studies evaluate, respectively, the attributable burden in worsening HRQoL in people suffering both from cancer and depression and the Type D personality as a risk factor for stress-related difficulties in women with breast cancer. Conclusion: This Special Issue is a contribution to enhance future research mainly about such interventions useful to assess and improve HRQoL and overall well-being in people with cancer.

The Quality of Life of People with Solid Cancer is Less Worse than Other Diseases with better Prognosis, Except in the Presence of Depression

Background: Suffering from Solid Cancer (SC) may adversely impact the Health-related Quality of Life (H-QoL). The aims of this study are to measure the H-QoL in a sample of people suffering from SC and to clarify the role of the co-occurrence of depressive episodes. Results were compared with a healthy control group and with groups of other disorders. Methods: In 151 patients with SC (mean±sd age 63.1±11.5; female 54.3%), H-QoL was assessed by SF-12, depressive episodes were identified by PHQ-9. The attributable burden of SC in impairing H-QoL was calculated as the difference between SF-12 score of a community sex and age ¼ matched healthy control group and that of the study sample. The attributable burden of SC was compared with other chronic diseases using specific diagnostic groups drawn from case-control studies that used the same database for selecting control samples. Results: H-QoL in people with SC was significantly worse than in the healthy control group (p<0.0001). The attributable burden in worsening the H-QoL due to SC was similar to those of severe chronic diseases, but lower than Multiple Sclerosis (p<0.0001) or Fibromyalgia (p<0.00001). Having a depressive episode was a strong determinant of decreasing H-QoL, regardless of the severity of cancer. Conclusion: The findings confirm a strong impact of SC but showed that H-QoL in SC was higher than in chronic diseases with better “quoad vitam” outcome. Since depression was a strong determinant, its prevention, early detection and therapy are the main objectives that must be reached in cancer patients.

Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia

The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.

Quantitative Analysis of SARS-CoV-2 Antibody Status between Patients with Cancer and Healthy Individuals with Extended Vaccination Dosing Intervals in Canada

(1) Background: To date, data addressing the antibody response of cancer patients to SARS-CoV-2 vaccines are limited. To our knowledge, this is the first report to evaluate humoral immunity. responses in Canadian cancer patients. (2) Methods: 116 cancer patients and 35 healthy participants were enrolled in this cross-sectional study. The interval between the first and second doses were closely matched during analysis. IgG antibodies against the SARS-CoV-2 spike receptor–binding domain were determined using an enzyme-linked immunosorbent assay (ELISA). (3) Results: Following two doses of SARS-CoV-2 vaccine (including BNT162b2, AZD1222, and mRNA-1273), the mean serum anti-spike protein antibody level was 382.4 BAU/mL (binding antibody unit, SD ± 9.4) in the control group, 265.8 BAU/mL (±145.7) in solid cancer patients, and 168.2 BAU/mL (±172.9) in hematological cancer patients. Observed differences were significantly lower in both solid and hematological groups when comparing to the control group (p ≤ 0.0001). In solid cancer group, patients with cytotoxic chemotherapy demonstrated significantly lower antibody levels (p < 0.01), whereas the rest of the patients showed similar antibody levels as the healthy control. Antibody levels were lower in those on treatment than those off treatment in patients with hematological malignancies (p < 0.0001) but not for those with solid cancers (p = 0.4553). (4) Conclusions: After two doses of the SARS-CoV-2 vaccination, patients with solid and hematological malignancies demonstrated impaired serological responses. This was particularly prominent if there was cytotoxic chemotherapy or systemic therapy in solid and hematological cancer, respectively.

Impact of the First Wave of the COVID-19 Pandemic on the Lyon University Hospital Cancer Institute (IC-HCL)

This article presents the protective measures put in place at the “Institut de Cancérologie des Hospices de Lyon” (IC-HCL) during the first wave of the COVID-19 pandemic in France (spring 2020) and how they impacted IC-HCL clinical activity. Spring 2020 activities were compared to winter 2019–2020. Results showed a decrease of activity of 9% for treatment dispensations, 17% for multidisciplinary team meetings, 20% for head and neck and thoracic surgeries, and 58% for new patient enrolment in clinical trials. Characteristics of patients treated for solid cancer and hospitalized for COVID-19 during spring 2020 were collected in a retrospective study. Mortality was attributed to COVID-19 for half of the cases, 82% being patients above 70 and 73% being stage IV. This is in concordance with current findings concluding that the risk of developing severe or critical symptoms of COVID-19 is correlated with factors co-occurring in cancer patients and not to the cancer condition per se. While a number of routines and treatment regimens were changed, there was no major decline in numbers of treatments conducted at the IC-HCL during the first wave of the COVID-19 pandemic that hit France between March and May 2020, except for clinical trials and some surgery activities.