BackgroundConcomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.MethodsWe conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids.ResultsFrom June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death.ConclusionWe confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

IntroductionChemokines represent a group of molecules that regulate cell migration and can be distinguished in inflammatory and homeostatic chemokines. These latter are involved in the homeostasis of the immune system. [1][2][3][4][5][6][7][8] Cells are exposed to a complex pattern of chemoattractant signals that, through a gradient of chemokine concentrations, drive the migration of lymphocytes to target tissues or lymphoid organs. Different chemokine receptors are able to bind the same chemokine and, in turn, different chemokines are able to bind the same receptor, indicating that redundancy is a definite feature of the chemokine network. Chemokine-receptor interactions are of crucial importance for homeostatic functions within the immune system, particularly for establishing the complex architecture of the secondary lymphoid organs. 3,4,9 The role of chemokines for B-cell lymphopoiesis has been primarily demonstrated for CXCL12 (stromal-derived factor 1␣ ) and its receptor CXCR4. 10 CXCL12 can induce chemotaxis of B-cell progenitors, indicating that the CXCL12/ CXCR4 system may be important in directing the migration of B-cell progenitors to the appropriate bone marrow microenvironment. [11][12][13] In addition, it is highly expressed on B lymphocytes and it is likely to play a key role in the architecture of spleen and lymph nodes. To date, most information in terms of chemokines and their receptors has been provided on normal human B cells and in the mouse; little data are available on the role of these molecules on malignant B lymphocytes. [14][15][16][17] In particular, it has been demonstrated that malignant B cells express CXCR3 in different neoplastic conditions and mediate migration following the binding of the chemokines CXCL10 (inflammatory protein 10 [IP-10]) and CXCL9 (Mig). 14,16 Furthermore, CXCR4, a receptor constitutively expressed on normal B lymphocytes, has been detected on malignant B lymphocytes from patients with chronic lymphocytic leukemia (CLL). 15 In this study, we investigated the expression and functional role of a large spectrum of chemokine receptors, including CCR1 to CCR6 and CXCR1 to CXCR5, in several B-cell non-Hodgkin lymphomas (NHLs). We demonstrated that these receptors recognize different B-cell malignancies and mediate chemotaxis following binding to their own ligands. Patients, materials, and methods Patient samplesForty-three patients with different B-cell malignancies were studied at the time of diagnosis. 18 This study was approved by the Università of Padova institutional review board. Informed consent was provided according to the Declaration of Helsinki. Thirteen patients (10 men and 3 women, ages 46-78 years) with the diagnosis of B-CLL were graded according to the Rai staging system 19 Preparation of cell suspensionsPeripheral blood mononuclear cells (PBMCs) from patients with NHL were obtained from freshly heparinized blood samples by centrifugation on Ficoll/Hypaque (F/H) gradient. 20 Normal B lymphocytes were obtained from 5 tonsils after mechanic disruption...

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The activity of this BCNU regimen is comparable with that reported in the past and with the newest therapies, such as temozolomide. However, BCNU toxicity is high and recovery is slow, thus compromising the administration of further drugs in patients with progressive disease.

The BCNU plus irinotecan regimen seems active and non-cross-resistant in patients with GBM with recurrence after temozolomide-based chemotherapy.