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CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT. A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort. Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.

Over the past decade, immune checkpoint inhibitors (ICI) have proven to be promising agents in a number of solid tumor malignancies. Pembrolizumab and nivolumab are ICIs that target programmed cell death protein 1 and both have been approved by the US Food and Drug Administration for the treatment of microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) colorectal cancer (CRC). In MSI-H/dMMR CRC, these agents were found to have considerable antitumor activity and are now used in the treatment of this disease. However, MSI-H/dMMR tumors account for only 5% of metastatic CRC and the remaining patients are identified as being microsatellite stable/DNA mismatch repair proficient (MSS/pMMR). In MSS/pMMR CRC, ICIs were found to have no antitumor activity and they are not currently used in the treatment of the disease. However, ongoing research is expanding our knowledge of how the human immune system interacts with cancer cells. Identifying mechanisms to improve our immune response to MSS/pMMR CRC is of utmost importance. In this review, we discuss available clinical data and the emerging role of immune-based strategies to overcome the resistance to ICI therapy in the treatment of MSS/pMMR CRC.

Patients with immune thrombocytopaenia (ITP) have a wide spectrum of disease severity and bleeding risk even at similar platelet counts. Hence, additional clinical and laboratory factors may be considered in the evaluation of bleeding risk in ITP. Risk stratification based on predicted bleeding risk may help to identify high-risk patients and guide the initial management of ITP in adults requiring treatment. Recent evidence supports the use of high-dose dexamethasone therapy over prednisone in the initial management of ITP because of improved initial response rates, shorter median time to response and better safety profile. A risk-stratified approach to management of ITP is hoped to reduce bleeding complications in high-risk patients; however, the outcomes of such management approach need to be studied prospectively. Additionally, whether therapy intensification or combination of dual therapy such as intravenous immunoglobulin or rituximab in combination with dexamethasone can reduce bleeding complications in high-risk ITP should be studied in the future.

Patients with immune thrombocytopenia (ITP) have wide spectrum of disease severity, and bleeding risk even at similar platelet counts. Hence, additional clinical and laboratory factors may be considered in the evaluation of bleeding risk in ITP. Risk stratification based on predicted bleeding risk may help to identify high-risk patients and guide the initial management of ITP in adults requiring treatment. Recent evidences support the use of high dose dexamethasone therapy over prednisone in the initial management of ITP because of improved initial response rates, shorter median time to response and better safety profile. A risk-stratified approach to management of ITP is hoped to reduce bleeding complications in high-risk patients, however, the outcomes of such management approach needs to be studied prospectively. Additionally, whether therapy intensification or combination of dual therapy such as intravenous immunoglobulin or rituximab in combination with dexamethasone can reduce bleeding complications in high-risk ITP should be studied in the future.

Background A subset of men with metastatic prostate cancer (mPC) responds to immune checkpoint inhibitors, and there is an unmet need to predict those most likely to benefit. We characterized circulating tumor cells (CTCs) for expression of immune checkpoint ligands in men with mPC as a non-invasive biomarker of immune evasion and immunotherapy benefit. Methods Three cohorts of patients were enrolled: 1) men with mCRPC starting abiraterone acetate/prednisone or enzalutamide (pre-ARSI), 2) men with mCRPC who were progressing on enzalutamide or abiraterone acetate/prednisone (post-ARSI), and 3) men with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy. CTCs were captured using the CellSearch® system and stained for PD-L1, PD-L2, B7-H3, and CTLA-4 at baseline, on treatment, and disease progression. Summary statistics on mean CTCs per cohort, as well as rates of ligand positivity were used to analyze CTCs by cohort and by timepoint. Results Men in all cohorts and timepoints had prevalent CTC B7-H3 expression (> 80%). We found evidence for CTC PD-L1 expression across disease states, in which > 1 positive CTC or > 50% of CTCs were positive for PD-L1 in 40 and 30% of men with mHSPC, respectively, 60 and 20% of men with mCRPC pre-ARSI, and 70 and 30% of men with mCRPC post-ARSI. CTC PD-L2 expression was present in 20–40% of men in each disease state, while CTC CTLA-4 expression was rare, present in 20% of men with mCRPC pre-ARSI and 10% of men with mCRPC post-ARSI or with mHSPC. CTC immune checkpoint expression was heterogeneous within/between men and across disease states. Conclusions We have identified that CTCs from men with mPC heterogeneously express immune checkpoints B7-H3, PD-L1, PD-L2, and CTLA-4, and the detection of these immune checkpoints may enable monitoring on immunotherapy.