Gastric adenocarcinoma is a leading cause of global cancer-related morbidity and mortality, and new therapeutic approaches are needed. Despite the improved outcomes with monoclonal antibodies targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor receptor 2, durable responses are uncommon. Targeting immune checkpoints including PD-1, PD-L1 and CTLA-4 have led to improved survival across several tumor types, frequently characterized by prolonged benefit in responding patients. Tumoral and lymphocyte-derived immunohistochemical staining for PD-1, PD-L1, and tumor mutational burden have shown potential as predictive response biomarkers in several tumor types. Optimal incorporation of immune-mediated therapies into gastric cancer (GC) is an area of intense ongoing investigation and benefit has been demonstrated in smaller studies of advanced patients. Important questions of biomarker selection, roles for molecular characterization, optimal combinatorial approaches, and therapeutic sequencing remain. In this study, current data are reviewed for immune checkpoint inhibitors in GC, and putative biomarkers, ongoing trials, and future considerations are discussed.
Key Clinical MessageHemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyper activation of the immune system. Rare cases associated with HELLP syndrome and other similar conditions in pregnancy have been reported. Despite the improved survival rates with etoposide and dexamethasone‐based regimens, HLH remains a challenging disease. Experience in pregnant patients is exceedingly rare.
Introduction: Chronic natural killer (NK) cell lymphoproliferative disorders comprise a rare subgroup of diseases characterized by proliferation of NK cells with expression of CD3-/CD16+ or CD56+ on flow cytometry. Clinically, these patients present with cytopenias as well as fatigue and B symptoms. The diagnosis can be challenging due to frequent lack of a unique clonal marker. Chronic NK cell lymphoproliferative disorder can be differentiated from NK cell leukemia based on the absence of chronic EBV infection. Macrophage activation syndrome (MAS) can occur in the setting of hematologic malignancies. Due to the rarity of this diagnosis, there are no randomized controlled trials to determine the optimal therapy. We report the case of an elderly gentleman whom we diagnosed with chronic NK cell lymphoproliferative disorder, complicated by transfusion-dependent autoimmune hemolytic anemia, and MAS, and who was successfully treated with oral cyclophosphamide. Case Report: In March 2014, a 75 year old Caucasian male, who was otherwise in good health, had a syncopal episode. Two months earlier, he had reported dyspnea on exertion and cough. He was diagnosed with bronchitis and these symptoms resolved with a course of antibiotics. Cardiac work-up was unremarkable. Complete blood count demonstrated white blood count of 16.8K with 84% lymphocytes, with hemoglobin of 7.8g/dL and platelets of 264K. Lactate dehydrogenase (LDH) was elevated at 615 IU/L, haptoglobin was undetectable, total bilirubin was mildly elevated at 1.5mg/dL and a Coomb's assay was negative. The patient had adequate iron stores with 50% saturation and erythropoietin level was 76.7ug/L. CT of the abdomen/pelvis demonstrated mild splenomegaly of 14cm. CT scan also revealed numerous thoracic-spine soft lesions. Bone marrow biopsy revealed a hypercellular marrow with appropriate trilineage hematopoiesis, erythroid hyperplasia and increased lymphocytes which were CD2+ CD7+ CD16+ and CD 56 negative cells as well as negative for T and B cell markers. This lymphocyte population was identified as NK cells and comprised 16% of his cells. The patient's transfusion dependence did not decrease despite oral prednisone. He transferred to our university medical center. Repeat flow cytometry after one month on prednisone demonstrated an increase to 70% of the lymphocytes. Further, there was a high suspicion for macrophage activation syndrome given his ferritin of 7,358ng/mL, triglycerides of 290mg/dL and interleukin-2 receptor of 7,250pg/mL. There was no evidence of active hemophagocytosis on the bone marrow biopsy. He continued on prednisone 60mg daily, and started on cyclophosphamide 50mg daily. His clinical course over the next several months was complicated by recurrent fevers, night sweats, mental status changes, and hyponatremia. Sepsis was ruled out as a cause of his fevers and his mental status changes were attributed to be secondary to hyponatremia and MAS. Work-up of his hyponatremia revealed syndrome of inappropriate antidiuretic hormone secretion (SIADH). After 2 months of treatment, his sodium level and mental status normalized. His cyclophosphamide was increased to 100mg daily and maintained at that dose. He was then tapered off prednisone. This patient's B symptoms of fevers and night sweats abated after several months of this therapy, and his transfusion dependence and underlying MAS resolved. The patient has been maintained on cyclophosphamide 100mg for 11 months and has shown resolution of his lymphocytosis and normalization of his blood counts. Discussion: Chronic lymphoproliferative disorders of NK cells continue to be a difficult group of diseases to recognize. Moreover, this case was further complicated by MAS based on elevated interleukine-2 receptor, triglycerides and ferritin levels in the setting of B-symptoms and liver enzyme elevations. This constellation of factors has not been previously described in the literature. Due to lack of clonal markers in NK cells, the diagnosis is frequently made by exclusion. The patient has done very well on oral cyclophosphamide and prednisone alone. We present this case to increase provider awareness and hopefully allow for improved diagnosis and treatment options in the future. Disclosures No relevant conflicts of interest to declare.
Immune checkpoint inhibitors are a novel approach to treat cancers. Firstly used for treatment of malignant melanomas with promising results, they were later expanded to treat other cancers including non-small cell lung cancers (NSCLC) expressing PD-L1. We present a case of a 66-year-old male who was admitted to the hospital for generalized gastrointestinal complaints consisting of abdominal pain, nausea, vomiting, and loose stools occurring five times daily. Labs were significant for acute transaminitis with hyperbilirubinemia and elevated lipase. All workup for infectious and noninfectious causes was negative. The patient was started pembrolizumab 15 days before admission and his previous labs had all been normal before the initiation of treatment. He was treated with high dose of steroids with initial improvement and discharged on oral steroids taper. He subsequently presented again with worsening liver function tests (LFTs) results and was restarted on a higher dose but unable to tolerate it due to steroid-induced psychosis and left the hospital against medical advice. Presented the third time with persistent elevation of LFTs and worsening hyperbilirubinemia, this time he was started on different class of steroid with atypical antipsychotic but left again a few days later seeking care at a tertiary care institute. This case highlights one of the severe side effects of the immune checkpoint inhibitors which is acute hepatitis that can sometimes lead to acute liver failure. Prompt treatment with steroids is indicated for these patients; and those who are refractory or intolerant to steroids can be treated with a multimodal approach using topical steroids, N-acetylcysteine (NAC), ursodeoxycholic acid and immune suppressant drugs.
Background: Although enzalutamide (ENZ) is initially effective for the treatment of castration-resistant prostate cancer (CRPC), development of ENZ resistance is inevitable. One mechanism for resistance is the emergence of ARV7, an alternative splicing variant of the full length androgen receptor (FL AR) which lacks the androgen binding and hinge region domains. Nuclear translocation of FL AR utilizes the hinge region for coupling to tubulin or importin. ARV7 protein appears to gain nuclear entry independent of the canonical pathway. FL AR has been reported to bind to Hypoxia Inducible Factor-1α (HIF1α). We hypothesized that ARV7 may also heterodimerize with HIF1α in the cytoplasm, facilitating its nuclear localization and transcriptional activity. We previously found that TPT blocks HIF1α translation by targeting topoisomerase I resident on HIF1α mRNA. We therefor determined if ARV7 was bound to HIF1α in ENZ resistant cells and if inhibition of HIF1α translation by topotecan (TPT) could block ARV7 nuclear localization, thereby resensitizing ARV7 expressing cells to ENZ. Methods: 22Rv1 ENZ resistant prostate cancer cells express comparable levels of full length AR and truncated ARV7 protein. 22Rv1 cells were treated with the hypoxia mimetic cobalt chloride to stabilize HIF1α. Cytoplasmic and nuclear extracts from 22Rv1 cells were used for co-immunoprecipitation (Co-IP) using anit-HIF1α antibody. The effect of TPT on HIF1α and AR/ARV7 expression, and interactions between Topo-1 and HIF1α and AR mRNA were determined by western blot and RNA-IP. The effects of ENZ and TPT on 22Rv1 cell viability were evaluated using the Luminescent cell viability assay. Results: Co-IP of 22Rv1 whole cell lysates and nuclear extracts with HIF1α-specific antibodies yielded both full length AR and ARV7 protein bands on western blots. Compared with control cells, TPT treatment of 22Rv1 cells under hypoxic conditions resulted in significantly reduced HIF1α accompanied by decreased ARV7 nuclear localization. Topo-I immunoprecipitation confirmed its linkage to HIF-1α mRNA. Surprisingly, we found that Topo-I RNA-IP pulled down AR mRNA as well. Dose-response curves for the TPT / ENZ combination demonstrated synergistic activity, with combination index values of 0.6. Under hypoxic conditions, TPT had an IC50 of 120 nM. pretreatment of 22Rv1 cells with a minimally toxic dose of 15 nM TPT reduced the ENZ IC50 from 93 nM to 60 nM. Conclusions: Our data indicate that Topo I residing on HIF-1α mRNA provided a druggable target for TPT-mediated inhibition of HIF1α mRNA translation. Clinically achievable TPT concentrations caused HIF1α knockdown in hypoxic 22Rv1 cells in association with diminished nuclear localization of ARV7. 22Rv1 cells showed a synergistic dose-response to the combination of TPT and enzalutamide. These findings support further exploration of TPT modulation of ENZ resistance in the clinic. Citation Format: John P. Fruehauf, Nathan Farrokh, Sarmen Sarkissian, Jai-Hyun Kim. Blockade of ARV7:HIF1α; heterodimers after toptoecan reverses enzalutamide resistance in 22Rv1 cells. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A37.
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