Receptor-interacting Protein Kinase 2 Is an Immunotherapy Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy because of its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of patients with PDAC. This is the result of a poor understanding of the unique tumor-immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that receptor-interacting protein kinase 2 (RIPK2) is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacologic targeting of RIPK2 sensitizes PDAC to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC class I (MHC-I) surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti-PD-1 immunotherapy for PDAC. SIGNIFICANCE: PDAC is resistant to almost all available therapies, including immune checkpoint blockade. Through in vivo CRISPR screen, we identified that RIPK2 plays a crucial role in facilitating immune evasion by impeding antigen presentation and cytotoxic T-cell killing. Targeting tumor-intrinsic RIPK2 either genetically or pharmacologically improves PDAC to anti-PD-1 immunotherapy. See related commentary by Liu et al., p. 208 . This article is featured in Selected Articles from This Issue, p. 201.

Effect of atorvastatin on resolution of chronic subdural hematoma: a prospective observational study [RETRACTED].

OBJECTIVE Chronic subdural hematoma (CSDH) is prevalent in the aged population and is commonly treated with bur hole drainage. This treatment, however, can lead to various surgical complications. Atorvastatin may cure CSDH via its antiinflammatory and proangiogenesis effects, but not all patients treated with this medication can avoid surgery. The authors' aim was to investigate the effect of atorvastatin and identify characteristics of patients with CSDH sensitive to atorvastatin therapy. METHODS A prospective, placebo-controlled observational study was conducted in 80 patients with evidence of CSDH. The patients were enrolled between February 2012 and August 2014 and were randomly assigned to either atorvastatin treatment (atorvastatin group) or placebo (control group). Patients were followed up for 12 months after initiation of treatment. Clinically relevant data were collected and compared between the 2 groups. The atorvastatin group was subdivided into patients who required surgery and those who did not, and characteristics of these subgroups were also compared. The relationship between atorvastatin treatment and need for surgery was investigated by means of multiple regression analysis using the following variables as predictors: age, sex, admission Markwalder grade, level of dependency in activities of daily living (ADL) as assessed with the modified Barthel Index, presence of hemiparesis, and hematoma volume. RESULTS The proportion of patients who required surgical intervention during the follow-up period was significantly lower in the atorvastatin group than in the control group (p = 0.001), and the mean time to surgery was longer in the atorvastatin group (p = 0.018). Within the atorvastatin group, there was a significant difference with respect to Markwalder grades, degree of dependency in ADL, percentage of patients with hemiparesis, and mean hematoma volume between the patients who required surgery during the follow-up period and those who did not (p = 0.002, p = 0.001, p = 0.001, and p = 0.012, respectively). The results of the logistic regression analysis showed that atorvastatin significantly reduced the probability of surgery and that female sex and favorable admission Markwalder grades and favorable dependency status with respect to ADL (independent, slightly dependent, or moderately dependent) were independent predictors of not requiring surgery. CONCLUSIONS Atorvastatin administration can promote the resolution of CSDH, especially for women with favorable Markwalder grades and favorable ADL dependency status at admission.

Atorvastatin May Attenuate Recurrence of Chronic Subdural Hematoma.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common form of intracranial hemorrhage with a substantial recurrence rate. Atorvastatin may reduce CSDH via its anti-inflammatory and pro-angiogenesis effects, but its effectiveness for preventing recurrent CSDH has never been explored. We hypothesized that atorvastatin is effective in reducing recurrence of CSDH after surgery and identified determining factors predictive of hematoma recurrence. METHODS: A prospective study was conducted in 168 surgical cases of CSDH.All patients were randomly assigned to the group treated with atorvastatin or control group. Clinically relevant data were compared between two groups, and subsequently between the recurrence and non-recurrence patients. Multiple logistic regression analysis of the relationship between atorvastatin treatment and the recurrence using brain atrophy, septated and bilateral hematoma was performed. RESULTS: Atorvastatin group conferred an advantage by significantly decreasing the recurrence rate (P = 0.023), and patients managed with atorvastatin also had a longer time-to-recurrence (P = 0.038). Admission brain atrophy and bilateral hematoma differed significantly between the recurrence and non-recurrence patients (P = 0.047 and P = 0.045). The results of logistic regression analysis showed that atorvastatin significantly reduced the probability of recurrence; severe brain atrophy and bilateral hematoma were independent risk factors for recurrent CSDH. CONCLUSIONS: Atorvastatin administration may decrease the risks of recurrence.Patients with severe brain atrophy and bilateral CSDH are prone to the recurrence.