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Background Inactivating missense mutations in the SPOP gene, encoding speckle-type poxvirus and zinc-finger protein, are one of the most common genetic alterations in prostate cancer. Methods We retrospectively identified 72 consecutive prostate cancer patients with somatic SPOP mutations, through next-generation sequencing analysis, who were treated at the Johns Hopkins Hospital. We evaluated clinical and genomic characteristics of this SPOP-mutant subset. Results SPOP alterations were clustered in the MATH domain, with hotspot mutations involving the F133 and F102 residues. The most frequent concurrent genetic alterations were in APC (16/72 [22%]), PTEN (13/72 [18%]), and TP53 (11/72 [15%]). SPOP-mutant cancers appeared to be mutually exclusive with tumors harboring the TMPRSS2-ERG fusion, and were significantly enriched for Wnt pathway (APC, CTNNB1) mutations and de-enriched for TP53/PTEN/RB1 alterations. Patients with mtSPOP had durable responses to androgen deprivation therapy (ADT) with a median time-to-castration-resistance of 42.0 (95% confidence interval [CI], 25.7-60.8) months. However, time-to-castration-resistance was significantly shorter in SPOP-mutant patients with concurrent TP53 mutations (hazard ratio [HR] 4.53; p = 0.002), HRD pathway (ATM, BRCA1/2, and CHEK2) mutations (HR 3.19; p = 0.003), and PI3K pathway (PTEN, PIK3CA, and AKT1) alterations (HR 2.69; p = 0.004). In the castration-resistant prostate cancer setting, median progression-free survival was 8.9 (95% CI, 6.7-NR) months on abiraterone and 7.3 (95% CI, 3.2-NR) months on enzalutamide. There were no responses to PARP inhibitor treatment. Conclusions SPOP-mutant prostate cancers represent a unique subset with absent ERG fusions and frequent Wnt pathway alterations, with potentially greater dependency on androgen signaling and enhanced responsiveness to ADT. Outcomes are best for SPOP-altered patients without other concurrent mutations.

XBP1 is a basic leucine zipper (bZIP) transcription factor and a key mediator of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR). XBP1-mediated transcription facilitates cell adaptation to ER stress and also promotes tumor progression, while suppressing anti-tumor immunity. Here we report a novel XBP1 variant, namely XBP1 variant 1 (XBP1v1, Xv1 for short), that is specifically required for survival of cancer cells. Xv1 contains a cryptic first exon that is conserved only in humans and great apes. Comparing to XBP1, Xv1 encodes a protein with a different N-terminal sequence containing 25 amino acids. Analysis of RNAseq database reveals that Xv1 is broadly expressed across cancer types but almost none in normal tissues. Elevated Xv1 expression is associated with poor survival of patients with several types of cancer. Knockdown of Xv1 induces death of multiple cancer cell lines but has little effect on non-cancerous cells in vitro. Moreover, knockdown of Xv1 also inhibits growth of a xenograft breast tumor in mice. Together, our results indicate that Xv1 is essential for survival of cancer cells.

Major burn injuries incite a hypermetabolic response, and the initiation of early enteral nutrition is the standard of care in patients with large burns and contributes to improved outcomes. Perioperative fasting is a common cause of caloric deficits in burn patients and can be obviated with intraoperative enteral nutrition. However, the risks and benefits of this practice are unknown, and there is a concern for aspiration. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of intraoperative enteral nutrition. We performed a systematic literature search using PubMed, Scopus, and OvidSP MEDLINE databases. We identified studies that evaluated the effects of intraoperative enteral nutrition in adult burn patients compared to those undergoing routine perioperative fasting. We performed a meta-analysis on the incidence of mortality, pneumonia, wound infections, and aspiration in burn patients receiving intraoperative enteral nutrition. We identified seven articles for qualitative review and four for quantitative review (N = 83 patients). There were no statistically significant increases in the risk of mortality (odds ratio [OR] = 1.28, 95% confidence interval [CI]: 0.49, 3.31), wound infections (OR = 0.71, 95% CI: 0.16, 3.24), pneumonia (OR = 2.1, 95% CI: 0.7, 6.1), and aspiration (OR = 1.14, 95% CI: 0.07, 18.75) in patients receiving intraoperative enteral nutrition. Within individual studies, intraoperative enteral nutrition patients received significantly more calories than standard fasting patients. Intraoperative enteral nutrition may increase nutritional intake in burn patients without an increase in complications; however, this is based on limited studies. Randomized controlled trials are needed before recommendations on intraoperative enteral nutrition practice can be made.

151 Background: Point mutations in the gene encoding speckle-type pox virus and zinc finger protein (SPOP) are the most frequently identified mutations in prostate cancer, occurring at a frequency of 6-15% across localized and disseminated cancers. Recently, SPOP gene alterations have gained attention as they appear to define a novel subclass of prostate cancers. Previous studies show that patients with mutant SPOP (mtSPOP) had superior responses to androgen deprivation therapy (ADT) and exhibit more favorable responses to abiraterone compared to wild type SPOP (wtSPOP). Methods: We retrospectively identified 59 prostate cancer patients at a single institution (Johns Hopkins) with somatic SPOP mutations from genomic testing of primary tumors (n=45), metastatic lesions (n=12), or liquid biopsies (n=2). Patient records were reviewed to determine baseline characteristics, therapies received, and clinical outcomes. The primary outcomes included best PSA response and progression-free survival (PFS) on ADT in the hormone sensitive prostate cancer (HSPC) setting and on abiraterone and/or enzalutamide in the first-line castration resistant prostate cancer (CRPC) setting. PFS was defined as either PSA, radiographic, or clinical progression. Results: The median age at diagnosis was 64 years (range 46 to 85). 17/59 (28.8%) were Black. F133 was the most frequently mutated residue, occurring in 33 (55.9%) instances (Table). There were two patients who harbored two mutations in the SPOP gene. The most frequently co-occurring mutation was in APC (15/59 [25.4%] patients), resulting in Wnt pathway activation. Concurrent ERG fusions were not observed with this cohort (0/59 [0%] patients). 41/59 (69.4%) were diagnosed with Gleason 8-10 disease. 21/59 (35.5%) were diagnosed with de novo metastatic disease. 50/59 (84.7%) patients received ADT for recurrent or metastatic disease. Median PFS on ADT was 40.7 (95% CI 23.4-71.9) months. Of the 27/59 (45.8%) patients who progressed to CRPC, 20/59 (33.9%) patients received abiraterone and 13/59 (22.0%) received enzalutamide; 9/59 (15.3%) patients received both agents. Median PFS was 7.8 (95% CI 6.7-NR) months on abiraterone and 7.3 (95% CI 3.2-NR) months on enzalutamide. Other notable therapies received in the CRPC setting include docetaxel (5/59 [8.5%] patients), cabazitaxel (5/59 [8.5%] patients), and PARP inhibitor olaparib or rucaparib (4/59 [6.8%] patients). Conclusions: SPOP mutations define a unique subset of prostate cancers enriched for black patients, high Gleason scores, absence of ERG fusions, and Wnt pathway activation. Clinical outcomes to first-line ADT appear longer than expected for genomically-unselected patients. [Table: see text]

We examined the comparative efficacies of first-line abiraterone and enzalutamide in pre- and postdocetaxel settings in castration-resistant prostate cancer (CRPC) through a trial level meta-analysis. A mixed method approach was applied to 19 unique studies containing 17 median overall survival (OS) estimates and 13 median radiographic progression-free survival (PFS) estimates. We employed a random-effects meta-analysis to compare efficacies of abiraterone and enzalutamide with respect to OS and PFS. In the predocetaxel setting, enzalutamide use was associated with an increase in median OS of 5.9 months (p<0.001), hazard ratio (HR) = 0.81, and an increase in median PFS of 8.3 months (p<0.001), HR = 0.47 compared to abiraterone. The advantage of enzalutamide improved after adjusting for baseline Gleason score to 19.5 months (p<0.001) and 14.6 months (p<0.001) in median OS and PFS, respectively. In the postdocetaxel setting, the advantage of enzalutamide use was nominally significant for median PFS (1.2 months p=0.02 without adjustment and 2.2 months and p=0.0007 after adjustment); there was no significant difference in median OS between the two agents. The results from this comprehensive meta-analysis suggest a survival advantage with the use of first-line enzalutamide over abiraterone in CRPC and highlight the need for prospective clinical trials.