Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

The retinal deep capillary plexus as a venous outflow system; insights from Sturge Weber Syndrome.

PURPOSE: To report on the venous abnormalities of a patient with Sturge-Weber syndrome (SWS). METHOD: Case report. PATIENT: A 29-year-old woman with a history of SWS since infancy was referred for evaluation of possible diffuse choroidal hemangioma. Multimodal imaging, including ultra-widefield fluorescein, indocyanine green, and optical coherence tomography-angiography (OCTA) were performed. RESULTS: Dilated fundus examination was remarkable for increased cupping of the optic disc in the right eye, venous tortuosity, and marked dilation of the choroidal vessels. Ultra-widefield fluorescein angiography confirmed marked venous tortuosity and dilation, as well as anastomoses of the retinal veins ipsilateral to the port wine stain. Indocyanine green angiography revealed marked engorgement of the vortex veins and choroidal vasculature. OCTA revealed dilated vascular channels in the deep capillary plexus (DCP) that were directly anastomosing to the superficial capillary plexus, but not the intermediate capillary plexus. Engorgement of the ampullae of the DCP vortex system was also observed. The normal contralateral eye was used as comparison for all imaging studies. CONCLUSION: These findings support the notion of generalized venous hypertension state in adult eyes with SWS and corroborate prior evidence that the deep capillary plexus acts as a venous outflow system.

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer.

Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through the re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates the recruitment of AR to genomic target sites and the inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. In addition, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

Integrative clinical and molecular characterization of translocation renal cell carcinoma.

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8+ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Influence of hamstring autograft diameter on graft failure rate in Chinese population after anterior cruciate ligament reconstruction.

BACKGROUND: There has been limited literature regarding the influence of hamstring autograft diameter on the outcome of anterior cruciate ligament (ACL) reconstruction in Asian population. This study was undertaken to investigate the failure rate after ACL reconstruction among Chinese patients treated with hamstring tendon autografts of different diameters. Our hypothesis was that an increase in hamstring tendon autograft diameter would reduce the risk of graft failure. METHODS: A retrospective review of 394 consecutive patients who underwent ACL reconstruction using quadrupled semitendinous and gracillis autografts from 2009 to 2018 at our centre was performed. Logistic regression analysis was used to determine the relationship between graft failure rate and predictor variables, including hamstring graft diameter, gender and age. RESULTS: Hamstring graft diameter of 8.0 mm or more was found to be associated with significant reduction of risk in graft failure rate (P = 0.001, Relative Risk 0.19). No significant association was found between graft failure rate and gender or age. CONCLUSION: Hamstring graft diameter 8.0 mm or greater is associated with decreased graft failure rate and revision rate in our local Chinese population.

Positive Oral Contrast Solution at MDCT for Suspected Acute Appendicitis in Adults: Rate of Appendiceal Luminal Filling of Normal and Inflamed Appendixes.

OBJECTIVE. The purpose of this study was to assess the rate of appendiceal filling with a positive oral contrast solution at MDCT performed for suspected acute appendicitis in adults. MATERIALS AND METHODS. We performed a retrospective review of MDCT in 684 consecutive adult patients with suspected acute appendicitis in a 19-month period. Patients were excluded if no positive oral contrast solution (500 mL each of water and polyethylene glycol and 30 mL diatrizoate) was given or if the appendix was not visible or absent. After exclusion, images of 519 patients (mean age ± SD, 37.4 ± 16.0 years; 335 women, 184 men) were reviewed for cecal contrast opacification and appendiceal filling. Imaging findings were recorded as positive or negative for acute appendicitis using all available clinical and pathologic data as a reference standard. A control series of CT colonography (CTC) screening examinations (overnight preparation with universal cecal opacification) in 2552 adults without symptoms of appendicitis was also reviewed. RESULTS. Cecal opacification was confirmed in 313/519 (60.3%) patients, with no difference between those considered to be positive (68/107, 63.6%) or negative (245/412, 59.5%) for appendicitis (p = 0.506). When positive oral contrast solution reached the cecum, appendiceal filling was seen in none of the 68 (0%) with appendicitis and in 205 of the 245 (83.7%) without appendicitis (p < 0.0001). Among CTC control subjects, appendiceal filling was similar to the cohort considered to be without appendicitis (2240/2552 [87.8%], p = 0.070). CONCLUSION. In MDCT for suspected acute appendicitis, luminal filling of the noninflamed appendix exceeds 80% when positive oral contrast solution reaches the cecum, indicating results similar to screening CTC. The appendix did not fill in proven acute appendicitis, indicating appendiceal filling may allow exclusion of appendicitis with high certainty. These results suggest positive oral contrast solution may augment diagnostic accuracy and confidence in cases of suspected acute appendicitis.

Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence after colorectal surgery: a meta-analysis.

BACKGROUND: Enhanced recovery after surgery protocols supports the post-operative use of nonsteroidal anti-inflammatory drugs (NSAIDs) to minimize the use of opioids. However, there is an increasing concern on the impaired wound healing of anastomosis associated with NSAID use, potentially causing a higher risk of anastomotic leakage. The aim was to conduct a meta-analysis to evaluate the association of NSAIDs with anastomotic leakage after colorectal surgery. METHODS: A literature search was conducted using the MEDLINE, PubMed, Cochrane Library and Clinicaltrial.gov. Studies identified were appraised with standard selection criteria. Data points were extracted and meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Seventeen studies comprising of 26 098 patients were examined. The analysis of all studies showed a significantly lower rate of anastomotic dehiscence in the no-NSAID group (pooled odds ratio (OR) = 2.00, 95% confidence interval (CI) = 1.48-2.71, P < 0.00001). The analysis of randomized controlled trials (RCTs) demonstrates similar dehiscence rates between both groups (P = 0.17). In subgroup analysis, non-selective NSAIDs was associated with a higher risk of anastomotic dehiscence (pooled OR = 2.02, 95% CI = 1.62-2.50, P < 0.00001). However, there was no difference in the incidence of anastomotic leakage between no-NSAID group and selective NSAID group (P = 0.05). CONCLUSION: Use of NSAIDs after colorectal surgery may be associated with a higher risk of anastomotic leakage. It is important to balance between the benefits of faster post-operative recovery and potential adverse effects of NSAIDs. Selective NSAIDs may be safer than non-selective ones. More RCTs are warranted to further evaluate the relationship between anastomotic leakage and use of NSAIDs, especially selective ones.

Measuring spleen stiffness to predict varices in chronic hepatitis B cirrhotic patients with or without receiving non-selective beta-blockers.

OBJECTIVES: we aimed to investigate the accuracy of liver (LSM) spleen stiffness measurement (SSM) with transient elastography (TE) to predict varices in the presence of non-selective beta-blockers (NSBB). METHODS: In this cross-sectional study of consecutive patients with chronic hepatitis B (CHB) and cirrhosis, all patients underwent TE and upper endoscopic examinations. LSM and SSM in predicting varices in patients receiving and not receiving NSBB were evaluated. RESULTS: Altogether 144 CHB patients (29 receiving NSBB; 35 with any varices, 31 and 11 with esophageal and gastric varices, respectively) were recruited. Their mean LSM and SSM were 13.3 ± 9.0 kPa and 32.8 ± 19.2 kPa, respectively. The correlation between LSM and SSM was better in the NSBB subgroup (r = 0.525, P = 0.003) than its counterpart (r = 0.329, P < 0.001). The area under receiver operating characteristic curve (AUROC) of LSM and SSM for any varices was 0.675 and 0.685 (P = 0.002 and 0.001), respectively. SSM of 18.9 kPa had a negative predictive value of 92.1% and negative likelihood ratio of 0.27 for ruling out any varices; and SSM of 54.9 kPa had a positive predictive value of 56.5% and a positive likelihood ratio of 4.05 to rule in varices. The AUROC of LSM for varices was 0.742 and 0.549 in patients with or without NSBB, respectively; the corresponding AUROC of SSM was 0.572 and 0.603, respectively. CONCLUSIONS: SSM only has modest accuracy to predict varices independent of NSBB use. An SSM cutoff value of 18.9 kPa may be adopted to achieve a high negative predictive value to rule out varices.

Risk factors for preoperative periventricular leukomalacia in term neonates with hypoplastic left heart syndrome are patient related.

BACKGROUND: Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury, called periventricular leukomalacia (PVL), in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS). METHODS: Neonates with HLHS or HLHS variants from 3 prospective magnetic resonance imaging studies (2003-2010) were selected for this cohort. Preoperative brain magnetic resonance imaging was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs vaginal), time of diagnosis (prenatal vs postnatal), HLHS subtypes, brain total maturation score, time to surgery, individual averaged daily preoperative blood gases, and complete blood cell count values was used to determine significant associations. RESULTS: A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks; 86% (49/57) had a prenatal diagnosis, with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, 71% (41/57). Preoperative PVL was identified in 19% (11/57). Male patients with AA (P = .004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL (P = .005). CONCLUSIONS: In neonates with HLHS, nonmodifiable patient-related factors, including male sex with AA (lack of antegrade blood flow) and lower total brain maturation score, placed neonates at the greatest risk for preoperative white matter injury.

Roles of Ras-Erk in apoptosis of PC12 cells induced by trophic factor withdrawal or oxidative stress.

To understand the role of Ras-MAPK (mitogen-activated protein kinase) in trophic factor withdrawal- and oxidative stress-induced apoptotic cell death processes, undifferentiated rat pheochromocytoma PC12 cells and a PC12 variant cell line stably expressing the Ras dominant-negative mutant (M-M17-26) were subjected to serum withdrawal in the absence or presence of H2O2 treatment. The extent of cell death was analyzed by lactate dehydrogenase release, internucleosomal DNA fragmentation, and caspase-3 assays. Both serum withdrawal and H2O2 treatment induced apoptotic cell death in PC12 cells, and the extent of cell death was greatly enhanced in M-M17-26 cells. DNA fragmentation induced by serum withdrawal or H2O2 treatment was blocked completely by a general caspase inhibitor, Z-VAD-FMK. A selective MAPK kinase inhibitor, U0126, blocked the H2O2-induced phosphorylation of Erk1/2 (extracellular signal-regulated kinase) in PC12 cells and increased the levels of active caspase-3 in M-M17-26 under serum withdrawal or H2O2 treatment. In addition, the short-term H2O2 treatment (5-30 min) was sufficient to cause DNA fragmentation in M-M17-26 cells even though H2O2 was removed and cells were incubated in regular growth medium with complete serum for 24 h. However, similar, short-term H2O2 treatment of PC12 cells did not induce DNA fragmentation 24 h later. These results suggest that the Ras-Erk pathway is critical in mediating protection against apoptotic cell death induced by either trophic factor withdrawal or increased oxidative stress.