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OBJECTIVE Pituitary adenoma is one of the most common primary intracranial neoplasms. Most of these tumors are soft, but up to 17% may have a firmer consistency. Therefore, knowing the tumor consistency in the preoperative setting could be helpful. Multiple imaging methods have been proposed to predict tumor consistency, but the results are controversial. This study aimed to evaluate the efficacy of MR elastography (MRE) in predicting tumor consistency and its potential use in a series of patients with pituitary adenomas. METHODS Thirty-eight patients with pituitary adenomas (≥ 2.5 cm) were prospectively evaluated with MRI and MRE before surgery. Absolute MRE stiffness values and relative MRE stiffness ratios, as well as the relative ratio of T1 signal, T2 signal, and diffusion-weighted imaging apparent diffusion coefficient (ADC) values were determined prospectively by calculating the ratio of those values in the tumor to adjacent left temporal white matter. Tumors were classified into three groups according to surgical consistency (soft, intermediate, and firm). Statistical analysis was used to identify the predictive value of the different radiological parameters in determining pituitary adenoma consistency. RESULTS The authors included 32 (84.21%) nonfunctional and 6 (15.79%) functional adenomas. The mean maximum tumor diameter was 3.7 cm, and the mean preoperative tumor volume was 16.4 cm 3 . Cavernous sinus invasion was present in 20 patients (52.63%). A gross-total resection was possible in 9 (23.68%) patients. The entire cohort’s mean absolute tumor stiffness value was 1.8 kPa (range 1.1–3.7 kPa), whereas the mean tumor stiffness ratio was 0.66 (range 0.37–1.6). Intraoperative tumor consistency was significantly correlated with absolute and relative tumor stiffness (p = 0.0087 and 0.007, respectively). Tumor consistency alone was not a significant factor for predicting gross-total resection. Patients with intermediate and firm tumors had more complications compared to patients with soft tumors (50.00% vs 12.50%, p = 0.02) and also had longer operative times (p = 0.0002). CONCLUSIONS Whereas other MRI sequences have proven to be unreliable in determining tumor consistency, MRE has been shown to be a reliable tool for predicting adenoma consistency. Preoperative knowledge of tumor consistency could be potentially useful for surgical planning, counseling about potential surgical risks, and estimating the length of operative time.

Abstract Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer–specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer–specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer–specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07–3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer–specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer–specific mortality and specific somatic mutated genes. Impact: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

This review article examines evidence supporting the use of oral therapies in treating idiopathic, actinic, and metabolically induced skin hyperpigmentation. A thorough review of the literature regarding oral treatments for hyperpigmentation was systematically conducted through PubMed. Keywords used in the primary search include “Hyperpigmentation,” “Melanosis” or “Melasma,” “Lightening,” “Oral,” and “Therapeutics.” The search was limited to the English language, and no timeframe restrictions were implemented. Numerous orally administered therapies have been proposed for the treatment of skin hyperpigmentation. There is an abundant body of literature demonstrating the efficacy of orally administered tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. It is reasonable to expect that the most effective oral therapies will address known underlying causes of hyperpigmentation such as thyroid disease, diabetes, and hormonal imbalance. Improvement due to oral therapy of otherwise unresponsive skin hyperpigmentation or hyperpigmentation of unknown cause is less predictable. This review is limited by the strength of evidence contained within the available studies. Clinical studies investigating the treatments discussed within this article are limited in number, at times lack blinding in the study design, and are based on small sample sizes. Based on existing research, the most promising oral remedies for hyperpigmentation appear to be tranexamic acid, glutathione, isotretinoin, and proanthocyanidin. Additional studies to better establish safety and efficacy are necessary.

Abstract Background and Aims Although magnetic resonance elastography (MRE) has been well‐established for detecting and staging liver fibrosis, its prognostic role in determining outcomes of chronic liver disease (CLD) is mostly unknown. Approach and Results This retrospective study consisted of 1269 subjects who underwent MRE between 2007 and 2009 and followed up until death or last known clinical encounter or end of study period. Charts were reviewed for cirrhosis development, decompensation, and transplant or death. The cohort was split into baseline noncirrhosis (group 1), compensated cirrhosis (group 2), and decompensated cirrhosis (group 3). Cox‐regression analysis with age, sex, splenomegaly, CLD etiology, Child‐Pugh Score (CPS), Fibrosis‐4 Index (FIB‐4) score, and Model for End‐Stage Liver Disease (MELD)–adjusted HR for every 1‐kPa increase in liver stiffness measurement (LSM) were used to assess the predictive performance of MRE on outcomes. Group 1 ( n = 821) had baseline median LSM of 2.8 kPa, and cirrhosis developed in 72 (8.8%) subjects with an overall rate of about 1% cirrhosis/year. Baseline LSM predicted the future cirrhosis with multivariable adjusted HR of 2.38 ( p < 0.0001) (concordance, 0.84). In group 2 ( n = 277) with baseline median LSM of 5.7 kPa, 83 (30%) subjects developed decompensation. Baseline LSM predicted the future decompensation in cirrhosis with FIB‐4 and MELD‐adjusted HR of 1.22 ( p < 0.0001) (concordance, 0.75). In group 3 ( n = 171) with median baseline LSM of 6.8 kPa (5.2, 8.4), 113 (66%) subjects had either death or transplant. Baseline LSM predicted the future transplant or death with HR of 1.11 ( p = 0.013) (concordance 0.53) but not in CPS and MELD‐adjusted models ( p = 0.08). Conclusion MRE‐based LSM is independently predictive of development of future cirrhosis and decompensation, and has predictive value in future transplant/death in patients with CLD.

Abstract The human RecQ helicase BLM is involved in the DNA damage response, DNA metabolism, and genetic stability. Loss of function mutations in BLM cause the genetic instability/cancer predisposition syndrome Bloom syndrome. However, the molecular mechanism underlying the regulation of BLM in cancers remains largely elusive. Here, we demonstrate that the deubiquitinating enzyme USP37 interacts with BLM and that USP37 deubiquitinates and stabilizes BLM, thereby sustaining the DNA damage response (DDR). Mechanistically, DNA double-strand breaks (DSB) promotes ATM phosphorylation of USP37 and enhances the binding between USP37 and BLM. Moreover, knockdown of USP37 increases BLM polyubiquitination, accelerates its proteolysis, and impairs its function in DNA damage response. This leads to enhanced DNA damage and sensitizes breast cancer cells to DNA-damaging agents in both cell culture and in vivo mouse models. Collectively, our results establish a novel molecular mechanism for the USP37–BLM axis in regulating DSB repair with an important role in chemotherapy and radiotherapy response in human cancers.

Abstract Background Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusions Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Abstract Post-remission strategies after dasatinib-corticosteroid induction in adult Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N = 65) with Ph-positive ALL received dasatinib-dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone, and dasatinib-based maintenance. Key end points were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87 years). The complete remission rate was 98.5%. With a median follow-up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFS were 49%, 29%, and 34%, and 5-year OS were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P = .002) and OS (median 16 months vs not reached, P = .05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib-dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse. This study was registered at www.clinicaltrials.gov as #NCT01256398.

Abstract Background Magnetic resonance imaging (MRI) and MRI‐based elastography (MRE) are the most promising noninvasive techniques in assessing liver diseases. The purpose of this study was to evaluate an advanced multiparametric imaging method for staging disease and assessing treatment response in realistic preclinical alcohol‐associated liver disease (ALD). Methods We utilized four different preclinical mouse models in our study: Model 1—mice were fed a fast‐food diet and fructose water for 48 weeks to induce nonalcoholic fatty liver disease; Model 2—mice were fed chronic‐binge ethanol (EtOH) for 10 days or 8 weeks to induce liver steatosis/inflammation. Two groups of mice were treated with interleukin‐22 at different time points to induce disease regression; Model 3—mice were administered CCl 4 for 2 to 4 weeks to establish liver fibrosis followed by 2 or 4 weeks of recovery; and Model 4—mice were administered EtOH plus CCl 4 for 12 weeks. Mouse liver imaging biomarkers including proton density fat fraction (PDFF), liver stiffness (LS), loss modulus (LM), and damping ratio (DR) were assessed. Liver and serum samples were obtained for histologic and biochemical analyses. Ordinal logistic regression and generalized linear regression analyses were used to model the severity of steatosis, inflammation, and fibrosis, and to assess the regression of these conditions. Results Multiparametric models with combinations of biomarkers (LS, LM, DR, and PDFF) used noninvasively to predict the histologic severity and regression of steatosis, inflammation, and fibrosis were highly accurate (area under the curve > 0.84 for all). A three‐parameter model that incorporates LS, DR, and ALT predicted histologic fibrosis progression ( r = 0.84, p < 0.0001) and regression ( r = 0.79, p < 0.0001) as measured by collagen content in livers. Conclusion This preclinical study provides evidence that multiparametric MRI/MRE can be used noninvasively to assess disease severity and monitor treatment response in ALD.

Background and Aims Sirtuin 1 (SIRT1) is a complex NAD+‐dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1‐induced destabilization of primary cilia in cholangiocarcinoma (CCA). Approach and Results A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)‐mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD ‐producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1‐overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α‐tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma‐associated oncogene 1, phosphorylated extracellular signal‐regulated kinase, and IL‐6) expression. Conclusions In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

AbstractAcute kidney injury (AKI) may develop in patients with coronavirus disease 2019 (COVID‐19) and is associated with in‐hospital death. We investigated the incidence of AKI in 223 hospitalized COVID‐19 patients and analyzed the influence factors of AKI. The incidence of cytokine storm syndrome and its correlation with other clinicopathologic variables were also investigated. We retrospectively enrolled adult patients with virologically confirmed COVID‐19 who were hospitalized at three hospitals in Wuhan and Guizhou, China between February 13, 2020, and April 8, 2020. We included 124 patients with moderate COVID‐19 and 99 with severe COVID‐19. AKI was present in 35 (15.7%) patients. The incidence of AKI was 30.3% for severe COVID‐19 and 4.0% for moderate COVID‐19 (p < 0.001). Furthermore, cytokine storm was found in 30 (13.5%) patients and only found in the severe group. Kidney injury at admission (odds ratio [OR]: 3.132, 95% confidence interval [CI]: 1.150–8.527; p = 0.025), cytokine storm (OR: 4.234, 95% CI: 1.361–13.171; p = 0.013), and acute respiratory distress syndrome (ARDS) (OR: 7.684, 95% CI: 2.622–22.523; p < 0.001) were influence factors of AKI. Seventeen (48.6%) patients who received invasive mechanical ventilation developed AKI, of whom 64.7% (11/17) died. Up to 86.7% of AKI patients with cytokine storms may develop a secondary bacterial infection. The leukocyte counts were significantly higher in AKI patients with cytokine storm than in those without (13.0 × 10⁹/L, interquartile range [IQR] 11.3 vs. 8.3 × 10⁹/L, IQR 7.5, p = 0.005). Approximately 1/6 patients with COVID‐19 eventually develop AKI. Kidney injury at admission, cytokine storm and ARDS are influence factors of AKI. Cytokine storm and secondary bacterial infections may be responsible for AKI development in COVID‐19 patients.