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Purpose: To determine the incidence of blepharoptosis after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections and compare the rates of blepharoptosis between patients injected with an eyelid speculum and those injected without a speculum., Design: Retrospective cohort study., Methods: International Classification of Diseases, Tenth Revision (ICD-10), codes were used to identify patients with exudative age-related macular degeneration (AMD) and those who developed ptosis after intravitreal injections. Patients with nonexudative AMD who did not receive intravitreal injections served as controls. The outcomes were the incidence of ptosis in the injection group compared to the noninjection group and incidence of ptosis in patients whose injections were performed with an eyelid speculum as compared to those whose injections were performed without a speculum., Results: We recruited 1100 exudative AMD patients who received at least 1 intravitreal anti-VEGF injection and 2258 nonexudative AMD patients who had not received an injection. In the injection group, 18 of 1100 patients (1.6%) developed ptosis, compared with 52 of 2258 patients (2.3%) in the noninjection group (P = .25). Within the injection group, ptosis was mostly bilateral, diagnosed on average 22.4 months after the initial injection, and after more than a 1-year injection-free period. Eleven of 537 patients (2.0%) injected without a speculum developed ptosis, compared with 8 of 444 patients (1.8%) injected with a speculum (P = .82)., Conclusions: No statistically significant differences in incidence rates of ptosis were observed. In this analysis, neither intravitreal anti-VEGF injections nor speculum use during injections appears to increase the risk of ptosis., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) in cochlear implant candidates., Study Design: Retrospective case review., Setting: Tertiary referral hospital., Patients: A total of 207 cochlear implanted patients with CT and/or MRI., Interventions: N/A., Main Outcome Measures: Age versus abnormal radiologic findings, imaging abnormality versus postoperative outcomes, postoperative outcomes versus electrode design, Cambridge Cochlear Implant Protocol (CCIP) status for imaging abnormalities, sensitivity and specificity of CT and MRI for round-window/cochlear occlusion, and MRI for incomplete partitions., Results: A total of 207 patients with CT, MRI, or both were reviewed retrospectively. Less than half (15.5%) of CT scans had findings that might affect surgical intervention compared with 5.9% of MRI. No significant difference was found between children and adults for relevant imaging abnormalities (grade 4 or higher) with either CT (p = 0.931) or MRI (p = 0.606). CCIP status correlated with cochlear abnormalities (p = 0.040); however, only 46.2% of radiographic abnormalities on CT would be identified by these criteria. For detecting cochlear occlusion requiring surgical intervention, the sensitivity and specificity for CT were 40% (4 of 10; 95% confidence interval [CI], 12.16-73.76) and 95.73% (95% CI, 91.40-98.27), respectively. For MRI, the sensitivity and specificity were 33.33% (1 of 3; 95% CI, 0.84-90.57) and 96.97% (63 of 65; 95% CI, 89.32-99.63), respectively. There was no difference for postoperative AzBio scores for higher-grade imaging abnormalities (p = 0.6012) or for electrode designs (p = 0.3699)., Conclusions: Significant radiographic abnormalities were relatively uncommon in cochlear implant patients on either CT or MRI at our single-center institution. If present, abnormal imaging findings rarely translated to management changes. CCIP status does not reliably predict which patients are likely to have abnormalities. Both MRI and CT have low sensitivity for round-window or cochlear occlusion, but detection likely leads to changes in surgical management., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Background: Poor sleep leads to poor health outcomes. Phase I of our sleep quality improvement project showed severe sleep disturbance in the ward setting. We implemented a novel PostOp Pack to improve sleep quality., Methods: Patients underwent elective, general surgery procedures. Fitbit trackers measured total sleep time. Patients completed the inpatient Richards-Campbell Sleep Questionnaire, which combines 5 domains into a cumulative score (0-100). Patients completed the outpatient Pittsburgh Sleep Quality Index preoperatively and postoperatively. Patients received the PostOp Pack, which included physical items and a sleep-protective order set to reduce nighttime awakenings. Patients from phase I served as the historical control. The primary outcome was the percentage of patients with Richards-Campbell Sleep Questionnaire total sleep score ≥50. The secondary outcomes included the mean Richards-Campbell Sleep Questionnaire domain scores and Fitbit total sleep time., Results: A total of 49 patients were compared with 64 historical controls. The percentage of patients with a total sleep score ≥50 was significantly higher in patients receiving a PostOp Pack versus historical control (69% vs. 44%, difference 26%, 95% confidence interval 6.1-45%, P = .01). The mean Richards-Campbell Sleep Questionnaire Total Sleep Score was significantly higher in patients with a PostOp Pack (62 vs 49, mean difference 13, 95% confidence interval 6-21, P ≤ .01). The PostOp Pack Richards-Campbell Sleep Questionnaire domain scores were significantly higher in various areas: Sleep Latency (68 vs 49, P ≤ .01), Awakenings (56 vs 40, P = .01), Sleep Quality (61 vs 49, P = .02), and Noise Disturbance (70 vs 59, P = .04). Of all patients, 92% would use PostOp Pack again in a future hospitalization. No patients had a failure to rescue event with PostOp Pack. The mean total sleep time was significantly improved with PostOp Pack on night 1 (6.4 vs 4.7 hours, P = .03)., Conclusion: The PostOp Pack improves inpatient sleep quality and is safe., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Despite growing scientific knowledge and research, it is still unknown if office flexible laryngoscopy (FL) is aerosol generating and thereby potentially increases the risk of SARS-CoV-2 transmission. The limited literature that exists is conflicting, precluding formal conclusions., Objective: To determine whether FL is aerosol generating., Design, Setting, and Participants: This prospective cohort study included 134 patients seen in the otolaryngology clinic at a single tertiary care academic institution between February and May 2021. Two optical particle sizer instruments were used, quantifying particles ranging from 0.02 μm to 5 μm. Measurements were taken every 30 seconds, with sample periods of 15 seconds throughout the patient encounter. Instruments were located 12 inches from the patient's nares. Timing of events was recorded, including the start and end of physical examination, topical spray administration, start and end of laryngoscopy, and other potential aerosol-generating events (eg, coughing, sneezing). Data analysis was performed from February to May 2021., Exposures: Office examination and office FL., Main Outcomes and Measures: Bayesian online change point detection (OCPD) algorithm was used to detect significant change points (CPs) in this time-series data. The primary outcome was significant CP after FL compared with baseline physiologic variations, such as breathing and phonation., Results: Data were collected from 134 patients between February and May 2021. Ninety-one encounters involved FL. Of this group, 51 patients (56%) wore no mask over their mouth during FL. There was no statistically significant CP in either visits involving FL or visits where FL was not performed. Use of nasal spray did not result in CP in aerosol levels. Overall, neither the number of people present in the examination room, masks over patients' mouth, the duration of the visit, nor the duration of FL were associated with mean aerosol counts, regardless of the exposure. For larger aerosol sizes (≥1 μm), however, rooms with higher air exchange rates had significantly higher reductions in mean aerosol counts for visits involving FL., Conclusions and Relevance: The findings of this cohort study support that FL, including topical spray administration, is not a significant aerosol-generating procedure. The Bayesian OCPD model has a promising application for future aerosol studies in otolaryngology.

Purpose The purpose of this study is to evaluate the impact in the development of intracerebral hemorrhage in elderly critically ill patients who received prophylactic subcutaneous unfractionated heparin (SCUFH) less than 24 hours after undergoing emergency neurosurgery.  Methods A retrospective analysis was performed on patients who underwent emergency neurosurgery and were admitted to the surgical intensive care unit (SICU) at a tertiary care center over a 10-year period. Administration of prophylactic SCUFH within 24 hours of neurosurgery was required for inclusion. Demographic and clinical characteristics were recorded. The primary outcome was a rate of postoperative hemorrhagic complications with respect to age. Results We identified 223 emergency neurosurgical patients: 100 (45%) patients did not receive prophylactic SCUFH and were excluded. The remaining 123 (55%) patients met all inclusion criteria, of whom 73 (59%) patients were under 65 years old, and 50 (41%) patients were over 65 years old. Patients under 65 years old had significantly lower body mass index (BMI), lower Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, and Simplified Acute Physiology Score (SAPS) scores, and shorter median SICU length of stay compared to patients over 65 years old. No statistically significant difference in the rate of postoperative hemorrhagic or non-hemorrhagic neurological complications was observed between patients in either age group.  Conclusion Age over 65 years was not associated with a higher risk of postoperative hemorrhage in patients who received SCUFH after emergency neurosurgery. SCUFH can be safely used as a chemoprophylactic agent against venous thromboembolism for elderly patients when used within 24 hours after emergency neurosurgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Tambo et al.)

Competing Interests: The authors report no conflicts of interest.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT 1 ) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT 1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT 1 . We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before ( T0 ), 60 ( T60 ) and 120 ( T120 ) min after an acute glucose challenge in the following groups of male rats: 1 ) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2 ) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3 ) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT 1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60 , IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT 1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT 1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT 1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis. NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

Background: To evaluate the efficacy of percutaneous and endoscopic therapeutic interventions for biliary strictures and leaks following LT in children., Methods: Retrospective analysis of 49 consecutive pediatric liver transplant recipients (27 girls, 22 boys, mean age at transplant 3.9 years) treated at our institution from 1989 to 2019 for biliary leak and/or biliary stricture was performed. Minimally invasive approach was considered clinically successful if it resulted in patency of the narrowed biliary segment and/or correction of the biliary leak., Results: Forty-two patients had a stricture at the biliary anastomosis; seven had a biliary leak. After an average 13.8 years of follow-up, long-term clinical success with minimally invasive treatment (no surgery or re-transplant) was achieved for 24 children (57%) with biliary stricture and 4 (57%) with biliary leaks. Eight patients required re-transplant; however, only one was due to failure of both percutaneous and surgical management. For biliary strictures, failure of non-surgical management was associated with younger age at stricture diagnosis (p < .02)., Conclusions: Percutaneous and endoscopic management of biliary strictures and leaks after LT in children is associated with a durable result in >50% of children., (© 2021 Wiley Periodicals LLC.)

Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP-1r additively decrease oxidative damage and urinary albumin excretion (U alb V) in the following groups: (a) untreated, lean LETO (n = 7), (b) untreated, obese OLETF (n = 9), (c) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d; n = 9), (d) OLETF + GLP-1 mimetic (EXE; 10 µg exenatide/kg/d; n = 7) and (e) OLETF + ARB +exenatide (Combo; n = 6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4-hydroxy-2-nonenal levels by 21%, 27% and 27%, respectively. At baseline, U alb V was nearly double in OLETF compared with LETO and increased to nearly 10-fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced U alb V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP-1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet-induced obesity., (© 2019 John Wiley & Sons Australia, Ltd.)

Background: Morbidly adherent placenta, also known as placenta accreta spectrum, is associated with severe maternal morbidity and mortality. Multiple adjunctive procedures have been proposed to improve outcomes, and at many institutions, interventional radiologists will play a role in assisting obstetricians in these cases., Objective: The objective of the study was to evaluate the outcomes of women with morbidly adherent placenta who underwent cesarean hysterectomy with aortic balloon occlusion or internal iliac artery balloon occlusion catheters, compared with cesarean hysterectomy with surgical ligation of the iliac arteries, or cesarean hysterectomy without adjunctive procedures., Study Design: A retrospective review of women with morbidly adherent placenta treated with cesarean hysterectomy was performed at 5 institutions from May 2014 to April 2018. The balloon occlusion group had either prophylactic aortic or iliac balloons placed prior to cesarean hysterectomy. Comparison groups included those who underwent internal iliac artery ligation prior to hysterectomy or a control group if they underwent cesarean hysterectomy without adjuvant procedures. Evaluated outcomes include estimated blood loss, transfusion requirements, intensive care unit admission, and adverse event rates., Results: There were 171 women with morbidly adherent placenta included in the study. Twenty-eight had balloon placement prior to cesarean hysterectomy, 18 had intraoperative internal iliac artery ligation, and there were 125 control women who underwent cesarean hysterectomy without any adjunctive procedures. Compared with the women who underwent cesarean hysterectomy without adjunctive procedures, women who underwent aortic or iliac artery balloon occlusion prior to hysterectomy had significantly lower estimated blood loss (30.9% decrease, P < .001), transfusion requirements (76.8% decrease, P < .001), intensive care unit admission rates (0% vs 15.2%, P < .001), and intensive care unit stay lengths (0.0 vs 3.1 days, P < .001). Compared with women who underwent surgical ligation of the internal iliac arteries prior to hysterectomy, women who underwent aortic or iliac artery balloon occlusion prior to cesarean hysterectomy had lower estimated blood loss (54.2% decrease, P < .01), transfusion requirements (90.5% decrease, P < .001), operating room times (40.0% decrease, P < .01), intensive care unit admissions rates (0% vs 77.8%, P < .001), intensive care unit stay lengths (0.0 vs 1.4 days, P < .001), and adverse events (3.6% vs 44.4%, P < .01)., Conclusion: Aortic and iliac artery balloon occlusion are associated with lower estimated blood loss, transfusion requirements, intensive care unit admission rates, and adverse event rates compared with women who underwent internal iliac artery ligation prior to cesarean hysterectomy or women who had no adjunctive interventions prior to cesarean hysterectomy for morbidly adherent placenta., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Juvenile aggressive ossifying fibromas (JAOF) are rare, typically benign pediatric tumors that are locally aggressive and have high recurrence rates. A 7-year old male presented with a palatal mass and a 3D printed model was created and used as a visual aide to highlight the importance of management in terms of functional, cosmetic, and disease-free outcomes with the family. The patient ultimately underwent successful enucleation with final pathology consistent with JAOF. To our knowledge, this is the first description of the use of 3D printing to help in the shared decision-making process for the treatment of this aggressive tumor., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We describe the case of a young boy with severe clinical symptoms which mimicked several findings consistent with a peritonsillar abscess (PTA). After the patient exhibited no improvement with medical management, imaging revealed an intramuscular medial pterygoid abscess secondary to parapharyngeal space lymphadenitis. This is the first reported case of a patient with a medial pterygoid abscess secondary to lymphadenitis. We also describe a minimally invasive surgical approach for incision and drainage of the abscess that has not previously been described in the literature., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The correlation between aspirin sensitivity, asthma, and nasal polyposis was recognized in the early 20th century. Today, this classic triad of symptoms, eponymously named Samter's Triad, is known as aspirin exacerbated respiratory disease (AERD). Aspirin exacerbated respiratory disease affects approximately 0.3⁻0.9% of the general population in the USA and approximately 7% of asthmatic patients. The management of AERD is challenging as no single modality has proven to have high rates of symptom control. Consequently, disease management typically involves a multimodality approach across both medical and surgical disciplines. This review describes the epidemiology of AERD and the current state-of-the-art as it relates to the underlying pathophysiologic mechanisms of this disease process. A significant proportion of the review is focused on the appropriate diagnostic workup for AERD patients including the utility of aspirin provocation testing. The spectrum of medical treatments, including aspirin desensitization and recently introduced immunotherapies, are discussed in detail. Furthermore, surgical approaches to disease control, including advanced endoscopic techniques, are reviewed and treatment outcomes presented.

Background: Unconfirmed penicillin allergy poses substantial public health consequences. The most widely accepted protocol to evaluate penicillin allergy is skin testing followed by an amoxicillin challenge., Objective: To evaluate the safety of direct oral graded challenges to amoxicillin., Methods: A prospective single-blind clinical trial with historical controls of patients ≥7 years old with historical non-life-threatening reactions to penicillin was conducted. Patients received placebo followed by a 2-step graded challenge to amoxicillin. The allergic reaction rate was compared with the rate observed in our previous study that included skin testing and with the currently reported penicillin allergy prevalence in the US population., Results: Of the 155 participants who completed an amoxicillin challenge, 120 patients (77.4%) experienced no reaction whereas 31 patients (20%) experienced nonallergic reactions to either placebo (n = 16) or amoxicillin (n = 15). Four patients (2.6%) developed mild allergic reactions. Significantly (P = .03) fewer patients (4 of 155, 2.6%, 95% confidence interval [CI]: 1.0%, 6.5%) were determined to be allergic compared with 14 of 170 subjects (8.2%, 95% CI: 5.0%, 13.4%) in our previous study where patients were determined to be allergic based on either positive skin tests (n = 11) or allergic challenge reactions after negative skin tests (n = 3). This 2.6% reaction rate was also significantly less than the 10% reported US prevalence of penicillin allergy (P = .003)., Conclusions: Placebo-controlled oral graded challenges to amoxicillin without prior skin testing may be safe for patients ≥7 years old with non-life-threatening historical reactions to penicillin. Amoxicillin can be tolerated by the majority of patients with self-reported penicillin allergy., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: The relative importance of the nasal valve relative to the remainder of the nasal airway remains unknown. The goal of this article was to objectively measure the shape of the nasal inlet and its effect on downstream airflow and nasal cavity volume using a physical model and a physiologic flow model., Methods: A patient who had isolated nasal valve surgery and had pre- and postoperative computed tomography scans available for analysis was studied. Nasal inlet shape measurements, computational fluid dynamics, and nasal volume analysis were performed using the computed tomography data. In addition, a physical model was used to determine the effect of nasal obstruction on downstream soft tissue., Results: The postoperative shape of the nasal inlet was improved in terms of length and degree of tortuosity. Whereas the operated-on region at the nasal inlet showed an only 25% increase in cross-sectional area postoperatively, downstream nonoperated sites in the nasal cavity revealed increases in area ranging from 33% to 51%. Computational fluid dynamics analysis showed that airway resistance decreased by 42%, and pressure drop was reduced by 43%. Intraluminal mucosal expansion was found with nasal obstruction in the physical model., Conclusion: By decreasing the degree of bending and length at the nasal valve, inspiratory downstream nonoperated sites of the nasal cavity showed improvement in volume and airflow, suggesting that the nasal valve could play an oversized role in modulating the aerodynamics of the airway. This was confirmed with the physical model of nasal obstruction on downstream mucosa.

Background: Bacteria, particularly in the biofilm state, may be implicated in the pathogenesis of chronic rhinosinusitis (CRS) and enhance antibiotic resistance. Nitric oxide (NO) is a gaseous immunomodulator with antimicrobial activity and a short half-life, complicating achievement of therapeutic concentrations. We hypothesized that a novel microparticle-based delivery platform, which allows for adjustable release of NO, could exhibit potent antibacterial effects., Methods: Porous organosilica microparticles (SNO-MP) containing nitrosylated thiol groups were formulated. Dissociation of the nitrosothiol groups generates NO at body temperature. The susceptibility of bacterial isolates from CRS patients to SNO-MP was evaluated through a colony forming unit (CFU) assay. Serial dilutions of SNO-MP in triplicate were incubated with isolates in suspension for 6 hours followed by plating on tryptic soy agar and overnight incubation followed by CFU quantification. Statistical analysis was performed with SPSS using one-way analysis of variance with Bonferroni correction., Results: SNO-MP displayed antibacterial activity against gram-positive (methicillin-resistant and -sensitive Staphylococcus aureus) and gram-negative (Pseudomonas aeruginosa, Enterobacter aerogenes, and Proteus mirabilis) isolates. SNO-MP induced dose-dependent reductions in CFU across all strains. Compared with controls and blank nanoparticles, SNO-MP (10 mg/mL) induced a 99.99%-100% reduction in CFU across all isolates, equivalent to a 5-9 log kill (p < 0.005). There was no statistically significant difference in CFU concentration between controls and blank microparticles., Conclusion: SNO-MP demonstrates potent bactericidal effect against antibiotic-resistant CRS bacterial strains., (© 2018 ARS-AAOA, LLC.)

Obesity is associated with an inappropriately activated renin-angiotensin-aldosterone system, suppressed glucagon-like peptide-1 (GLP-1), increased renal Na + reabsorption, and hypertension. To assess the link between GLP-1 and angiotensin receptor type 1 (AT 1 ) signaling on obesity-associated impairment of urinary Na + excretion (U Na V) and elevated arterial pressure, we measured mean arterial pressure (MAP) and heart rate by radiotelemetry and metabolic parameters for 40 days. We tested the hypothesis that stimulation of GLP-1 signaling provides added benefit to blockade of AT 1 by increasing U Na V and further reducing arterial pressure in the following groups: (1) untreated Long-Evans Tokushima Otsuka (LETO) rats (n = 7); (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 9); (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 9); (4) OLETF + GLP-1 receptor agonist (EXE; 10 µg exenatide/kg/day; n = 7); and (5) OLETF + ARB + EXE (Combo; n = 6). On day 2, U Na V was 60% and 62% reduced in the EXE and Combo groups, respectively, compared with that in the OLETF rats. On day 40, U Na V was increased 69% in the Combo group compared with that in the OLETF group. On day 40, urinary angiotensinogen was 4.5-fold greater in the OLETF than in the LETO group and was 56%, 62%, and 58% lower in the ARB, EXE, and Combo groups, respectively, than in the OLETF group. From day 2 to the end of the study, MAP was lower in the ARB and Combo groups than in the OLETF rats. These results suggest that GLP-1 receptor activation may reduce intrarenal angiotensin II activity, and that simultaneous blockade of AT 1 increases U Na V in obesity; however, these beneficial effects do not translate to a further reduction in MAP.

[This corrects the article DOI: 10.1371/journal.pone.0194234.].

Background: Intensity-modulated radiation therapy (IMRT) has been used to limit treatment-related toxicity for patients with anal squamous cell carcinoma (SCC). The treatment outcomes and HPV characteristics for a cohort of patients receiving definitive concurrent chemotherapy and IMRT are reported., Materials and Methods: 52 patients with anal SCC were treated with IMRT and concurrent chemotherapy. Radiation was delivered sequentially to the pelvis and inguinal lymph nodes (45 Gy) and anal tumor (median dose, 54 Gy). Multiplex real-time PCR for 7 high-risk HPV subtypes (n = 22) and p16 immunohistochemistry (n = 21, rated on a 0, 1, and 2+ scale) were performed on available specimens. Survival was estimated using Kaplan-Meier analysis, and toxicities were recorded., Results: Median follow-up was 33 months. Three-year freedom from locoregional failure (FFLRF), freedom from distant metastasis (FFDM), freedom from colostomy (FFC), and overall survival (OS) were 94%, 85%, 91%, and 90%, respectively. Acute grade 2+ skin, GI, and GU toxicities occurred in 83%, 71%, and 19% of evaluable patients, respectively. The rates of late grade 2+ GI and GU toxicities for evaluable patients (n = 32) were 28% and 9%, respectively. Of patients with available pathology, 91% and 71% were positive for HPV and p16 (2+), respectively. HPV genotypes included 16 (n = 17), 33 (n = 2), 18 (n = 1), and 45 (n = 1). HPV and p16 status were associated on Chi-square analysis (p = 0.07). Neither HPV nor p16 status was significantly associated with any clinical outcome. For HPV+ patients, 3-year FFLRF, FFDM, FFC, and OS were 100%, 69%, 100%, and 88%, respectively., Conclusions: In this patient cohort, disease control was excellent for anal SCC treated with definitive concurrent chemotherapy and IMRT, and treatment was well tolerated. HPV and p16 status were not prognostic for treatment outcomes which may be related to our small sample size.

Objective: The purpose of this study is to determine the correlation between malignancy risk of focal liver observations in patients at risk for hepatocellular carcinoma (HCC) implied by phrases used in nonstructured radiology reports with the risk inferred by hepatologists., Materials and Methods: We performed a retrospective review of nonstructured radiology reports issued before Liver Imaging and Reporting Data System (LI-RADS) adoption from four-phase liver CT examinations of patients at risk for HCC. The phrase used by the radiologist in the report impression to describe each focal liver observation was recorded. Five hepatologists independently inferred the LI-RADS category from each phrase. Two abdominal radiologists independently reviewed the images and, blinded to all other information, assigned a LI-RADS category to each observation. Discrepancies were resolved by consensus., Results: One hundred five observations in 77 patients were reported by 23 radiologists using 29 phrases. The most common phrase, "consistent with HCC" (n = 20), was applied to radiologist-assigned LR-3 (n = 1), LR-4 (n = 5), LR-5 (n = 11), and LR-5V (n = 3) observations. Eleven phrases were used more than once. Sixteen phrases were associated with LR-4 or higher observations; among these, hepatologists misinterpreted 37% of LR-4 or lower observations as definitely HCC and 46% of LR-5 and LR-5V observations as not definitely HCC. Overall, there was modest correlation (r = 0.69) between radiologist-assigned and hepatologist-inferred categories., Conclusion: Nonstandardized terminology results in inaccurate communication of HCC risk. Structured reporting systems such as LI-RADS may improve communication by conveying unambiguous estimates of malignancy risk.

The convergence of technology and medicine has led to many advances in surgical training. Novel surgical simulators have led to significantly improved skills of graduating surgeons, leading to decreased time to proficiency, improved efficiency, decreased errors, and improvement in patient safety. Endoscopic sinus surgery poses a steep learning curve given the complex 3-dimensional anatomy of the nasal and paranasal cavities, and the necessary visual-spatial motor skills and bimanual dexterity. This article focuses on surgical simulation in rhinological training and how innovative high-fidelity and low-fidelity simulators can maximize resident training and improve procedural skills before operating in the live environment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective Our objective was to compare the accuracy of preoperative positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced CT (CECT) in detecting cervical nodal metastases in patients treated with neck dissection and to scrutinize the ability of each modality to determine nodal stage. Study Design Case series with chart review. Setting Montefiore Medical Center, Bronx, New York. Subjects and Methods Patients who underwent neck dissection at our institution for primary treatment of head and neck squamous cell carcinoma (HNSCC) and had received preoperative PET/CT and CECT were included in this study. Imaging studies were reinterpreted by 3 specialists within the field and compared for interreader agreement. Concordance between radiology and histopathology was measured using neck levels and sides, along with patient nodal stage. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and agreement coefficients were calculated. Results Seventy-three patients were included in the study. Sensitivity was 0.69 and 0.94 (level and side) for PET/CT vs 0.53 and 0.66 for CECT ( P = .056, P = .001). Specificity was 0.86 and 0.56 for PET/CT vs 0.91 and 0.76 for CECT ( P = .014, P = .024). No significant difference was found in overall accuracy ( P = .33, P = .88). The overall agreement percentages between N stage called by imaging modality and pathology were 52% and 55% for PET/CT and CECT, respectively. Conclusion No significant difference in sensitivity was found between PET/CT and CECT. CECT was found to have superior specificity compared with PET/CT. The information gleaned from each modality in the pretreatment evaluation of HNSCC appears to be complementary.

Purpose: Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity., Methods and Materials: Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood counts at a standardized time point to identify predictors of initial blood count nadirs., Results: Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P=.02), grade 3+ neutropenia (33% vs 8%, P=.04), and grade 2+ thrombocytopenia (32% vs 7%, P=.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 (P<.1)., Conclusions: Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total "marrow reserve" can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate the outcomes and toxicity of concurrent full-dose gemcitabine and intensity-modulated radiation therapy (IMRT) for patients with borderline resectable and locally advanced pancreatic adenocarcinoma after induction chemotherapy., Materials and Methods: From 2009 to 2012, 32 patients were treated with concurrent gemcitabine and IMRT for borderline resectable or locally advanced pancreatic adenocarcinoma. All patients received induction FOLFIRINOX or gemcitabine-based chemotherapy before chemoradiation. The radiotherapy volume was limited to the primary tumor, and the median dose was 55 Gy in 25 fractions. Gemcitabine was administered weekly during radiotherapy on days 1, 8, 22, and 29 at a median weekly dose of 800 mg/m²., Results: Twenty-five patients had locally advanced disease and 7 had borderline resectable disease. The median follow-up time was 14.6 months. The median progression-free and overall survival were 13.9 and 23.1 months, with a trend toward improved overall survival for patients receiving induction FOLFIRINOX compared with gemcitabine-based therapy. A radiographic complete or partial response was achieved in 13 patients (41%), with 4 (13%) having complete radiographic responses. Surgical resection was performed in 10 patients (31%)--6 patients with locally advanced disease and 4 with borderline resectable disease. Grade 3/4 hematologic toxicity during and up to 6 weeks after chemoradiation occurred in 12 patients (38%); grade 3 nonhematologic toxicity occurred in 7 patients (22%), with no grade 4 or 5 toxicity. All patients completed their radiotherapy., Conclusions: Concurrent full-dose gemcitabine and limited-field IMRT after induction chemotherapy for the treatment of borderline resectable and locally advanced pancreatic cancer is promising with acceptable toxicity rates.

Fibroblast growth factor (FGF)-21 is secreted from the liver, pancreas, and adipose in response to prolonged fasting/starvation to facilitate lipid and glucose metabolism. Northern elephant seals naturally fast for several months, maintaining a relatively elevated metabolic rate to satisfy their energetic requirements. Thus, to better understand the impact of prolonged food deprivation on FGF21-associated changes, we analyzed the expression of FGF21, FGF receptor-1 (FGFR1), β-klotho (KLB; a co-activator of FGFR) in adipose, and plasma FGF21, glucose and 3-hydroxybutyrate in fasted elephant seal pups. Expression of FGFR1 and KLB mRNA decreased 98% and 43%, respectively, with fasting duration. While the 80% decrease in mean adipose FGF21 mRNA expression with fasting did not reach statistical significance, it paralleled the 39% decrease in plasma FGF21 concentrations suggesting that FGF21 is suppressed with fasting in elephant seals. Data demonstrate an atypical response of FGF21 to prolonged fasting in a mammal suggesting that FGF21-mediated mechanisms have evolved differentially in elephant seals. Furthermore, the typical fasting-induced, FGF21-mediated actions such as the inhibition of lipolysis in adipose may not be required in elephant seals as part of a naturally adapted mechanism to support their unique metabolic demands during prolonged fasting., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: Identification of microRNAs (miRNAs) that regulate lipid metabolism is important to advance the understanding and treatment of some of the most common human diseases. In the liver, a few key miRNAs have been reported that regulate lipid metabolism, but since many genes contribute to hepatic lipid metabolism, we hypothesized that other such miRNAs exist. To identify genes repressed by miRNAs in mature hepatocytes in vivo, we injected adult mice carrying floxed Dicer1 alleles with an adenoassociated viral vector expressing Cre recombinase specifically in hepatocytes. By inactivating Dicer in adult quiescent hepatocytes we avoided the hepatocyte injury and regeneration observed in previous mouse models of global miRNA deficiency in hepatocytes. Next, we combined gene and miRNA expression profiling to identify candidate gene/miRNA interactions involved in hepatic lipid metabolism and validated their function in vivo using antisense oligonucleotides. A candidate gene that emerged from our screen was lipoprotein lipase (Lpl), which encodes an enzyme that facilitates cellular uptake of lipids from the circulation. Unlike in energy-dependent cells like myocytes, LPL is normally repressed in adult hepatocytes. We identified miR-29a as the miRNA responsible for repressing LPL in hepatocytes, and found that decreasing hepatic miR-29a levels causes lipids to accumulate in mouse livers., Conclusion: Our screen suggests several new miRNAs are regulators of hepatic lipid metabolism. We show that one of these, miR-29a, contributes to physiological lipid distribution away from the liver and protects hepatocytes from steatosis. Our results, together with miR-29a's known antifibrotic effect, suggest miR-29a is a therapeutic target in fatty liver disease., (© 2014 by the American Association for the Study of Liver Diseases.)

The limited soft tissue visualization provided by computed tomography, the standard imaging modality for radiotherapy treatment planning and daily localization, has motivated studies on the use of magnetic resonance imaging (MRI) for better characterization of treatment sites, such as the prostate and head and neck. However, no studies have been conducted on MRI-based segmentation for the abdomen, a site that could greatly benefit from enhanced soft tissue targeting. We investigated the interobserver and intraobserver precision in segmentation of abdominal organs on MR images for treatment planning and localization. Manual segmentation of 8 abdominal organs was performed by 3 independent observers on MR images acquired from 14 healthy subjects. Observers repeated segmentation 4 separate times for each image set. Interobserver and intraobserver contouring precision was assessed by computing 3-dimensional overlap (Dice coefficient [DC]) and distance to agreement (Hausdorff distance [HD]) of segmented organs. The mean and standard deviation of intraobserver and interobserver DC and HD values were DC(intraobserver) = 0.89 ± 0.12, HD(intraobserver) = 3.6mm ± 1.5, DC(interobserver) = 0.89 ± 0.15, and HD(interobserver) = 3.2mm ± 1.4. Overall, metrics indicated good interobserver/intraobserver precision (mean DC > 0.7, mean HD < 4mm). Results suggest that MRI offers good segmentation precision for abdominal sites. These findings support the utility of MRI for abdominal planning and localization, as emerging MRI technologies, techniques, and onboard imaging devices are beginning to enable MRI-based radiotherapy., (Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Background: This study tested the hypothesis that time of day of treatment with stereotactic radiosurgery (SRS) has an effect on local control (LC) and overall survival (OS) in a large cohort of patients with non-small cell lung cancer (NSCLC) brain metastases., Methods: At Washington University in St. Louis, 437 patients with NSCLC were treated with SRS for NSCLC brain metastases. Receiver operating characteristics analysis was used to identify an optimal cut-point for OS relative to time of day. Kaplan-Meier log-rank statistics, and Cox regression univariate and multivariate analysis were employed to isolate any independent effect of treatment time on OS and LC. Matched-pair analysis was performed to isolate any independent effect of time on OS and LC of day while controlling for confounding variables., Results: Receiver operating characteristics analysis identified a cut-point of 11:41 AM as providing the highest predictive value for OS. On univariate analysis, late SRS was associated with decreased OS, as was age, Karnofsky performance status, risk-stratification schemes, extracranial disease status, and overall burden of brain metastases. On univariate analysis for LC, late SRS was associated with decreased LC, as was burden of brain metastases. On multivariate analysis, only Graded Prognostic Assessment remained predictive of OS, and total number of targets and total tumor volume remained predictive of LC. Matched-pair analysis demonstrated no significant effect of time of day on LC or OS., Conclusions: Although earlier treatment appears to be associated with improved LC and OS, treatment time fails to remain significant when accounting for confounding variables., (Copyright © 2013 American Cancer Society.)

Purpose: To assess clinical outcomes of metal stent insertion in patients with bilobar bile duct obstruction by malignant tumors., Materials and Methods: Records of 120 consecutive patients who underwent placement of metallic stents for palliation of malignant bilobar biliary obstruction between 1995 and 2010 were retrospectively reviewed. Single-duct stent insertion was performed in 44 patients with one liver lobe that accounted for more than 70% of total liver volume or only one patent lobar portal vein (group 1). Bilobar stent insertion was performed in 60 patients with approximately equal lobe sizes, patent lobar portal veins, or cholangitis at presentation (group 2). In 16 patients with discontiguous right anterior and posterior segmental ducts (group 3), three stents were deployed in the left lobar and right anterior and posterior segmental ducts. Overall survival, primary patency, and patient morbidity rates following stent insertion were assessed., Results: No significant differences in mean overall survival (group 1, 7.3 mo; group 2, 10.3 mo; group 3, 6.5 mo; P = .21) or mean primary stent patency (group 1, 4.2 mo; group 2, 5.9 mo; group 3, 3.5 mo; P = .17) were demonstrated. However, patients in group 3 were significantly more likely to require hospitalizations for cholangitis and additional invasive procedures for recurrent biliary obstruction than patients in groups 1 and 2., Conclusions: Unilobar and bilobar metal stent insertion led to similar outcomes when treatment decision was based on relative liver lobe volumes, lobar portal vein patency, and presence of cholangitis on presentation., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy of percutaneous balloon dilation of biliary-enteric anastomotic strictures resulting from surgical repair of laparoscopic cholecystectomy-related bile duct injuries., Material and Methods: A total of 61 patients were referred to our institution from 1995 to 2010 for treatment of obstruction at the biliary-enteric anastomosis following surgical repair of laparoscopic cholecystectomy-related bile duct injuries. Of these 61 patients, 27 underwent surgical revision upon stricture diagnosis, and 34 patients were managed using balloon dilation. Of these 34 patients, 2 were lost to follow up, leaving 32 patients for analysis. The primary study objective was to determine the clinical success rate of balloon dilation of biliary-enteric anastomotic strictures. Secondary study objectives included determining anastomosis patency, rates of stricture recurrence following treatment, and morbidity., Results: Balloon dilation of biliary-enteric anastomotic strictures was clinically successful in 21 of 32 patients (66%). Anastomotic stricture recurred in one of 21 patients (5%) after an average of 13.1 years of follow-up. Patients who were unsuccessfully managed with balloon dilation required significantly more invasive procedures (6.8 v. 3.4; p = 0.02) and were left with an indwelling biliary catheter for a significantly longer period of time (8.8 v. 2.0 months; p = 0.02) than patients whose strictures could be resolved by balloon dilation. No significant differences in the number of balloon dilations performed (p = 0.17) or in the maximum balloon diameter used (p = 0.99) were demonstrated for patients with successful or unsuccessful balloon dilation outcomes., Conclusion: Percutaneous balloon dilation of anastomotic biliary strictures following surgical repair of laparoscopic cholecystectomy-related injuries may result in lasting patency of the biliary-enteric anastomosis.

Introduction: Little is known about splenic rupture in patients who develop systemic acquired A amyloidosis. This is the first report of a case of atraumatic splenic rupture in a patient with acquired A amyloidosis from chronic injection drug use., Case Presentation: A 58-year-old Caucasian man with a long history of injection drug use, hospitalized for infective endocarditis, experienced atraumatic splenic rupture and underwent splenectomy. Histopathological and microbiological analyses of the splenic tissue were consistent with systemic acquired A amyloidosis, most likely from injection drug use, that led to splenic rupture without any recognized trauma or evidence of bacterial embolization to the spleen., Conclusion: In patients with chronic inflammatory conditions, including the use of injection drugs, who experience acute onset of left upper quadrant pain, the diagnosis of atraumatic splenic rupture must be considered.

Background & Aims: Due to the shortage of donor organs, many patients needing liver transplantation cannot receive one. For some liver diseases, hepatocyte transplantation could be a viable alternative, but donor cells currently are procured from the same sources as whole organs, and thus the supply is severely limited., Methods: Here, we investigated the possibility of isolating viable hepatocytes for liver cell therapy from the plentiful source of morgue cadavers. To determine the utility of this approach, cells were isolated from the livers of non-heart-beating cadaveric mice long after death and transplanted into fumarylacetoacetate hydrolase-deficient mice, a model for the human metabolic liver disease hereditary tyrosinemia type I and a stringent in vivo model for hepatic cell transplantation., Results: Surprisingly, complete and therapeutic liver repopulation could be achieved with hepatocytes derived up to 27 hours post mortem., Conclusions: Competitive repopulation experiments showed that cadaveric liver cells had a repopulation capacity similar to freshly isolated hepatocytes. Importantly, viable hepatocytes also could be isolated from cadaveric primate liver (monkey and human) efficiently. These data provide evidence that non-heart-beating donors could be a suitable source of hepatocytes for much longer time periods than previously thought possible., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The ability to generate induced pluripotent stem (iPS) cells from a patient's somatic cells has provided a foundation for organ regeneration without the need for immune suppression. However, it has not been established that the differentiated progeny of iPS cells can effectively reverse failure of a vital organ. Here, we examined whether iPS cell-derived hepatocytes have both the functional and proliferative capabilities needed for liver regeneration in mice with fumarylacetoacetate hydrolase deficiency. To avoid biases resulting from random genomic integration, we used iPS cells generated without viruses. To exclude compensation by hepatocytes not derived from iPS cells, we generated chimeric mice in which all hepatocytes were iPS cell derived. In vivo analyses showed that iPS cells were intrinsically able to differentiate into fully mature hepatocytes that provided full liver function. The iPS cell-derived hepatocytes also replicated the unique proliferative capabilities of normal hepatocytes and were able to regenerate the liver after transplantation and two-thirds partial hepatectomy. Thus, our results establish the feasibility of using iPS cells generated in a clinically acceptable fashion for rapid and stable liver regeneration.

Unlabelled: MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G(1) to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH., Conclusion: Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.

Small GTPase Ras homologue enriched in brain (RHEB) binds and activates the key metabolic regulator mTORC1, which has an important role in cancer cells, but the role of RHEB in cancer pathogenesis has not been shown. By performing a meta-analysis of published cancer cytogenetic and transcriptome databases, we defined a gain of chromosome 7q36.1-q36.3 containing the RHEB locus, an overexpression of RHEB mRNA in several different carcinoma histotypes, and an association between RHEB upregulation and poor prognosis in breast and head and neck cancers. To model gain of function in epithelial malignancy, we targeted Rheb expression to murine basal keratinocytes of transgenic mice at levels similar to those that occur in human squamous cancer cell lines. Juvenile transgenic epidermis displayed constitutive mTORC1 pathway activation, elevated cyclin D1 protein, and diffuse skin hyperplasia. Skin tumors subsequently developed with concomitant stromal angio-inflammatory foci, evidencing induction of an epidermal hypoxia-inducible factor-1 transcriptional program, and paracrine feed-forward activation of the interleukin-6-signal transducer and activator of transcription 3 pathway. Rheb-induced tumor persistence and neoplastic molecular alterations were mTORC1 dependent. Rheb markedly sensitized transgenic epidermis to squamous carcinoma induction following a single dose of Ras-activating carcinogen 7,12-dimethylbenz(a)anthracene. Our findings offer direct evidence that RHEB facilitates multistage carcinogenesis through induction of multiple oncogenic mechanisms, perhaps contributing to the poor prognosis of patients with cancers overexpressing RHEB., ((c) 2010 AACR.)

Accumulation of toxic metabolites in hereditary tyrosinemia type I (HT1) patients leads to chronic DNA damage and the highest risk for hepatocellular carcinomas (HCCs) of any human disease. Here we show that hepatocytes of HT1 mice exhibit a profound cell-cycle arrest that, despite concomitant apoptosis resistance, causes mortality from impaired liver regeneration. However, additional loss of p21 in HT1 mice restores the proliferative capabilities of hepatocytes and renal proximal tubular cells. This growth response compensates cell loss due to uninhibited apoptosis and enables animal survival but rapidly leads to HCCs, renal cysts, and renal carcinomas. Thus, p21's antiproliferative function is indispensable for the suppression of carcinogenesis from chronically injured liver and renal epithelial cells and cannot be compensated by apoptosis.