Comparison of Outcomes Between Surveillance Ultrasound and Completion Lymph Node Dissection in Children and Adolescents With Sentinel Lymph Node-Positive Cutaneous Melanoma.

OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. BACKGROUND: The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. METHODS: Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. RESULTS: Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. CONCLUSIONS: Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.

Differential RNA Expression Between Metastatic and Primary Neuroblastoma Cells.

INTRODUCTION: Neuroblastoma (NB) is the most common extra-cranial malignancy in children. Poor survival in high-risk NB is attributed to recurrent metastatic disease. To better study metastatic disease, we used a novel mouse model to investigate differential gene expression between primary tumor cells and metastatic cells. We hypothesized that metastatic NB cells have a different gene expression profile from primary tumor cells and cultured cells. METHODS: Using three human NB cell lines (NGP, CHLA255, and SH-SY5Y), orthotopic xenografts were established in immunodeficient nod/scid gamma mice via subcapsular renal injection. Mice were sacrificed and NB cells were isolated from the primary tumor and from sites of metastasis (bone marrow, liver). RNA sequencing, gene set analysis, and pathway analysis were performed to identify differentially expressed genes and molecular pathways in the metastatic cells compared to primary tumor cells. RESULTS: There were 266 differentially expressed genes in metastatic tumor cells (bone marrow and liver combined) compared to primary tumor cells. The top upregulated gene was KCNK1 and the top downregulated genes were PDE7B and NEBL. Top upregulated pathways in the metastatic cells were involved in ion transport, cell signaling, and cell proliferation. Top downregulated pathways were involved in DNA synthesis, transcription, and cellular metabolism. CONCLUSIONS: In metastatic NB cells, our study identified the upregulation of biologic processes involved in cell cycle regulation, cell proliferation, migration, and invasion. Ongoing studies aim to validate downstream translation of these genomic alterations, as well as target these pathways to more effectively suppress and inhibit recurrent metastatic disease in NB.

A Multi-Institutional Study Comparing Stoma Location in Neonates With Intestinal Perforation.

INTRODUCTION: Neonates with intestinal perforation often require laparotomy and intestinal stoma creation, with the stoma placed in either the laparotomy incision or a separate site. We aimed to investigate if stoma location is associated with risk of postoperative wound complications. METHODS: A multi-institutional retrospective review was performed for neonates ≤3 mo who underwent emergent laparotomy and intestinal stoma creation for intestinal perforation between January 1, 2009 and April 1, 2021. Patients were stratified by stoma location (laparotomy incision versus separate site). Outcomes included wound infection/dehiscence, stoma irritation, retraction, stricture, and prolapse. Multivariable regression identified factors associated with postoperative wound complications, controlling for gestational age, age and weight at surgery, and diagnosis. RESULTS: Overall, 79 neonates of median gestational age 28.8 wk (interquartile range [IQR]: 26.0-34.2 wk), median age 5 d (IQR: 2-11 d) and median weight 1.4 kg (IQR: 0.9-2.42 kg) had perforated bowel from necrotizing enterocolitis (40.5%), focal intestinal perforation (31.6%), or other etiologies (27.8%). Stomas were placed in the laparotomy incision for 41 (51.9%) patients and separate sites in 38 (48.1%) patients. Wound infection/dehiscence occurred in 7 (17.1%) neonates with laparotomy stomas and 5 (13.2%) neonates with separate site stomas (P = 0.63). There were no significant differences in peristomal irritation, stoma retraction, or stoma stricture between the two groups. On multivariable regression, separate site stomas were associated with increased likelihood of prolapse (odds ratio 6.54; 95% confidence interval: 1.14-37.5). CONCLUSIONS: Stoma incorporation within the laparotomy incision is not associated with wound complications. Separate site stomas may be associated with prolapse. Patient factors should be considered when planning stoma location in neonates undergoing surgery for intestinal perforation.

Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Intercostal Nerve Cryoablation is Associated with Reduced Opioid Use in Pediatric Oncology Patients.

INTRODUCTION: Intercostal nerve cryoablation reduces postoperative pain in adults undergoing thoracotomy and children undergoing pectus excavatum repair. We hypothesize that cryoablation is associated with decreased post-thoracotomy pain and opioid use in pediatric oncology patients. METHODS: A single-center retrospective cohort study was performed for oncology patients who underwent thoracotomy from January 1, 2017 to May 31, 2021. Outcomes included postoperative opioid use measured in morphine milligram equivalents per kilogram (MME/kg), pain scores (scale 0-10), and opioid prescription at discharge. Univariable analysis compared patients who received cryoablation to patients who did not receive cryoablation. Multivariable regression analysis controlling for age and prior thoracotomy evaluated associations between cryoablation and postoperative pain. RESULTS: Overall, 32 patients (19 males:13 females) underwent thoracotomy with 16 who underwent >1 thoracotomy resulting in 53 thoracotomies included for analysis. Cryoablation was used in 14 of 53 (26.4%) thoracotomies. Throughout the postoperative hospitalization, patients receiving cryoablation during thoracotomy consumed less opioids compared to patients who did not receive cryoablation (median 0.38 MME/kg, interquartile range [IQR] 0.20-1.15 versus median 1.47 MME/kg, IQR 0.71-4.02, P < 0.01). Maximum pain scores were lower in cryoablation patients (median 6, IQR 5-8) than noncryoablation patients (median 8, IQR 6-10), with a significant difference observed on postoperative day 4 (P = 0.01). Cryoablation patients were also less frequently prescribed opioids at discharge (21.4% versus 58.97%, P = 0.02). Multivariable regression demonstrated that cryoablation was associated with 2.59 MME/kg less opioid use (95% confidence interval -4.56 to -0.63) and decreased likelihood of opioid prescription at discharge (adjusted odds ratio 0.14, 95% confidence interval 0.03-0.67). CONCLUSIONS: Cryoablation is significantly associated with decreased post-thoracotomy pain and opioid use in pediatric cancer patients and should be considered in postoperative pain regimens.

Epidural Analgesia Is Associated With Reduced Inpatient Opioid Consumption and Length of Stay After Wilms Tumor Resection.

INTRODUCTION: Wilms' tumor (WT) is the most common renal malignancy in children and requires an extensive laparotomy for resection. Epidural analgesia (EA) is commonly used in postoperative pain management, but previous literature suggests it may prolong length of stay (LOS). We hypothesized that EA is associated with prolonged LOS but decreased postoperative opioid use in children undergoing WT resection. MATERIALS AND METHODS: A retrospective chart review was performed for all WT patients who underwent nephrectomy between January 1, 1998, and December 31, 2018, at a tertiary children's hospital. Patients with incomplete records, bilateral WT, caval or cardiac tumor extension, or intubation postoperatively were excluded. Outcomes included postoperative opioid consumption measured in oral morphine equivalents per kilogram, receipt of opioid prescription at discharge, and postoperative LOS. Mann-Whitney and multivariable regression analyses were performed. RESULTS: Overall, 46/77 children undergoing WT resection received EA. Children with EA used significantly less inpatient opioids than children without EA (median 1.0 vs. 3.3 oral morphine equivalents per kilogram; P < 0.001). Comparing patients with EA to patients without, there was no significant difference in opioid discharge prescriptions (57% vs. 39%; P = 0.13) or postoperative LOS (median 5 d vs. 6 d; P = 0.10). Controlling for age and disease stage, EA was associated with shorter LOS by multivariable regression (coefficient -0.73, 95% confidence interval: -1.4, -0.05; P = 0.04). CONCLUSIONS: EA is associated with decreased opioid use in children without an associated increase in postoperative LOS following WT resection. EA should be considered as part of multimodal pain management for children undergoing WT resection.

Screening for Child Abuse in Children With Isolated Skull Fractures.

OBJECTIVE: Head trauma is the most common cause of death from child abuse, and each encounter for recurrent abuse is associated with greater morbidity. Isolated skull fractures (ISF) are often treated conservatively in the emergency department (ED). We determined patterns of physical abuse screening in a children's hospital ED for children with ISF. METHODS: A retrospective review was performed for children aged 3 years and younger who presented to the ED with ISF from January 1, 2015 to December 31, 2019. Children were stratified by age (<12 mo, ≥12 mo) and witnessed versus unwitnessed injury. Primary outcome was social work (SW) assessment to prescreen for abuse. Secondary outcomes were suspicion for abuse based on Child Protective Services (CPS) referral and subsequent ED encounters within 1 year. RESULTS: Sixty-six ISF patients were identified. Of unwitnessed injury patients aged younger than 12 months (n = 17/22), 88.2% (n = 15/17) underwent SW assessment and 47.1% (n = 8/17) required CPS referral. Of witnessed injury patients aged younger than 12 months (n = 23/44), 60.9% (n = 14/23) underwent SW assessment, with no CPS referrals. Overall, 18.2% (n = 4/22) unwitnessed and 20.5% (n = 9/44) witnessed injury patients returned to our ED: 2 were aged younger than 12 months and had recurrent trauma. CONCLUSIONS: To decrease risk of missed physical abuse, SW consultation should be considered for all ISF patients.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Tramadol Use in Pediatric Surgery: Trends After the Food and Drug Administration Black-Box Warning.

INTRODUCTION: The U.S. Food and Drug Administration (FDA) issued a black-box warning in 2017 contraindicating tramadol in children <12 y. Longitudinal trends and factors associated with perioperative tramadol use in children remain unclear. METHODS: A retrospective, multi-institutional cohort study utilizing the Pediatric Health Information System database was performed for children 2-18 y who underwent one of ten common surgeries from 1/2009-2/2020. Temporal trends correlated with the FDA tramadol contraindication were evaluated. Hierarchical multivariable logistic regression analysis identified factors associated with tramadol use. RESULTS: Of 477,153 children undergoing surgery, 5857(1.2%) received tramadol during hospitalization. Tramadol use occurred in 942 (16.1%) children after the black-box warning, 390 of whom were <12 y. For children <12 y, annual tramadol use peaked at 1.87% (2016) and decreased to 0.66% (2019). Female sex (odds ratio OR 1.32; 95% confidence interval CI:1.24,1.40), age ≥12 y (OR 2.79; 95%CI: 2.62,2.97), and Midwest location (OR 4.07; 95% CI:1.64,10.11) increased likelihood of receiving tramadol. Tramadol use was more likely after cholecystectomy (OR 1.17; 95% CI:1.04,1.32) and in children with gastrointestinal (OR 2.39; 95% CI: 2.19,2.60), metabolic (OR 1.39; 95% CI:1.26,1.53) or transplant-related (OR 1.82; 95% CI: 1.57,2.10) comorbidities. Children of Hispanic/Latino ethnicity and those with public insurance had decreased likelihood of receiving tramadol. Adjusting for patient and hospital characteristics, children <12 y were less likely to receive tramadol following the black-box warning (OR 0.65; 95% CI: 0.59,0.70). CONCLUSIONS: Despite the FDA contraindication, tramadol prescribing continues among children <12 y undergoing surgery, with use varying by patient and institutional factors. Interventions are required to reduce perioperative tramadol use in children.

Factors Associated With Safe Prescription Opioid Disposal After Surgery in Adolescents.

INTRODUCTION: Unused prescription opioids contribute to diversion, unintended exposure, and poisonings in adolescents. Factors associated with safe prescription opioid disposal for adolescents undergoing surgery are unknown. METHODS: Parents of adolescents (13-20 y) undergoing surgery associated with an opioid prescription were enrolled preoperatively. Parents completed a baseline survey measuring sociodemographics and family history of substance abuse and two postoperative surveys capturing opioid use and disposal at 30 and 90 d. Safe disposal was defined as returning opioids to a healthcare facility, pharmacy, take-back event, or a police station. Factors associated with safe opioid disposal were assessed using bivariate analysis. RESULTS: Of 119 parent-adolescent dyads, 90 (76%) reported unused opioids after surgery. The majority of parents reporting unused opioids completed the surveys in English (80%), although many (44%) spoke another language at home. Most reported income levels <$60,000 (54%), did not attend college (69%), and had adequate health literacy (66%). Most parents (78%) did not report safe opioid disposal. Safe opioid disposal was associated with younger patient age, (median 14 y, IQR 13-16.5 versus median 15.5 y, IQR 14-17, P = 0.031), fewer days taking opioids (median 5, IQR 2-6 versus median 7, IQR 4-14, P = 0.048), and more leftover pills (median 20, IQR 10-35 versus median 10, IQR 5-22, P = 0.008). CONCLUSIONS: Most parents fail to safely dispose of unused opioids after their adolescent's surgery. Younger patient age, shorter duration of opioid use, and higher number of unused pills were associated with safe disposal. Interventions to optimize prescribing and educate parents about safe opioid disposal are warranted.

Outcomes Following Percutaneous Cholecystostomy Tube Placement for Acalculous Versus Calculous Cholecystitis.

BACKGROUND: Acute acalculous cholecystitis (AAC) is often diagnosed in critically ill patients. Percutaneous cholecystostomy tube (PCT) placement facilitates less invasive gallbladder decompression in patients who are poor surgical candidates. Specific guidelines for optimal management of AAC patients following PCT placement remain to be defined. We hypothesize that AAC patients are at lower risk of recurrent cholecystitis than acute calculous cholecystitis (ACC) patients and do not require cholecystectomy after PCT placement. METHODS: A retrospective review of patients who underwent PCT placement for AAC or ACC between 6/1/2007 and 5/31/2019 was performed. Primary outcome was recurrent cholecystitis and interval cholecystectomy for patients surviving 30 days after PCT placement. Secondary outcome was 30 day mortality. A cox regression model calculated the adjusted hazard ratio (AHR) for the outcomes. RESULTS: Eighty-four AAC and 85 ACC patients underwent PCT placement. Compared to ACC patients, more AAC patients were male (72.6 vs. 48.2%; p < 0.01), younger (median age 62 vs. 73 years; p < 0.01), and required intensive care (69.0 vs. 52.9%; p = 0.04), with lower median Charlson Comorbidity Index (4.0 vs. 6.0; p < 0.01). 30 day mortality was higher among AAC patients than ACC patients (45.2 vs. 21.2%; p < 0.01). 2/24 (8.3%) AAC patients and 5/31 (16.1%) ACC patients developed recurrent cholecystitis at a median 208.0 days (IQR:64.0-417.0) after PCT placement and 115.0 days (IQR:7.0-403.0) following PCT removal. Cox regression analysis demonstrated that AAC patients had lower likelihood of interval cholecystectomy compared to ACC patients (AHR 2.35; 95% CI:1.11,4.96). CONCLUSION: Recurrent cholecystitis is rare in patients surviving 30 days following PCT placement. When compared with ACC patients, fewer AAC patients require cholecystectomy.

Outcomes of Central Hepatectomy for Pediatric Liver Tumors.

BACKGROUND: Central hepatectomy (CH) is an uncommon surgical technique that is an option for resection of centrally located tumors, with the advantage of sparing normal hepatic parenchyma. Few studies have described outcomes in children undergoing CH. MATERIALS AND METHODS: An IRB-approved, retrospective chart review of patients who underwent CH at Children's Hospital Los Angeles between 2005 and 2016 was performed. Data included patient demographics, peri-operative factors, and post-operative outcomes. The IRB approved waiver of consent. RESULTS: Eight patients (4F:4M) with median age of 1.9 Y underwent CH: 7 patients for HB and 1 patient for focal nodular hyperplasia. Two of the seven HB patients had metastatic disease at diagnosis. Six of the seven HB patients received a median of 4 rounds (3-7 rounds) of pre-operative chemotherapy. The median operative time was 197.5 Min (143-394 Min) with median blood loss of 175 mL (100-1200 mL). Complications included a bile fluid collection requiring aspiration. Seven patients had negative margins on pathology. One patient with a positive margin successfully completed therapy, without recurrent disease. All patients survived to follow-up, with a median follow-up duration of 1.1 Y (0.1-12.1 Y). Two patients developed recurrent disease requiring formal hepatic lobectomy and orthotopic liver transplantation. These patients had negative pathologic margins, with tumor within 1 mm of resection margins. CONCLUSION: CH is an effective alternative to extended hepatectomy for patients with centrally located liver tumors and is associated with good clinical and pathologic outcomes.

20 pack-year smoking history as strongest smoking metric predictive of HPV-positive oropharyngeal cancer outcomes.

OBJECTIVES: While smoking is associated with worse outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), the magnitude of this association is unclear given the heterogenous smoking definitions and outcomes. Our objective was to investigate the association between smoking, survival, and recurrence in HPV-related OPSCC using multiple smoking metrics reported in the literature. MATERIALS AND METHODS: This was a retrospective cohort study of 375 adults with p16+ OPSCC undergoing surgical resection (n = 272) or definitive chemoradiation (n = 103) at a tertiary academic institution from 2006 to 2017. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), disease-specific survival (DSS), and recurrence. We used multiple smoking metrics commonly cited in previous studies, including ever versus never smokers, current versus former/never smokers, ≤10 versus >10 pack-year, ≤20 versus >20 pack-year, and continuous pack-year. RESULTS: There were 375 patients, median age 58 years, with 326 (87%) males, and median follow-up of 52 months. Of all smoking metrics, >20 pack-year history was the strongest predictor of both OS (HR 2.24, 95% CI: 1.19-4.20) and DFS (HR 1.67, 95% CI: 1.04-2.66) on univariable and multivariable analysis after adjusting for age, overall stage, and comorbidities. Patients with >20 pack-year smoking history were also more likely to have recurrence (HR 1.59, 95% CI: 0.95-2.67) after adjusting for overall stage. CONCLUSION: Heavier smoking >20 pack-years was the strongest smoking metric associated with 2-times worse survival and recurrence. Our findings suggest that >20 pack-year smoking history may be a more useful cutoff for risk stratification models but requires further validation.

The association of smoking and outcomes in HPV-positive oropharyngeal cancer: A systematic review.

PURPOSE: While smoking is linked to worse outcomes for human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC), the magnitude of this association and the amount of smoking exposure necessary to confer clinically significant differences in outcomes is unclear. Recent studies suggested that greater tobacco exposure results in higher risk of cancer progression and death. Our study objective was to perform a systematic review of the association between smoking and HPV-related OPSCC outcomes. MATERIALS AND METHODS: A literature search was conducted in April 2019 to identify relevant articles using Embase, Medline, Scopus, CENTRAL, and Cochrane databases. All studies were independently screened by two investigators to identify studies that assessed HPV-positive patients as an independent cohort, specified smoking measures, and reported locoregional recurrence (LRR), overall survival (OS), disease-specific survival (DSS), or disease-free survival (DFS) in association with smoking. RESULTS: Of 1130 studies identified, 10 met final inclusion criteria with 2321 total patients, mean age 57.5 years. Smoking measures included ever vs never, current vs never/former smokers, ≤10 vs >10 pack-year, and continuous pack-years. Of these studies, 8 (80%) showed a significant effect of smoking on increasing recurrence and mortality. Adjusted HRs for LRR ranged from 0.6 to 5.2, OS from 1.3 to 4.0, DSS from 2.3 to 7.2, and DFS from 1.02 to 4.2 among heavier smokers compared to lighter/non-smokers. CONCLUSIONS: While there was significant variability in smoking metrics and reported outcomes, all studies reporting statistically significant HRs showed that smoking was associated with worse outcomes. Further studies using uniform smoking measures are necessary to better understand this association.

Non-Neural (S-100 Negative) Bronchial Granular Cell Tumor Causing Acute Respiratory Failure.

Introduction: Endobronchial granular cell tumors are uncommon in the pediatric population. Case report: A 9-year-old female presented with respiratory failure due to an endobronchial tumor. After debulking and diagnosis, she underwent thoracotomy with right upper lobe resection and bronchoplasty. Pathology demonstrated an endobronchial S-100 negative granular cell tumor, which to our knowledge, is the first such report in the literature. Conclusion: Endobronchial granular cell tumors may cause obstructive respiratory failure, are amenable to surgery, and may be S-100 negative.

Fact or myth? The long shared common wall between the fistula and the urethra in male anorectal malformation with urethral bulbar fistula.

AIM: It has long been considered surgical dogma that the length of the shared common wall (CW) between a fistula and the urethra in males with anorectal malformation (ARM) and rectourethral bulbar fistula (RUBF) is considerably longer than in males with ARM and rectourethral prostatic fistula (RUPF). This belief has led surgeons who perform laparoscopic-assisted anorectoplasty (LAARP) for RUPF to avoid LAARP for RUBF for risk of potential injury to the urethra or incomplete removal of the fistula. In this study, we compared CW between RUBF and RUPF using distal colostography (DCG) and direct intraoperative measurements. METHODS: DCG of rectourethral fistula patients (n = 63; RUBF: n = 44; RUPF: n = 19) were used to measure CW retrospectively. Results were expressed as a ratio of the height of L4; i.e., CW:L4. If less than 0.7, the CW was classified as being "short"; if 0.71-1.4, as being "medium"; and if greater than 1.41, as being "long". CW that could not be measured was classified as indeterminate. 24 of these patients also had CW measured intraoperatively during LAARP as previously described. The results obtained using both techniques were also compared. RESULTS: Surprisingly, CW:L4 in RUBF patients was short in 47.7%, medium in 27.3%, long in 20.5%, and indeterminate in 4.5% on DCG, equivalent to mean lengths of 7 mm, 8.5 mm, and 10.3 mm obtained using direct intraoperative measurement for short, medium, and long CW:L4 categories, respectively. CW:L4 in RUPF was short in 73.6%, medium in 10.5%, and long in 5.2% on DCG, while mean intraoperative measurements were 5 mm, 7 mm, and 10 mm, respectively. Differences in CW measured intraoperatively were not significantly different between RUBF and RUPF (p = NS). CONCLUSION: From our findings, 47.7% of CWs in RUBF were short using two independent methods, with only 20.5% being long. Thus, LAARP should be considered actively for treating selected RUBF cases and not be excluded on the basis of CW length.

Beliefs About the Causal Structure of the Self-Concept Determine Which Changes Disrupt Personal Identity.

Personal identity is an important determinant of behavior, yet how people mentally represent their self-concepts and their concepts of other people is not well understood. In the current studies, we examined the age-old question of what makes people who they are. We propose a novel approach to identity that suggests that the answer lies in people's beliefs about how the features of identity (e.g., memories, moral qualities, personality traits) are causally related to each other. We examined the impact of the causal centrality of a feature, a key determinant of the extent to which a feature defines a concept, on judgments of identity continuity. We found support for this approach in three experiments using both measured and manipulated causal centrality. For judgments both of one's self and of others, we found that some features are perceived to be more causally central than others and that changes in such causally central features are believed to be more disruptive to identity.

Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1).

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.