Increasing Pancreatic Cancer Incidence in Young Women in the United States: A Population-Based Time-Trend Analysis, 2001-2018.

BACKGROUND & AIMS: Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS: PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS: A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION: Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.

Analysis of the Application of Professional Society Screening Guidelines for Colorectal Polyposis Syndromes at a Single Institution.

Several professional society guidelines suggest germline genetic testing for colorectal polyposis syndromes in patients with ≥10 lifetime adenomatous polyps. This study evaluated factors associated with genetic testing decisions and outcomes when germline testing was recommended per guidelines. Surgical archives revealed 145 patients with a recommendation for germline genetic polyposis testing based on guidelines. Demographic data and medical history were collected to examine for association with testing decisions and results. Germline genetic testing was ordered in 90/145 patients and was ordered in younger patients with more lifetime adenomas. Pathogenic alterations were detected in 12/53 patients who completed testing. Younger age and higher numbers of lifetime adenomas were not associated with the detection of germline genetic alterations. In fact, patients with a pathogenic germline alteration had higher median ages and fewer lifetime adenomas than those without an alteration. Half of the twelve patients with a pathogenic germline mutation were not White non-Hispanic, though White non-Hispanic patients comprised 75.5% of those tested. This study supports the 10 adenomatous polyp threshold for recommending germline genetic polyposis testing, as an alteration was detected in a sizable proportion (>20%) of patients tested. Though younger age and a higher number of lifetime adenomas were associated with an increased likelihood of ordered tests, no evidence was found to support these additional factors in testing decisions.

Keratin 17 modulates the immune topography of pancreatic cancer.

BACKGROUND: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. METHODS: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. RESULTS: K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. CONCLUSIONS: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.

Markedly increased duodenal villous surface apoptosis in patients taking pre-exposure prophylaxis (PrEP) against human immunodeficiency virus.

AIMS: Pre-exposure prophylaxis (PrEP) consists of combination antiretroviral therapy and is increasingly utilized to prevent human immunodeficiency virus (HIV) in high-risk populations. Two index cases noted during routine care showed markedly increased duodenal villous surface apoptosis in patients on PrEP. We sought to examine the prevalence of this finding and identify any clinicopathologic correlations. METHODS: Gastrointestinal biopsy specimens from 23 male patients aged 18-40 years taking PrEP and 23 control patients were reviewed. Patients with HIV, inflammatory gastrointestinal diseases, and celiac disease were excluded. Apoptoses were counted on surface epithelium and deep crypts. The highest apoptotic body count per tissue fragment was recorded. Clusters were defined as groups of ≥5 apoptoses. Apoptotic counts between patients taking PrEP and controls were compared using t-tests. RESULTS: In PrEP patients, the median age was 35 years (range 25-40) and 83% (19/23) were white. The control patients were demographically similar (median age: 32 years [range 23-40]; 70% [16/23] white). Duodenal apoptosis in villous surface epithelium was increased in PrEP patients, with 14/23 (60.9%) patients having ≥10 surface apoptoses compared to 2/23 (8.7%) controls (P = 2.1 × 10-3 ) and 14/23 (61%) having clusters compared to 3/23 (13%) controls (P = 2.0 × 10-3 ). There was no significant association between increased surface apoptosis or clusters and clinical symptoms or duration of PrEP use. CONCLUSION: Markedly increased villous surface apoptosis, particularly in clusters, is often seen in the duodenum of patients taking PrEP. Although the mechanism and significance are unknown, knowledge of this peculiar finding may prevent unnecessary additional testing.

Gastrointestinal Polyps and Polyposis in Individuals Harboring Germline CHEK2 Mutations.

BACKGROUND: Checkpoint kinase 2 is a tumor suppressor gene in the deoxyribonucleic acid damage checkpoint system that may be mutated in several cancers. Patients with germline checkpoint kinase 2 mutations and multiple colon polyps were noted during routine care, and genetic testing is recommended for patients with as few as 10 lifetime polyps. OBJECTIVE: This study assessed whether checkpoint kinase 2 is associated with attenuated or oligopolyposis and characterized the gastrointestinal clinicopathologic profile. DESIGN: Retrospective observational study. SETTINGS: Records from patients harboring germline checkpoint kinase 2 mutations from 1999-2020 were reviewed. PATIENTS: A total of 45 patients with germline checkpoint kinase 2 mutations with endoscopic examinations. MAIN OUTCOME MEASURES: Description of clinicopathologic variables. RESULTS: Twenty-five of 45 patients had polyps: 3 with only upper gastrointestinal polyps, 17 with only lower gastrointestinal polyps and 5 with both upper and lower gastrointestinal polyps. The most common germline checkpoint kinase 2 mutations in patients with polyps were p.S428F (n = 10), p.I157T (n = 4) and p.T476M (n = 2), with other mutations present in 1 patient each. Among patients with lower gastrointestinal polyps, 9 had adenomas, 6 had serrated polyps, 1 had an inflammatory polyp and 6 had both adenomatous and serrated polyps. Three patients (p.I157T, n = 2; p.R117G, n = 1) had >10 adenomas, and 1 (p.G259fs) had 18 serrated polyps. Five patients (11.1%) developed colorectal adenocarcinoma, including 2 with >10 adenomas. Five patients with p.S428F (50%) exclusively had right- sided adenomas. LIMITATIONS: Single-center descriptive study. CONCLUSIONS: Germline checkpoint kinase 2 mutations should be considered in patients with polyposis. The preponderance of right- sided adenomas in patients with p.S428F mutations suggests the importance of right-sided colonoscopy in these patients. See Video Abstract.

Glycogenic hepatopathy is associated with type 1 diabetes mellitus in only a minority of cases in a contemporary adult population.

OBJECTIVES: This study examines the clinical-pathological profiles of patients with glycogenic hepatopathy in a contemporary cohort of patients at an adult acute care hospital. METHODS: Liver biopsies with glycogenic hepatopathy were retrieved from the departmental surgical pathology database, the histological findings were studied, and the clinical findings were reviewed. RESULTS: Five cases of glycogenic hepatopathy were found, including cases associated with type 1 diabetes mellitus (n = 1), type 2 diabetes mellitus (n = 1), corticosteroids (n = 2), and anorexia (n = 2, including the patient with type 1 diabetes). AST and ALT were normal to mildly elevated (13-115 U/L and 7-126 U/L, respectively). Trace ascites was present in two patients. Hepatomegaly was only present in the patient with type 1 diabetes at the time of diagnosis. CONCLUSIONS: Four of five cases were associated with etiologies other than type 1 diabetes, which is widely reported as the most common etiology of glycogenic hepatopathy. This study suggests that etiologies currently only rarely recognized may actually be more common causes of glycogenic hepatopathy than type 1 diabetes in a contemporary adult population. It is important not only to recognize that these rarely reported causes of glycogenic hepatopathy may be underrecognized, but that the clinical presentation may also be mild.

Assessment of artificial intelligence-based remote monitoring of clear aligner therapy: A prospective study.

INTRODUCTION: Artificial intelligence remote monitoring of clear aligner therapy has recently gained popularity. It uses deep learning algorithms on a patient's mobile smartphone to determine readiness to progress to the next aligner (ie, GO vs NO-GO) and identify areas in which the teeth are not tracking with the clear aligners. This study aimed to assess the repeatability of the Go or No-Go instructions provided by the application and to determine the 3-dimensional discrepancies that constitute an unseat. METHODS: Thirty patients in treatment with clear aligners at an academic clinic were scanned twice using a remote monitoring application on a smartphone, and the results were compared. Gauge repeatability and reproducibility analysis were performed. Intraoral and remote monitoring scans were obtained on the same day from 24 additional clear aligner patients that completed treatment using their final aligners. The intraoral scan after using the final aligner and the stereolithography file of the planned position at the final aligner was compared with measure the maximum discrepancies between the actual and planned position of the teeth. RESULTS: Gauge compatibility of 44.7% was noted. In total 83.3% of patient instructions agreed between Scan 1 and 2, but 0% agreed completely on which and/or how many teeth had tracking issues. Patients who received GO instruction had mean greatest discrepancies of 1.997 mm, 1.901 mm, 0.530 mm, 8.911°, 7.827°, and 7.049° in mesiodistal, buccolingual, occlusogingival, tip, torque, and rotational dimensions, respectively. These discrepancies were not significantly different from patients receiving NO-GO instruction (1.771 mm, 1.808 mm, 0.606 mm, 8.673°, 8.134°, and 6.719° for the corresponding categories). CONCLUSIONS: Despite the study's limitations, these findings suggest concerns with the consistency of remote monitoring instructions because of gauge compatibility over the industry standard. Similarly, large discrepancies in tooth position for patients receiving GO and NO-GO instruction suggest that artificial intelligence decisions were inconsistent with quantitative findings.

Novel Endoscopic Polypectomy Surveillance Technique for Fundic Gland Polyps in Familial Adenomatous Polyposis Can Improve Early Detection of Dysplasia and Gastric Cancer.

INTRODUCTION: Fundic gland polyps (FGPs) are commonly found in patients with familial adenomatous polyposis (FAP) and are considered benign. Biopsies are not routinely performed, and conventional forceps may be time-consuming and/or yield nonrepresentative histology. The purpose of this study was to evaluate the role of a novel endoscopic polypectomy surveillance (EPS), a large volume cold-snare polypectomy technique of random FGPs, in the incidence of dysplasia and gastric cancer (GC) in FAP. METHODS: This is a retrospective longitudinal cohort of patients with FAP referred to a tertiary care center for duodenal adenoma surveillance and who underwent EPS of FGPs between 2001 and 2019. Demographic, endoscopic, and clinicopathologic information was reviewed. RESULTS: Thirty-five patients with FAP were identified at initial endoscopy by the mean age of 43.4 years (±12.8). One hundred thirteen surveillance endoscopies were performed in total using EPS. Dysplasia of FGPs was present on initial esophagogastroduodenoscopy in 7 patients (20%), and 13 additional patients (46.4%) progressed to low-grade dysplasia. Three patients (15%) who subsequently had progression to GC were found to have signet ring cell cancer within the foci of FGPs through EPS. One patient presented as metastatic GC. Progression from nondysplastic FGP to low-grade dysplasia occurred over 63 months (±46.3) with further progression to GC over 34 months (±8.5). Endoscopic risk factors for cancer were polyps >10 mm in size ( P < 0.001) and carpeting of polyps ( P < 0.001). The 5-year cumulative incidence of developing dysplasia was 35.7%. DISCUSSION: We identified that the incidence of dysplasia and GC is higher than previously reported in patients with FAP. Our study used a novel EPS technique and was able to identify GC within the foci of FGPs. Upper endoscopic guidelines should include a more rigorous sampling method for FGPs, such as EPS, to optimize early detection of dysplasia and GC.

Hyaluronan heterogeneity in pancreatic ductal adenocarcinoma: Primary tumors compared to sites of metastasis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor survival. The dense desmoplastic stroma in PDAC contributes to treatment resistance. Among the components comprising the tumor stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci of PDAC. However, the effects of treatment and location of HA expression as a biomarker signature remain unknown; this study sought to compare HA expression in primary and metastatic sites of PDAC. METHODS: Tissue from primary and metastatic PDACs were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained for H&E, HA, and CD44. Associations between HA levels and the evaluated variables were examined including progression free survival and overall survival. RESULTS: HA score was significantly higher in primary PDACs compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastases compared to metastases at other sites (p = 0.0478). In the treatment-naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p = 0.0032 and p = 0.0478, respectively). CONCLUSIONS: HA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma.

Three-dimensional cone-beam computed technology evaluation of skeletal and dental changes in growing patients with Class II malocclusion treated with the cervical pull face-bow headgear appliance.

INTRODUCTION: This study aimed to 3-dimensionally quantify and compare the outcomes of growing patients with Class II malocclusion treated with the cervical pull face-bow headgear appliance in combination with full fixed orthodontic appliances. METHODS: The study sample consisted of 22 patients with Class II malocclusion with the following inclusion criteria: ANB >4.75°, Class II molar relationship, and SN-GoGn <37°. The mean age of patients was 12.5 ± 1.1 years at baseline. The average treatment time was 27.7 ± 7.3 months. Cone-beam computed tomography scans were superimposed in the cranial base, maxillary regional, and mandibular regional to evaluate growth, treatment displacements, and bone remodeling. RESULTS: Relevant statistically and clinically significant skeletal changes included average decreases in ANB (2.1 ± 1.1°) and SNA (1.8 ± 1.1°); posterior (1.3 ± 1.4 mm) and inferior (4.6 ± 2.2 mm) displacement of A-point; inferior displacements of B-point (5.4 ± 2.8 mm) and Pogonion (5.8 ± 2.6 mm); superior displacement of Condylion (6.9 ± 2.4 mm); increase in mandibular length (5.4 ± 2.0 mm); and clockwise rotation of palatal plane (1.9 ± 1.9°). Significant proclination of the maxillary incisors (9.8 ± 11.1°) and nonsignificant proclination of the mandibular incisors (4.7 ± 9.6°) were also noted. CONCLUSIONS: Class II skeletal correction was primarily achieved by posterior, inferior displacement of the sagittal position of the maxilla. Change in the sagittal position of the mandible/chin (B-point, Pogonion) was not significant; rather, mandibular displacement was significant in an inferior vertical direction without backward rotation, as seen from marked condylar and ramus growth.

Assessment of orthodontic treatment efficacy of Clarity Aligners using the Peer Assessment Rating index and the American Board of Orthodontics Cast-Radiograph Evaluation.

INTRODUCTION: 3M Oral Care Solutions (St Paul, Minn) has recently introduced Clarity Aligners into the market. This cohort study evaluated the orthodontic treatment efficacy of this clear aligner system using the Peer Assessment Rating (PAR) index and the American Board of Orthodontics Cast-Radiograph Evaluation (CR-Eval). METHODS: Pretreatment and posttreatment dental models of 87 subjects who had undergone orthodontic treatment using Clarity Aligners in both arches to align their teeth to a target setup were independently evaluated by 4 examiners using the PAR index and the American Board of Orthodontics CR-Eval. Changes in CR-Eval and PAR scores from pretreatment to posttreatment were calculated, with PAR score reductions also expressed as percentages. RESULTS: Treatment with Clarity Aligners reduced the CR-Eval scores from 39.05 ± 14.98 to 30.34 ± 8.76, resulting in a statistically significant difference of 8.76 ± 11.45 between pretreatment and posttreatment scores. Similarly, aligner treatment reduced the weighted PAR scores from 13.40 ± 9.26 to 5.80 ± 4.84, resulting in a statistically significant difference of 7.50 ± 7.56 between pretreatment and posttreatment scores. The overall median PAR reduction was 53%, with 94% of the subjects having reduced PAR scores after treatment. Seventy-eight percent of subjects had >30% PAR reduction, 57% had >50% PAR reduction, and 33% had >70% PAR reduction. CONCLUSIONS: The results suggest that Clarity Aligners may be an effective treatment modality in mild to moderate malocclusions.

Lymphogranuloma venereum (LGV) of the anorectum: evaluation of clinicopathological associations and the utility of a novel RNA in-situ hybridisation stain.

AIMS: Recent studies from multiple global regions have reported a resurgence of lymphogranuloma venereum (LGV) proctitis, which is caused by Chlamydia trachomatis (CT). LGV proctitis is histologically indistinguishable from other forms of sexually transmitted proctitis and is difficult to differentiate from inflammatory bowel disease. While immunohistochemical stains are available for syphilis, there is no commonly available stain for the tissue identification of CT. MATERIALS AND METHODS: From 200 positive CT nucleic acid tests (NAT) from anorectal swabs, we identified 12 patients with biopsies collected from the distal colorectum or anus within 90 days of the positive NAT. We collected basic demographic information and tabulated clinical and histological findings. We examined the performance of a novel RNA in-situ hybridisation (ISH) stain targeting CT 23s rRNA on these 12 cases and 10 controls from the anorectum. RESULTS: All 12 patients were male; nine were HIV+, two had concurrent gonococcal infection, one had concurrent syphilis and one had cytomegalovirus co-infection. The majority of biopsies (11 of 12) showed mild or moderate acute inflammation, had a prominent lymphoplasmacytic infiltrate (eight of 11) and lacked marked crypt distortion (10 of 10). The RNA ISH stain was positive in 10 of 12 cases (sensitivity 83%). One case showed equivocal staining. No controls showed definitive positive staining (specificity 100%). One had equivocal staining. CONCLUSION: Our series showed that anorectal LGV had similar histological findings to those of prior STI proctitis series predominantly comprised of syphilis. The novel RNA ISH stain was sensitive and specific and may show utility in differentiating types of STI proctitis.

Applying criteria for hepatocellular neoplasm of uncertain malignant potential reclassifies more than half of hepatocellular adenomas.

OBJECTIVES: Hepatocellular adenoma (HCA) is a benign well-differentiated hepatocellular neoplasm that can be difficult to distinguish from well-differentiated hepatocellular carcinoma (HCC). The term "well-differentiated hepatocellular neoplasm of uncertain malignant potential" (HUMP) has been proposed for neoplasms resembling HCAs, but arising in atypical clinical situations (in females over 50 years old or under 15, in males, with anabolic steroid use, or in some congenital conditions), and/or with atypical pathological features (focal cytological/architectural atypia, ß-catenin activation, or focal reticulin loss) insufficient for an unequivocal diagnosis of HCC. METHODS: This study evaluated HUMP criteria on 42 previously diagnosed HCAs from 33 patients. RESULTS: Twenty-six (62%) masses from 21 patients were classified as HUMPs. Eleven (42%) had focal cytological atypia, and two (8%) had focal architectural atypia. Four (15%) showed focal reticulin loss. Five (19%) showed evidence of ß-catenin activation. Four (12%) HUMP patients were male. CONCLUSIONS: In this series, HUMP did not correlate with an increased rate of synchronous or metachronous HCC compared to HCA. Clinical colleagues may not accept such a high rate of tumors placed in a category of "uncertain malignant potential". Additional study is warranted to refine criteria for designating well-differentiated hepatocellular neoplasms as of uncertain malignant potential.

Midpalatal suture density ratio: Assessing the predictive power of a novel predictor of skeletal response to maxillary expansion.

INTRODUCTION: Rapid maxillary expansion (RME) is a common orthodontic treatment to correct maxillary transverse deficiency; however, the inability to determine the precise timing of fusion of the midpalatal suture creates difficulty for clinicians to prescribe the appropriate treatment, surgical or nonsurgical expansion. The purpose of this study was to assess the predictive power of the midpalatal suture density ratio (MPSD) for a skeletal response to RME. METHODS: Pre- and posttreatment cone-beam computed tomography scans were obtained from 78 orthodontic patients aged from 8 to 18 years treated with RME. MPSDs were calculated from pretreatment scans, and a prediction was made for the amount of skeletal expansion obtained at the level of the palate after comprehensive orthodontic treatment. Predicted values were compared with actual outcomes as assessed from posttreatment scans, followed by regression analyses to investigate correlations between MPSD and skeletal expansion and equivalence testing to analyze the performance of the predicted measurements. RESULTS: The MPSDs were not statistically significantly (P >0.05) correlated with the amount of skeletal expansion achieved. In addition, the predicted skeletal expansion using MPSD was not statistically equivalent to the skeletal expansion achieved using an equivalence margin of ±0.05. CONCLUSIONS: The results suggest that the MPSD obtained from pretreatment cone-beam computed tomography scans were not correlated well enough with the amount of skeletal expansion achieved to be an effective predictor of the amount of long-term skeletal expansion after RME.

Three-dimensional condylar changes from Herbst appliance and multibracket treatment: A comparison with matched Class II elastics.

INTRODUCTION: The purpose of this study was to quantify and qualify the 3-dimensional (3D) condylar changes using mandibular 3D regional superimposition techniques in adolescent patients with Class II Division 1 malocclusions treated with either a 2-phase or single-phase approach. METHODS: Twenty patients with Herbst appliances who met the inclusion criteria and had cone-beam computed tomography (CBCT) images taken before, 8 weeks after Herbst removal, and after the completion of multibracket appliance treatment constituted the Herbst group. They were compared with 11 subjects with Class II malocclusion who were treated with elastics and multibracket appliances and who had CBCT images taken before and after treatment. Three-dimensional models generated from the CBCT images were registered on the mandible using 3D voxel-based superimposition techniques and analyzed using semitransparent overlays and point-to-point measurements. RESULTS: The magnitude of lateral condylar growth during the orthodontic phase (T2-T3) was greater than that during the orthopedic phase (T1-T2) for all condylar fiducials with the exception of the superior condyle (P <0.05). Conversely, posterior condylar growth was greater during the orthopedic phase than the subsequent orthodontic phase for all condylar fiducials (P <0.05). The magnitude of vertical condylar development was similar during both the orthopedic (T1-T2) and orthodontic phases (T2-T3) across all condylar fiducials (P <0.05). Posterior condylar growth during the orthodontic phase (T2-T3) of the 2-phase approach decreased for all condylar fiducials with the exception of the posterior condylar fiducial (P <0.05) when compared with the single-phase approach. CONCLUSIONS: Two-phase treatment using a Herbst appliance accelerates condylar growth when compared with a single-phase regime with Class II elastics. Whereas the posterior condylar growth manifested primarily during the orthopedic phase, the vertical condylar gains occurred in equal magnitude throughout both phases of the 2-phase treatment regime.

Neuroendocrine proliferations in inflammatory bowel disease: differentiating neuroendocrine tumours from neuroendocrine cell micronests.

AIMS: A wide spectrum of well-differentiated neuroendocrine proliferations (NEPs) are observed in inflammatory bowel disease (IBD), ranging from neuroendocrine tumours (NETs) to microscopic neuroendocrine cell clusters, best described as neuroendocrine cell micronests (NCMs). Finding NCMs in surveillance biopsies of IBD patients often poses a diagnostic conundrum. While such lesions may have been referred to as 'microcarcinoids' in the literature, it is unclear whether these represent early neoplasms. The study was undertaken to characterise NCMs and to differentiate NCMs from NETs. METHODS AND RESULTS: Institutional surgical pathology archives were searched to identify cases of NEPs in IBD patients. Clinicopathological features were examined. NCMs were defined as scattered, indistinct neuroendocrine cell clusters without confluent growth or new stroma formation, located in the lamina propria and muscularis mucosae. NETs were defined as discrete, mass-forming lesions. Seventeen NEPs were identified, including eight NCMs and nine NETs. All NEPs were incidentally discovered. While NETs were commonly found in the rectum and appendix, NCMs were only noted in the rectosigmoid area. Unlike NETs, NCMs could not be measured as a discrete lesion as these clusters were non-confluent and scattered. None of the patients with NCMs developed NETs after a mean follow-up of 4.1 years (range = 0.5-21.0 years). None of the NETs showed NCMs in the background mucosa. CONCLUSIONS: NCMs have distinct pathological features, are not associated with NETs in IBD patients and should not be misinterpreted as 'microcarcinoids'. Identification of NCMs in surveillance biopsies may not require further clinical work-up or invasive procedures usually performed for NETs.

Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration.

Chronic pancreatitis is a prominent risk factor for the development of pancreatic ductal adenocarcinoma. In both conditions, the activation of myofibroblast-like pancreatic stellate cells (PSCs) plays a predominant role in the formation of desmoplastic reaction through the synthesis of connective tissue and extracellular matrix, inducing local pancreatic fibrosis and an inflammatory response. Yet the signaling events involved in chronic pancreatitis and pancreatic cancer progression and metastasis remain poorly defined. Cadherin-11 (Cad-11, also known as OB cadherin or CDH11) is a cell-to-cell adhesion molecule implicated in many biological functions, including tissue morphogenesis and architecture, extracellular matrix-mediated tissue remodeling, cytoskeletal organization, epithelial-to-mesenchymal transition, and cellular migration. In this study, we show that, in human chronic pancreatitis and pancreatic cancer tissues, Cad-11 expression was significantly increased in PSCs and pancreatic cancer cells. In particular, an increased expression of Cad-11 can be detected on the plasma membrane of activated PSCs isolated from chronic pancreatitis tissues and in pancreatic cancer cells metastasized to the liver. Moreover, knockdown of Cad-11 in cancer cells reduced pancreatic cancer cell migration. Taken together, our data underline the potential role of Cad-11 in PSC activation and pancreatic cancer metastasis.

Comparative assessment of bonding time and 1-year bracket survival using flash-free and conventional adhesives for orthodontic bracket bonding: A split-mouth randomized controlled clinical trial.

INTRODUCTION: A new flash-free adhesive promises to eliminate the flash removal step in bonding and to reduce bonding time by as much as 40% per bracket, with a bond failure rate of less than 2%. The aim of this trial was to compare bonding time and bracket failure rate over a 1-year period between the flash-free adhesive and a conventional adhesive for orthodontic bracket bonding. METHODS: Forty-five consecutive patients had their maxillary incisors, canines, and premolars bonded with ceramic brackets (Clarity Advanced; 3M Unitek, Monrovia, Calif) using a flash-free adhesive (APC Flash-Free Adhesive Appliance System; 3M Unitek) on 1 side and a conventional adhesive (APCII Adhesive Appliance System; 3M Unitek) on the other side. The side allocation was randomized. Bonding was timed to the nearest second. Bond failure was recorded at standardized intervals of 4 weeks. The primary outcome was bonding time (average per tooth for each patient and per quadrant). Secondary outcomes were bracket failure rate within 1 year, time to first-time failure of a bracket, and bond failure type (adhesive remnant index score). Bonding times and adhesive remnant index scores upon bond failure were compared using paired t tests, with P <0.05 considered statistically significant. The adhesives were considered equivalent if the confidence interval for the difference between bracket failure rates fell within a margin of equivalence of ±5%. RESULTS: The bonding times were significantly shorter with the flash-free adhesive than with the conventional adhesive, both per tooth (P <0.001) and per quadrant (P <0.001). Compared with the conventional adhesive, the average bonding times per tooth and per quadrant with the flash-free adhesive were 37.3% and 32.9% shorter, respectively. The bracket failure rates at 1 year were 3.7% for the flash-free adhesive and 0.9% for the conventional adhesive. This was statistically equivalent. The average times to first-time failure of a bracket were 25 weeks for the flash-free adhesive and 11 weeks for the conventional adhesive. Although there were no significant differences in the adhesive remnant index scores upon failure (P >0.05), the flash-free adhesive tended to fail more often at the enamel-adhesive interface than did the conventional adhesive. CONCLUSIONS: The use of the flash-free adhesive may result in bonding time savings of approximately one third compared with the conventional adhesive. With regard to bracket survival, a statistically significant difference was not found between the 2 adhesives when ceramic brackets were bonded. REGISTRATION: This trial was registered on December 3, 2013 (ClinicalTrials.gov ID, NCT02030002). PROTOCOL: The protocol was not published before trial commencement.

Alternative cone-beam computed tomography method for the analysis of bone density around impacted maxillary canines.

INTRODUCTION: Genetic and environmental etiologic factors have been described for maxillary canine impaction, except for the trabecular bone characteristics in the impacted area. The aim of this study was to evaluate the surface area and fractal dimension of the alveolar bone on cone-beam computed tomography (CBCT) images of patients with maxillary impacted canines. METHODS: The sample comprised preorthodontic treatment CBCT images of 49 participants with maxillary impacted canines (31 unilateral and 18 bilateral). CBCT images were acquired in portrait mode (17 × 23 cm high field of view) at 120 kV, 5 mA, 8.9-seconds exposure time, and 0.3-mm voxel size. Coronal slices (0.3 mm) were obtained from the right and left alveolar processes between the first and second maxillary premolars. We collected 64 × 64-pixel regions of interest between the premolars to assess maxillary bone area and fractal dimension using ImageJ software (National Institutes of Health, Bethesda, Md). Comparisons were made using paired t tests and linear regression. Repeated measurements were obtained randomly from about 20% of the sample. RESULTS: In subjects with unilateral impactions, the maxillary bone area (P = 0.0227) was higher in the impacted side, with a mean difference of 245.5 pixels (SD, 569.2), but the fractal dimension (P = 0.9822) was not, -0.0003 pixels (SD, 0.082). Comparisons of unilateral and bilateral subjects using a general linear mixed model test confirmed the increased bone area in the impacted side (P = 0.1062). The repeated measurements showed similar results. CONCLUSIONS: The maxillary alveolar bone area is increased in the impacted side compared with the nonimpacted side.