Solitary fibrous tumor of deep parotid gland preoperatively classified as salivary gland neoplasm of uncertain malignant potential by the Milan system for reporting salivary gland cytopathology: A common diagnosis for a rare entity.

Solitary fibrous tumor (SFT) is a rare fibroblastic tumor with spindle cell morphology, which is characterized by a prominent branching vasculature and a NAB2-STAT6 gene rearrangement. SFT may occur in any anatomical site and may involve salivary glands, including the parotid gland. We present a young female with a primary parotid SFT diagnosed as "neoplasm-Salivary gland neoplasm of uncertain malignant potential (SUMP)" per the Milan system for reporting salivary gland cytopathology by fine-needle aspiration (FNA) with surgical pathology follow-up. Cytomorphology of SFT is diverse and overlaps with more common entities causing a diagnostic challenge. Non-diagnostic FNA results are not uncommon. Thankfully, the majority of SFTs involving the salivary gland can be identified as "neoplasm" on FNA. The Neoplasm-SUMP subcategory is considered for the majority of cases, which would warrant a diagnostic excision with clear surgical margins, which is also curative in most cases. The Neoplasm-SUMP also perfectly encompasses the neoplastic behavior of SFT, which runs on a scale from indolent to malignant.

Succinate dehydrogenase-deficient gastrointestinal stromal tumor of stomach diagnosed by endoscopic ultrasound-guided fine-needle biopsy: Report of a distinct subtype in cytology.

Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are characterized by the lack of mutations in KIT receptor tyrosine kinase complex and platelet derived growth factor receptor-alpha (PDGFRA) that are commonly found in the majority of GISTs. SDH-deficient GISTs comprise approximately 5%-10% of all GISTs. This subset may be associated with Carney Triad and Carney-Stratakis syndrome. SDH-deficient GISTs show unique demographic, radiologic, morphologic findings, clinical behavior, and treatment response. To our knowledge, the identification and characterization of this subset of GISTs have not yet been described in the cytopathology literature. By understanding the clinical as well as the other unique features of this tumor, in addition to the rapidly evolving identification of specific molecular alterations and targeted therapies, cytopathologists may play an important role in the diagnosis and work-up of these patients to allow clinicians to better manage and treat them. We present a young female with gastric SDH-deficient GIST diagnosed by fine-needle biopsy with supporting surgical pathology follow-up and molecular confirmation. This report suggests that the diagnosis of SDH-deficient GIST can be made on cytology in the appropriate clinical setting by using cytomorphologic features and demonstrating SDH loss by IHC on the cell block. In addition, molecular testing may be possible on the cytology cell block or supernatant to confirm the diagnosis.

Copper Deficiency after Gastric Bypass for Morbid Obesity: a Systematic Review.

A large number of patients undergoing bariatric surgery are deficient in copper, and Roux-en-Y gastric bypass can further aggravate it. Delays in diagnosis and treatment of copper deficiency can leave patients with residual neurological disability. This has led to recommendation from the British Obesity and Metabolic Surgery Society that copper levels should be monitored annually after gastric bypass. This review concludes that copper deficiency in adequately supplemented patients is rare and can be adequately treated if a related haematological or neurological disorder is diagnosed. The cost of routine monitoring may therefore not be justified for adequately supplemented, asymptomatic patients who have undergone Roux-en-Y gastric bypass. The screening may however be necessary for high-risk patient groups to prevent severe complications and permanent disability.

Area postrema undergoes dynamic postnatal changes in mice and humans.

The postnatal period in mammals represents a developmental epoch of significant change in the autonomic nervous system (ANS). This study focuses on postnatal development of the area postrema, a crucial ANS structure that regulates temperature, breathing, and satiety, among other activities. We find that the human area postrema undergoes significant developmental changes during postnatal development. To characterize these changes further, we used transgenic mouse reagents to delineate neuronal circuitry. We discovered that, although a well-formed ANS scaffold exists early in embryonic development, the area postrema shows a delayed maturation. Specifically, postnatal days 0-7 in mice show no significant change in area postrema volume or synaptic input from PHOX2B-derived neurons. In contrast, postnatal days 7-20 show a significant increase in volume and synaptic input from PHOX2B-derived neurons. We conclude that key ANS structures show unexpected dynamic developmental changes during postnatal development. These data provide a basis for understanding ANS dysfunction and disease predisposition in premature and postnatal humans.

Deterministic transfection drives efficient nonviral reprogramming and uncovers reprogramming barriers.

Safety concerns and/or the stochastic nature of current transduction approaches have hampered nuclear reprogramming's clinical translation. We report a novel non-viral nanotechnology-based platform permitting deterministic large-scale transfection with single-cell resolution. The superior capabilities of our technology are demonstrated by modification of the well-established direct neuronal reprogramming paradigm using overexpression of the transcription factors Brn2, Ascl1, and Myt1l (BAM). Reprogramming efficiencies were comparable to viral methodologies (up to ~9-12%) without the constraints of capsid size and with the ability to control plasmid dosage, in addition to showing superior performance relative to existing non-viral methods. Furthermore, increased neuronal complexity could be tailored by varying BAM ratio and by including additional proneural genes to the BAM cocktail. Furthermore, high-throughput NEP allowed easy interrogation of the reprogramming process. We discovered that BAM-mediated reprogramming is regulated by AsclI dosage, the S-phase cyclin CCNA2, and that some induced neurons passed through a nestin-positive cell stage. FROM THE CLINICAL EDITOR: In the field of regenerative medicine, the ability to direct cell fate by nuclear reprogramming is an important facet in terms of clinical application. In this article, the authors described their novel technique of cell reprogramming through overexpression of the transcription factors Brn2, Ascl1, and Myt1l (BAM) by in situ electroporation through nanochannels. This new technique could provide a platform for further future designs.

A multi-resolution textural approach to diagnostic neuropathology reporting.

We present a computer aided diagnostic workflow focusing on two diagnostic branch points in neuropathology (intraoperative consultation and p53 status in tumor biopsy specimens) by means of texture analysis via discrete wavelet frames decomposition. For intraoperative consultation, our methodology is capable of classifying glioblastoma versus metastatic cancer by extracting textural features from the non-nuclei region of cytologic preparations based on the imaging characteristics of glial processes, which appear as anisotropic thin linear structures. For metastasis, these are homogeneous in appearance, thus suitable and extractable texture features distinguish the two tissue types. Experiments on 53 images (29 glioblastomas and 24 metastases) resulted in average accuracy as high as 89.7 % for glioblastoma, 87.5 % for metastasis and 88.7 % overall. For p53 interpretation, we detect and classify p53 status by classifying staining intensity into strong, moderate, weak and negative sub-classes. We achieved this by developing a novel adaptive thresholding for detection, a two-step rule based on weighted color and intensity for the classification of positively and negatively stained nuclei, followed by texture classification to classify the positively stained nuclei into the strong, moderate and weak intensity sub-classes. Our detection method is able to correctly locate and distinguish the four types of cells, at 85 % average precision and 88 % average sensitivity rate. These classification methods on the other hand recorded 81 % accuracy in classifying the positive and negative cells, and 60 % accuracy in further classifying the positive cells into the three intensity groups, which is comparable with neuropathologists' markings.

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (

Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice.

Late embryonic and postnatal cerebellar folial surface area expansion promotes cerebellar cortical cytoarchitectural lamination. We developed a streamlined sampling scheme to generate unbiased estimates of murine cerebellar surface area and volume using stereologic principles. We demonstrate that, during the proliferative phase of the external granular layer (EGL) and folial surface area expansion, EGL thickness does not change and thus is a topological proxy for progenitor self-renewal. The topological constraints indicate that, during proliferative phases, migration out of the EGL is balanced by self-renewal. Progenitor self-renewal must, therefore, include mitotic events yielding 2 cells in the same layer to increase surface area (ß events) and mitotic events yielding 2 cells, with 1 cell in a superficial layer and 1 cell in a deeper layer (α events). As the cerebellum grows, therefore, ß events lie upstream of α events. Using a mathematical model constrained by the measurements of volume and surface area, we could quantify intermitotic times for ß events on a per-cell basis in postnatal mouse cerebellum. Furthermore, we found that loss of CCNA2, which decreases EGL proliferation and secondarily induces cerebellar cortical dyslamination, shows preserved α-type events. Thus, CCNA2-null cerebellar granule progenitor cells are capable of self-renewal of the EGL stem cell niche; this is concordant with prior findings of extensive apoptosis in CCNA2-null mice. Similar methodologies may provide another layer of depth to the interpretation of results from stereologic studies.

Perioperative Enteral Immunonutrition Modulates Systemic and Mucosal Immunity and the Inflammatory Response in Patients With Periampullary Cancer Scheduled for Pancreaticoduodenectomy: A Randomized Clinical Trial.

OBJECTIVES: Nutritional deficiencies and immune dysfunction in cancer patients may contribute to postoperative septic morbidity. This trial compared the effects of perioperative enteral immunonutrition (EIN) versus standard enteral nutrition (SEN) on systemic and mucosal immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer. METHODS: Thirty-seven patients were randomized (EIN, n = 17; SEN, n = 20) to receive feed for 14 days preoperatively and 7 days postoperatively. Mediators of systemic immunity (interleukin 1α, tumor necrosis factor α, lymphocytes subsets, and complement components) and of mucosal immunity in duodenal biopsies, nutritional markers and parameters were evaluated. RESULTS: The groups were comparable for demographics, the concentrations of mediators of systemic and mucosal immunity at time of recruitment, and for the duration and amount of feed received. Preoperative EIN rather than SEN was associated with significant reductions in plasma tumor necrosis factor α and total hemolytic complement. Enteral immunonutrition-fed patients had significantly higher total lymphocyte count on the third postoperative day and significantly greater rise in CD4/CD8 ratio from day 3 to day 7 postoperatively compared with SEN-fed patients. CONCLUSIONS: The perioperative administration of EIN rather than SEN is associated with a favorable modulation of the inflammatory response and enhancement of systemic immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer.

Admission levels of serum amyloid a and procalcitonin are more predictive of the diagnosis of acute appendicitis compared with C-reactive protein.

BACKGROUND: Acute appendicitis is the commonest surgical emergency, but its diagnosis can be elusive with a negative appendicectomy rate of 20%. The aims of this study were to investigate the potential value of the markers of acute inflammation, serum amyloid A (SAA), and serum procalcitonin (ProCT), in the diagnosis of acute appendicitis in adults and to compare that with the commonly used serum C-reactive protein (CRP). METHODS: Adult patients presenting with acute right lower abdominal pain and a clinical suspicion of acute appendicitis were included. Blood samples were obtained within 6 hours of admission for rapid serum CRP assay and for end-of-recruitment batch analysis of SAA and serum ProCT concentrations. RESULTS: A total of 147 patients (81 males) with a mean (±SD) age of 36 (±17) years were recruited. Appendicitis was confirmed histologically in 61 of 72 patients (84.7%) who underwent appendicectomy. A post hoc analysis revealed a diagnostic sensitivity and specificity for SAA of 92% and 72%, ProCT of 85% and 74%, and CRP of 75% and 72%, respectively. The receiver operator characteristics for the area under the curves showed that SAA (P=0.011) and ProCT (P=0.037) significantly exceeded CRP in the prediction of acute appendicitis on admission. CONCLUSIONS: The measurement of SAA and serum ProCT on admission in patients with clinically suspected acute appendicitis seems to outperform serum CRP in aiding that diagnosis.

Cerebellar cortical lamination and foliation require cyclin A2.

The mammalian genome encodes two A-type cyclins, which are considered potentially redundant yet essential regulators of the cell cycle. Here, we tested requirements for cyclin A1 and cyclin A2 function in cerebellar development. Compound conditional loss of cyclin A1/A2 in neural progenitors resulted in severe cerebellar hypoplasia, decreased proliferation of cerebellar granule neuron progenitors (CGNP), and Purkinje (PC) neuron dyslamination. Deletion of cyclin A2 alone showed an identical phenotype, demonstrating that cyclin A1 does not compensate for cyclin A2 loss in neural progenitors. Cyclin A2 loss lead to increased apoptosis at early embryonic time points but not at post-natal time points. In contrast, neural progenitors of the VZ/SVZ did not undergo increased apoptosis, indicating that VZ/SVZ-derived and rhombic lip-derived progenitor cells show differential requirements to cyclin A2. Conditional knockout of cyclin A2 or the SHH proliferative target Nmyc in CGNP also resulted in PC neuron dyslamination. Although cyclin E1 has been reported to compensate for cyclin A2 function in fibroblasts and is upregulated in cyclin A2 null cerebella, cyclin E1 expression was unable to compensate for loss-of cyclin A2 function.

Duration of surgery independently influences risk of venous thromboembolism after laparoscopic bariatric surgery.

BACKGROUND: Obesity is a recognized risk factor for venous thromboembolism (VTE). The aims of the present study were to determine the risk factors for symptomatic VTE in morbidly obese patients undergoing laparoscopic bariatric surgery. METHODS: This was a retrospective study that included consecutive patients who had undergone bariatric surgery from January 2007 to May 2010. Thromboprophylaxis included routine application of low-molecular-weight heparin, pneumatic calf compression, and early ambulation. Extensive measures, such as temporary insertion of a caval filter (n = 5) and anticoagulation (n = 11), were used in selected higher risk patients. The patients were followed up for a minimum of 3 months after surgery to determine the incidence of clinical VTE. The results are presented as the mean and range. RESULTS: A total of 500 consecutive patients aged 44.7 years (range 19-77) with a body mass index of 49.2 kg/m(2) (range 32.1-84.3) underwent laparoscopic bariatric surgery (442 gastric bypass, 20 sleeve gastrectomy, and 38 gastric banding). No conversions to open surgery occurred, and the operative time, morbidity rate, and mortality rate was 93.7 minutes (range 20-325), 2.8%, and .2%, respectively. No clinical deep vein thrombosis was encountered, although 3 patients (.6%) developed pulmonary embolism. Cox regression multivariate analysis identified the operative time as the only independent predictor of postoperative VTE (relative risk .0002 per min, P = .009). Multivariate analysis identified the body mass index as an independent predictor of the operating time. CONCLUSION: Increasing obesity was associated with a longer operative time, which consequently increased the risk of VTE.

Incidence of perforated gastrojejunal anastomotic ulcers after laparoscopic gastric bypass for morbid obesity and role of laparoscopy in their management.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (RYGB) is a well-established procedure to treat morbid obesity. Gastrojejunal anastomotic (GJA) ulcers can develop after surgery with subsequent perforation. Our aim was to evaluate the incidence, presentation and outcome of management of perforated GJA ulcer disease after laparoscopic RYGB. METHODS: The database of all patients at the senior author's bariatric institutions was retrospectively reviewed. The results are presented as mean (range). RESULTS: From April 2002 to April 2010, 1213 patients underwent laparoscopic RYGB, which included 1184 primary and 29 revision procedures. The operative mortality was .15%. Ten patients developed perforated GJA ulcers (.82%) at a mean of 13.5 (6-19) months. The patients who presented to bariatric surgeons (n = 5) were treated with laparoscopic closure and an omental patch, and those who presented to nonbariatric surgeons (n = 5) were treated with laparotomy. The morbidity and mortality rate was 30% and 10%, respectively, and the mean postoperative hospital stay for the survivors was 14 (5-44) days. CONCLUSION: Perforated GJA ulcers can develop in 1 of 120 patients after laparoscopic RYGB and can be effectively managed by laparoscopic repair with an omental patch, if expertise is available.

Predictors of remission of type 2 diabetes mellitus after laparoscopic gastric banding and bypass.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with obesity and results in considerable morbidity and mortality. Our objectives were to evaluate the effect of laparoscopic bariatric surgery on the control of T2DM in morbidly obese patients in a U.K. population and to determine the predictors of T2DM remission after bariatric surgery. The study was performed at teaching university hospitals and affiliated private hospitals. METHODS: Of 487 patients who underwent laparoscopic bariatric procedures from 2002 to 2007, 74 patients (15.2%) had established T2DM. The results are presented as the mean values. Multivariate analysis was used to identify the factors predictive of remission of T2DM after bariatric surgery. RESULTS: The body mass index before laparoscopic gastric bypass (LGB; n = 48) and laparoscopic adjustable gastric banding (LAGB; n = 26) were comparable (52 versus 51 kg/m(2), P = .508). At a mean follow-up of 16.9 months, 41% had remission and 59% had experienced improvement in T2DM. Although the duration of follow-up was significantly longer for the patients who had undergone LAGB than for those who had undergone LGB (23 versus 13.4 months, P = .001), the percentage of excess weight loss (%EWL) was significantly greater after LGB than after LAGB (59.4% versus 48.8%, P = .031), with an associated greater remission rate of T2DM (50% versus 24%, P = .034). Multivariate analysis revealed a greater %EWL and younger age to be independent predictors of postoperative remission of T2DM, and LGB, longer follow-up, and female gender were independent predictors of a greater %EWL. CONCLUSION: The %EWL was the only predictor of remission of T2DM that was influenced by the choice of bariatric procedure. In our study, LGB offered greater weight loss and a chance of remission of T2DM compared with LAGB and within 2 years of surgery.

Gut barrier dysfunction in critically ill surgical patients with abdominal compartment syndrome.

OBJECTIVES: This study investigated the effects of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) on gut barrier function in critically ill surgical patients. METHODS: A prospective observational cohort study on patients with severe acute pancreatitis or abdominal sepsis admitted to an intensive care or high-dependency unit. Intra-abdominal pressure (IAP) and plasma levels of immunoglobulin G (IgG) and IgM antiendotoxin core antibodies (EndoCAb) and procalcitonin (ProCT) were measured serially. RESULTS: Among 32 recruited patients, 24 (75%) and 8 patients (25%) developed IAH and ACS, respectively. The state of ACS was associated with significant reductions in plasma IgG EndoCAb (P = 0.015) and IgM EndoCAb (P = 0.016) and higher concentrations of plasma ProCT (P = 0.056) compared with absence of ACS. Resolution of IAH and ACS was associated with significant recovery of plasma IgG EndoCAb (P = 0.003 and P = 0.009, respectively) and IgM EndoCAb (P = 0.002 and P = 0.003, respectively) and reduction in plasma ProCT concentration (P = 0.049 and P = 0.019, respectively). Negative correlations were observed between IAP and plasma IgG EndoCAb (P = 0.003) and IgM EndoCAb (P = 0.002). CONCLUSIONS: Intra-abdominal hypertension and ACS are associated with significantly higher endotoxin exposure and ProCT concentrations, suggestive of gut barrier dysfunction. Resolution of IAH and ACS is associated with evidence for recovery of gut barrier function.

Revision laparoscopic gastric bypass: an effective approach following failure of primary bariatric procedures.

BACKGROUND: The laparoscopic approach plays an important role in the primary surgical management of morbid obesity. This study evaluated the potential role of the laparoscopic approach to revision Roux-en-Y gastric bypass (LRYGB) in the management of selected patients who fail to lose adequate weight or regain weight after primary bariatric surgery. METHODS: Revision LRYGB was carried out to remedy early or delayed failure of primary bariatric procedures. Patients who underwent laparoscopic revision surgery to re-establish a functioning gastric band were not included in this report. The results are presented as mean (SD). RESULTS: Between April 2002 and March 2009, 21 patients underwent 21 laparoscopic revision procedures. The initial bariatric operations were laparoscopic gastric band (n = 10), open vertical banded gastroplasty (n = 6), open Magenstrasse and Mill (n = 2), open gastric bypass with pouch dilatation (n = 2), and open gastric band (n = 1). All revision procedures were completed laparoscopically and included conversion to LRYGB (n = 19), and others (n = 2). The postoperative hospital stay was 2.0 (1.3) days. The anastomotic leak, morbidity, and mortality rates were 0%, 4.8%, and 0% respectively. At a follow-up of 12.9 (7.9) months, the prerevision body mass index has decreased significantly from 43.9 (7.4) to 32.7 (6.6) kg/m(2) (p < 0.001) with a percentage excess weight loss of 61.1 (21.2). CONCLUSIONS: The laparoscopic approach to revision Roux-en-Y gastric bypass is safe and effective even in patients with previous open bariatric surgery and is associated with rapid recovery and short hospital stay.

Laparoscopic drainage of pancreatic pseudocysts: a methodological approach.

BACKGROUND: This paper describes our tailored and methodological approach to laparoscopic drainage of pancreatic pseudocysts (PPs) based on an anatomical classification. METHODS: We adopted the laparoscopic approach in "all comers" who had PPs requiring surgical drainage. The recipient organ for drainage (e.g., cystgastrostomy, cystjejunostomy, or cystduodenostomy) and method of access (e.g., transgastric, endogastric, exogastric or lesser sac, and infracolic) were decided based on preoperative computed tomography (CT) and intraoperative findings. The results shown represent median (range). RESULTS: Between 2001 and 2009, 30 laparoscopic drainage procedures for PPs were performed in 28 consecutive patients. The surgical approach included transgastric (n = 17) or endogastric (n = 3) cystgastrostomy for large retrogastric PPs (n = 20), exogastric cystgastrostomy for small perigastric PPs (n = 4), cystduodenostomy (n = 1) under ultrasound guidance, cystjejunostomy for infracolic PPs (n = 4), and one external drainage. The operative time was 118 (25-300) min. There was one conversion to laparotomy (3.3%), low morbidity (3.3%), and no mortality. The postoperative hospital stay was 2 (1-7) days. At a follow-up of 15 (1-48) months, PPs recurred in two patients (7.1%) and were drained by laparoscopic cystgastrostomy. CONCLUSION: CT findings and laparoscopic exploration demonstrate the anatomical characteristics of PPs and enable successful planning and execution of their laparoscopic drainage.

Do we need histology for a normal-looking gallbladder?

BACKGROUND/PURPOSE: Gallbladder cancer (GBC) is a rare malignancy with poor overall prognosis. Simple cholecystectomy is curative if the cancer is limited to mucosa. We aimed here to investigate the need for routine histological examination of gallbladder. METHODS: We carried out a retrospective review of 2890 final pathology reports of processed gallbladder specimens following cholecystectomy due to gallstones disease. The review covered the 10-year period from 1994 to 2004. The notes of all cases of gallbladder cancer were scrutinized, with particular emphasis on presentation, preoperative diagnostic tools using abdominal ultrasound and computed tomography scan, operative findings, and the histology results. RESULTS: Gallbladder cancer (GBC) was detected in five specimens (0.17%), dysplasia in six (0.2%), and secondaries to gallbladder in three (0.1%). Histological findings confirmed gallstone disease in 97% and rare benign pathology in 3%. The median age of patients with GBC was 61 years (range, 59-84 years). In all five patients, cancer was isolated from thickened fibrotic wall on macroscopic appearance and spread through all layers of the gallbladder wall. The percentage of thickened-wall gallbladder in this study was 38.02% and the cancer incidence in the thickened wall was 0.45%. CONCLUSIONS: A selective policy rather than routine histological examination of nonfibrotic or thickened-wall gallbladder has to be considered. This will reduce the burden on pathology departments, with significant cost savings.