High Risk Of Malignant Transformation Research Articles

PDCT-08. SUPERIOR OUTCOME FOR BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION

Abstract BACKGROUND Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined. METHODS We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters. RESULTS Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003). CONCLUSION The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.

Intraductal Papillary Neoplasia of Bile Duct: A Rare Liver Tumor

Intraductal biliary papillary neoplasia (IPNB) is a rare disease involving both the intrahepatic and the extrahepatic biliary tract. It usually occurs in the 6th and 7th decades of life and may present with acute cholangitis. The pathogenesis, clinical features and outcome are not well documented. Because of the high risk of malignant transformation, surgical resection is the best choice of treatment. We present the case of IPNB of the left intrahepatic biliary tract in a 49-year-old male, who was admitted to the hospital with right upper quadrant abdominal pain. Laboratory tests showed mild elevation of C reactive protein (CRP), alanine aminotransferase (ALT), aspartate transaminase (AST) and gamma glutamyl trans-peptidase (GGT). Imaging demonstrated dilatation of the intrahepatic and common bile ducts, and a 2x3 cm mass in the left lobe of the liver. A 3D magnetic resonance cholangiopancreatography (MRCP) confirmed an intraductal polypoid lesion. A typical left hepatectomy was performed. A papillary tumor was found in the left intrahepatic biliary duct. Histolopathological examination demonstrated biliary papillomatosis with high grade dysplasia, but no malignant transformation. No recurrence was detected at 6-month follow-up. Intrahepatic biliary papillomatosis is a rare tumor of the biliary ducts, both intrahepatic and extrahepatic. Surgical resection is considered the optimal treatment for biliary papillomatosis because of the risk of malignant transformation. Magnetic resonance cholangiopancreatography is a useful preoperative diagnostic examination that can show papillary lesions in the bile ducts. In patients without distant organ and lymph node metastasis, resection provides long-term survival.

3224 A Rare Case of Duodenal Adenocarcinoma in Situ Arising in the Background of Villous Adenoma

INTRODUCTION: Villous adenomas (VA) of the small bowel are the most common benign periampullary neoplasms with the highest potential for malignant transformation to adenocarcinoma. Adenocarcinoma of the small bowel accounts for only 1% of all gastrointestinal malignancies and duodenal adenocarcinoma (DA) constitutes approximately half of these cases. Although a rare and aggressive cancer, DA has the more favorable outcomes than other periampullary malignancies. Hence, it is important to understand the pathogenesis of DA as well as pre-malignant lesions such as VA. We present a male with long standing history of iron deficiency anemia found to have a duodenal mass identified as adenocarcinoma in situ arising in the background of VA. CASE DESCRIPTION/METHODS: A 73-year-old male, with a medical history of hypertension, Hepatitis C status post treatment and iron-deficiency anemia was referred for anemia with a hemoglobin of 6.2. He reported recent fatigue with no dyspnea, chest pain, melena, hematochezia or hematemesis. Colonoscopy 1-year ago was significant for a tubular adenoma with recommendation to repeat procedure in 5 years. Patient was transfused 1 unit of red blood cells on admission and started on oral iron supplement. He remained hemodynamically stable. Push enteroscopy showed a circumferential mass in the 3rd portion of the duodenum without obstruction. Biopsy noted adenocarcinoma in situ arising in the background of villous adenoma. Patient was evaluated by the surgical team with a plan for resection and subsequent follow-up with an Oncologist. DISCUSSION: VA accounts for only 1% of all duodenal tumors. Given their rarity, pathogenesis and rate of transformation to adenocarcinoma is unclear. Symptoms associated with VA depends on their location in the duodenum and can range from vague abdominal complains to biliary or small bowel obstruction, pancreatitis or iron deficiency anemia. Iron deficiency anemia in our patient was likely secondary to impaired absorption of iron in the duodenum due to the mass. Duodenal adenomas are associated with an increased risk of colonic adenomas, similar to our patient given his history of tubular adenoma in the colon. Hence, concomitant colonoscopy is warranted for early diagnosis of potentially pre-malignant colonic lesions in patients with duodenal adenomas. With regards to treatment, complete resection of VA is recommended given their high risk of malignant transformation.

POTENTIAL IDENTIFICATION OF PREVIOUSLY UNRECOGNIZED GARDNER SYNDROME DURING RADIOLOGIC EXAMINATION: A CASE REPORT

<h3>Background</h3> Familial adenomatous polyposis coli (FAP) is an autosomal dominant inherited disorder characterized by the development of multiple colonic adenomas with high risk for malignant transformation. FAP is caused by mutation of the adenomatous polyposis coli (APC) gene, a tumor suppressor. Several <i>APC</i> codon mutations result in a spectrum of intra- and extra-colonic manifestations. Gardner syndrome is a subset of FAP with potential extraintestinal findings, including epidermoid and sebaceous cysts, lipomas, supernumerary and impacted teeth, odontomas, jaw osteomas, and desmoid tumors/desmoplastic fibromas. Desmoplastic fibromas are benign aggressive neoplasms with potential tissue morbidity. <h3>Discussion/Conclusions</h3> A 15-year-old Caucasian male was referred to the oral and maxillofacial radiology clinic for radiologic evaluation of a left posterior mandibular radiolucency. The patient complained of pain at the site. His medical and dental histories was positive for biopsy of multiple epidermoid cysts, a fibrous tissue mass on the lower back, and 2 odontomas. Thus far, the patient had not been identified to be at risk for Gardner syndrome. Panoramic and cone beam computed tomography (CBCT) radiographs were made and showed nonuniform hyperdensities throughout the jaws, impacted teeth, and a well-defined, multilocular, radiolucent lesion at the angle of the left mandible demonstrating expansion. Impressions favored a benign aggressive entity of the left mandibular angle, and biopsy was recommended. The biopsy results were consistent with desmoplastic fibroma. Surgical resection was performed. Based on the collective findings, the diagnosis of Gardner syndrome was proposed. The patient was referred for genetic counselling and genetic testing for himself and his immediate family members. The results of molecular diagnosis are pending. Identification of FAP-related clinical and radiographic manifestations is crucial to early identification of FAP, which has important considerations in periodic evaluation for colon neoplasms and surgical prophylaxis. Early referral by an attentive radiologist can increase the opportunity for more effective disease management.

The Interplay between Colon Cancer Cells and Tumour-Associated Stromal Cells Impacts the Biological Clock and Enhances Malignant Phenotypes.

Cancer cells interrelate with the bordering host microenvironment that encompasses the extracellular matrix and a nontumour cellular component comprising fibroblasts and immune-competent cells. The tumour microenvironment modulates cancer onset and progression, but the molecular factors managing this interaction are not fully understood. Malignant transformation of a benign tumour is among the first crucial events in colorectal carcinogenesis. The role of tumour stroma fibroblasts is well-described in cancer, but less well-characterized in benign tumours. In the current work we utilized fibroblasts isolated from tubulovillous adenoma, which has high risk for malignant transformation, to study the interaction between benign tumour stroma and the circadian clock machinery. We explored the role of the biological clock in this interplay taking advantage of an experimental model, represented by the co-culture of colon cancer cells with normal fibroblasts or tumour-associated fibroblasts, isolated from human colorectal tumour specimens. When co-cultured with tumour-associated fibroblasts, colon cancer cells showed alterations in their circadian and metabolic parameters, with decreased apoptosis, increased colon cancer cell viability, and increased resistance to chemotherapeutic agents. In conclusion, the interactions among colon cancer cells and tumour-associated fibroblasts affect the molecular clockwork and seem to aggravate malignant cell phenotypes, suggesting a detrimental effect of this interplay on cancer dynamics.

Anti-gastric parietal cell antibodies for autoimmune gastritis screening in juvenile autoimmune thyroid disease.

Patients with autoimmune thyroid disease (ATD) have a higher prevalence of autoimmune gastritis (AIG) compared with the general population. The association between ATD and AIG is poorly characterized in the pediatric age. We reviewed the prevalence of anti-gastric parietal cell antibodies (PCA) in young patients with ATD to evaluate its usefulness as a marker for AIG screening. We evaluated 220 children and adolescents (11.28 ± 6.37years) with ATD (186 with autoimmune thyroiditis (AT) and 34 with Graves' disease (GD). At ATD diagnosis and annually thereafter, blood counts and PCA levels were measured. In patients positive for PCA, plasma gastrin, chromogranin A, vitamin B12, iron and ferritin levels and H. pylori antigen were measured. PCA-positive patients > 18years were invited to undergo a gastroscopic exam. PCA positivity was detected in ten (4.5%) subjects (5F/5M; 12.6 ± 3.4years). The prevalence of PCA positivity was not significantly different in the comparison of GD and AT patients (p = 0.9). PCA positivity was detected after 2.7 ± 2.7years of follow-up in AT and 4.4 ± 4.0years in GD (p = 0.4). Autoantibody positivity was more prevalent in female patients, in both AT and GD (p = 0.02 and p = 0.03, respectively). At detection of PCA positivity, five out of ten PCA-positive patients had iron deficiency, four vitamin B12 deficiency, two anemia, three hypergastrinemia and two elevated chromogranin values. Two patients had H. pylori infection. Gastroscopy was performed in the five ATD patients and in all patients, AIG was confirmed. In the juvenile population, ATD and AIG may also be associated. PCA screening is useful to detect subjects at risk for this condition. Due to the longer life expectancy of the pediatric population and considering the relatively high risk of malignant transformation, early surveillance monitoring is mandatory for children and adolescents with ATD.

Oral lichenoid dysplasia and not oral lichen planus undergoes malignant transformation at high rates.

Oral potentially malignant disorders (OPMD) include a variety of mucosal lesions such as oral lichen planus (OLP), oral lichenoid lesions (OLL) and oral lichenoid dysplasia (OLD). Their rate of malignant transformation ranges from 0% to 34% and is dependent on OPMD type, lesion site and a range of risk factors. This study seeks to determine the proportion of oral lichenoid conditions that transform into oral squamous cell carcinoma (OSCC) in an Australian population. The study is a retrospective audit of patients from a private oral medicine clinic, diagnosed with OLP, OLL or OLD using clinical and histopathological data between 2006 and 2014. Patients were cross-matched with Cancer Registry data for OSCC, and the rate and time to malignant transformation determined. OLP and OLL patients displayed a low risk of malignant transformation; 0.49% (1/206) for OLP and 0% (0/31) for OLL. In contrast, OLD patients, all of whom presented clinically as OLP, were at much higher risk with 6.81% (3/44) developing OSCC over an average time of 4.6years (±2.4 SD). Rates of smoking and alcohol consumption were no higher in OLD patients compared to others. Compared with other oral lichenoid conditions, OLD lesions are at a particularly high risk of malignant transformation and should be managed based on the presence of dysplasia and not the lichenoid inflammatory infiltrate. OLP demonstrates a relativelylow rate of malignant transformation. Diagnostic histopathology is important for discriminating OLP from OLD.

An analysis of surveillance screening for SDHB-related disease in childhood and adolescence.

ObjectivePhaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected.MethodWe undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations.ResultsClinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation-positive asymptomatic carriers with 175 patient years of follow-up data. Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening.ConclusionsSurveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.

Malignant transformation of sacrococcygeal teratoma with voluminous mesentery cyst: a case study conducted in Bamako

Malignant sacrococcygeal teratoma is a rare congenital embryonal tumor at high risk of malignant transformation. We report the case of a 20-month old female infant. She was the couple's fourth child. Her mother was 29 years old, she had four pregnancies with vaginal deliveries. All the infants were born alive. The woman was not properly followed during pregnancy. She had vaginal delivery at term and had correctly attended expanded programme on immunization (EPI) with positive reaction to BCG vaccine. The child walked autonomously at 13 months. She had painful fluctuating inguinal and left labium major swelling (A), distended abdomen with oozing wound measuring 4cm/3cm on the right buttock (A). Frontal x-rays of abdomen without preparation showed distended flaccid abdomen with opacity in the periumbilical region as well as in the hypogastric region (B). Ultrasound objectified voluminous calcified sub-vescical tissue mass measuring 87*54 mm (C). Thoracoabdominal CT scan showed calcified sacrococcygeal tissue mass measuring 83*59 mm, with modest fissure in the left pubis and abdominal cyst without wall (D,E). Moreover, there were nodules of variable size in the lungs and the liver (F,G). The infant was treated by an oncopediatric team.

Bio-impedance analysis of mucosal tissues of the oral cavity: a comparison between healthy patients and patients affected by oral lichen planus

Event Abstract Back to Event Bio-impedance analysis of mucosal tissues of the oral cavity: a comparison between healthy patients and patients affected by oral lichen planus Christian Bacci1*, Matteo Cocco1, Alessia Cerrato1, Elisa Bardhi1, Ludovica Pampaloni1 and Gastone Zanette1 1 University of Padova, Department of Neurosciences - section of Clinical Dentistry, Italy Aim. Lichen Planus is a chronic inflammatory autoimmune disease that may affect the skin, the mucous membranes of the oral cavity and also other mucosae. The prevalence is estimated to be around 1–2% among population worldwide and oral manifestations may appear under various aspects, namely reticular, plaque-like, erosive, atrophic or bullous. The buccal mucosa, the tongue and the gingivae are the most commonly involved, but other areas may be affected too. Erosive OLP shows the highest risk of malignant transformation among the various subtypes. Biolelectrical Impedance analysis is a method used for an accurate evaluation of tissues composition. The bioelectrical impedance data are a combination of capacitive and resistive type elements which, as a result, provide reactance and resistance. Reactance (Xc) should be representative of the opposition of body tissues to the flow of electrical current or voltage and resistance (R) should be representative of the conduction of fluid of the direct or alternating current. According to resistance and reactance, a phase angle (PA, φ) is calculated. PA values may range from 90° to 0° and a correlation between PA values and body cell mass is demonstrated. For example, if a tissue would have been composed of cells membranes only, it would have higher resistance, lower capacitance and a PA value of 90°, whereas a tissue composed mainly by fluids would show lower resistance, higher capacitance a PA value of 0°. According to these evidences, the PA values of neoplastic tissue are expected be lower than those of normal tissue. The aim of the present study is to compare the values of bioimpedance analysis of healthy patients to the values of patients affected by OLP and, if possible, to establish some cut-off values, which could be related to an higher or lower risk of malignant transformation. Materials and Methods. Bioelectrical impedance analysis and PA measurements have been obtained using a special device, (Akern, Bia 101 Anniversary). The measurements were carried out by the same clinician. We evaluated 57 consecutive cases affected by reticular LPalready confirmed at the histological examination (case-group) and 60 heathy patients (control-group). The measurements have been performed in the buccal mucosae, the tongue, hard palate and upper anterior gingiva. Results. Reactance and resistance of hard plate and gum were generally higher in the case-group than in the control-group the results are statistically significant. The mean resistance of hard plate was 75,7 (±13,8) for the control-group and 80,6 (±16,7) for the case group (p 0,044) and the mean reactance was 14,5 (±5,5) for the control group and 17,0 (±6,3) for the case group (p 0,020). The mean resistance of gum was 59,0 (±13,8) in the control group and 78,6 (±30,5) in the case group (p <.0001) and the mean reactance was 13,6 (±5,7) in the control group and 19,6 (±11,8) in the case group (p <.0001). In the case group the mean phase angle of healthy mucosae and reticular lesions were higher than the phase angle of erosive lesions. The mean phase angle of mucosae with no lesions was 12,6 (±1.2), of reticular lesions was 12,4 (±1.7) and of erosive lesions was 11.1 (±0,6). There were no statistically significant differences between healthy mucosae and reticular lesions (p 0,79) but there were statistically significant differences between healthy mucosae than erosive lesions (p 0,005) and reticular lesions than erosive lesions (p 0,04). Discussion. These results provide evidence of the usefulness of bioimpedance assay for the characterization of healthy and clinically OLP affected mucosa. Bioimpedance is a valid aid in the early detection and clinical monitoring of the suspicious lesions which could lead to a potentially malignant evolution.

OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy.

Hepatobiliary phase (HBP) Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has increased the accuracy in differentiating focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). However, the ability of this technique to distinguish HCA subtypes remains controversial. The aim of this study was to investigate the expression of hepatocyte transporters (OATPB1/B3, MRP2, MRP3) in HCA subtypes, hence to understand their MRI signal intensity on HBP Gd-EOB-DTPA-enhanced MRI. By means of immunohistochemistry (IHC), we scored the expression of OATPB1/B3, MRP2 and MRP3, in resected specimens of FNH (n=40), subtyped HCA (n=58) and HCA with focal malignant transformation (HCA-HCC, n=4). Results were validated on a supplementary set of FNH (n=6), subtyped HCA (n=17) and HCA-HCC (n=1) with Gd-EOB-DTPA MR images. All FNH showed a preserved expression of hepatocytes transporters. Beta-catenin-activated HCA (at highest risk of malignant transformation) and HCA-HCC were characterized by preserved/increased OATPB1/B3 expression (predictor of hyperintensity on HBP), as opposed to other HCA subtypes (P<0.01) that mostly showed OATPB1/B3 absence (predictor of hypointensity on HBP). HCA-HCC showed an additional MRP3 overexpressed profile (P<0.01). On HBP Gd-EOB-DTPA-enhanced MRI, FNH and HCA signal intensity reflected the profile predicted by their specific OATPB1/B3 tissue expression. The hyperintense vs hypointense HBP signal criterion was able to distinguish all higher risk HCA and HCA-HCC (100% accuracy). OATPB1/B3 and MRP3 IHC and signal intensity on HBP Gd-EOB-DTPA-enhanced MRI can help to stratify HCA according to their risk of malignant transformation.

Improved Detection of Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasms.

Background Recent work has demonstrated early shedding of circulating epithelial cells (CECs) from premalignant intraductal papillary mucinous neoplasms (IPMNs). However, the potential use of CECs as a "liquid biopsy" for patients with IPMNs has been limited by antigen dependence of CEC isolation devices and the lack of robust detection biomarkers across CEC phenotypes. Materials and methods We utilized a negative depletion microfluidic platform to purify CECs from contaminating leukocytes and coupled this platform with immunofluorescence, RNA in situ hybridization, and RNA sequencing (RNA-seq) detection and enumeration. Results Using established protein (EpCAM, cytokeratins) and novel noncoding RNA (HSATII, cytokeratins) biomarkers, we detected CECs in 88% of patients bearing IPMN lesions. RNA-seq analysis for MUC genes confirm the likely origin of these CECs from pancreatic lesions. Conclusion Our findings increase the sensitivity of detection of these cells and therefore could have clinical implications for cancer risk stratification. Implications for practice This work describes a high-sensitivity platform for detection of epithelial cells shed from preneoplastic lesions at high risk of malignant transformation. Further research efforts are underway to define the transcriptional programs that might allow discrimination between circulating cells released from tumors that will become malignant and cells released from tumors that will not. After further refinement, this combination of technologies could be deployed for monitoring and early detection of patients at high risk for developing new or recurrent pancreatic malignancies.

Is the immunohistochemical classification of resected hepatocellular adenoma < 5 cm of potential clinical interest?

Introduction: Hepatocellular adenomas (HCA)>5cm are usually resected to prevent complications: bleeding, malignant transformation. Immunohistochemical (IHC) classification, based on molecular data is thought to be useful to identify HCA at high risk of malignant transformation if ex 3 b-cat mutated and high risk of bleeding if ASS1+, independently of their size. Unfortunately those HCA are presently not identified by imaging. The aim of this study was to know if complications occur in HCA ≤ 5 cm using IHC for their subtyping. Methods: We reviewed our 218 resected cases with IHC data which include LFABP, CRP/or SAA, GS/b cat, ASS1. We had 65 LFABP negative cases, 70 CRP/SAA+ cases, 33 diffuse or starry sky GS cases meaning ex 3 mutations (20 b-IHCA and 13 b-HCA); 19 other type GS cases interpreted as possible ex 7/8 b-catenin HCA (10 b-IHCA and 9 b-HCA), 22 ASS1+HCA and 9 not classifiable HCA (massive necrosis, or hemorrhage). Among them, we retrieved HCA ≤ 5 cm with complications: clinically significant bleeding or borderline/HCC lesion. Results: In 69 cases, main nodule was ≤5cm. There was no complications among all 23 LFABP negative or 21 CRP/SAA+ HCA. On the opposite: a) borderline/HCC lesions were found in 1 ex3 b-HCA/16 b-HCA/b-IHCA and 2/7 ASS1+HCA; b) clinical hemorrhage was present in 4/16 b-HCA/b-IHCA, 2/7 ASS1+HCA and 2/2 not classifiable HCA. Conclusion: Complications (malignancy, severe hemorrhage) for nodules ≤5cm exist only for b-HCA and ASS1 subtypes, showing the potential interest of IHC HCA classification hoping that data obtained on liver biopsy will confirm these data.

Paradoxes of evidence-based medicine in lower-grade glioma: To treat the tumor or the patient?

Brain lower-grade gliomas (LGG) usually occur in young adults who enjoy an active life. This tumor has a high risk of malignant transformation resulting in neurologic deterioration and finally death. Early and multistage therapeutic management can increase survival over 10 years. Preservation of functional neural networks and quality of life is crucial. In the era of evidence-based medicine, the issues discussed are those associated with the design, analysis, and clinical application of randomized controlled trials (RCTs) for LGG. RCTs should take account of the following: considerable variability in the natural course of LGG; limited prognostic value of molecular biology at the individual level; large variability of brain organization across patients; technical and conceptual progress of therapies over years; combination or repetition of iterative treatments, taken as a whole and not only in isolation; and long-term consequences on oncologic and functional outcomes. As it is difficult to translate the results of an RCT into benefits for a unique patient with LGG, personalized decisions must be made by considering the tumor behavior, individual pattern of neuroplasticity, and patient needs, and not by administrating a standardized protocol exclusively based on an RCT.

Embryological etiology of pancreaticobiliary system predicted from pancreaticobiliary maljunction with incomplete pancreatic divisum: a case report

BackgroundThe genesis of the “complex type” classification of pancreaticobiliary maljunction (PBM) is unclear, and the pancreaticobiliary anatomy is also varied according to each case. We encountered a patient with PBM and incomplete pancreatic divisum (PD). We herein discussed about the embryological etiology of pancreaticobiliary system predicted from PBM with incomplete PD.Case presentationA 67-year-old man was found to have a dilatation of the common bile duct (CBD) during a medical examination at 62 years of age. The dilatation of the CBD subsequently progressed, and he was admitted to our hospital for surgical treatment. Magnetic resonance cholangiopancreatography revealed a dilatation from the common hepatic duct to the middle bile duct with PBM. Endoscopic retrograde cholangiopancreatography from the papilla of Vater revealed the pancreatic main duct via the pancreatic branch duct, and PBM with dilatation of the CBD and incomplete PD were revealed. We performed an extrahepatic bile duct resection and hepaticojejunostomy because of high risk of malignant transformation. Taping and transection of the bile duct without dilatation on the pancreatic side were performed, and thereafter, two orifices of the common channel and ventral pancreatic duct were ligated. The level of amylase in the bile was 7217 IU/L, and a histological examination of the CBD showed an inflammatory change of CBD, not a malignant transformation.ConclusionIt is somewhat easy to identify the pancreatobiliary anatomy when the cause of embryology of both PBM and PD is thought to be an abnormal embryology of the ventral pancreas.

Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver

BackgroundUpregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis (NASH) patients are at high risk for malignant transformation into HCC.MethodsA steatohepatitis-HCC model was established in male C57L/J mice treated with N-nitrosodiethylamine (DEN) and high-fat diet (HFD). A mouse HCC cell line (Hepa1–6) and a mouse hepatocyte line (FL83B) were used to elucidate the mechanism by free fatty acids (FFA) treatment. FGF15, the mouse orthologue of FGF19, and it receptor fibroblast growth factor receptor4 (FGFR4) as well as co-receptor β-klotho were studied. FGF19 signaling was also studied in human samples of HCC with steatohepatitis.ResultsHCC incidence and tumor volume were significantly increased in the DEN+HFD group compared to that in the DEN+control diet (CD) group. Increased levels of FGF15/FGFR4/β-klotho, aberrant epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling were detected in DEN+HFD mice. Blockage of the FGF15 signal can attenuate cell migration ability and aberrant EMT and Wnt/β-catenin signaling.ConclusionsUp-regulated FGF15/FGFR4 signaling promoted the development of HCC by activation of EMT and Wnt/β-catenin signaling in the lipid metabolic disorder microenvironment. Further investigation of FGF19/FGFR4 signaling is important for potential early diagnosis and therapeutic targeting in HCC patients.

Intra-abdominal Sertoli Cell Tumor in Dog with Local and Systemic Repercussions

Background: In dogs, abdominal testes have higher risk of malignant transformation, and the Sertoli cell tumor is the most common type of testicular cancer in the species. This neoplasia can lead to an increase on estrogen production, causing a paraneoplastic feminization syndrome with dermatologic, behavioral and blood repercussions. When located inside theabdomen, the Sertoli cell tumor can compress adjacent organs, worsening the prognosis. Thus, this study aimed to report a case of an intra-abdominal Sertoli cell tumor in a dog associated to multiple organic complications.Case: A 4-year-old male Shih-tzu was admitted at the Veterinary Hospital of Universidade Federal Rural do Semi-Árido (UFERSA), with a history of abdominal cryptorchidism and the development of dermatological signs, such as alopecia and hyperpigmentation, with an evolution of two months. At physical examination it was observed alopecia on lumbosacral regionand on hind limbs, hyperpigmentation, gynecomastia and pendulous prepuce, suggestive of feminization syndrome. A firm mass was palpated on caudal abdomen. The following exams were requested: complete blood cell count, serum biochemistry (alanine aminotransferase, alkaline phosphatase, creatinine and urea), abdominal ultrasonography and fine needle aspiration cytology of the abdominal mass. Hematological and biochemistry profile were within the normal range for the species. Onthe ultrasonography, regular and rounded structures were observed, suggesting ectopic testes (left testis: 2.37 x 2.95 cm; right testis: 1.92 x 1.38 cm). The left testis presented characteristics of malignant transformation. The cytology of the abdominal mass suggested Sertoli cell tumor. The dog was submitted to an exploratory laparotomy. The right testis was atrophied and its orchiectomy was performed. The contralateral testis was completed adhered to great vessels, such as abdominal aorta and caudal vena cava, and also to adjacent viscera. Thus, the exeresis of the tumor was not possible and fragments of the mass were collected and referred to histopathology. The left testicle presented tumoral polyedric cells, alonged at the longitudinal axis, propagating disorderly, and with central rounded nucleus, and a clear and vacuolar cytoplasm. It was alsoobserved desmoplasia, anisocytosis, anisocariasis, nuclear atypia and evident nucleoli. The mitotic index was less than one mitotic figure/40x, with aberrant mitotic figures. The histopathological evaluation was compatible with Sertoli cell tumor, confirming the presumptive diagnosis. Chemotherapy was proposed, but the animal’s owner refused. After four months the dog was readmitted presenting a series of complications due to the tumor growth, including bone marrow hypoplasia, gallbladder compression and hydronephrosis. Because of the poor prognosis and severity of complications a decision to euthanize the animal was made.Discussion: Intra-abdominal Sertoli cell tumors have good prognosis when the diagnosis and surgical treatment are made early. Nevertheless, this neoplasia can be associated to critical and irreversible damages to various organs, such as bone marrow hypoplasia, and compression of abdominal organs when the tumor grows rapidly and invades adjacent structures,making the complete surgical exeresis impossible. Therefore, the orchiectomy of cryptorchidic dogs is recommended as soon as possible to prevent the development of testicular cancer in these animals.Keywords: cryptorchidism, testicular neoplasia, Canis lupus familiaris.

Effect of Xylosyltransferase-I Silencing on Implanting Growth of Salivary Pleomorphic Adenoma.

BackgroundSalivary pleomorphic adenoma is one of the most common salivary gland tumors. It has a relatively high tendency to recur and a high risk of malignant transformation. The present study aimed to study the effect of XT-I gene silencing on the implanting growth of salivary pleomorphic adenoma.Material/MethodsPrimary cultures of SPA cells and fibroblasts from the same patient were assessed. The adenovirus vector Ad-shRNA-XT-I was constructed and transfected into SPA cells. The expression of XT-I gene and XT-I protein was detected by real-time PCR and Western blot. The contents of proteoglycans were detected. The SPA cells transfected with Ad-shRNA-XT-I (group SPA-XT-I) and Ad-shRNA-HK (group SPA-HK), as well as without transfection (group SPA), were implanted into ADM scaffold with fibroblasts and then transferred into 18 BALB/C-nu nude mice for 3 months.ResultsPrimary cultures showed SPA cells were positive for human CK and S-100 protein and the fibroblasts were positive for human vimentin. The expressions of XT-I gene and protein were decreased by 51% and 51.31%, respectively. The content of proteoglycans was reduced by 48.45%. The results of the implanting growth in vitro and in vivo of nude mice indicated that no tumors grew in the SPA-XT-I group, whereas SPA grew in groups SPA-HK and SPA positive for human α-SMA, S-100 protein, and calponin.ConclusionsXT-I gene silencing effectively inhibited the implanting growth of SPA.

Analysis of intratumor heterogeneity in Neurofibromatosis type 1 plexiform neurofibromas and neurofibromas with atypical features: Correlating histological and genomic findings.

Plexiform neurofibromas (PNFs) are benign peripheral nerve sheath tumors involving large nerves present in 30%-50% Neurofibromatosis type 1 (NF1) patients. Atypical neurofibromas (ANF) are distinct nodular lesions with atypical features on histology that arise from PNFs. The risk and timeline of malignant transformation in ANF is difficult to assess. A recent NIH workshop has stratified ANFs and separated a subgroup with multiple atypical features and higher risk of malignant transformation termed atypical neurofibromatous neoplasms with uncertain biological potential (ANNUBP). We performed an analysis of intratumor heterogeneity on eight PNFs to link histological and genomic findings. Tumors were homogeneous although histological and molecular heterogeneity was identified. All tumors were 2n, almost mutation-free and had a clonal NF1(-/-) origin. Two ANFs from the same patient showed atypical features on histology and deletions of CDKN2A/B. One of the ANFs exhibited different areas in which the degree of histological atypia correlated with the heterozygous or homozygous loss of the CDKN2A/B loci. CDKN2A/B deletions in different areas originated independently. Results may indicate that loss of a single CDKN2A/B copy in NF1(-/-) cells is sufficient to start ANF development and that total inactivation of both copies of CDKN2A/B is necessary to form an ANNUBP.

Potentially malignant disorders revisited-The lichenoid lesion/proliferative verrucous leukoplakia conundrum.

Clinically identifiable potentially malignant disorders (PMD) precede oral squamous cell carcinoma development. Oral lichenoid lesions (OLL) and proliferative verrucous leukoplakia (PVL) are specific precursor lesions believed to exhibit both treatment resistance and a high risk of malignant transformation (MT). A retrospective review of 590 PMD patients treated in Northern England by CO2 laser surgery between 1996 and 2014 was carried out. Lesions exhibiting lichenoid or proliferative verrucous features were identified from the patient database and their clinicopathological features and outcome post-treatment determined at the study census date of 31 December 2014. One hundred and 98 patients were identified as follows: 118 OLL and 80 PVL, most frequently leukoplakia at ventrolateral tongue and floor of mouth sites, equally distributed between males and females. Most exhibited dysplasia on incision biopsy (72% OLL; 85% PVL) and were treated by laser excision rather than ablation (88.1% OLL; 86.25% PVL). OLL were more common in younger patients (OLL 57.1year; PVL 62.25years; P=.008) and more likely than PVL to present as erythroleukoplakia (OLL 15.3%; PVL 2.5%; P=.003). Whilst no significant difference was seen between OLL and PVL achieving disease-free status (69.5% and 65%, respectively; P=.55), this was less than the overall PMD cohort (74.2%). MT was identified in 2 OLL (1.7%) and 2 PVL (2.5%) during follow-up. One-third of PMD cases showed features of OLL or PVL, probably representing a disease presentation continuum. Post-treatment disease-free status was less common in OLL and PVL, although MT was infrequent.