Unclassified Type Research Articles

Treatment Strategy for Persistent Sciatic Artery and Novel Classification Reflecting Anatomic Status

Persistent sciatic artery (PSA) is a relatively rare congenital variant of the lower limb vasculature and can have highly variable clinical presentations. The purpose of this study was to analyze the relationship between PSA anatomy and clinical presentation, and to suggest an optimal management strategy. Between 2001 and 2014, 24 PSAs in 19 patients were diagnosed by computed tomography and referred to the vascular surgery department. Patient demographics, types of PSA and femoral artery, aneurysmal changes, symptoms, and treatment methods were assessed. Additionally, all English literature from 1964 to 2014 was reviewed and compared using the PubMed database (224 PSAs in 171 patients). PSA was diagnosed in 10 men (52.6%) and nine women (47.4%). PSAs were bilateral in five patients (26.3%) and symptomatic in 12 patients, while in seven patients PSA was found incidentally. According to the Pillet-Gauffre classification, Type 2a was the most common variant (n=15/24, 62.5%), with unclassifiable types in two limbs. Compared with cases in the literature, the PSA occlusion rate in this study was higher (n=10/24, 41.7% vs. n=54/224, 27.5%), but aneurysm incidence was higher in the literature cases (n=5/24, 20.8% vs. n=112/224; 50.7%). In this study, 16 limbs (66.6%) were treated conservatively, and six limbs were treated by open surgery, including four bypasses, one amputation, and one thrombo-embolectomy. Endovascular coil embolization was performed in one limb, and a hybrid procedure with stent graft was performed in one limb with PSA aneurysm. Based on the present series and the literature review, a new classification system and treatment option is proposed according to the anatomic status and the presence of aneurysm. According to the new classification, class III was the most common in both the present study (18/24; 75%) and the literature review, and the presence of aneurysm was the most important determinant of surgical treatment. The new classification system is simple and provides guidance for management. Limb anatomy of the femoral artery system and the presence of PSA aneurysm should be considered when selecting the optimal treatment. The risk of embolism from the presence of aneurysm is an important factor for treatment, and bypass surgery is mostly required in classes III and IV.

Frequency of Uveitis in the Central Tokyo Area (2010–2012)

ABSTRACTPurpose: To investigate the frequency of conditions of newly arrived patients with uveitis from 2010 to 2012 and compare this frequency with that since 2004.Methods: We retrospectively analyzed clinical records of patients who visited the outpatient clinic from January 2010 to December 2012, and compared them with those from 2004–2009.Results: From 2010 to 2012, 695 new patients with uveitis visited Tokyo University Hospital, with a definite diagnosis made in 431 (62.0%). The most common diagnosis was scleritis (8.3%), followed by sarcoidosis (8.1%); herpetic iridocyclitis (5.5%); Behçet disease (4.6%); Vogt–Koyanagi–Harada disease (4.0%); acute anterior uveitis (3.7%); Posner–Schlossman syndrome (3.6%); intraocular malignant lymphoma (3.0%); and bacterial endophthalmitis (1.9%). The most frequent unclassified type of uveitis was sarcoidosis-suspected (14.8%).Conclusions: When compared with years 2004–2009, the present series showed an increasing trend of intraocular malignant lymphoma, bacterial endophthalmitis, and chronic iridocyclitis, and a notable increase in chronic iridocyclitis in young girls, with decreasing trends of scleritis and Vogt–Koyanagi–Harada disease.

A Prospective Randomised Trial of Targeted Therapy for Diffuse Large B-Cell Lymphoma (DLBCL) Based upon Real-Time Gene Expression Profiling: The Remodl-B Study of the UK NCRI and SAKK Lymphoma Groups (ISRCTN51837425)

Introduction: DLBCL subtypes may be classified by gene expression corresponding to germinal centre (GCB) or activated peripheral blood (ABC) B-cells. Treatment outcomes with R-CHOP therapy were inferior for ABCs in retrospective series, and this study investigated whether adding bortezomib could reverse the adverse prognosis. The trial used gene expression profiling (GEP) to stratify cases, with adaptive design to analyse the outcome by subtypes at predefined timepoints.Methods: Newly diagnosed patients with DLBCL underwent staging and commenced standard R-CHOP. During cycle 1, formalin-fixed paraffin-embedded (FFPE) tissue was used to extract messenger RNA for GEP using the Illumina DASL array platform. Cases were allocated to GCB, ABC or Unclassifiable (Unc) type before starting cycle 2, using an established algorithm based upon 20 genes. Patients with successful GEP were randomised 1:1 to receive R-CHOP +/- bortezomib 1.6 mg/m2 s/c on days 1+8 in cycles 2-6. The study was powered to detect a difference in progression-free survival (PFS) of 10% with bortezomib, with a 2-sided significance, 5% and 90% power. The adaptive design allowed for closure of randomization for GCB cases if 1-year PFS was <70% after 55 received RB-CHOP (interim safety analysis) or if 1-year PFS was <85% after 73 received RB-CHOP and followed for 1 year (futility analysis).Results: Between 6/2011 and 5/2015 1132 patients were enrolled from 109 sites, with 1078 samples analysed. Of these, 157 (15%) biopsies had inadequate material for GEP, but the remaining 921 were classified as 246 (27%) ABC, 476 (52%) GCB and 199 (22%) Unc. Successful classification was possible from both surgical and needle core biopsies. Median laboratory turnaround time was 12 working days and all results were available prior to the scheduled administration of cycle 2. Characteristics of the patients of different subtypes are shown in the table. Following both interim analyses the DMEC recommended continued recruitment of patients with a GCB phenotype.TableABCGCBUncAge (years): median676363Age (years) : range23 to 8620 to 8220 to 85% performance status 0-1888890% at least one extranodal site535462% bone marrow involved151423% LDH>ULN697679% IPI score 0/1292726% IPI score 2/3575555% IPI score 4/5151919% B symptoms464349% Bulk>10cm172621Conclusions: This study has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy in a large multicentre trial. Although patients with ABC type lymphoma were in general slightly older, they did not appear to have other adverse prognostic features at diagnosis vs GCB. All patients will have completed therapy by the time of the meeting, allowing the initial response and toxicity data to be available for presentation. DisclosuresDavies:GIlead: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; CTI: Honoraria; Takeda: Honoraria, Research Funding; Bayer: Research Funding; GSK: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: The addition of bortezomib to R-CHOP chemotherapy in diffuse large B-cell lymphoma. Pocock:Janssen: Honoraria. Jack:Jannsen: Research Funding. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding.

Safety and efficacy of sunitinib for advanced non-clear cell renal cell carcinoma.

This study evaluated the safety and efficacy of sunitinib in the treatment of advanced non-clear cell renal cell carcinoma. Thirty-seven Chinese patients with advanced non-clear cell renal cell carcinoma were enrolled from October 2008 to October 2013. Sunitinib monotherapy was administered in repeated 6-week cycles of daily oral administration of 50 mg for 4 weeks, followed by 2 weeks off. Computed tomography scan was used to evaluate the efficacy every two cycles. All 37 patients received sunitinib treatment according to the schedule and were evaluated for response and toxicity. Thirty (81.1%) patients underwent nephrectomy before sunitinib treatment and seven (18.9%) patients had kidney biopsy. Twenty-five patients were diagnosed with papillary renal cell carcinoma, two with spindle cell-type renal cell carcinoma, two with chromophobe renal cell carcinoma and eight with unclassified cell types. The disease control rate was 73.0%, with partial response in 5 (13.5%), stable disease in 22 (59.5%) and progression disease in 10 (27.0%), the best tumor response. The median progression-free survival (PFS) was 6 months and the median overall survival (OS) was 9 months. In patients with papillary renal cell carcinoma, the median PFS was 6 months and the median OS was 10 months. The most common adverse events were hand-foot syndrome, fatigue, leukopenia, anemia, thrombocytopenia, mucositis, edema and hypertension. All adverse events were ameliorated by supportive treatment, dose reduction or treatment interruption. Sunitinib was efficacious in the treatment of advanced non-clear cell renal cell carcinoma. Most adverse events were tolerable.

Validation and utilization of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinoma and alveolar soft part sarcoma.

BackgroundXp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS.MethodsRepresentative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data.ResultsThree out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS.ConclusionOur study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS.

The Interrater and Intrarater Agreement of a Modified Neer Classification System and Associated Treatment Choice for Lateral Clavicle Fractures

Background: As there is substantial variation in the classification and diagnosis of lateral clavicle fractures, proper management can be challenging. Although the Neer classification system modified by Craig has been widely used, no study has assessed its validity through inter- and intrarater agreement. Purpose: To determine the inter- and intrarater agreement of the modified Neer classification system and associated treatment choice for lateral clavicle fractures and to assess whether 3-dimensional computed tomography (3D CT) improves the level of agreement. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: Nine experienced shoulder specialists and 9 orthopaedic fellows evaluated 52 patients with lateral clavicle fractures, completing fracture typing according to the modified Neer classification system and selecting a treatment choice for each case. Web-based assessment was performed using plain radiographs only, followed by the addition of 3D CT images 2 weeks later. This procedure was repeated 4 weeks later. Fleiss κ values were calculated to estimate the inter- and intrarater agreement. Results: Based on plain radiographs only, the inter- and intrarater agreement of the modified Neer classification system was regarded as fair (κ = 0.344) and moderate (κ = 0.496), respectively; the inter- and intrarater agreement of treatment choice was both regarded as moderate (κ = 0.465 and 0.555, respectively). Based on the plain radiographs and 3D CT images, the inter- and intrarater agreement of the classification system was regarded as fair (κ = 0.317) and moderate (κ = 0.508), respectively; the inter- and intrarater agreement of treatment choice was regarded as moderate (κ = 0.463) and substantial (κ = 0.623), respectively. There were no significant differences in the level of agreement between the plain radiographs only and plain radiographs plus 3D CT images for any κ values (all P > .05). Conclusion: The level of interrater agreement of the modified Neer classification system for lateral clavicle fractures was fair. Additional 3D CT did not improve the overall level of interrater or intrarater agreement of the modified Neer classification system or associated treatment choice. To eliminate a common source of disagreement among surgeons, a new classification system to focus on unclassifiable fracture types is needed.

Screening of RET gene mutations in Chinese patients with medullary thyroid carcinoma and their relatives.

The rearranged during transfection (RET) gene is a proto-oncogene; active mutations frequently occur in medullary thyroid carcinoma (MTC). This study investigated the spectrum of germline RET mutations and clinical features in Chinese hereditary MTC patients. A total of 53 family members from 11 different hereditary MTC families were recruited for detection of RET exon 8, 10, 11, 13, 14, 15, and 16 mutations, in genomic DNA from peripheral blood leucocytes using polymerase chain reaction (PCR) and direct DNA sequencing. Of the 53 participants, eight different germline RET mutations were detected in 37 individuals. These RET mutations were distributed in exons 10, 11, 13, and 16. The most frequent RET mutation was localized at exon 11 codon 634 (67.6 %; 25/37) and the most prevalent mutation was C634R (37.8 %; 14/37). The most frequent phenotype was multiple endocrine neoplasia type 2A (MEN2A). The incidences of MTC, pheochromocytoma, and hyperparathyroidism in the MEN2A patients were 100, 36.4 and 18.2 %, respectively. The phenotype of families with Y606C or L790F mutation was categorized as familial medullary thyroid carcinoma. Moreover, one proband was identified with multiple endocrine neoplasia type 2B and carried a de novo mutation of M918T. Two families with C618S/Y mutation were categorized as unclassified multiple endocrine neoplasia type 2. Our results further substantiate that most germline mutations of the RET proto-oncogene were localized at codon 634 in Chinese hereditary MTC patients and carriers. RET mutation at codon 634 was always associated to the phenotype of MEN2A. Screening of RET mutations should be probably limited to exons 10, 11, 13 and 16 initially to be cost-effective in China.

Abstract 3783: High resolution telomere FISH analysis of testicular germ cell tumors reveals telomere anomalies specific to cancer subtypes and demonstrates telomere shortening as an early event in TGCT carcinogenesis

Abstract Testicular germ cell tumor (TGCT) is the most common malignancy of young men between 15 and 40 years of age. TGCT is exceptional, as most men can be completely cured. We evaluated 76 TGCT cases using high resolution (single-cell) telomere-specific fluorescence in situ hybridization (FISH) combined with Oct4 immunofluorescence staining to delineate telomere length patterns in different TGCT subtypes, as well as in the precursor lesion, intratubular germ cell neoplasia unclassified type (ITGCNU). Telomere lengths were qualitatively scored by comparing the intensity of the telomere signals from cancer cells to benign reference cell types and then grouped (short, medium, and long). For isolated tumors and for those part of a mixed germ cell tumor (containing 2 or more TGCT types), we determined the overall trends in telomere length in comparison to reference cell populations. This comparison demonstrated medium telomeres for normal germ cells, short telomeres for ITGCNU and seminomas (p = 0.006 and p = 0.0005, respectively), and a wide range of average telomere lengths in the non-seminomas. Among the non-seminomas, embryonal carcinomas displayed the longest telomeres, on average, and were the only subtype (27% of cases) to display the alternative lengthening of telomeres (ALT) phenotype, as evident from abnormally large telomeric foci and telomere length heterogeneity. ATRX and DAXX protein expression was not absent in a subset of embryonal carcinoma cases. Compared to somatic tissues, germ cells have a high basal telomerase activity and longer telomeres. Hence, short telomeres in ITGCNU are surprising. Telomere attrition does not occur in normal germ cells; therefore, telomere shortening in ITGCNU may play a role in TGCT tumorigenesis. Embryonal carcinoma, the TGCT subtype that is most aggressive and has the worst prognosis, showed very long telomeres. Seminomas, with short telomeres, are exquisitely sensitive to standard platinum based chemotherapy. A recent study implicates telomere damage as a consequence of platinum based chemotherapeutic agents in a male germ cell line. Thus, the knowledge of telomere length differences and that of chemotherapeutic agents’ damage to telomeres together may help shed light on the differential sensitivities of TGCT subtypes to certain chemotherapeutic agents. In summary, TGCT can demonstrate varied telomere lengths depending on lesion subtype and whether the lesion occurs in the context of a mixed tumor. The presence of short telomeres in ITGCNU suggests a major role of telomere shortening in the pathogenesis of TGCT. In the future, telomere length information may also inform point-of-care diagnostic and treatment decisions for clinicians caring for TGCT patients. Citation Format: Mohammed T. Shekhani, John Barber, Christopher M. Heaphy, Leonardo Reis, Gunes Guner, Corinne Joshu, George J. Netto, Alan K. Meeker. High resolution telomere FISH analysis of testicular germ cell tumors reveals telomere anomalies specific to cancer subtypes and demonstrates telomere shortening as an early event in TGCT carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3783. doi:10.1158/1538-7445.AM2015-3783

Ullrich-Turner Syndrome and Tumor Risk: Is There Another Chance to Early Gonadectomy in Positive TSPY and SRY Patients?

The presence of the Y chromosome in the karyotype of patients with disorders of sex differentiation is significantly associated with an increased risk to develop specific types of malignancies, predominantly type II germ cell tumors (GCTs). Gonadoblastoma in the gonads without an obvious testicular differentiation and intratubular germ cell neoplasia of unclassified type in testicular tissue are the precursor lesions of most GCTs. Gonadal dysgenesis, the characteristic feature of Ullrich-Turner syndrome (UTS), further contributes to increase this tumor risk. The reported incidence of Y chromosome material in UTS is 6 to 8% and in these cases an early gonadectomy is strongly recommended to prevent the risk of a malignancy. The aim of this work was to retrospectively analyze the clinical outcome and the histopathological and cytogenetic findings of our UTS patients who underwent gonadectomy to establish strict selection criteria aimed at promoting an organ-sparing surgery.

V7-02 ROBOTIC PARTIAL NEPHRECTOMY FOR A COMPLEX HILAR MASS IN A 14 YEAR OLD BOY

You have accessJournal of UrologyPediatrics1 Apr 2015V7-02 ROBOTIC PARTIAL NEPHRECTOMY FOR A COMPLEX HILAR MASS IN A 14 YEAR OLD BOY Abhishek Srivastava, Aryeh Keehn, Amanda North, and Reza Ghavamian Abhishek SrivastavaAbhishek Srivastava More articles by this author , Aryeh KeehnAryeh Keehn More articles by this author , Amanda NorthAmanda North More articles by this author , and Reza GhavamianReza Ghavamian More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1933AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Robotic surgery still poses many challenges in pediatric patients and there has been limited use of minimally invasive approaches for treatment of renal masses in pediatric population. We present a case of 14 year old boy with history of recurrent urinary tract infections and bilateral hydronephrosis, who underwent bilateral pyeloplasty several years ago and presented to the emergency room after a right renal mass was seen on a follow-up renal ultrasound. METHODS CT scan showed 4.2cm, infrahilar renal mass. Renal scan revealed a split differential function of 42% on the right and 52% on the left. Serum creatinine was 1.1. Given the patient's young age, prior history of bilateral renal surgery on both kidneys, the increased risk of CKD in the long-term and the equivalent oncologic efficacy of partial vs. radical nephrectomy, we considered nephron-sparing surgery. Plan was for a Robotic Right Partial Nephrectomy with intraoperative ultrasonography. If partial nephrectomy was not deemed possible, we would have proceeded with radical nephrectomy. RESULTS We were able to successfully perform Robotic partial nephrectomy without any complications. Pathology revealed Renal cell carcinoma, unclassified type, 5.5 × 5.4 × 3.4 cm (High Grade). Postoperative creatinine was 1.3. Surgical resection margins were negative for tumor. Patient was discharged on postoperative day 4. CONCLUSIONS Robotic partial nephrectomy is feasible in complex hilar mass and in pediatric population. It should be attempted if nephron sparing is indicated. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e659 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhishek Srivastava More articles by this author Aryeh Keehn More articles by this author Amanda North More articles by this author Reza Ghavamian More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP35-16 PILOT STUDY EVALUATING 99MTC-SESTAMIBI SPECT/CT FOR THE DIFFERENTIATION OF ONCOCYTOMA FROM RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Evaluation and Staging I1 Apr 2015MP35-16 PILOT STUDY EVALUATING 99MTC-SESTAMIBI SPECT/CT FOR THE DIFFERENTIATION OF ONCOCYTOMA FROM RENAL CELL CARCINOMA Michael Gorin, Steven Rowe, Jennifer Gordetsky, Mark Ball, Phillip Pierorazio, Jonathan Epstein, Mehrbod Javadi, and Mohamad Allaf Michael GorinMichael Gorin More articles by this author , Steven RoweSteven Rowe More articles by this author , Jennifer GordetskyJennifer Gordetsky More articles by this author , Mark BallMark Ball More articles by this author , Phillip PierorazioPhillip Pierorazio More articles by this author , Jonathan EpsteinJonathan Epstein More articles by this author , Mehrbod JavadiMehrbod Javadi More articles by this author , and Mohamad AllafMohamad Allaf More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1117AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Currently available cross-sectional imaging techniques are unable to reliably distinguish oncocytoma from renal cell carcinoma (RCC). As a result, a large number of patients harboring an oncocytoma undergo unnecessary surgical resection. Compared to RCC, oncocytomas are unique in that at the ultra-structural level these tumors are comprised of cells with numerous densely packed mitochondria. In this study we tested the hypothesis that oncocytomas can be differentiated from RCC on the basis of increased uptake of the mitochondrial imaging agent 99mTc-sestamibi. METHODS In total, 6 patients (3 with oncocytoma and 3 with RCC [1 clear cell, 1 Xp11.2 translocation and 1 unclassified type]) were imaged with 99mTc-sestamibi SPECT/CT. Relative quantification was performed by measuring tumor to normal renal parenchyma background ratios. RESULTS All 3 oncocytomas demonstrated radiotracer uptake near or above that of the normal renal parenchyma (uptake ratios: 0.85, 1.10 & 1.78; Figure 1). In contrast, the three RCCs were profoundly photopenic relative to renal background (uptake ratios: 0.21, 0.26 & 0.31; Figure 2). CONCLUSIONS 99mTc-sestamibi SPECT/CT appears to be of value in distinguishing oncocytoma from RCC. To more rigorously assess the diagnostic accuracy of this imaging modality, we have initiated a trial (ClinicalTrials.gov identifier NCT02160925) to prospectively study patients with clinical T1 renal tumors scheduled to undergo surgical resection. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e425-e426 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Gorin More articles by this author Steven Rowe More articles by this author Jennifer Gordetsky More articles by this author Mark Ball More articles by this author Phillip Pierorazio More articles by this author Jonathan Epstein More articles by this author Mehrbod Javadi More articles by this author Mohamad Allaf More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Preserved or enhanced OATP1B3 expression in hepatocellular adenoma subtypes with nuclear accumulation of β-catenin.

Recent studies have indicated that hepatocellular adenoma (HCA) is a heterogenous group of benign tumors with various genetic and clinicopathological characteristics. We delineated the clinicopathological characteristics of HCA subtypes and evaluated the expression of transporter protein OATP1B3 in HCA. HCA in 34 Japanese patients were investigated immunohistochemically and classified into four subtypes (HNF1α-inactivated type, H-HCA; β-catenin-activated type, b-HCA; inflammatory type, I-HCA; unclassified type, u-HCA). Immunostaining of OATP1B3 protein in HCA tissue sections was performed to determine the association between OATP1B3 expression and HCA subtypes. HCA was categorized into the following four subtypes and two combined subtypes: 10 H-HCA (29%), 10 I-HCA (29%), seven b-HCA (21%), two b-HCA/H-HCA (6%), two b-HCA/I-HCA (6%) and three u-HCA (9%). The male-to-female ratio was 18:16. Oral contraceptive use was rare but seven HCA were found in patients with glycogen storage disease, congenital absence of the portal vein and idiopathic portal hypertension. OATP1B3 expression was decreased in 24 HCA but was preserved or increased in 10 HCA. All nine HCA with nuclear staining for β-catenin showed preserved or enhanced OATP1B3 expression, indicating a significant association between nuclear β-catenin accumulation and OATP1B3 expression in HCA. HCA subtype classification was validated in 91% of our Japanese subjects although their clinical backgrounds including rare contraceptive use were different from European subjects. A close association between preserved or enhanced OATP1B3 expression and b-HCA subtype indicated important modalities for clinical decisions in the treatment and follow up of patients with HCA.

Evaluation of the HPV typing INNO-LiPA EXTRA assay on formalin-fixed paraffin-embedded cervical biopsy samples

BackgroundThe HPV genotyping line probe assay INNO-LiPA EXTRA allows the detection of a wider spectrum of viral types compared to the earlier V2 version of the assay. Its performance in formalin-fixed paraffin-embedded tissues is unknown. ObjectivesTo test the EXTRA assay in HPV genotyping of paired cervical scrapings and corresponding FFPE biopsy specimens. Study designPaired samples from 188 women with abnormal cytology were examined using the INNO-LiPA HPV genotyping assay, version EXTRA. The assay can simultaneously detect 18 high-risk, 7 low-risk, and 2 unclassified HPV types. Kappa statistics were used to measure interrater agreement between groups. ResultsThe evaluation of paired cervical scraping and biopsy samples gave a 100% overall agreement for HPV status and of 72.9% (kappa 0.6554) for the number of infecting HPVs. 392 out of 507 individual HPV types were concordant, corresponding to a positive agreement rate of 87.2% (95% CI 84.1–90.3). As to the individual genotypes, the agreement was absolute for HPV 45, 68, 73 (kappa 1), excellent for HPV 6, 11, 16, 18, 31, 35, 39, 44, 51, 52, 53, 54, 56, 69/71 and 82 (kappa 0.7796–0.9714), good for HPV26, 33, 43, 58, 66 and 74 (kappa 0.6768–0.7449), and poor for HPV 59 and 40. These agreement values were comparable to those obtained with the V2 assay. ConclusionsThe EXTRA assay provided excellent performance in HPV typing on FFPE samples comparable to the earlier version of the test despite higher complexity and increased coverage of types.

Clinical genetic study in juvenile myoclonic epilepsy

PurposeTo evaluate clinical features of probands with juvenile myoclonic epilepsy (JME) and affected members of their families in order to study clinical genetics of JME. MethodThirteen unrelated families with at least two members with history of seizures were identified; clinical and genealogic data were collected from JME probands and family members. ResultsAll probands had myoclonic and generalized tonic–clonic seizures (GTCS), while absences occurred in 25% of them. The average age of seizure onset was 13 years. Totally 22 members from 13 families had history of seizures with average age of seizure onset at 18 years. Ten family members had JME, three had epilepsy with GTCS, two had juvenile absence epilepsy, one had adult onset myoclonic epilepsy and six of the affected individuals had unclassified type of epilepsy. In five families, JME was the solely clinical feature. JME dominated among siblings, while phenotypic heterogeneity was observed in second and third degree relatives. In three multi-generation families, members with adult onset genetic generalized epilepsies (GGE) were identified. ConclusionWe found phenotypic heterogeneity regarding epilepsy type and age of seizure onset. Using pedigree analysis, we found no evidence for preferential maternal or any other distinctive inheritance pattern. Further study is needed to confirm and clarify the results.

C-kit overexpression is not associated with KIT gene mutations in chromophobe renal cell carcinoma or renal oncocytoma

IntroductionC-kit overexpression has previously been described in chromophobe renal cell carcinoma (cpRCC) and renal oncocytoma (RO). However, so far no KIT mutations have been found. The objective of our study was to analyse c-kit in a large cohort of renal tumors and to perform KIT mutation analysis in a subset cpRCC and RO cases with overexpression of c-kit. Materials and methodsWe studied the immunohistochemical expression of c-kit on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 948 patients with renal tumors. CpRCC and RO cases with c-kit overexpression (n=23) were analyzed for KIT mutations in exons 9, 11, 13, 14, 15, and 17. ResultsExpression of c-kit was found in 6/642 (0.9%) clear cell RCC, 3/154 (1.9%) papillary RCC, 54/69 (78.3%) cpRCC, 37/45 (82.2%) RO and 2/30 (6.7%) of other unclassified tumor types. In none of the RO and cpRCC cases analyzed, a KIT gene mutation was found. ConclusionC-kit expression is found in the majority of cpRCC and RO, but these tumors do not harbor the usual c-kit activating mutations. This may have implications for the use of tyrosine kinase inhibitors in patients with advanced cpRCC and c-kit expression.

Non-seminomatous germ cell tumours

The group of non-seminomatous germ cell tumors can be morphologically and therapeutically distinguished from the group of seminomas. The group of non-seminomatous germ cell tumors includes embryonal carcinoma, yolk sac tumor, choriocarcinoma and teratoma. All entities can occur rarely in pure form or much more commonly in mixed germ cell tumors consisting of more than one histological type. The non-seminomatous germ cell tumors are also characterized by the appearance of an isochromosome12p, i(12p) and arise from a common precursor lesion called intratubular germ cell neoplasia of the unclassified type (ITGCNU). Various immunohistochemical markers are used to distinguish the different tumor components in addition to morphological characteristics.

Human Papillomavirus Community in Healthy Persons, Defined by Metagenomics Analysis of Human Microbiome Project Shotgun Sequencing Data Sets

Human papillomavirus (HPV) causes a number of neoplastic diseases in humans. Here, we show a complex normal HPV community in a cohort of 103 healthy human subjects, by metagenomics analysis of the shotgun sequencing data generated from the NIH Human Microbiome Project. The overall HPV prevalence was 68.9% and was highest in the skin (61.3%), followed by the vagina (41.5%), mouth (30%), and gut (17.3%). Of the 109 HPV types as well as additional unclassified types detected, most were undetectable by the widely used commercial kits targeting the vaginal/cervical HPV types. These HPVs likely represent true HPV infections rather than transitory exposure because of strong organ tropism and persistence of the same HPV types in repeat samples. Coexistence of multiple HPV types was found in 48.1% of the HPV-positive samples. Networking between HPV types, cooccurrence or exclusion, was detected in vaginal and skin samples. Large contigs assembled from short HPV reads were obtained from several samples, confirming their genuine HPV origin. This first large-scale survey of HPV using a shotgun sequencing approach yielded a comprehensive map of HPV infections among different body sites of healthy human subjects. This nonbiased survey indicates that the HPV community in healthy humans is much more complex than previously defined by widely used kits that are target selective for only a few high- and low-risk HPV types for cervical cancer. The importance of nononcogenic viruses in a mixed HPV infection could be for stimulating or inhibiting a coexisting oncogenic virus via viral interference or immune cross-reaction. Knowledge gained from this study will be helpful to guide the designing of epidemiological and clinical studies in the future to determine the impact of nononcogenic HPV types on the outcome of HPV infections.

Clinical analysis of seborrheic keratoses in the ear: a retrospective study and literature review

The pathogenesis of a seborrheic keratosis has not been fully elucidated. In the present study, we reviewed the literature to increase the awareness of this disease among otolaryngologists and to stress the need for prompt diagnosis and treatment. This was a retrospective study in seven patients presenting with seborrheic keratoses in the ear. We included only those patients in whom keratoses were confirmed by pathology after a complete excision. In six patients, seborrheic keratoses were observed in the external auditory canal, and in one patient, they were observed in the auricle. The subtype of keratoses was classified as acanthotic in six patients; one patient had an unclassified type associated with basal cell carcinoma. Seborrheic keratoses are benign skin tumors; however, the lesions can recur after removal. Moreover, an association between seborrheic keratoses and malignant skin tumors has been reported. Therefore, otolaryngologists should consider a complete removal and histological examination of seborrheic keratoses.

Prognostic and diagnostic implications of epithelial cell adhesion/activating molecule (EpCAM) expression in renal tumours: a retrospective clinicopathological study of 948 cases using tissue microarrays

To evaluate the expression and prognostic value of epithelial cell adhesion/activating molecule (EpCAM) in a large set of renal cell carcinomas (RCCs) using a tissue microarray (TMA) approach. We studied the immunohistochemical expression and overexpression of EpCAM on TMAs containing formalin-fixed, paraffin-embedded samples of 948 patients with documented renal tumours. EpCAM expression was defined as the presence of a specific membranous staining in >5% of the tumour cells. EpCAM overexpression was specified by calculating a total staining score (score range 0-12) as the product of a proportion score and an intensity score, and defined as a score >4. Of 948 cases, 927 (97.8%) were evaluable morphologically (haematoxylin and eosin stain). EpCAM expression was found in 233/642 (36.3%), 126/155 (81.3%), 54/68 (78.3%), 17/45 (37.8%), 13/30 (43.3%) of clear-cell RCC, papillary RCC (pRCC), chromophobe RCC (cpRCC), oncocytomas and other unclassified tumour types, respectively. Log-rank tests showed a significantly longer overall survival (OS [P = 0.047]) and a trend of EpCAM expression to be associated with a longer progression-free survival (PFS) in all RCC entities (P = 0.065). EpCAM overexpression was significantly correlated with a better PFS in all RCC subtypes, cpRCC and pRCC (P = 0.011, 0.043 and 0.025, respectively). In multivariate analysis EpCAM overexpression was an independent marker for longer PFS in all RCC entities as well as in high grade RCC (P = 0.009 and P = 0.010, respectively). The histological subtypes associated with a high rate of EpCAM expression were cpRCC and pRCC. This retrospective analysis demonstrated a trend towards longer OS and PFS for all major RCC subtypes. EpCAM expression had significant prognostic value in patients with cpRCC and pRCC. Furthermore, EpCAM overexpression in high grade RCC may be a helpful marker for prognostication.

Hippocampal sclerosis: a pathological study of 45 Thai patients using modified blumke classification

Hippocampal sclerosis (HS) constitutes the majority of cases undergoing epilepsy surgery, and the recent classification by Blumke in 2007 has shown to predict post-operative outcome. According to the scheme, neuronal density in the hippocampal subfields was compared between case and control, and HS was classified into 4 types: 0, no neuronal loss; 1a, neuronal loss in CA1, CA3, CA4; 1b, neuronal loss in all CA regions; 2, neuronal loss in CA1; and 3, neuronal loss in CA4. In the present study, neuronal density was evaluated with NeuN immunostain performed on normal hippocampi and HS samples. With the normal reference values, neuronal loss in each hippocampal subfield was considered when Z score was less than -1. Of the 45 HS specimens studied, there were 18 cases of type 1a, 2 cases of 1b, and 25 cases of unclassified type 1 HS due to an absence of CA2 in the tissue samples. The lack of other HS types (0, 2 and 3) in our cohort might be due to surgery that selectively performed in patients with expected good outcome (type 1 HS). For the complete classification of HS, CA2 is crucial to separate types 1a and 1b.