A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness.

BACKGROUND: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown. METHODS: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology. RESULTS: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability. CONCLUSIONS: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted.

A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with extended intra-familial phenotypic heterogeneity.

OBJECTIVE: To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn's disease, associated with a novel homozygous truncating variant in LACC1. METHODS: Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1-knockout macrophages (Mϕ). RESULTS: A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (Mϕ) showed no endogenous p.Glu348Ter-LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter-LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1-associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1-disrupted as compared with wild-type Mϕ. CONCLUSIONS: Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways.

Primary high-grade myoepithelial carcinoma of the lung: A study of three cases illustrating frequent SMARCB1-deficiency and review of the literature.

Primary myoepithelial carcinoma of the lung is exceptionally rare and, hence, remained poorly characterized. We present 3 tumors affecting 2 males and 1 female aged 60 to 84 years. Tumor size ranged from 4 to 10 cm. All presented as well circumscribed non-encapsulated peripheral solitary masses. One patient died postoperatively. The other two were lost to follow-up. Histologically, all tumors were high-grade with predominance of myxoid/chordoid (2) and rhabdoid (1) pattern. Immunohistochemistry (IHC) showed reactivity with vimentin, pankeratin, EMA and smooth muscle actin. Two tumors were SMARCB1-deficient (one with additional loss of SMARCA2 and PBRM1). RNA sequencing revealed no gene fusions. Review of reported cases (total: 16) showed that pulmonary myoepithelial carcinoma affects both sexes equally at a median age of 60 years (24-84), presents predominantly as peripheral masses (69%) in the lower lobes (66%) of smokers (70%) with a median size of 6 cm (1.5-13), and originates as high-grade de novo carcinoma. Forty percent of patients died of disease at a median of 12.5 months (0 to 62). Only 40% of patients were disease free at last follow-up (median, 9.5 months). Prominent lobulation and myxoid stroma were frequent histological features. Most tumors displayed variable combinations of epithelioid, spindle, plasmacytoid, clear, ovoid or round cells. Three of 6 tumors subjected to different RNA panels showed EWSR1 rearrangements (fused to PBX1, ZNF444 or to unknown partner). Two of 3 tumors lacking gene fusions were SMARCB1-deficient (both showed secondary EWSR1 FISH abnormalities due to 22q deletion). Primary pulmonary myoepithelial carcinoma is a rare aggressive malignancy that recapitulates its soft tissue and salivary counterpart. Exclusion of metastasis from other primaries is mandatory and can only be achieved by detailed clinical history and imaging.

Mutant KRAS Circulating Tumor DNA Is an Accurate Tool for Pancreatic Cancer Monitoring.

BACKGROUND: Many new pancreatic cancer treatment combinations have been discovered in recent years, yet the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains grim. The advent of new treatments highlights the need for better monitoring tools for treatment response, to allow a timely switch between different therapeutic regimens. Circulating tumor DNA (ctDNA) is a tool for cancer detection and characterization with growing clinical use. However, currently, ctDNA is not used for monitoring treatment response. The high prevalence of KRAS hotspot mutations in PDAC suggests that mutant KRAS can be an efficient ctDNA marker for PDAC monitoring. SUBJECTS, MATERIALS, AND METHODS: Seventeen metastatic PDAC patients were recruited and serial plasma samples were collected. CtDNA was extracted from the plasma, and KRAS mutation analysis was performed using next-generation sequencing and correlated with serum CA19-9 levels, imaging, and survival. RESULTS: Plasma KRAS mutations were detected in 5/17 (29.4%) patients. KRAS ctDNA detection was associated with shorter survival (8 vs. 37.5 months). Our results show that, in ctDNA positive patients, ctDNA is at least comparable to CA19-9 as a marker for monitoring treatment response. Furthermore, the rate of ctDNA change was inversely correlated with survival. CONCLUSION: Our results confirm that mutant KRAS ctDNA detection in metastatic PDAC patients is a poor prognostic marker. Additionally, we were able to show that mutant KRAS ctDNA analysis can be used to monitor treatment response in PDAC patients and that ctDNA dynamics is associated with survival. We suggest that ctDNA analysis in metastatic PDAC patients is a readily available tool for disease monitoring. IMPLICATIONS FOR PRACTICE: Avoiding futile chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) patients by monitoring response to treatment is of utmost importance. A novel biomarker for monitoring treatment response in PDAC, using mutant KRAS circulating tumor DNA (ctDNA), is proposed. Results, although limited by small sample numbers, suggest that ctDNA can be an effective marker for disease monitoring and that ctDNA level over time is a better predictor of survival than the dynamics of the commonly used biomarker CA19-9. Therefore, ctDNA analysis can be a useful tool for monitoring PDAC treatment response. These results should be further validated in larger sample numbers.

Cancer-associated fibroblasts are an infrequent finding in the microenvironment of proliferative verrucous leukoplakia-associated squamous cell carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are generally associated with negative prognostic factors. This study compares the clinicopathologic impact of CAFs in oral squamous cell carcinoma in patients with a history of proliferative verrucous leukoplakia (p-scca) and patients with conventional squamous cell carcinoma of the buccal mucosa, gingiva, and palate (c-scca). METHODS: A retrospective clinicopathologic and immunohistochemical analysis of 97 tumor specimens from 78 patients (13 patients with proliferative verrucous leukoplakia-associated squamous cell carcinoma (n = 32) and conventional squamous cell carcinoma from the buccal mucosa, gingiva, and palate (n = 65) was conducted. Immunostaining with anti-alpha-smooth muscle actin (α-SMA) antibody was used to evaluate the presence of CAFs. RESULTS: α-SMA expression was an infrequent finding in p-scca and seen in only 6% of p-scca compared to 40% of c-scca (P < 0.0004). In the c-scca subgroup, α-SMA significantly correlated with tumor size (T) (P = 0.009), tumor thickness (P < 0.0009), perineural invasion (P = 0.009), and microscopic grade (P = 0.018). CONCLUSIONS: The presence of CAFs was an infrequent finding in our p-scca cohort which may contribute to its seemingly slower growing and less invasive growth pattern. In the cohort of c-scca patients, higher levels of CAFs correlated with microscopic invasiveness, tumor size, and perineural invasion. Practically, these are important observations as targeting strategies are being developed to combat carcinoma types where CAFs significance has been validated.

The Role of Histopathology and Immunohistochemistry in the Diagnosis of Cutaneous Leishmaniasis Without "Discernible" Leishman-Donovan Bodies.

BACKGROUND: Histopathology plays an important role in the diagnosis of cutaneous leishmaniasis (CL) but Leishman-Donovan (LD) bodies may not always be discernible. Recently, anti-CD1a antibody (Ab), clone MTB1, was found to decorate LD bodies immunohistochemically. OBJECTIVE: Can histopathology without discernible LD bodies be used to diagnose CL, and can immunohistochemistry using anti-CD1a Ab, clone MTB1, detect LD bodies in these cases. METHODS: Suspected CL lesions were studied histopathologically and immunohistochemically, and the patients' clinical files were reviewed. RESULTS: Of the 196 patients with suspected CL, direct smear demonstrated LD bodies in 50 (25.5%). Of the remaining 146 patients, 118 underwent biopsy. In 56 (47.5%) patients, the hematoxylin-eosin-stained sections revealed LD bodies. In 47 (39.8%) patients, LD bodies were not discerned but the histopathology demonstrated histiocytic infiltrates with varying numbers of plasma cells along with other inflammatory cells, and negative Ziehl-Neelsen and periodic acid-Schiff stains. This pattern was termed "histopathology consistent with leishmaniasis." The history, clinical findings, and response to anti-leishmania therapy supported the diagnosis of CL in all of them, and immunostains for CD1a, clone MTB1, detected LD bodies in 11 (23.4%) of these 47 patients. CONCLUSIONS: "Histopathology consistent with CL" along with appropriate clinical findings supports the diagnosis of CL in an endemic area, and immunostains with CD1a Ab, clone MTB1, may help in the minority of the cases.

Angiosarcoma arising in association with vascular Dacron grafts and orthopedic joint prostheses: clinicopathologic, immunohistochemical, and molecular study.

Angiosarcoma may rarely arise near an inert foreign body material including vascular grafts and metal joint prostheses. Sixteen such cases have been reported since 1972 but mostly in the radiologic or surgical literature without detailed histologic or molecular analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association with Dacron grafts for vascular repair (n=3) or related to orthopedic metal prostheses for joint replacement (n=2). All patients were men aged 50 to 84 years (median, 71 years). Mean time to development of angiosarcoma was 9 years (range, 4.6-17 years). Symptoms were recurrent bleeding/loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients died of disease within 1 to 24 months (mean, 8 months). One patient was alive after radical surgery, radiochemotherapy, and embolization of pulmonary metastases (17 months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern and variable vasoformation. All tumors expressed CD31, ERG, FLI-1, and variably pancytokeratin (diffuse in 3 cases), but none expressed D2-40, MDM2, or CDK4. Fluorescence in situ hybridization analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC amplified by fluorescence in situ hybridization. Angiosarcomas are exceedingly rare fatal complications of long-standing metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2/CDK4 alterations underlines their distinction from intimal-type sarcomas.

[KIDNEY DISEASES IN NORTH ISRAEL ACCORDING TO KIDNEY BIOPSIES - BNAI-ZION MEDICAL CENTER 14 YEARS' EXPERIENCE].

INTRODUCTION: Little is known about the prevalence of kidney diseases according to renal biopsy in Israel. Since updated literature worldwide emphasizes changing etiologies of chronic kidney disease, it is crucial to research and define the epidemiology and pathology of kidney disease in Israel. Hereby, we introduce an original review of the prevalence of kidney diseases in our study population, which we believe reflects the prevalence of kidney diseases in the population of Israel. AIMS: To investigate the prevalence of kidney diseases diagnosed by renal biopsy, according to age, gender, race and clinical symptoms. METHODS: A total of 155 kidney biopsies were conducted in the years 2000-2014 in Bnai-Zion Medical Center in Haifa, according to formal accepted indications. Most of the biopsies (65%) were needle aspirations in a retroperitoneal approach, in which 90% were ultrasound guided and the rest computed tomography guided, while the other 35% of biopsies involved laparoscopic approaches. RESULTS: The most common indications for kidney biopsy were nephrotic syndrome, nephritic syndrome and proteinuria (37.4%, 25.8% and 24.5%, respectively). Average glomeruli number per biopsy was 17.5 vs. 82.2 for needle aspiration and laparoscopic approach, respectively (statistically significant). The most common diagnosis was focal segmental glomerulosclerosis (FSGS), followed by chronic glomerulonephritis, IgA nephropathy, lupus nephritis, minimal change disease (MCD), membranous nephropathy and tubulointerstitial disease (20%, 11.5%, 11.5%, 10.1%, 9.5%, 8.1% and 6.1%, respectively). CONCLUSIONS: FSGS was the most common diagnosis in patients presented with nephrotic syndrome or proteinuria, men, and patients above 60 years of age. Patients below 30 years of age were mainly diagnosed with IgA nephropathy. DISCUSSION: In recent years, FSGS is becoming more prevalent compared with other chronic kidney disease especially in the older population. IgA nephropathy is still the most common diagnosis in young patients and in patients presented with hematuria. To the best of our knowledge, no data exists on the prevalence of kidney diseases in Israel, and our study is an important contribution to the epidemiological and clinical knowledge on the subject.

Heparanase induces signal transducer and activator of transcription (STAT) protein phosphorylation: preclinical and clinical significance in head and neck cancer.

Activity of heparanase is implicated strongly in dissemination of metastatic tumor cells and cells of the immune system. In addition, heparanase enhances the phosphorylation of selected signaling molecules, including SRC and EGFR, in a manner that requires secretion but not enzymatic activity of heparanase and is mediated by its C-terminal domain. Clinically, heparanase staining is associated with larger tumors and increased EGFR phosphorylation in head and neck carcinoma. We hypothesized that signal transducer and activator of transcription (STAT) proteins mediate the protumorigenic function of heparanase downstream of the EGFR. We provide evidence that heparanase enhances the phosphorylation of STAT3 and STAT5b but not STAT5a. Moreover, enhanced proliferation of heparanase transfected cells was attenuated by STAT3 and STAT5b siRNA, but not STAT5a or STAT1 siRNA. Clinically, STAT3 phosphorylation was associated with head and neck cancer progression, EGFR phosphorylation, and heparanase expression and cellular localization. Notably, cytoplasmic rather than nuclear phospho-STAT3 correlated with increased tumor size (T-stage; p = 0.007), number of metastatic neck lymph nodes (p = 0.05), and reduced survival of patients (p = 0.04).

Normal colon tissue and colon carcinoma show no difference in heparanase promoter methylation.

INTRODUCTION: Heparanase, the sole heparan sulfate degrading enzyme, has a role in cellular invasion. Accordingly, a large number of studies have demonstrated an association between heparanase expression and tumor stage and patients' prognosis. In colon carcinoma, heparanase shows increased expression in tumor compared to normal tissue and its expression correlates with the presence of metastasis. One of the regulatory mechanisms of heparanase expression is de-methylation on its promoter. In the present study we evaluated the role of heparanase promoter methylation in colon carcinoma. MATERIAL AND METHODS: Analysis of heparanase promoter methylation was done on 32 samples of colon carcinoma as well as 30 samples of normal colonic mucosa. DNA was extracted from FFPE tissue and subjected to bisulfite conversion. The relative fraction of methylated and unmethylated DNA was evaluated using quantitative real-time PCR. RESULTS: The fraction of methylated DNA was 1 ± 3.4% in the colon carcinoma group, and 2.5 ± 3.3% in the normal colon group (P=0.11). Only one case in the normal group and one case in the tumor group showed more than 10% methylation in the heparanase promoter. CONCLUSION: We did not find any significant difference in heparanase promoter methylation between colon carcinoma and normal colonic mucosa, suggesting that heparanase overexpression in colon carcinoma is mediated by other mechanisms.

KRAS mutation positive mucinous adenocarcinoma originating in mature ovarian teratoma: case report and review of literature.

Mature ovarian teratomas rarely undergo transformation into malignancy. Carcinomas, mostly squamous cell carcinoma, are the most common malignancy arising in mature cystic teratoma. In the present report we describe a 13-year-old girl who developed a large mass in her ovary. Fine needle biopsy identified intestinal type mucinous adenocarcinoma, which was also identified in the full surgical specimen. Extensive sampling of the surgical specimen also identified areas of mature cystic teratoma. Interestingly, molecular analysis of DNA extracted from various components of the lesion identified KRAS mutation in the carcinoma, borderline mucinous tumor and benign intestinal-type epithelium but not in the epidermal component of the teratoma. To the best of our knowledge this is the first report of KRAS mutation in mucinous carcinoma originating in mature cystic teratoma. We discuss the importance of extensive tissue sampling to differentiate between carcinoma originating in teratoma and metastatic colorectal carcinoma to the ovary. Additionally, the identification of KRAS mutation in the morphologically benign intestinal-type epithelium indicated that it is an early event in the carcinogenic sequence and that the molecular pathway of carcinogenesis in teratoma is similar to that in the carcinogenic process of somatic tissue.

Oral cancer, cigarette smoke and mitochondrial 18kDa translocator protein (TSPO) - In vitro, in vivo, salivary analysis.

Oral cancer features high rates of mortality and morbidity, and is in dire need for new approaches. In the present study we analyzed 18 kDa translocator protein (TSPO) expression in oral (tongue) cancer tumors by immunohistochemistry. We also assayed TSPO binding in human tongue cancer cell lines and in the cellular fraction of saliva from tongue cancer patients, heavy cigarette smokers, and non-smoking healthy people as controls. Concurrently, TSPO protein levels, cell viability, mitochondrial membrane potential (Deltapsi(m)), and general protein levels were analyzed. TSPO expression could be significantly enhanced in oral cancer tumors, compared to unaffected adjacent tissue. We also found that five-year survival probability dropped from 65% in patients with TSPO negative tumors to 7% in patients with highly expressed TSPO (p<0.001). TSPO binding capacity was also pronounced in the human oral cancer cell lines SCC-25 and SCC-15 (3133+/-643 fmol/mg protein and 6956+/-549 fmol/mg protein, respectively). Binding decreased by 56% and 72%, in the SCC-25 and SCC-15 cell lines, respectively (p<0.05) following CS exposure in cell culture. In the cellular fraction of saliva of heavy smokers TSPO binding was lower than in non-smokers (by 53%, p<0.05). Also the cellular fraction of saliva exposed to CS in vitro showed decreased TSPO binding compared to unexposed saliva (by 30%, p<0.001). Interestingly, oral cancer patients also displayed significantly lower TSPO binding in the cellular fraction of saliva compared to healthy controls (by 40%, p<0.01). Our results suggest that low TSPO binding found in the cellular fraction of saliva may depend on genetic background as well as result from exposure to CS. We suggest that this may be related to a predisposition for occurrence of oral cancer.

SATB2 is not a reliable diagnostic marker for distinguishing between oral osteosarcoma and fibro-osseous lesions of the jaws.

OBJECTIVE: Special AT-rich binding protein 2 (SATB2) is an immunohistochemical marker for osteoblast differentiation. Our aim was to investigate SATB2 expression in oral osteosarcoma and other bone-producing oral tumors/reactive lesions to evaluate its usefulness as a diagnostic marker. STUDY DESIGN: A total of 74 intraosseous and soft tissue bone-producing surgical samples and 10 samples of reactive bone tissue were stained with SATB2, including osteosarcoma/chondrosarcoma (n = 16), fibro-osseous lesions (n = 42), central giant cell granuloma (n = 6), osteoblastoma (n = 1), and gingival lesions (n = 9). Nuclear labeling of the stromal spindle cells and intensity of staining was scored and analyzed. RESULTS: The intraosseous (n = 65/65) and soft tissue samples (n = 9/9) diffusely expressed SATB2. The strongest expression was observed in juvenile aggressive ossifying fibroma (n = 2/2). Weak SATB2 expression was observed in the stromal spindle cells adjacent to reactive bone tissue (periosteal bone reaction). CONCLUSIONS: Our results indicate that SATB2 is not a reliable diagnostic marker for oral osteosarcoma but has practical use in detecting cells with osteoblast differentiation in histologic samples with scant bone production or in differentiating between a periosteal bone reaction and neoplastic bone induced by the tumor mesenchymal cells. Targeting SATB2 as an alternative therapy in oral osteosarcoma, fibro-osseous lesions, and central giant cell granuloma should be further investigated.

p27 and salivary cancer.

This study examined p27 expression in a cohort of salivary malignancies (n = 74) for a prolonged period (20 years). Reduction of p27 expression was found to be a most powerful predictor for poor survival and more so when the tumor concurrently expressed high levels of p53, TUNEL and heparanase markers, dramatically dropping the patient survival probability to 0! While no patient whose tumor-staining profile included: p27 > 50%, p53 = 0, TUNEL = 0 and heparanase = 0, died of the disease during the 20-year follow up, the median of survival of the group with p27 0, TUNEL > 0 and heparanase > 0 was only 39 months. The survival probabilities of these two groups at 5 years were 100 and 50%, respectively, and at 20 years they were 100 and 0%, respectively (P = 0.05). Significant p27 reduction also resulted in significantly larger tumor size (T value), higher spread of neck metastasis and extra capsular spread and in more advanced disease (higher stage). Significant correlation rates were found between age and poor survival, age and reduced p27 expression, and reduced p27 expression and other general co-existing malignancies, indicating p27 reduction as part of a general phenomenon-age related mutagenesis. Significantly more extensive therapy applied to patients with salivary reduced-p27 tumors could not prevent the rise in mortality rate, questioning the justification for extensive therapy which is naturally accompanied by higher morbidity. Additional therapeutic tools for fighting salivary cancer, possibly based on the new understanding of the p27, p53, TUNEL and heparanase carcinogenic network, are necessary.

Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression.

Enzymatic activity responsible for the cleavage of heparan sulfate, commonly known as heparanase, is abundant in tumor-derived cells. Heparanase cleaves heparan sulfate side chains, presumably at sites of low sulfation, thus facilitating structural alterations of the extracellular matrix and basement membrane underlying epithelial and endothelial cells. Traditionally, heparanase activity was correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter post-operative survival of cancer patients. Although heparanase upregulation and its pro-malignant features are well documented, the instance of its induction in the course of tumor development was less investigated. Here, we used immunohistochemical analysis to investigate heparanase expression in normal esophagus, Barrett's esophagus without dysplasia, Barrett's esophagus with low-grade dysplasia, Barrett's esophagus with high-grade dysplasia, and adenocarcinoma of the esophagus. We report that heparanase expression is already induced in Barrett's epithelium without dysplasia, and is further increased during progression through distinct pathological stages, namely, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Notably, heparanase induction correlated with increased cell proliferation index revealed by Ki-67 staining. These findings suggest that heparanase function is not limited to the process of tumor metastasis, but rather is engaged at the early stages of esophagus carcinoma initiation and progression.

The expression and prognostic significance of Cks1 in salivary cancer.

Cks1 is an essential factor in facilitating Skp2-dependent degradation of p27, but its role in salivary malignancies is unknown. Expression of cyclin-dependent kinase subunit 1 (Cks1) was examined in 64 salivary malignancies, compared with p27, S-phase kinase protein 2 (Skp2), Ki-67, p53, and TDT-mediated dutp-biotin nick end labeling (TUNEL) expression, and with THE patient's clinical and pathological parameters. Cks1 expression was markedly increased in 30 patients (47%) and strongly correlated with increased expression of Skp2, Ki-67, p53, and TUNEL, but inversely with p27 levels. High expression of Cks1 WAS strongly associated with lymph node metastases and poor prognosis and survival. Cks1 alterations may have a significant biological role in the pathogenesis of salivary cancer.

Urinary excretion of endothelin receptors ET A and ET B in hypertensive patients and normotensive subjects.

BACKGROUND/AIMS: Endothelin (ET)-1 is produced by most renal cell types. Renal tubular and vascular cells express both the ET receptors ET(A) and ET(B). Since significant amounts of ET-1 of renal origin were detected in human urine, urinary ET-1 has been used as an index for the capacity of renal ET-1 production. Here, we determine the existence of additional components of the intrarenal ET system, namely the ET(A) and ET(B) receptor subtypes, in the urine of normal and hypertensive subjects. METHODS: ET(A) and ET(B) receptors were detected in urine samples that were concentrated by TCA precipitation, Speedvac or ProteoSpin. RESULTS: Analysis of the human urine extracts revealed the existence of approximately 50 and 55 kDa of immunoreactive proteins, corresponding to ET(B) and ET(A), respectively, indicating that intact ET(A) and ET(B) are excreted in the urine of healthy subjects and hypertensive patients. Normotensive and hypertensive subjects had statistically comparable ET(B) excretion normalized to creatinine (0.58 +/- 0.16 vs. 0.83 +/- 0.17 microg/mg creatinine, respectively; p = 0.304). In contrast, ET(A) excretion was higher among hypertensive subjects (0.05 +/- 0.01 vs. 0.11 +/- 0.02 microg/mg creatinine; p = 0.0451). Immunostaining of ET(A) and ET(B) in the human urinary system revealed expression of both receptors, principally in tubular cells (mainly in medullary collecting ducts) and in the bladder urothelium, and ET(A) expression in the peritubular capillaries and arterioles. Urinary ET receptors closely and inversely correlated with indices of urine concentration, suggesting that their shedding is principally affected by urine flow. CONCLUSION: ET receptors are present in human urine, conceivably originating within the urinary system. Their excretion is principally affected by urinary concentration. It remains to be determined whether urinary ET(A)/ET(B) is of physiological/pathophysiological relevance.

Clinicopathologic analysis of verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma as part of the clinicopathologic spectrum of oral proliferative verrucous leukoplakia: A literature review and analysis.

OBJECTIVE: Proliferative verrucous leukoplakia is classified as a potentially malignant disorder because of its high rate of malignant transformation. PVL progresses in a series of clinical stages where the early stage represents multiple, multifocal leukoplakias with a high recurrence rate. The intermediate and late stages are clinically exophytic lesion, diagnosed microscopically as verrucous hyperplasia that often progresses into verrucous carcinoma and/or squamous cell carcinoma. There is no single histologic definition and the diagnosis is retrospective following observed progression of the disorder. The goal of the current study was to conduct a literature review and analysis of PVL in the later stages to gain further knowledge on their clinicopathologic features. DATA SOURCES: Medline's PubMed and Google Scholar were searched for adequately documented cases from 1985 to 2018. References of published articles were searched for additional cases. REVIEW METHODS: Overall, 57 manuscripts were analyzed. 35/57 manuscripts provided adequate data on the clinicopathologic features in the premalignant and malignant stages. RESULTS: Malignant transformation rate was 50% (average of 57 months). Gingiva, palate and buccal mucosa were the most common locations. Clinicopathologic features included; well differentiated carcinoma (78%), perineural invasion (3%), lymph node metastasis (4%); distant metastasis (0%), average duration of illness (65 months), DOD-dead of disease (44%). Moderate dysplasia, severe dysplasia and carcinoma in situ were exceptionally uncommon in the premalignant stages (0.8%). CONCLUSION: Prognostic factors such as perineural invasion, lymph node metastasis and distant metastasis were uncommon occurrences which may have practical implications on treatment. Further studies are needed to substantiate our findings.

Three-step management of a newborn with a giant, highly vascularized, cervical teratoma: a case report.

BACKGROUND: A giant congenital cervical teratoma is often highly vascularized; thus, in addition to a life-threatening airway occlusion at birth it comprises a high risk for significant and lethal blood loss during resection. In the case presented, an endovascular embolization of the carotid artery that supplied a giant congenital cervical teratoma was done as part of a three-stage treatment soon after birth and contributed to an overall good outcome. Embolization in cases of cervical teratomas was not described previously. CASE PRESENTATION: We present a case of a preterm newborn from a Sephardic jewish origin with a giant, highly vascularized, congenital cervical teratoma that was managed successfully in three stages: (1) delivery by an ex utero intrapartum treatment procedure after extensive preoperative planning and followed by tracheostomy, (2) endovascular embolization of the carotid artery that supplied the tumor in order to decrease blood loss during resection, and (3) complete surgical resection. The parents were involved in all the ethical and medical decisions, starting just after the cervical mass was diagnosed prenatally. CONCLUSION: The management of giant congenital cervical teratoma is often challenging from both a medical and ethical prospective. Meticulous perinatal planning and parents' involvement is crucial. Endovascular embolization of the tumor feeding vessels can significantly improve the resection outcome and overall prognosis.

Over-expression of Skp2 is associated with resistance to preoperative doxorubicin-based chemotherapy in primary breast cancer.

INTRODUCTION: Preoperative chemotherapy is often used in patients with locally advanced breast cancer. However, commonly used clinical and pathological parameters are poor predictors of response to this type of therapy. Recent studies have suggested that altered regulation of the cell cycle in cancer may be involved in resistance to chemotherapy. Over-expression of the ubiquitin ligase Skp2 results in loss of the cell cycle inhibitor p27Kip1 and is associated with poor prognosis in early breast cancer. The purpose of the present study was to examine the role of these proteins as predictors of clinical outcome and response to chemotherapy in locally advanced breast cancer. METHODS: The expression levels of Skp2 and p27Kip1 were determined by immunohistochemistry both before and after preoperative chemotherapy in 40 patients with locally advanced breast cancer. All patients were treated with cyclophosphamide/doxorubicin (adriamycin)/5-fluorouracil (CAF) and some patients received additional treatment with docetaxel. Expression data were compared with patients' clinical and pathological features, clinical outcome, and response to chemotherapy. RESULTS: Skp2 expression before preoperative chemotherapy was inversely related to p27Kip1 levels, tumor grade, and expression of estrogen and progesterone receptors. Both Skp2 and p27Kip1 were found to be accurate prognostic markers for disease-free and overall survival. High preoperative expression of Skp2 was associated with resistance to CAF therapy in 94% of patients (P < 0.0001) but not with resistance to docetaxel. CONCLUSION: Skp2 expression may be a useful marker for predicting response to doxorubicin-based preoperative chemotherapy and clinical outcome in patients with locally advanced breast cancer.