Is there a Role for Frozen Section Evaluation of Parotid Masses After Preoperative Cytology or Biopsy Diagnosis?

Fine-needle aspiration (FNA) biopsy reliably diagnoses parotid gland lesions preoperatively, whereas intraoperative frozen section (FS) has the additional benefit of assessing surgical margins and refining diagnoses; however, the role of FS in the setting of prior FNA diagnosis is not well established. Our aim was to determine whether FS should still be performed after a prior FNA/ CNB diagnosis. Parotid gland resections from January 2009 to January 2020 were identified; however, only patients who had both FNA and FS constituted our study population. For the purpose of statistical analysis, FNA diagnoses were classified into non-diagnostic (ND), non-neoplastic (NN), benign neoplasm (BN), indeterminate, and malignant. FS diagnoses were classified into benign, indeterminate, or malignant. Resections were dichotomized into benign and malignant and regarded as the gold standard to subsequently calculate diagnostic accuracy of FNA and FS. A total of 167 parotid gland resections were identified, but only 76 patients (45.5%) had both FNA and FS. In 35 cases deemed as benign preoperatively, three (8.6%) were reclassified as malignant on FS. Out of 18 lesions reported as malignant on FNA, four (22.2%) were interpreted as benign on FS, with three of these benign lesions confirmed on permanent slides. In addition, in patients with both FNA and FS, compared to FNA, FS was able to provide a definitive diagnosis in all five ND cases and in 61.1% (11/18) of indeterminate tumors. Intraoperative assessment provided a relative increase of 33.3% in specificity and 38.5% in positive predictive value when compared to preoperative FNA. The addition of FS to FNA was helpful to further refine the diagnoses of parotid gland lesions, which may provide better guidance for surgical intervention.

[Cancers of the external genital organs of male in Hérault: Results from the Hérault tumor register (RTH) over a period of 30 years (1987-2016)]. / Le cancer des organes génitaux externes de l'homme dans le département de l'Hérault: résultats de 30 ans d'enregistrement du registre des tumeurs de l'Hérault (1987­2016).

AIM: The objective of this study is to present the history of cancers of the external genital organs of male in Hérault using data from the Hérault tumor register (RTH) over a period of 30 years. PATIENTS AND METHODS: Using the RTH database, we studied the development of testicular germ cell tumors (TGCT) and penile cancer (PC) over 30 years, from 1987 to 2016. We analyzed the incidence and mortality data for these tumors. We compared these results to French, European and global data. RESULTS: In 30 years of registration we have recorded 725 cases of TGCT and 175 cases of PC. The age standardized incidence rate (ASR) of TGCT has doubled between 1987 and 2016 (4.2 per 100,000 in 1987 and 9.3 per 100,000 in 2016). It was multiplied by 2.63 in the population of patients aged 30 to 44. There is a decrease of the mortality rate with a ASR of 0.8 deaths per 100,000 in 1987, and 0.4/100 000 in 2016. The PC incidence ASR was stable between 1987 and 2016 (0.4-0.9/100,000). Mortality is stable with a ASR between 0.1 and 0.3 deaths per 100,000 between 1987 and 2016. CONCLUSION: The incidence of TGCT has increased sharply in the Hérault over the past 30 years, while a decrease in mortality has been observed. The proportion of seminomas is increasing; it has gone from 53 % to 60 % in 30 years in the Hérault. The incidence and mortality of PC shows a stability in the Hérault over the past 30 years.

Microcracks in subchondral bone plate is linked to less cartilage damage.

OBJECTIVES: Osteoarthritis (OA) is a disease of the whole joint characterized by cartilage loss and subchondral bone remodeling. The role of microcracks in cartilage integrity and subchondral bone homeostasis is not fully understood. The main goal of this work was to evaluate microcrack density in both calcified cartilage and subchondral bone plate in relation to cartilage damage in humans and to better define the association of microcracks and osteocyte density in subchondral bone. METHODS: We investigated 18 bone cores from cadaveric human knees that were stained with En-Bloc Basic Fuchsin. We quantified microcrack density, osteocyte density, cartilage surfaces and cartilage damage. The presence of microcracks was confirmed for each bone core by scanning electron microscopy. Finally, trabecular subchondral bone parameters were measured by micro-CT. RESULTS: Microcracks were detected in both calcified cartilage and subchondral bone plate. The density of microcracks in both calcified cartilage (CC) and subchondral bone plate (SBP) was negatively correlated with cartilage damage (r = -0.45, p < 0.05). The presence of microcracks in SBP was associated with a lower histological OA score. Osteocytes formed a dendrite network that abruptly stopped at the border of calcified cartilage. Osteocyte density in subchondral bone plate was increased in the presence of microcracks in calcified cartilage. CONCLUSIONS: Subchondral bone plate microcracks might be required for maintaining cartilage homeostasis. Microcracks in calcified cartilage may trigger osteocyte density in subchondral bone plate with subsequent regulation of subchondral bone remodeling to prevent cartilage damage.

Therapeutic Approaches to ModulatingGlutathione Levels as a Pharmacological strategy in Alzheimer's Disease.

Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD).The main endogenousantioxidant,glutathione (GSH),has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteineHowever, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacyto elevatedepleted GSH levels in several in vivo and in vitro models of disease.It has beensuggestedthat the decline in GSH levels in AD, may be associated with down regulation ofGSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulatedby non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor γ-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves asa crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH,andthe administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD.

Comparative evaluation of three commercial systems for detection of high-risk human papillomavirus in cervical and vaginal ThinPrep PreservCyt samples and correlation with biopsy results.

Genital human papillomavirus (HPV) is the etiologic agent of more than 99% of all cervical cancers worldwide, with 14 genotypes being considered oncogenic or "high risk" because of their association with severe dysplasia and cervical carcinoma. Among these 14 high-risk types, HPV-16 and -18 account for approximately 70% of cervical cancers. The aim of this study was to evaluate three FDA-approved HPV nucleic acid-based tests for the ability to predict high-grade cervical intraepithelial neoplasias (CIN2 or worse) in corresponding tissue biopsy specimens. Residual specimens (total n = 793, cervical n = 743, vaginal n = 50) collected in ThinPrep PreservCyt medium with a cytologic result of ≥ atypical squamous cells of undetermined significance were tested by the Hybrid Capture 2 (HC2) assay (Qiagen, Gaithersburg, MD), the cobas HPV test (Roche Diagnostics, Indianapolis, IN), and the APTIMA HPV assay (Hologic, San Diego, CA). Genotyping for HPV-16 and HPV-18 was simultaneously performed by the cobas HPV test. Results were compared to cervical or vaginal biopsy findings, when they were available (n = 350). Among the 350 patients with corresponding biopsy results, 81 (23.1%) showed ≥ CIN2 by histopathology. The ≥ CIN2 detection sensitivity was 91.4% by the cobas and APTIMA assays and 97.5% by HC2 assay. The specificities of the cobas, APTIMA, and HC2 assays were 31.2, 42.0, and 27.1%, respectively. When considering only positive HPV-16 and/or HPV-18 genotype results, the cobas test showed a sensitivity and a specificity of 51.9 and 86.6%, respectively. While the HC2, cobas, and APTIMA assays showed similar sensitivities for the detection of ≥ CIN2 lesions, the specificities of the three tests varied, with the greatest specificity (86.6%) observed when the HPV-16 and/or HPV-18 genotypes were detected.

Safety assessment of gamma-glutamylcysteine sodium salt.

γ-Glutamylcysteine (GGC) is a relatively unexplored option for the treatment of chronic glutathione depletion related disorders that involve down regulation of GGC synthetase. High purity GGC (sodium salt) has only recently become available and, given its reactive capacity, required an investigation of its safety profile. In this report, GGC sodium salt was demonstrated to be safe according to Organisation for Economic Cooperation and Development (OECD) toxicology protocols for acute and repeated doses. No mortalities or adverse effects were observed in Wistar rats following the acute oral (gavage) administration of 2000mg sodium GGC /kg body weight. No animal deaths occurred with daily administration (1000mg/kg sodium GGC) over 90days, with a post trial 28day observation period. GGC had no significant effect on feed consumption, body weights, physical appearance, neurological behaviour and urine chemistry. No consistent significant differences between treatment groups were observed in haematological and clinical chemistry parameters. Similarly, no post-mortem necroscopically identified abnormalities could be attributed to GGC. Based on these observations, sodium GGC can be classed as not acutely toxic at 2000mg/kg, with a no-observed-adverse-effect level (NOAEL) of at least 1000mg/kg/day for systemic toxicology from repeated dose oral gavage administration.

Assisting cytopathology training in medically under-resourced countries: defining the problems and establishing solutions.

Cytology is able to deliver rapid accurate diagnoses with minimal equipment and laboratory infrastructure at minimal cost, and this is especially so for fine needle biopsy (FNB), which is a powerful diagnostic tool in medically resource-poor environments, where histopathology laboratories are small in number and poorly supported financially. The crucial element in the development of cytology services is to train a sufficient number of well trained cytopathologists and cytotechnologists to create a 'critical mass' of personnel who not only provide routine diagnostic services, but also can train an ever expanding number of pathologists, cytotechnologists, and health workers. A review of practical programs to train cytopathologists and cytotechnologists in their own countries will be presented, including a recent series of FNB and cytology tutorials run in sub Saharan Africa. The need for local cytopathology programs and the potential for both local and visiting cytopathologists to provide a faculty will be discussed, as well as a range of possible programs which can bring African pathologists and trainee pathologists to Western institutions for periods of their training. Ideally, the regional Societies of Cytology, including the recently formed West African Society of Cytology, will establish their own diagnostic protocols, training programs, syllabuses, examinations and accreditation and career pathways for both cytopathologists and cytotechnologists, and organize tutorials where they will invite overseas faculty to contribute. Crucially, these new societies will empower cytopathologists and cytotechnologists to approach health services and governments to state the need for cytology services as a cost-effective accurate diagnostic service that enhances patient care.

Increase in synthesis of human monoclonal antibodies by transfected Sp2/0 myeloma mouse cell line under conditions of microgravity.

Microgravity can influence cell growth and function. A transfected Sp2/0 myeloma cell line P3A2 producing a human IgG1 anti-TNFa monoclonal antibody was cultivated in static culture, spinner flasks and simulated microgravity using a rotating wall vessel bioreactor. Microgravity significantly decreased cell growth (from 1.7 x 10(6) to 7.9 x 10(5) cells/ml), but facilitated the synthesis of antibodies, (1.8, 1.3 and 0.5 microg of anti-TNFalpha hmAb per 10(6) viable cells for cells cultivated under microgravity, in spinner flasks and static cultures, respectively). The results suggest that microgravity could be applied to improve the specific productivity of cell lines producing potentially important therapeutic proteins.

Amphiphilic polymer supports for the asymmetric hydrogenation of amino acid precursors in water.

This paper describes the synthesis and characterization of a new class of amphiphilic, water-soluble diblock copolymers based on 2oxazoline derivatives with pendent (2S,4S)-4-diphenylphosphino-2-(diphenylphosphinomethyl)pyrrolidine (PPM) units in the hydrophobic block. The synthetic strategy involves the preparation of a diblock copolymer precursor with ester functionalities in the side chain; which were converted into carboxylic acids in a polymer-analogous step and finally reacted with the PPM ligand. The structures of the copolymers were characterized by (1)H and (31)P NMR spectroscopy and GPC measurements. Subsequently, these polymers were successfully utilized as a polymeric support for the asymmetric hydrogenation of 1) (Z)-alpha-acetamido cinnamic acid and 2) methyl (Z)-alpha-acetamido cinnamate in water, showing 90 % substrate conversion at 25 degrees C within 20 minutes at atmospheric H(2) pressure (1 bar) for methyl (Z)-alpha-acetamido cinnamate.

Lysosome proteins are redistributed during expression of a GTP-hydrolysis-defective rab5a.

The functioning of the endocytic pathway is influenced by a distinct set of rab GTPases, including rab5a, which regulates homotypic fusion of early endosomes. Expression of a dominant active, GTPase-defective rab5a accelerates endosome fusion, causing the formation of a greatly enlarged endocytic compartment. Here we present evidence that rab5a also regulates trafficking between endosomes and lysosomes and may play a role in lysosome biogenesis. The GTPase defective rab5aQ79L mutant was inducibly expressed as an EGFP fusion in HEK293 cells, and the distribution of lysosome proteins and endocytic markers then assessed by deconvolution fluorescence microscopy. During expression of EGFP-rab5aQ79L, the lysosome proteins LAMP-1, LAMP-2 and cathepsin D were found in dilated EGFP-rab5aQ79L-positive vesicles, which also rapidly labeled with transferrin Texas Red. Exogenous tracers that normally traffic to lysosomes after prolonged chase (dextran Texas Red and DiI-LDL) also accumulated in these vesicles. Dextran Texas Red preloaded into lysosomes localized with subsequently expressed EGFP-rab5a Q79L, suggesting the existence of lysosome to endosome traffic. Cells expressing EGFP-rab5a wt or the dominant negative EGFP-rab5aS34N did not exhibit these abnormalities. Despite the dramatic alterations in lysosome protein distribution caused by expression of EGFP-rab5a Q79L, there was little change in the endocytosis or recycling of a cell-surface receptor (beta2-adrenergic receptor). However, there was a deficiency of dense beta-hexosaminidase-containing lysosomes in cells expressing EGFP-rab5aQ79L, as assessed by Percoll gradient fractionation. These results suggest that expression of a GTPase-defective rab5a affects lysosome biogenesis by alteration of traffic between lysosomes and endosomes.

Transthoracic needle biopsy.

Transthoracic needle biopsy (TNB) has emerged as the semi-invasive technique of choice for the diagnosis of localized intrathoracic lesions. Using CT, fluoroscopic, or sonographic guidance, TNB is highly accurate and safe when combined with expert pathologic interpretation of the aspirated specimen. This article details the preprocedural evaluation of the patient referred for TNB and discusses the technical aspects of performing the biopsy and processing and interpreting the material obtained. The reported results and complications of TNB are reviewed and followed by a brief description of the cost effectiveness of the technique and a comparison with alternative semi-invasive diagnostic techniques including bronchoscopic and video-assisted thoracoscopic biopsy.

Formalin instillation for ischemic proctitis with unrelenting hemorrhage: report of a case.

A case report of an elderly male with multiple medical problems and hemorrhagic, ischemic proctitis is presented. The proctitis was refractory to all other medical options but responded to topical instillation of 4 percent formalin.

Desmoplastic small round cell tumour of unknown primary origin with lymph node and lung metastases: histological, cytological, ultrastructural, cytogenetic and molecular findings.

Desmoplastic small round cell tumour (DSRCT) is an extremely aggressive neoplasm belonging to the family of "small round blue cell tumours", which includes primitive neuroectodermal tumour (PNET), Wilms' tumour and Ewing's sarcoma. DSRCT is considered to be a neoplasm derived from a primitive cell. It is immunohistochemically reactive with epithelial, neuronal and mesenchymal cell markers, demonstrating divergent differentiation along three cell lines. Originally thought to arise from serosal surfaces, the tumour has recently been reported in the central nervous system and ovary. The tumour in this case is a neoplasm that meets the histological, immunohistochemical, cytological and cytogenetic criteria of DSRCT; it is not associated with serosal membranes, and it has supraclavicular and axillary lymph node deposits and multiple pulmonary and brain metastases. Tumour cells from our case show cytogenetic similarities with Ewing's sarcoma and PNET. Electron microscopic findings suggest similarities between DSRCT and Wilms' tumour. Cloning and sequencing of PCR products showed in-frame fusion of EWS exon 7 to WT1 exon 8.

Evaluation of the ThinPrep Pap test in clinical practice. A seven-month, 16,314-case experience in northern Vermont.

OBJECTIVE: To compare the cytologic diagnoses and specimen adequacy of the ThinPrep Pap Test with historical data within a distinct patient population to assess test performance and its impact on clinical practice. STUDY DESIGN: A total of 16,314 ThinPrep Pap tests were processed and evaluated at Fletcher Allen Health Care over a seven-month period. A subset of 8,574 tests from a selected provider group (cohort) was compared to the historical conventional cervical cytologic smear data from the cohort population for both cytologic diagnoses and specimen adequacy. The cohort consisted of 12 practice groups, including 60 physicians and providers, utilizing the ThinPrep Pap Test as their primary cervical cancer screening sampling technique. Cytologic diagnoses and specimen adequacy were classified using the Bethesda system. RESULTS: Using a three-tiered diagnostic system similar to the Cytyc clinical trials (within normal limits [WNL], atypical squamous cells of undetermined significance [ASCUS]/atypical glandular cells of undetermined significance [AGUS] and low grade squamous intraepithelial lesion and higher [LSIL]+), the ThinPrep method increased the percentage of cases that could be definitively diagnosed as WNL by 1.71%, lowered the percentage of ambiguous or borderline cases diagnosed as ASCUS/AGUS by 26.59% and increased the percentage of cases diagnostic of LSIL+ by 52.15% in the cohort population. Further subdivision by the Bethesda classification showed that the identification of infectious agents increased 25.51% and the detection of high grade squamous intraepithelial lesion/carcinoma increased 55.14%. Concurrently, cases reported as benign cellular changes (reactive/reparative) decreased 23.1%, and the percentage of cases reported as unsatisfactory/"limited by ..." was reduced 52.71%. Histologic correlation of cases reported as squamous intraepithelial lesion revealed that the percentage of patients with subsequent benign biopsies was reduced by 31.7% utilizing the ThinPrep technique. Further, the percentage of ThinPrep patients with histologically confirmed cervical intraepithelial neoplasia (CIN) 1 and CIN 2/3 increased by 16.3% and 9.3%, respectively. CONCLUSION: Implementation of the ThinPrep Pap Test resulted in statistically significant improvements in both diagnostic yield and specimen adequacy, as seen by others in clinical trials. Comparison of results to historical data within a cohort population reinforced earlier data and lent further support to the claim that the ThinPrep Pap Test is "significantly more effective" than the conventional smear in clinical practice.

Transthoracic needle biopsy: an overview.

The parallel development of cross-sectional detection and characterization of thoracic lesions with advances in biopsy needle design and increased access to expert cytopathology has led to an expanded role for image-guided transthoracic needle biopsy (TNB) in the diagnostic evaluation of thoracic lesions. There is a growing list of indications for TNB, the most important of which is the evaluation of a solitary pulmonary nodule. A key preparatory step in planning TNB is conducting a preprocedural consultation with the pathologist, which maximizes the likelihood of a positive diagnostic outcome. Computed tomography (CT) has rapidly become the guidance modality of choice for performing TNB. While TNB is highly sensitive in the diagnosis of carcinoma, methods used to enhance the diagnostic yield for other neoplasms and benign conditions include coaxial needle placement for multiple samplings, selective use of core biopsy needles to obtain histologic specimens, and the performance of ancillary tests on the aspirated material. The complications of TNB are well recognized and include pneumothorax, hemorrhage, and systemic air embolism. Although the results of recent cost-analysis studies suggest a central role for TNB in the diagnosis of the indeterminate lung lesion, the availability and yield of alternative diagnostic and therapeutic techniques including positron-emission tomography scanning and video-assisted thoracoscopic surgery will determine its true utility.

Diagnostic accuracy of a rural live video telepathology system.

Accuracy of diagnoses rendered using a live video telepathology network was assessed for permanent sections of surgical pathology specimens. To determine accuracy, telepathology diagnoses were compared with those obtained by directly viewing the glass slide using a standard microscope. A total of 294 cases were read via both telepathology and glass slide by attending pathologists at a tertiary care medical center. Overall accuracy was defined as exact concordance between diagnoses. Clinically insignificant differences in diagnoses were excluded to determine clinically significant accuracy. For the 285 cases with complete data, the overall accuracy for telepathology was 0.912 (95% confidence interval [CI], 0.872-0.941), whereas the overall accuracy for glass slide readings was 0.968 (95% CI, 0.939-0.985). This difference is statistically significant (p = 0.009). When focusing on clinically significant discrepancies, where the difference in diagnosis might affect therapeutic decisions, the video accuracy was only slightly less than the glass slide accuracy (0.965 [95% CI, 0.934-0.982] vs. 0.982 [95% CI, 0.957-0.994], respectively), but this difference is not statistically significant (p = 0.302). Most of the cases with clinically significant differences involved lesions with inherently high interobserver variation. Certainty of diagnosis did not differ between video and glass slide readings (p = 0.911), but there was an association between certainty of diagnosis and diagnostic accuracy for video (p = 0.003 for clinically significant accuracies). Based on these findings, we recommend when using this telepathology system that only preliminary diagnoses should be given in the following situations: for diagnostic areas with known high interobserver variability; when the consultant has any degree of uncertainty about the presence or absence of the lesion in question; and when there is insufficient experience using telepathology as a diagnostic medium.

Fine-needle aspiration of the salivary glands.

Fine-needle aspiration is increasingly used in community practices for the diagnosis of salivary gland lesions, and it often renders an unequivocal diagnosis. This chapter discusses in detail the technical considerations of FNA, non-neoplastic and inflammatory conditions, benign neoplasms, common malignant neoplasms, and rare malignant neoplasms.