Neuroendocrine Carcinoma of the Cervix: Review of a Series of Cases and Correlation With Outcome.

Introduction Neuroendocrine carcinoma (NEC) of the cervix is associated with a poor prognosis despite multimodal treatment. The correct diagnosis of this tumor type is imperative to provide clinicians and patients with prognostic information and ensure that appropriate treatment is provided. Methods A clinicopathological study was undertaken on all cervical tumors registered as NEC with the West Midlands Cancer Intelligence Unit between January 1, 1998 and December 31, 2009. Of the 45 cases diagnosed during the study period, the tumor samples of 41 cases were traced, anonymized, and then independently reviewed by 2 gynecological pathologists. Results The review confirmed 31/41 (78%) cases to be NEC, which overall, represented 1.3% of all the cervical cancers registered in the West Midlands over the period of the study. In the correct histological context, synaptophysin was the most sensitive and specific positive immunohistochemical marker of NEC differentiation. The cases that on review were confirmed as NEC had a significantly worse outcome than the non-NEC cases: median survival for NEC cases was 33.3 months versus 315.0 months for the non-NEC cases, P = .013. Conclusions Histological review of a series of NECs has shown significantly reduced survival in those patients with confirmed NEC in comparison with those patients where a diagnosis of NEC was not confirmed. We propose morphological and immunohistochemical criteria for the diagnosis of cervical NEC; and discourage unqualified use of the term "small cell carcinoma" as this does not accurately convey the diagnosis of SCNEC. We urge pathologists to use the 2014 World Health Organization classification when reporting these tumors.

The Effect of Country of Birth on the Pattern of Disease and Survival From Cervical Cancer.

OBJECTIVE: The aim of the study was to investigate the impact of country of birth on the pattern of disease and survival from cervical cancer in women living in the United Kingdom. MATERIALS AND METHODS: A retrospective database evaluation study was performed to review all cases of cervical cancer diagnosed in the Pan-Birmingham Cancer Network between 2005 and 2009. Population characteristics and survival data were obtained from the West Midlands Cancer Registry and National Health Authority Information System, United Kingdom. Women's country of birth was classified as being high- (including patients born in the United Kingdom and Ireland), middle-, or low-income countries according to the World Bank country classification. Screening histories data were obtained from the West Midlands Cancer Screening Quality Assurance Reference Centre. Overall survival data were analyzed using the nonparametric Kaplan-Meier method with log-rank tests to compare between groups. RESULTS: Four hundred eighty-four cases were identified. A country of birth was available for 459 cases (94.8%). Cancers detected through screening or interval cancers accounted for 140 (28.9%) of cases compared with 226 (46.7%) where women had not complied with screening. Of the women born outside of the United Kingdom/Ireland, 40 (59.7%) originated from low-income, 23 (34.3%) from middle-income, and 4 (6.0%) from high-income countries. Multivariate analysis identified age (p < .001) and stage (p < .001) at diagnosis as having a significant effect on survival, but no effect was seen from social deprivation (p = .18) or economic status of country of birth (p = .30). DISCUSSION: Country of birth is not an independent prognostic indicator for cervical cancer survival.

Should All Cases of High-Grade Serous Ovarian, Tubal, and Primary Peritoneal Carcinomas Be Reclassified as Tubo-Ovarian Serous Carcinoma?

INTRODUCTION: The dualistic theory of ovarian carcinogenesis proposes that epithelial "ovarian" cancer is not one entity with several histological subtypes but a collection of different diseases arising from cells of different origin, some of which may not originate in the ovarian surface epithelium. METHODS: All cases referred to the Pan-Birmingham Gynaecological Cancer Centre with an ovarian, tubal, or primary peritoneal cancer between April 2006 and April 2012 were identified from the West Midlands Cancer Registry. Tumors were classified into type I (low-grade endometrioid, clear cell, mucinous, and low-grade serous) and type II (high-grade serous, high-grade endometrioid, carcinosarcoma, and undifferentiated) cancers. RESULTS: Ovarian (83.5%), tubal (4.3%), or primary peritoneal carcinoma (12.2%) were diagnosed in a total of 583 woman. The ovarian tumors were type I in 134 cases (27.5%), type II in 325 cases (66.7%), and contained elements of both type I and type II tumors in 28 cases (5.7%). Most tubal and primary peritoneal cases, however, were type II tumors: 24 (96.0%) and 64 (90.1%), respectively. Only 16 (5.8%) of the ovarian high-grade serous carcinomas were stage I at diagnosis, whereas 240 (86.6%) were stage III+. Overall survival varied between the subtypes when matched for stage. Stage III low-grade serous and high-grade serous carcinomas had a significantly better survival compared to clear cell and mucinous cases, P = 0.0134. There was no significant difference in overall survival between the high-grade serous ovarian, tubal, or peritoneal carcinomas when matched for stage (stage III, P = 0.3758; stage IV, P = 0.4820). CONCLUSIONS: Type II tumors are more common than type I and account for most tubal and peritoneal cancers. High-grade serous carcinomas, whether classified as ovarian/tubal/peritoneal, seem to behave as one disease entity with no significant difference in survival outcomes, therefore supporting the proposition of a separate classification of "tubo-ovarian serous carcinoma".

SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis.

A non-synonymous single nucleotide polymorphism in the human SLC24A5 gene is associated with natural human skin color variation. Multiple sequence alignments predict that this gene encodes a member of the potassium-dependent sodium-calcium exchanger family denoted NCKX5. In cultured human epidermal melanocytes we show using affinity-purified antisera that native human NCKX5 runs as a triplet of approximately 43 kDa on SDS-PAGE and is partially localized to the trans-Golgi network. Removal of the NCKX5 protein through small interfering RNA-mediated knockdown disrupts melanogenesis in human and murine melanocytes, causing a significant reduction in melanin pigment production. Using a heterologous expression system, we confirm for the first time that NCKX5 possesses the predicted exchanger activity. Site-directed mutagenesis of NCKX5 and NCKX2 in this system reveals that the non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue that is important for NCKX5 and NCKX2 activity. We suggest that NCKX5 directly regulates human epidermal melanogenesis and natural skin color through its intracellular potassium-dependent exchanger activity.

Efficient catalytic promiscuity in an enzyme superfamily: an arylsulfatase shows a rate acceleration of 10(13) for phosphate monoester hydrolysis.

We report a second catalytic activity of Pseudomonas aeruginosa arylsulfatase (PAS). Besides hydrolyzing sulfate monoesters, this enzyme catalyzes the hydrolysis of phosphate monoesters with multiple turnovers (>90), a k(cat) value of 0.023 s(-1), a K(M) value of 29 microM, and a kcat/K(M) ratio of 790 M(-1) s(-1) at pH 8.0. This corresponds to a remarkably high rate acceleration of 10(13) relative to the nonenzymatic hydrolysis [(k(cat)/K(M))/k(w)] and a transition-state binding constant (K(tx)) of 3.4 pM. Promiscuous phosphatase and original sulfatase activities only differ by a factor of 620 (measured by k(cat)), so the enzyme provides high accelerations for both reactions. The magnitudes and relative similarity of the kinetic parameters suggest that a functional switch from sulfatase to phosphatase activities is feasible, either by gene duplication or by direct evolution via an intermediate enzyme with dual specificity.

Cloning, expression, and site-directed mutagenesis of the propene monooxygenase genes from Mycobacterium sp. strain M156.

Propene monooxygenase has been cloned from Mycobacterium sp. strain M156, based on hybridization with the amoABCD genes of Rhodococcus corallinus B276. Sequencing indicated that the mycobacterial enzyme is a member of the binuclear nonheme iron monooxygenase family and, in gene order and sequence, is most similar to that from R. corallinus B-276. Attempts were made to express the pmoABCD operon in Escherichia coli and Mycobacterium smegmatis mc(2)155. In the former, there appeared to be a problem resolving overlapping reading frames between pmoA and -B and between pmoC and -D, while in the latter, problems were encountered with plasmid instability when the pmoABCD genes were placed under the control of the hsp60 heat shock promoter in the pNBV1 vector. Fortuitously, constructs with the opposite orientation were constitutively expressed at a level sufficient to allow preliminary mutational analysis. Two PMO active-site residues (A94 and V188) were targeted by site-directed mutagenesis to alter their stereoselectivity. The results suggest that changing the volume occupied by the side chain at V188 leads to a systematic alteration in the stereoselectivity of styrene oxidation, presumably by producing different orientations for substrate binding during catalysis. Changing the volume occupied by the side chain at A94 produced a nonsystematic change in stereoselectivity, which may be attributable to the role of this residue in expansion of the binding site during substrate binding. Neither set of mutations changed the enzyme's specificity for epoxidation.