Open reduction and internal fixation versus closed reduction and percutaneous fixation in the treatment of Bennett fractures: A systematic review.

PURPOSE: Open reduction and internal fixation (ORIF) of Bennett fractures is increasingly preferred over closed reduction and percutaneous fixation (CRIF) in an attempt to prevent the development of post-traumatic arthrosis. The aim of this systematic review was to determine whether the preference for ORIF is justified based on the available literature regarding functional outcome and complications after surgery. METHODS: A systematic review was performed in Medline, Embase, Cochrane CENTRAL, Web of science, and Google scholar. Duplicates were removed and title and abstract were screened after which full text articles were analysed. The reference lists of selected articles were screened for additional relevant studies. Study characteristics were recorded and methodological qualities were assessed after which data was extracted from the included articles. The Eaton-Littler score for post-traumatic arthrosis (primary outcome) on follow-up X-rays was used as primary outcome. Secondary outcomes were Grip strength, Pinch strength, persistent pain, fixation failure, functional impairment, infection and surgery time. RESULTS: Ten studies were included; three retrospective comparative studies and seven retrospective case series. Of the 215 patients in these studies, 138 had been treated using an open technique and 77 by a closed percutaneous technique. The pooled rate of post-traumatic arthrosis was 57.5% (26.6-85.5) in the ORIF group versus 26.1% (3.9-59.0) in the CRIF group. Mean surgical operation time was 71.9 min for ORIF and 30.2 min for percutaneous patients. Fixation failure was significantly more often seen in the ORIF patients, 8.2% (0.7-22.8) vs. 2.9% (0.8-9.1), Risk Ratio 1.132 (0.01-176.745); p = 0.048. Infection was only seen in 5 CRIF patients. Persistent pain was seen in 32.9% (0.6-83.1) in ORIF patients versus 22.3% (8.1-41.1) in the CRIF patients. The pooled means Grip strength was 48.3 kg (95% CI; 39.7-56.9) versus 43.4 kg (95% CI; 22.9-63.8) for ORIF and CRPF, respectively. Functional impairment was similar between the two groups, 1.4% (0.1-4.4) vs 1.8% (0.1-5.7) respectively. CONCLUSION: The analysed data do not confirm ORIF to prevent post-traumatic arthrosis, secondly more fixation failure and pain was seen in the ORIF group. The pooled data show percutaneous fixation to be preferable over ORIF in the surgical treatment of Bennett fractures.

Changes in nationwide use of preoperative radiotherapy for rectal cancer after revision of the national colorectal cancer guideline.

BACKGROUND: The rate of preoperative radiotherapy (RT) for rectal cancer in the Netherlands has been the highest among European countries. Revision of the national guideline on colorectal cancer, officially published in 2014, specifically focussed on the indication for RT and MRI criteria to evaluate mesorectal lymph nodes. The objective of this study was to evaluate implementation of the revised guideline using a national audit. METHODS: Data of the Dutch Surgical Colorectal Audit (DSCA) between 2009 and 2014 were used to evaluate RT use and RT regimen for relevant subgroups of cM0 rectal cancer patients, as well as accuracy of pre-operative MRI. RESULTS: 14,018 patients were included for analysis. Overall RT use in cT1-4N0-2M0 stage ranged from 81.4% to 84.2% between 2009 and 2013, and decreased to 64.4% in 2014. The absolute decrease in RT use from 2013 to 2014 for cT1N0, cT2N0 and cT3N0 stage was 32.8%, 43.5% and 31.6%, respectively. Short course RT with delayed surgery was used as an alternative to chemoradiotherapy up to 2013 in 30.6% of patients over 80 years, and in 12.1% of patients with an ASA score >2; these percentages increased to 45.8% and 19.9% in 2014, respectively. Specificity of MRI for N-stage decreased from 82.9% in 2009 to 62.9% in 2013, with an increase to 73.2% in 2014. CONCLUSION: The revised national guideline on colorectal cancer was rapidly implemented in the Netherlands with a substantial decrease in RT use for low risk resectable rectal cancer, and increased specificity of MRI for N-staging.

[Surgery for colorectal cancer since the introduction of the Netherlands national screening programmeInvestigations into changes in number of resections and waiting times for surgery]. / Darmkankerchirurgie sinds het bevolkingsonderzoek.

OBJECTIVE: To investigate the impact of the Netherlands national colorectal cancer screening programme on the number of surgical resections for colorectal carcinoma and on waiting times for surgery. DESIGN: Descriptive study. METHOD: Data were extracted from the Dutch Surgical Colorectal Audit. Patients with primary colorectal cancer surgery between 2011-2015 were included. The volume and median waiting times for the years 2011-2015 are described. Waiting times from first tumor positive biopsy until the operation (biopsy-operation) and first preoperative visit to the surgeon until the operation (visit-operation) are analyzed with a univariate and multivariate linear regression analysis. Separate analysis was done for visit-operation for academic and non-academic hospitals and for screening compared to non-screening patients. RESULTS: In 2014 there was an increase of 1469 (15%) patients compared to 2013. In 2015 this increase consisted of 1168 (11%) patients compared to 2014. In 2014 and 2015, 1359 (12%) and 3111 (26%) patients were referred to the surgeon through screening, respectively. The median waiting time of biopsy-operation significantly decreased (ß: 0.94, 95%BI) over the years 2014-2015 compared to 2011-2013. In non-academic hospitals, the waiting time visit-operation also decreased significantly (ß: 0.89, 95%BI 0.87-0.90) over the years 2014-2015 compared to 2011-2013. No difference was found in waiting times between patients referred to the surgeon through screening compared to non-screening. CONCLUSION: There is a clear increase in volume since the introduction of the colorectal cancer screening programme without an increase in waiting time until surgery.

Molecular mechanisms underlying the MiT translocation subgroup of renal cell carcinomas.

Renal cell carcinomas (RCCs) represent a heterogeneous group of neoplasms, which differ in histological, pathologic and clinical characteristics. The tumors originate from different locations within the nephron and are accompanied by different recurrent (cyto)genetic anomalies. Recently, a novel subgroup of RCCs has been defined, i.e., the MiT translocation subgroup of RCCs. These tumors originate from the proximal tubule of the nephron, exhibit pleomorphic histological features including clear cell morphologies and papillary structures, and are found predominantly in children and young adults. In addition, these tumors are characterized by the occurrence of recurrent chromosomal translocations, which result in disruption and fusion of either the TFE3 or TFEB genes, both members of the MiT family of basic helix-loop-helix/leucine-zipper transcription factor genes. Hence the name MiT translocation subgroup of RCCs. In this review several features of this RCC subgroup will be discussed, including the molecular mechanisms that may underlie their development.

Isolation and characterization of the Xenopus laevis orthologs of the human papillary renal cell carcinoma-associated genes PRCC and MAD2L2 (MAD2B).

Recently we found that the human papillary renal cell carcinoma-associated protein PRCC interacts with the cell cycle control protein Mad2B, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function. Here we have successfully isolated Xenopus laevis Mad2B and PRCC cDNAs. The full-length xMad2B cDNA encodes a 211 amino acid protein that is highly homologous to human Mad2B, thus pointing to an important function for this protein in higher eukaryotes. The full-length xPRCC cDNA encodes a 544 amino acid protein. Remarkably, this protein contains an amino-terminal region distinct from that in mouse and human, whereas the C-terminal region is highly conserved. Northern blot and RT-PCR analyses revealed a relatively low expression of both xMad2B and xPRCC in most tissues examined. However, an abundant expression was observed in testis and oocyte, indicating a role in meiotic division processes. Coimmunoprecipitation and immunofluorescence analyses revealed that, despite its distinct amino terminus, the xPRCC-protein is still capable of interacting with xMad2B and of shuttling this protein to the nucleus. Therefore, the well-established animal model Xenopus laevis can be used as a powerful system to study in detail the role of xPRCC and xMad2B in the intricate processes of cell cycle control.

Impairment of MAD2B-PRCC interaction in mitotic checkpoint defective t(X;1)-positive renal cell carcinomas.

The papillary renal cell carcinoma (RCC)-associated (X;1)(p11;q21) translocation fuses the genes PRCC and TFE3 and leads to cancer by an unknown molecular mechanism. We here demonstrate that the mitotic checkpoint protein MAD2B interacts with PRCC. The PRCCTFE3 fusion protein retains the MAD2B interaction domain, but this interaction is impaired. In addition, we show that two t(X;1)-positive RCC tumor cell lines are defective in their mitotic checkpoint. Transfection of PRCCTFE3, but not the reciprocal product TFE3PRCC, disrupts the mitotic checkpoint in human embryonic kidney cells. Our results suggest a dominant-negative effect of the PRCCTFE3 fusion gene leading to a mitotic checkpoint defect as an early event in papillary RCCs.

Genomic structure, chromosomal localization, and embryonic expression of the mouse homolog of PRCC, a gene associated with papillary renal cell carcinoma.

In a subset of papillary renal cell carcinomas a t(X;1)(p11;q21) chromosome translocation has repeatedly been reported. Positional cloning has demonstrated that, as a result of this translocation, the transcription factor TFE3 gene on the X-chromosome becomes fused to a novel gene, PRCC, on chromosome 1. Since as yet little is known about the function of PRCC, we sought to identify the mouse counterpart of the PRCC gene. Isolation and sequence analysis of a mouse Prcc cDNA revealed a high level of conservation between man and mouse, both at the nucleotide and protein level. As the human PRCC gene, the mouse Prcc gene is ubiquitously expressed. It shows low expression in all mouse fetal tissues examined. In addition, we identified a genomic cosmid clone containing the complete Prcc gene. The mouse Prcc gene consists of seven exons, all of which contain coding sequences. The small second exon, which was found to be located adjacent to the t(X;1) breakpoint in the human gene on chromosome 1, is also conserved between man and mouse. In mouse, Prcc is located on chromosome 3. These cDNA and genomic clones will be instrumental in the creation of mouse models for a further elucidation of the function of PRCC.

Transformation capacities of the papillary renal cell carcinoma-associated PRCCTFE3 and TFE3PRCC fusion genes.

A recurrent chromosomal abnormality associated with a subset of papillary renal cell carcinomas is t(X;1)(p11;q21). This translocation leads to the formation of two fusion genes, TFE3PRCC and the reciprocal product PRCCTFE3. Both fusion genes are expressed in t(X;1)-positive renal cell carcinomas and contain major parts of the coding regions of the parental transcription factor PRCC and TFE3 genes, respectively. To find out whether these fusion genes possess transforming capacity, we transfected NIH3T3 and rat-1 cells with the fusion products, either separately or combined. When using soft agar assays, we observed colony formation in all cases. NIH3T3 cells transfected with PRCCTFE3 or PRCCTFE3 together with TFE3PRCC yielded the highest colony forming capacities. Examination of other characteristics associated with malignant transformation, i.e., growth under low-serum conditions and formation of tumors in athymic nude mice, revealed that cells transfected with PRCCTFE3 exhibited all these transformation-associated characteristics. Upon transfection of the fusion products into conditionally immortalized kidney cells, derived from the proximal tubules of an H-2Kb-tsA58 transgenic mouse, and consecutive incubation under non-permissive conditions, growth arrest was observed, followed by differentiation except for those cells transfected with PRCCTFE3. Therefore, we conclude that PRCCTFE3 may be the t(X;1)-associated fusion product that is most critical for the development of papillary renal cell carcinomas.

Nuclear localization and transactivating capacities of the papillary renal cell carcinoma-associated TFE3 and PRCC (fusion) proteins.

The papillary renal cell carcinoma-associated t(X;1)(p11;q21) leads to fusion of the transcription factor TFE3 gene on the X-chromosome to a novel gene, PRCC, on chromosome 1. As a result, two putative fusion proteins are formed: PRCCTFE3, which contains all known domains for DNA binding, dimerization, and transactivation of the TFE3 protein, and the reciprocal product TFE3PRCC. Upon transfection into COS cells, both wild type and fusion proteins were found to be located in the nucleus. When comparing the transactivating capacities of these (fusion) proteins, significant differences were noted. PRCCTFE3 acted as a threefold better transactivator than wild type TFE3 both in a TFE3-specific and in a general (Zebra) reporter assay. In addition, PRCC and the two fusion proteins were found to be potent transactivators in the Zebra reporter assay. We propose that, as a result of the (X;1) translocation, fusion of the N-terminal PRCC sequences to TFE3 alters the transactivation capacity of the transcription factor thus leading to aberrant gene regulation and, ultimately, tumor formation.

Depot medroxyprogesterone acetate (Depo-Provera) and levonorgestrel (Norplant) use in adolescents among clinicians in Northern Europe and the United States.

PURPOSE: To compare attitudes and practices related to clinicians' use of depot medroxyprogesterone acetate [Depo-Provera (DMPA)] and levonorgestrel implants in adolescents in three northern European countries and the United States. METHODS: Between the fall of 1993 and the winter of 1995, surveys eliciting clinician attitudes and practices with the two contraceptive methods were collected from practitioners who provide contraceptive care to teens in Sweden (n = 282), The Netherlands (n = 197), Great Britain (n = 108), and the United States (n = 548). RESULTS: Clinicians in Great Britain and the United States reported prescribing of DMPA, selected DMPA in their top three choices for contraception in teens, and had patients ask about DMPA more frequently than clinicians in Sweden or The Netherlands (p < 0.0001). U.S. clinicians were more likely to report prescribing of the implants, list them as a top choice, and have patients ask for it more frequently than were providers in the other three countries (p < 0.0001). Noncompliance with previous contraceptives was the most common indication for use of either method in this age group. "Worst fears" with DMPA use included infertility, particularly among Swedish clinicians (p < 0.0001), as was pregnancy and loss to follow-up, particularly among British clinicians (p < 0.0001). Condom nonuse was a concern associated with both methods. Breakthrough uterine bleeding was a concern related to implant use, particularly among Swedish practitioners (p < 0.0001). CONCLUSION: Clinicians in the United States and Great Britain display more enthusiasm toward the use of the long-term progestins in adolescents than do clinicians in Sweden or The Netherlands. Continuing education programs could be designed to educate clinicians to allay their concerns about these contraceptives in countries where teen pregnancy is considered a problem.

MEMD, a new cell adhesion molecule in metastasizing human melanoma cell lines, is identical to ALCAM (activated leukocyte cell adhesion molecule).

From a differential mRNA display comparing a non- and a highly metastasizing human melanoma cell line, we isolated and characterized memD. memD is preferentially expressed in the highly metastasizing melanoma cell lines of a larger panel. The encoded protein, MEMD, is identical to activated leukocyte cell adhesion molecule (ALCAM), a recently identified ligand of CD6. ALCAM is involved in homophylic (ALCAM-ALCAM) and heterophylic (ALCAM-CD6) cell adhesion interactions. We have studied MEMD/ALCAM cell-cell interactions between human melanoma cells. The expression of this cell adhesion molecule not only correlates with enhanced metastatic properties and with aggregational behavior of human melanoma cells as tested by FACS analysis, but transfection experiments also make clear that MEMD/ALCAM expression is essential for cell-cell interaction of the investigated human melanoma cells. As the melanoma cell lines analyzed are all CD6 negative, these results strongly suggest that MEMD/ALCAM is an adhesion molecule mediating homophylic clustering of melanoma cells. MEMD/ALCAM expression is not restricted to subsets of leukocytes and melanoma cells, it can also be found in healthy organs and in several other malignant tumor cell lines. Besides, MEMD/ALCAM is also expressed in cultured endothelial cells, pericytes and melanocytes, in xenografts derived from the radial and vertical growth phase and in 4 of 13 melanoma metastasis lesions. The potential role is discussed of MEMD/ALCAM mediated cell-cell interactions in migration of mobile cells (ie, activated leukocytes, metastasizing tumor cells) through tissues.

Transcription factor C/EBPalpha: novel sites of expression and cloning of the human gene.

We describe the characterization of recombinant clones for the human transcription factor CCAAT/enhancer binding protein alpha (hC/EBP alpha). The intronless hC/EBP alpha gene is almost 90% homologous to its rat and mouse counterparts. The gene copies of more distant species are less conserved, but the alignment reveals a striking homology in five regions, of which four may be involved in transactivation functions while the fifth concerns the carboxy-terminal bZip sequences (basic region and leucine zipper) mediating sequence specific DNA-binding. In addition to the usual expression sites, significant transcript levels were detected in the epidermal compartment of human skin and in rat aorta by northern analysis. The presence of hC/EBP alpha is further documented by immunohistochemical analysis of human skin biopsies and cultured keratinocytes showing the nuclear presence of the protein, notably in the suprabasal layers of the epidermis and in human keratinocytes induced to differentiate.

nmd, a novel gene differentially expressed in human melanoma cell lines, encodes a new atypical member of the enzyme family of lipases.

nmd, a novel gene, was isolated by applying the differential mRNA display method to human melanoma cell lines with different metastatic capacity. In a panel of 17 other human tumor cell lines, nmd RNA expression could only be detected at low levels in T24 (bladder carcinoma) and Caco-2 (colon adenocarcinoma). Furthermore, it was found in placenta and liver, but not in skin, colon, spleen, lung, muscle, prostate and kidney. Sequence analysis classified the nmd gene product as a new member of the enzyme family of lipases (almost 30% identity in amino acid sequence with other human lipases). Active site residues of lipases were conserved in NMD, but NMD lacks the regulatory lid domain, which controls entry to the active site in classical lipases. A similar deletion was earlier reported by others in the guinea pig pancreatic (phospho)lipase GPLRP2 and the phospholipase A1 from hornet venom (DolmI).

Simultaneous suppression of progression marker genes in the highly malignant human melanoma cell line BLM after transfection with the adenovirus-5 E1A gene.

The highly metastatic human melanoma cell line BLM was transfected with the E1A or E1A + E1B regions of adenovirus 5 (Ad5). A series of progression markers, correlated with the malignant phenotype of parental BLM (including calcyclin, thymosin beta 10, plasminogen activator inhibitors types 1 and 2, urokinase type and tissue type plasminogen activators, vimentin, tissue type transglutaminase, and interleukin-6), was collectively repressed in the transfectants, whereas several control genes were not affected or even induced. The apparently coordinate repression of a set of markers by the same regulator gene, Ad5 E1A in this case, suggests the existence of one pathway under the control of a main switch and predicts that one or more as yet unidentified cellular master genes normally exert this function. A reduced oncogenicity was observed after subcutaneous inoculation of the E1A transfectants into nude mice and provides additional evidence in support of a tumor suppressor function of Ad5 E1A.

Expression of nma, a novel gene, inversely correlates with the metastatic potential of human melanoma cell lines and xenografts.

nma, a novel gene, was isolated by using a subtractive hybridization technique in which the gene expression was compared in a panel of human melanoma cell lines with different metastatic potential. nma mRNA expression (1.5 kb) is high in poorly metastatic human melanoma cell lines and xenografts and completely absent in highly metastatic human melanoma cell lines. Fluorescence in situ hybridization combined with the analysis of a panel of human-rodent somatic cell hybrids indicated that the nma gene is located on human chromosome 10, in the region p11.2-p12.3. Sequence analysis of nma showed no homologies with other known genes or proteins, except for several partially sequenced cDNAs. The predicted amino acid sequence suggests that the protein encoded by nma contains a transmembrane domain. Expression of nma is high in human kidney medulla, placenta and spleen, low in kidney cortex, liver, prostate and gut and absent in lung and muscle. Whereas nma is not expressed in normal skin tissue, expression is high in melanocytes and in 3 out of 11 melanoma metastases tested.

Identification of melanoma inhibitory activity and other differentially expressed messenger RNAs in human melanoma cell lines with different metastatic capacity by messenger RNA differential display.

The differential display technique was used to identify mRNAs differentially expressed in human melanoma cell lines with different metastatic capacity. We report the isolation of nine different clones, of which four were uniquely expressed in the highly metastatic human melanoma cell line MV3, whereas the other five clones were uniquely expressed in the poorly metastatic human melanoma cell line 530. The differences in expression identified by differential mRNA display were confirmed by Northern blot analyses. DNA sequencing followed by computer search analyses indicated that of the nine differentially expressed clones, five represented novel gene products. The other four were histocompatibility antigen HLA-DR, laminin B2, melanoma inhibitory activity (MIA), and tissue inhibitor of metalloproteinases 3. MIA was also identified in RNA from human melanoma metastasis lesions in a comparison by differential display with pooled human nevi. Northern blot analysis confirmed MIA mRNA expression in nonmetastasizing melanoma cell lines and in melanoma metastasis lesions, while expression was absent in highly metastasizing cell lines and pretumor stages. In the 11 metastasis lesions examined, MIA mRNA expression was apparently inversely correlated with pigmentation.

Functional analysis of the human calcyclin gene promoter in a panel of human melanoma cell lines.

By comparing two subsequent human tumor stages we previously described calcyclin as a new potential melanoma associated neoplastic progression marker positively linked with metastasis. In this study the calcyclin expression levels in a representative panel of human melanoma cell lines were correlated with the occurrence of DNase I hypersensitive (DH) regions and potential enhancer elements in a 6 kb genomic fragment spanning the human calcyclin gene. Examination of the chromatin structure of the transcription unit revealed no qualitative differences in DH sites within the panel of tested human melanoma cells, but especially the sequences around the transcription start site and a 1.5 kb upstream region appeared more accessible to the nuclease in frequently (BLM, MV3) as compared to poorly (530, 1F6) metastasizing cells. The genomic fragments that harbor one or more DH sites were subjected to functional analysis by luciferase reporter gene assays. Thus, an enhancer element was detected between 361 and 167 bp upstream of the transcription start site. This enhancer displayed equal activating potential (2-3 fold) both in weakly and in frequently metastasizing cells and was apparently recognized by transcription factors present in both types of human melanoma cells lines. We conclude that, in addition to a slight amplification of the encoding gene, the elevated calcyclin mRNA levels are only reflected in a selectively increased accessibility of the chromatin structure to DNaseI in metastasizing melanoma cells.

Expression of tissue-type transglutaminase correlates positively with metastatic properties of human melanoma cell lines.

In this study the relationship between tissue-type transglutaminase (TGase2) activity and the propensity to metastasize was investigated in human melanoma cell lines with different metastatic behavior. TGase2 catalyzes an acyl-transfer reaction between peptide-bound glutamine residues and primary amines, including the epsilon-amino group of lysine residues. Northern-blot analysis demonstrated that TGase2 RNA-expression (3.7 kb) was elevated in highly metastatic cell lines (MV3 and BLM) as compared to weakly metastatic ones (IF6 and 530). Immunoprecipitation and enzyme assays of TGase2 showed that the differential expression at the mRNA level was also reflected at the protein level. These findings reveal a positive relation between the expression of TGase2 and the metastatic properties of the human melanoma cell lines.

Rat desmin gene structure and expression.

The isolation of two partial genomic clones and a near full length cDNA clone encoding the rat intermediate filament protein desmin is reported. Desmin is a differentiation marker for all types of muscle cells. The nucleotide order of the coding region and 0.1 kb of 5'-flanking sequences of the rat desmin gene has been determined. One genomic clone encompasses exons I-III and approx. 12 kb of 5'-flanking sequences, while the other clone contains exons VII-IX and about 12 kb of 3'-flanking sequences. Northern analysis of RNA from different organs reveals that, as expected, desmin is expressed in striated, heart and smooth muscle cells containing tissues; among other tissues, lung displays relatively high expression levels, while desmin mRNA is barely detectable in spleen, kidney and liver. S1 mapping reveals that the same transcription initiation site is used in all desmin mRNA containing tissues.

Increased expression of retroviral sequences in progressionally advanced rat prostatic tumors.

Differential hybridization analysis revealed two cDNA clones, pBUS19 and pBUS30, to be overexpressed in progressionally advanced rat prostatic tumors. Northern blot analysis suggested the clones to be related although no homology in nucleotide sequence could be shown. Isolation and characterization of a pBUS19-related clone, pJG116, and computer-assisted database comparison showed that all three clones could be mapped within a rat-specific endogenous retrovirus. The importance of overexpression of retroviral sequences in advanced prostatic cancer remains unclear.