Are melanomas averse to cerebellum? Cerebellar metastases in a surgical series.

OBJECTIVES: To study the propensity of different cancers to metastasize to the cerebrum and cerebellum, and to study overall survival (OS) and prognostic factors for patients after surgical resection for cerebellar metastases. MATERIALS AND METHODS: From a prospectively collected tumor database, all patients that underwent a craniotomy for intracranial metastases between 2003 and 2011 at Oslo University Hospital were included. RESULTS: One hundred and forty patients underwent resection for cerebellar metastases. Most common primary tumor sites were lung, colon/rectum, and breast in 45%, 19%, and 14%, respectively. None were prostate cancers. Melanoma metastases were significantly underrepresented, and colorectal cancer metastases significantly overrepresented in cerebellum, compared to the overall proportion of cerebellar/supratentorial metastases surgically resected (P < 0.05). Thirty-day post-operative mortality rate was 4.3%. Median OS was 7.7 months (95% CI 6.0-9.5 months) irrespective of post-operative adjuvant therapy. Median OS was 51.8, 8.4, and 3.4 months, respectively, for recursive partitioning analysis class 1(n = 11), 2 (n = 78) and 3 (n = 34). Significant negative prognostic factors were age ≥65 years, Karnofsky performance score (KPS) <70, extracranial metastases and uncontrolled systemic disease. CONCLUSIONS: Melanoma metastases were significantly underrepresented in cerebellum, whereas colorectal cancer metastases were significantly overrepresented. Surgical mortality and OS after surgical treatment of cerebellar metastases were similar to the results of supratentorial metastases.

Outcome following surgery for intracranial meningiomas in the aging.

OBJECTIVE: To prospectively assess mortality, morbidity and the functional and symptomatic outcome following intracranial surgery for meningiomas in elderly patients at two neurosurgical institutions in Norway. METHODS: Patients ≥60 years who underwent craniotomies for intracranial meningiomas at Oslo University Hospital and Haukeland University Hospital in 2008 and 2009 were included (n = 54). Outcome was assessed at 6 months. RESULTS: Thirty-five females and 19 males of median age 70 (60-84) years were assessed pre- and post-operatively, 87% attended follow-up at 6 months. The surgical mortality rate was 5.6% at 30 days and 7.4% at 3 and 6 months. The rates of complications were: post-operative hematomas 5.6%, deep venous thrombosis 1.9%, osteitis 1.9%, cerebrospinal fluid disturbances 13.0% and neurological sequelae 13.0%. Surgery resulted in a significant improvement in the MMSE score, with a further 14.9% obtaining scores of ≥25 without a significant change in the level of independence according to the Karnofsky performance scale. QoL assessments showed good functioning post-operatively compared to other cancer patient groups, yet slightly reduced when compared to data from the general population. CONCLUSION: In our series, we found that meningioma surgery in the aging patient carries a higher risk of mortality and morbidity compared to intracranial tumor surgery in general. Our findings indicate, however, that the survivors have improved cognitive function and acceptable QoL, and we did not see any significant decrease in the proportion of independent patients according to the KPS.

Craniotomy for brain metastases: a consecutive series of 316 patients.

OBJECTIVE: To assess the incidence of craniotomy for brain metastases, overall survival (OS), surgical mortality, and prognostic factors in a large, contemporary, consecutive series from a well-defined catchment area. MATERIAL AND METHODS: All patients ≥ 18 years who underwent craniotomies for intracranial metastases at Oslo University Hospital, Rikshospitalet and Ullevål, between 2005 and June 30, 2009 were included (n = 316). Patients were identified from our prospectively collected database and a thorough review of all charts to validate the entered data was performed. RESULTS: The annual incidence of first-time craniotomy for a brain metastasis was 2.6/100,000 inhabitants. Patient age ranged from 25 to 87 years (median 64 years). The 30-day mortality rate was 3.8%. Median OS was 9.2 months. Recursive partitioning analysis was class I in 19.6%, class II in 59.2%, and class III in 21.2% with median OS of 16.2, 8.9, and 5.6 months, respectively (P < 0.001). Lung cancer and melanoma were associated with a higher risk (>1% per year) of developing brain metastases. Significant negative prognostic factors were age ≥ 65, a poor performance score, unstable extracranial disease, presence of extracranial metastases, multiplicity, metastasis in eloquent area, and no post-operative radiotherapy. CONCLUSIONS: In this population study, the annual incidence of a first-time craniotomy for a brain metastasis was 2.6/100,000, the 30-day mortality rate was 3.8%, and median OS was 9.2 months. The well-known prognostic factors were confirmed.

Intracranial tumor surgery in patients >70 years of age: is clinical practice worthwhile or futile?

OBJECTIVES: To study survival and functional outcome after intracranial tumor surgery in elderly patients. MATERIALS AND METHODS: This is a retrospective study of 289 consecutive patients of age > or =70 years, who underwent primary surgery (resection or biopsy) in the time period 2003-2007 for an intracranial tumor (87 astrocytomas, 79 meningiomas, 62 brain metastases, 33 pituitary adenomas and 28 other tumors). RESULTS: The surgical mortality was 2.8%. Overall survival at 6 months, 1, 2 and 5 years was 73%, 57%, 46% and 38% respectively. Histology, pre-operative Eastern Cooperative Oncology Group (ECOG) performance score and resection, as opposed to biopsy, were significantly associated with survival. Gender, age and American Association of Anaesthetists (ASA) score were not significantly related to survival. One-year survival after surgery for astrocytoma, meningioma, brain metastases and pituitary adenoma were 24%, 94%, 31% and 96% respectively. More than 85% of the patients who were alive 6 months after surgery had a stable or improved ECOG score compared with their pre-operative score. CONCLUSIONS: Surgery for intracranial tumors in selected elderly patients is worthwhile, not futile. Age alone should not be used as a selection criterion for treatment.

Evolutionary conservation of the apolipoprotein E-C1-C2 gene cluster on bovine chromosome 18q24.

We have constructed a long-range restriction map spanning about 250 kb on bovine chromosome 18q24. Our results show that the apolipoprotein C2 (APOC2) gene is located about 25 kb from the APOE gene. Four putative CpG islands are also indicated in the map. Interestingly, a minisatellite located in the third intron of the human and mouse APOC2 genes was also found at identical position in the bovine gene and revealed high sequence identity comparing with the two corresponding sequences. By means of cosmid mapping, we further demonstrate that the APOE-APOC1-APOC2 gene cluster is evolutionary conserved in cattle.

Mapping of bovine FcgammaR (FCGR) genes by sperm typing allows extended use of human map information.

Polymorphic sites within the bovine FcgammaRI (FCGR1), FcgammaRII (FCGR2), and FcgammaRIII (FCGR3) genes were used for proximal mapping of these genes to bovine Chromosome (Chr) 3 (BTA3) with paternal half-sib families from Norwegian Cattle. A fine-structure genetic map of the region was obtained by the analysis of 288 sperm cells from three bulls that were heterozygous for the loci included in the study. No recombinants were observed between FCGR2 and FCGR3 (242 sperm cells). Considering FCGR2 and FCGR3 as a single locus, a three-point linkage analysis for [FCGR2/FCGR3], FCGR1, and INRA003 was carried out. The best-supported order of the loci was found to be INRA003-FCGR1-[FCGR2/FCGR3]. Map distances in a two-point linkage analysis were 10.3 cM between [FCGR2/FCGR3] and FCGR1, and 25.5 cM between FCGR1 and INRA003, respectively. This linkage mapping of the bovine FCGR gene family resembles the human situation where all FCGR genes are located at Chr 1 (HSA1), at position q21-q24. Moreover, the results locate the evolutionary breakpoint between HSA1q and BTA3 within the human 1q24 region.

Associations between casein haplotypes and milk yield traits.

The genotyping of 13 sires and 250 of their sons for casein polymorphisms revealed 10 different haplotypes for Norwegian Cattle. Associations between haplotypes and yields of protein, milk, and fat were studied using a granddaughter design. Three subsets of data containing families with haplotypes 1, 5, and 10 were analyzed independently and denoted by analyses 1, 5, and 10, respectively. In addition, all sire families of all haplotypes were pooled and analyzed in analysis T. No associations were found between haplotypes and traits for milk yield in analyses 1, 10, and T. However, the null hypothesis of an equal effect within sire of bulls was rejected in analysis 5 for yields of protein and milk. The increase in protein yield associated with haplotype 5 ranged from 2.52 to 14.58 kg (from .09 to .51 phenotypic standard deviations). These results may indicate the presence of at least one quantitative trait locus in the region of the casein genes that affects protein yield of Norwegian Cattle. The findings were confirmed with a new analysis of two large sire families segregating haplotype 5 (analysis 5N).

Cloning and characterization of two forms of bovine polymeric immunoglobulin receptor cDNA.

The polymeric immunoglobulin receptor (transmembrane secretory component) mediates transcellular transport of dimeric immunoglobulin A (IgA) and pentameric IgM in glandular and mucosal epithelial cells. cDNAs encoding two forms of the bovine polymeric immunoglobulin receptor (pIgR) have been cloned and sequenced. The long form contains 3,527 bp and predicts a single open reading frame of 2,271 bp encoding a protein of 757 bp. The extracellular part contains five immunoglobulin (Ig)-like domains. The shorter form lacks the region from residues 458-1,111 corresponding to Ig-like domains 2 and 3. In Northern blot analysis of various bovine tissues, only the long form of pIgR mRNA was detected. By using the reverse transcription-polymerase chain reaction (RT-PCR), both forms were detected. An alignment of the cytoplasmic tail of the pIgR from bovine, human, rabbit, and rat revealed highly conserved areas that may reflect the importance of these regions for intracellular sorting of the receptor.

Chromosomal localization and detection of DNA polymorphisms in the bovine polymeric immunoglobulin receptor gene.

Polymeric immunoglobulin receptor (PIGR) mediates transcellular transport of secretory antibodies in glandular and mucosal epithelial cells. By use of a bovine-rodent somatic cell hybrid panel the bovine PIGR locus has been assigned to syntenic group U1. Using in situ hybridization, PIGR was localized to bovine chromosome 16, segment q13, thus confirming the recent assignment of syntenic group U1 to this chromosome. Two common restriction fragment length polymorphisms (RFLPs) with the enzymes BamHI and MspI were detected using the PIGR cDNA as probe. Direct PCR sequencing of a segment in the PIGR coding region (nucleotides 162-413) from 13 bulls of Norwegian Cattle revealed single nucleotide exchanges at two positions. An efficient PCR-RFLP method for detection of these mutations was developed.

Cloning and characterization of the bovine immunoglobulin J chain cDNA and its promoter region.

The immunoglobulin J (joining) chain plays an important role in the assembly of polymeric immunoglobulins (dimeric IgA and pentameric IgM) and in the selective transport of these across epithelial cell layers. The primary structure of the bovine J chain has been determined by sequencing of three cDNAs. The cDNA has an open reading frame of 471 nucleotides encoding a putative protein of 157 amino acids. The 3' untranslated region consists of 698 nucleotides and a poly(A) tail. The 5' untranslated region and the promoter were isolated from a genomic clone. By comparison with the murine J chain gene, the 5' untranslated region was predicted to be 37 bp, giving the bovine J chain cDNA a total length of 1,206 bp. This size was confirmed by Northern blot analysis of total RNA from colon and mammary gland. The amino acid sequence of the bovine J chain shows extensive homology with the J chain from human, mouse, rabbit, and bullfrog. Analysis of the J chain secondary structure showed a high propensity for forming beta-sheets. An alignment of the predicted secondary structure of the J chain from bovine, human, mouse, rabbit, and bullfrog revealed a highly conserved "beta-profile." The promoter sequence of the bovine J chain gene is presented and shown to contain a conserved interleukin-2 (IL-2)-responsive element previously characterized in the murine J chain gene.

Bovine casein haplotypes: number, frequencies and applicability as genetic markers.

Three casein loci, tightly linked on bovine chromosome 6, have been studied as haplotypes within families of bulls. The polymorphisms included in the study were CASAS1 (B, C), CASB (A1, A, A5, B), CASK (A, B, E) and a microsatellite in intron III of CASK. A new A5 variant of CASB, caused by a silent mutation in the triplet coding for amino acid 110, was detected by direct polymerase chain reaction sequencing. Our analysis of 306 sons and 15 sires revealed 10 different casein haplotypes with a cumulative polymorphic information content (PIC) of 0.78.

A simple and powerful method for linkage analysis by amplification of DNA from single sperm cells.

Haplotypes of three bovine casein loci were analyzed as a way of determining genetic linkage. A total of 330 individual sperm cells from a triply heterozygous bull were selected by means of a new method involving fixing the sperm cells into low-melting-point agarose gels. The method is simple and very accurate with an efficiency close to 100% for picking sperm cells and producing amplifiable DNA templates, circumventing the complicated statistical analysis mandated by automated cell sorting. The DNA was amplified in a two-step polymerase chain reaction (PCR) to achieve the necessary high specificity of amplification. In the first reaction, primers flanking the polymorphic site at each locus were used. The PCR product from the first reaction was then reamplified in a second PCR using primers that create allele-specific restriction sites (ACRS) in the PCR products for two of the three loci, allowing the alleles to be determined by gel electrophoresis. No recombinants were found among the 330 single sperm cells analyzed, giving a lod score higher than 30 and proving a very strong linkage between bovine casein genes.

The sequence of porcine apolipoprotein E (APOE) cDNA.

Porcine cDNA clones encoding apolipoprotein E (APOE) were isolated and sequenced. The porcine APOE cDNA sequence is 1122 bp in length and encodes a pre-protein of 317 amino acids. The inferred porcine amino acid sequence corresponds to the human APOE-4 isoform.

Detection of multiple beta-casein (CASB) alleles by amplification created restriction sites (ACRS).

Direct sequencing of polymerase chain reaction (PCR) amplified DNA has been used to detect the DNA sequences for bovine beta-casein (CASB) A3 and B variants. Based on these sequences we have designed primers which create allele-specific restriction sites in the PCR product. Restriction analysis of PCR product generated in one reaction enable us to identify the A1, A2, A3 and B alleles of CASB rapidly without the use of radioactivity.

The human genes for complement components 6 (C6) and 9 (C9) are closely linked on chromosome 5.

We have used a cDNA probe for human complement component 9 (C9), which detects three DNA polymorphisms, to analyse the inheritance of C9 in families informative for C6 protein variants. We found that these genes are closely linked with a lod score of 9.28 at recombination fraction 0.00. There is not indication of allelic association.

Association analysis of lipid levels and apolipoprotein restriction fragment length polymorphisms.

We have analyzed the correlation between restriction site variants (RFLPs; restriction fragment length polymorphisms) of the apolipoprotein AI, AII, B, CI and CII genes and serum lipid levels in a sample of male Norwegians. We find no significant association between any of the RFLPs and lipid levels.

The gene for the human putative apoE receptor is on chromosome 12 in the segment q13-14.

We have previously described the cDNA coding for a new lipoprotein receptor that contains domains closely related to the ligand-binding domain of the LDL receptor. We have now investigated the localization of the gene for this new receptor by hybridization of the cDNA to panels of rodent cells containing subsets of human chromosomes and by in situ hybridization of the cDNA to chromosomes. The gene maps to 12q13-14, a known hot spot for chromosomal rearrangements in human neoplasia. Of particular interest is the frequent involvement of the 12q13-14 segment in clonal abnormalities in lipomas and myxoid liposarcomas, and it is possible that LRP may play a role in the pathogenesis of such tumors.

The gene for human complement C9 is on chromosome 5.

By hybridizing a cloned cDNA coding for human complement factor C9 to hybrid cells containing subsets of human chromosomes on a rodent background, we have determined that the human gene for C9 is localized on chromosome 5.