A Radiologists' Guide to En Bloc Resection of Primary Tumors in the Spine: What Does the Surgeon Want to Know?

En bloc resection in the spine is performed for both primary and metastatic bone lesions and has been proven to lengthen disease-free survival and decrease the likelihood of local recurrence. It is a complex procedure, which requires a thorough multi-disciplinary approach. This article will discuss the role of the radiologist in characterizing the underlying tumor pathology, staging the tumor and helping to predict possible intraoperative challenges for en bloc resection of primary bone lesions. The postoperative appearances and complications following en bloc resection in the spine will be considered in subsequent articles.

A guide to assessing post-operative complications following en bloc spinal resection.

En-bloc resection of spinal tumours is a complex procedure with significant morbidity and mortality. The extensive resection leaves a large soft tissue and osseous defect requiring reconstruction. Following en-bloc resection, there may be complications relating to both the removal of the tumour and the subsequent reconstruction. This paper outlines the imaging appearances of the frequently encountered complications in our experience. The primary aim is to improve the confidence of the radiologist when reporting imaging following spinal en-bloc resection, however we believe this is also useful for the spinal and orthopaedic surgeons in assessing the patients following en block resection.

The diagnosis and management of a vertebral artery loop causing cervical radiculopathy.

BACKGROUND: Cervical radiculopathies are rarely caused by vertebral artery loop formation, which is estimated to be present in less than 3% of patients. It is uncertain what causes the loop formation: some propose an association with spondylotic changes or trauma, whilst others suggest hypertension and atherosclerosis may be responsible. CASE REPORT 1: A 35-year-old male patient presented with signs and symptoms of cervical radiculopathy that was not improved with anterior cervical discectomy and fusion surgery performed 2 years beforehand. Vertebral artery loop was discovered at the level C5/6 on the MRI. Vertebral artery transposition surgery via a lateral approach was performed at the level of the left C5/6 for symptoms of left C6 radiculopathy. Deroofing of the transverse process was performed with post-surgical complete improvement in weakness and pain. CASE REPORT 2: A 48-year-old female patient presented with a 10-year history of left shoulder pain with occasional radiation into her middle three fingers accompanied by intermittent paraesthesia and weakness. Numerous shoulder surgeries, Botox injections and suprascapular nerve blocks had not provided any significant benefit. A vertebral artery loop was identified at the level of C3/4 and C4/5 on the left with cervical MRI. Transposition surgery of these two levels provided some post-surgical improvement in pain. CONCLUSION: Vertebral artery loop formations are a rare but potential cause for cervical radiculopathy. In two cases, the loop formations were not radiographically reported on MRI, thus clinicians should be aware of this as a differential diagnosis in the management of cervical radiculopathy. The presented surgical approach may be useful in managing future cases of vertebral artery loop formation causing cervical radiculopathy resistant to conservative measures.

A rare case of Paget's disease affecting the cervical spine.

We present the case of a 75-year-old man with a rapidly progressive cervical myelopathy on a background of a 3-year history of neck pain and a severely degenerative cervical spine. The patient developed progressive myelopathy over a six-month period and suffered from worsening kyphosis. Suspicion of an underlying oncological process prompted transfer to our tertiary referral unit. Biopsy was consistent for Paget's disease, an extremely rare diagnosis of the cervical spine. Magnetic resonance imaging revealed cord compression between C4 and C6 with associated cord signal change indicative of myelopathy. A three-level corpectomy and posterior instrumented fusion was performed. There was significant blood loss (3.5l) intraoperatively, consistent with a diagnosis of Paget's disease of the bone. Cell salvage was used, as was neuromonitoring for both the anterior and posterior part of the procedure. Postoperatively, neurological function improved slightly and the patient required community neurorehabilitation to allow independent living.

A visible-light photocatalytic thiolation of aryl, heteroaryl and vinyl iodides.

The general catalytic synthesis of aryl and vinyl thioethers from readily available halides remains a challenge. Herein we report a unified method for the thiolation of aryl and vinyl iodides with dialkyl disulfides using visible light photoredox catalysis. A range of thioether products bearing diverse functional groups can be accessed in high yield and with excellent chemoselectivity. We demonstrate the versatility of this method through the expedient synthesis of a family of thioether-rich natural products. A detailed investigation of the photocatalytic mechanism is presented from both steady-state and time-resolved luminescent quenching as well as transient absorption spectroscopy experiments.

Evaluation of selected angiogenic and inflammatory markers in endometriosis before and after danazol treatment.

Angiogenesis and inflammation are pivotal processes in developing endometriosis in the peritoneal cavity. The aim of the present study was to evaluate these two processes in women with endometriosis who had been treated with danazol to determine the sensitivity of a non-invasive test in diagnosing endometriosis. The clinical follow-up study was conducted in a group of 103 women diagnosed laparoscopically with endometriosis. Thirty-five patients qualified for danazol treatment. Pain was assessed using a visual analogue scale, whereas endometriosis was assessed using the revised American Society of Reproductive Medicine (rASRM) scale. Cancer antigen (CA)-125 and C-reactive protein (CRP) concentrations in plasma and peritoneal fluid were determined by immunoenzymatic methods, whereas vascular endothelial growth factor (VEGF) and interleukin (IL)-1ß concentrations in plasma and peritoneal fluid were determined by ELISA. Endometrial expression of IL-8 and platelet-derived growth factor alpha polypeptide (PDGF-A) was determined using real-time polymerase chain reaction (PCR). Women with endometriosis (68.9% of patients) had higher plasma concentrations of CA-125, as well as higher concentrations of both CA-125 and VEGF in the peritoneal fluid. Endometrial expression of IL-8 mRNA was significantly higher, whereas that of PDGF-A was significantly lower, in contrast. After danazol treatment the patients reported lower pain scores; in addition, CA-125 concentrations in the plasma were decreased (P<0.001), whereas VEGF concentration in the plasma increased (P=0.009). For the diagnosis of endometriosis, none of the combinations of given markers had a sensitivity >60%. Danazol treatment is highly effective in relieving pain and decreasing CA-125 concentrations in the plasma. Higher plasma concentrations of VEGF after treatment could imply stimulation of angiogenesis.

The safety and effectiveness of low field intraoperative MRI guidance in frameless stereotactic biopsies of brain tumours-design and interim analysis of a prospective randomized trial.

The aim of the study was to assess the safety and effectiveness of stereotactic brain tumour biopsy (STx biopsy) guided by low-field intraoperative magnetic resonance imaging (iMRI) in comparison with its frameless classic analogue based on a prospective randomized trial. A pilot group of 42 brain tumour patients was prospectively randomized into a low-field iMRI group and a control group that underwent a frameless STx biopsy. The primary endpoints of the analysis were postoperative complication rate and diagnostic yield, and the secondary endpoints were length of hospital stay and duration of operation. The iMRI group (21 patients) and the control group (21 patients) did not differ significantly according to demographic and epidemiological data. No major postoperative complications were noted in either group. In addition, no significant differences in the diagnostic yield (p = 1.00) and length of hospital stay (p = 0.16) were observed. The mean total OR time was 111 ± 24 min in iMRI and 78 ± 29 min in the control group (p = 0.0001). Usage of iMRI may prolong the time of the procedure but seems to be comparable in safety and effectiveness to the standard frameless STx biopsy.

Neuroendoscopy combined with intraoperative low-field magnetic imaging for treatment of multiloculated hydrocephalus in a 7-month-old infant: technical case report.

BACKGROUND: Treatment of multiloculated hydrocephalus in children remains a difficult neurosurgical problem because of the high recurrence rate. Endoscopic septostomy with subsequent ventriculoperitoneal shunting is one of the most widely accepted therapeutic methods. Intraventricular endoscopic surgery combined with intraoperative magnetic resonance (MR) has been used very seldom in infants. CASE REPORT: A 7-month-old infant presented with a history of postnatal hydrocephalus from the germinal matrix and intraventricular hemorrhage, treated with a ventriculoperitoneal shunt. Treatment was complicated by bacterial meningitis. On admission the child presented with symptoms of elevated intracranial pressure, an MR investigation gave evidence of multiloculated hydrocephalus. The patient underwent endoscopic pellucidotomy, followed by fenestration of the septa inside the third ventricle, third ventriculostomy and aqueductoplasty. Endoscopic navigation was supported by serial intraoperative non-contrast T1-weighted MR (0.15 T, Polestar N20, Medtronic) images. They also served for confirmation of the patency of performed fenestrations and for the planning of further steps of the operation. CONCLUSION: Intraoperative low-field MR imaging provided an excellent tool for correct navigation of the endoscope inside the pathological ventricular compartments and for intraoperative assessment of surgical goals.

Cell context-dependent activities of parthenolide in primary and metastatic melanoma cells.

BACKGROUND AND PURPOSE: Growing evidence implicates NF-kappaB as an important contributor to metastasis and increased chemoresistance of melanoma. Here, we report the effects of parthenolide on either untreated, cisplatin- or TNFalpha-treated melanoma cell lines A375, 1205Lu and WM793, exhibiting different levels of constitutive NF-kappaB activity. EXPERIMENTAL APPROACH: Electrophoretic mobility shift assay was used to assess changes in NF-kappaB activity, and real-time PCR to evaluate expression of NF-kappaB-regulated genes. Cell cycle arrest and apoptosis were assessed by flow cytometry. Cell death was also visualized by fluorescence microscopy. Migration was determined by scratch assay and invasiveness by Matrigel assay. KEY RESULTS: Parthenolide suppressed both constitutive and induced NF-kappaB activity in melanoma cells. This was accompanied by down-regulation of cancer-related genes, with NF-kappaB-binding sites in their promoters, including: Bcl-X(L), survivin, cyclin D1, interleukin 8 and matrix metalloproteinase 9. When the various effects of 6 microM parthenolide were compared, apoptosis associated with loss of mitochondrial membrane potential was most efficiently induced in 1205Lu cells, cell cycle arrest in G(0)/G(1) phase was observed in WM793 cells, and high metastatic potential was markedly reduced in A375 cells. These findings not only reflected differences between melanoma cell lines in basal expression of NF-kappaB-regulated genes, but also suggested other parthenolide targets involved in cell cycle progression, migration, invasiveness and survival. CONCLUSIONS: Inhibition of constitutive and therapeutically induced NF-kappaB pathway by parthenolide might be useful in the treatment of melanoma, although the diversity of changes induced in melanoma cells with different genetic backgrounds indicate context-dependent poly-pharmacological properties of this compound.

Tautomerization of 2-nitroso-N-arylanilines by coordination as N,N'-chelate ligands to rhenium(I) complexes and the anticancer activity of newly synthesized oximine rhenium(I) complexes against human melanoma and leukemia cells in vitro.

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(I) complexes are described. The reaction of the halogenido complexes (CO)(5)ReX (X = Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C(6)H(3)ClNO)NH(C(6)H(4)R)} (R = p-Cl, p-Me, o-Cl, H) (3a-d) in tetrahydrofurane (THF) yields the complexes fac-(CO)(3)XRe{(C(6)H(3)ClNO)NH(C(6)H(4)R)} (6a-d, 7a-d) with the tautomerized ligand acting as a N,N'-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by (1)H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their (1)H and (13)C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N'-chelating ligands for all Re(I) complexes. Biological activity of four oximine rhenium(I) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(I) complexes than leukemia cells. None of the ligands (3a-d) showed any significant anticancer activity.

A non-apoptotic function of caspase-3 in pharmacologically-induced differentiation of K562 cells.

BACKGROUND AND PURPOSE: Several anticancer drugs with diverse chemical structures can induce differentiation of cancer cells. This study was undertaken to explore the potential contribution of caspase-3 to pharmacologically-induced differentiation of K562 cells. EXPERIMENTAL APPROACH: We assessed differentiation by measuring the expression of glycophorin A and haemoglobin synthesis in K562 cells treated with low concentrations of doxorubicin, hydroxyurea, cytosine arabinoside, cisplatin and haemin. Caspase-3 activation, mitochondrial membrane potential dissipation and viability were assessed by FACS. GATA-1-binding activity was evaluated by EMSA. KEY RESULTS: Treatment of K562 cells with low concentrations of the tested drugs activated caspase-3 but did not trigger detectable apoptosis. Instead, elevated levels of haemoglobin-positive and glycophorin A/caspase-3-double-positive cells were observed, suggesting involvement of caspase-3 in drug-induced differentiation. Inhibition of caspase-3 activity significantly reduced the ability of K562 cells to execute the differentiation programme. Mitochondrial membrane potential dissipation was observed, indicating involvement of the mitochondrial pathway. Binding activity of GATA-1, transcription factor responsible for differentiation and cell survival, was not diminished by increased caspase-3 activity during drug-stimulated differentiation. CONCLUSIONS AND IMPLICATIONS: Our results could explain how anticancer drugs, with diverse structures and modes of action, can stimulate erythroid differentiation in leukaemic cells with appropriate genetic backgrounds. Our findings imply that some similarities exist between pharmacologically-induced differentiation of erythroleukaemic cells and normal erythropoiesis, both involving caspase-3 activation at high levels of anti-apoptotic protein Bcl-X(L) and chaperone protein Hsp70 (heat shock protein 70). Therefore, the functions of caspase-3, unrelated to cell death, can be extended to pharmacologically-induced differentiation of some cancer cells.

Effects of anticancer drugs on transcription in vitro.

The effects of DNA interacting drugs on: (1) total RNA synthesis catalyzed by E. coli and T7 RNA polymerase; (2) synthesis of the initiating dinucleotide (pppApU) by E. coli RNA polymerase ("abortive initiation"); (3) elongation of RNA chains synthesized by T7 RNA polymerase on pT7-7 plasmid DNA bearing T7 RNA polymerase promoter phi 10 with human Cu/Zn superoxide dismutase coding sequence, (4) interaction of transcription factor Sp1 and its binding site were studied. Intercalating ligands which form quickly dissociating complexes with DNA (anthracyclines, proflavine, ethidium bromide) are compared with the slowly dissociating drug of d(G x C) specificity (actinomycin D), the non-intercalating, d(A x T) specific pyrrole antibiotics (netropsin and distamycin A) and covalently binding to DNA 1-nitroacridine derivative (nitracrine). The obtained results indicate that rapidly dissociating ligands, proflavine and ethidium bromide, inhibit total RNA synthesis in vitro and the abortive initiation to a similar extent while they do not induce discrete elongation stops of RNA polymerase. Actinomycin D and nitracrine exhibit a high inhibitory effect on total RNA synthesis and induce stops of RNA polymerase while not affecting abortive initiation. Pyrrole antibiotics primarily inhibit the initiation, while no elongation stops are induced. Actinomycin D inhibits complex formation between nuclear proteins and the Sp1 binding site. Netropsin, ethidium bromide, proflavine and other intercalating acridines do not affect Sp1 binding. The results indicate that the effects primarily depend on sequence specificity and secondarily on the dissociation rate of ligands from their complexes with DNA.

Transcription factors as targets of anticancer drugs.

Several general and gene- and cell-selective transcription factors are required for specific transcription to occur. Many of them exert their functions through specific contacts either in the promoter region or at distant sequences regulating the initiation. These contacts may be altered by anticancer drugs which form non-covalent complexes with DNA. Covalent modifications of DNA by alkylating agents may prevent transcription factors from recognizing their specific sequences or may constitute multiple "unnatural" binding sites in DNA which attract the factors thus decreasing their availability in the cell. The anticancer drug-transcription factor interplay which is based on specific interactions with DNA may contribute to pharmacological properties of the former and provide a basis for the search for new drugs.

Selective Sp1 and Sp3 binding is crucial for activity of the integrin alphaV promoter in cultured endothelial cells.

Human integrin alphavbeta receptors are expressed in a number of cells and their expression is regulated at the level of transcription and by post-transcriptional mechanisms. A substantial body of research exists on the structure, function, molecular biology and physiological significance of alphav integrin receptors. However, the importance of particular cis-acting DNA elements or trans-acting nuclear factors in the regulation of the alphav gene promoter is still not adequately understood. Previous functional analysis of the alphav gene 5' flanking region in transfected cultured cells identified cis elements critical for alphav transcription within a 222-bp region. To define further the location of this enhancing element, we performed DNase I footprinting of the human alphav gene promoter between -522 and the translation initiation site. For this purpose, nuclear extracts of alphavbeta3-positive cells, human umbilical vein endothelial cells, were used. Nuclear proteins of endothelial cells strongly protected essentially one region corresponding to the sequence between -194 and -172 of the alphav promoter region. Electrophoretic mobility shift assays with different oligonucleotides, and competition analysis identified a CTCCTCCTC sequence that is directly involved in the transcriptional activity of the alphav promoter. Purified Sp1 alone produced an identical footprint, and DNA binding assays using anti-Sp1 and anti-Sp3 antibodies showed that transcription factors Sp1 and Sp3 were the major nuclear proteins bound to this region.

Actinomycin D specifically inhibits the interaction between transcription factor Sp1 and its binding site.

The mode of action of many anticancer drugs involves DNA interactions. We here examine the ability of actinomycin D to alter the specific binding of transcription factors Spl and NFkappaB to their DNA sequences. Employing an electrophoretic mobility shift assay, it is shown that actinomycin D inhibits complex formation between nuclear proteins present in the extracts from stimulated human umbilical vein endothelial cells and the Sp1-binding site. Actinomycin D is also able to induce disruption of preformed DNA-protein complexes, pointing to the importance of an equilibrium of three components: actinomycin D, protein and DNA for drug action. The effect of actinomycin D is sequence-specific, since no inhibition is observed for interaction of nuclear proteins with the NFkappaB binding site. The results support the view that DNA-binding drugs displaying high sequence-selectivity can exhibit distinct effects on the interaction between DNA and different DNA-binding proteins.

Inhibition of RNA synthesis in vitro by acridines--relation between structure and activity.

The effects of acridine derivatives (proflavine and 2,7-dialkyl derivatives, diacridines and triacridines, 9-aminoacridine carboxamides, and 9-anilinoacridine, amsacrine and its congeners) on overall RNA synthesis in vitro, on synthesis of initiating oligonucleotides and the binding of the enzyme to DNA were studied. The primary mechanism of action is related to inhibition of the enzyme binding to DNA. The acridines (intercalating or non-intercalating and bis-intercalating ligands) assayed here differ in the properties of their complexes with DNA. Correlation is generally observed between inhibition of RNA synthesis in vitro and cytotoxicity in cell cultures for di- and triacridines and 9-aminoacridine carboxamide derivatives. No relationship was found between the effect on RNA polymerase system and biological effects for amsacrine and its derivatives in contrast to the other series of acridines studied here. The aniline ring seems to decrease the inhibitory potency of a ligand. The discrepancy between the biological effect and RNA synthesis inhibition may be due to a different mechanism of cytotoxicity action of amsacrine which is a potent topoisomerase II poison.