Deric M. Park, M.D.

• Department of Neurology
• The University of Chicago
• Chicago, IL

Olson a hypertension signs buy 180mg cardizem overnight delivery,b blood pressure erratic buy 60 mg cardizem free shipping,c Purpose of review Most children diagnosed with cancer today are expected to be cured 5 hypertension buy discount cardizem 180 mg. Medulloblastoma heart attack friend can steal toys order 180 mg cardizem visa, the most common pediatric malignant brain tumor, is an example of a disease that has benefitted from advances in diagnostic imaging, surgical techniques, radiation therapy and combination chemotherapy over the past decades. It was an incurable disease 50 years ago, but approximately 70% of children with medulloblastoma are now cured of their disease. However, the pace of increasing the cure rate has slowed over the past 2 decades, and we have likely reached the maximal benefit that can be achieved with cytotoxic therapy and clinical risk stratification. Recent findings Using genome-based high-throughput analytic techniques, several groups have independently reported methods of molecular classification of medulloblastoma within the past year. Summary Novel classification and risk stratification based on biologic subtypes of disease will form the basis of further study in medulloblastoma and identify specific subtypes that warrant greater research focus. Risk stratification in medulloblastoma is currently based on age, metastatic status, extent of surgical resection and histological presence or absence of diffuse anaplasia. Standard risk patients are over the age of 3 years with localized disease and without anaplastic subtype. Incorporation of molecular factors will greatly improve risk stratification for pediatric patients with medulloblastoma. Several studies are ongoing to incorporate children who are 4 or 5 years old into this strategy [20]. High-throughput technology has facilitated the rapid study of the cancer genome in cohorts of patient tumor samples. In addition, a gene expression signature was identified, consisting of only eight differentially expressed genes, which could predict patient survival more accurately than clinical risk stratification. These side-effects are most closely related to dose of radiation therapy and age at diagnosis, as well as factors at presentation such as hydrocephalus and shunting [5,6]. Patients with medulloblastoma who relapse after standard therapy have a dismal prognosis, with few long-term survivors [7,8]. The treatment strategy for standard risk medulloblastoma patients has aimed to reduce the dose of craniospinal radiation therapy. Children with high-risk medulloblastoma over the age of 3 years continue to have a lower 5-year survival of 70% even with full-dose 36 Gy of craniospinal radiation therapy [10], and dose reduction to 24 Gy resulted in survival under 40% for patients with metastatic disease inappropriately treated with standard risk regimens [9]. Therefore, current strategies for high-risk patients include further therapy intensification or introduction of new agents such as isotretinoin (13-cis retinoic acid) based on preclinical studies showing apoptosis of medulloblastoma cells treated with isotretinoin [16]. Intensity of therapy, including high-dose chemotherapy with stem cell rescue, appears to 34 In addition, a strong association was observed between patient age, metastatic status and expression-based subtype. Within the last year, the results of four separate international collaborative genome-based studies of medulloblastoma have been published. The potential for further study using these now publicly available datasets is nearly unlimited. One thing is clear; the time has come to clinically view medulloblastoma as a group of molecularly distinct subtypes (summarized in Table 1) [44,45, 46,47,49,50]. In the past few decades, the ability to create genetically engineered mouse models of disease has facilitated the detailed study of a large variety of cancers as well as insight into developmental pathways [53]. In the infant population, nodular desmoplastic subtype predicts survival, and these young patients represent a group in which radiation therapy may be successfully eliminated [19,20,55,56]. This finding supports the idea that metastatic status itself may be a marker for biologic subtype rather than temporal disease progression. Mouse models that are currently being generated will greatly accelerate preclinical work in this important area. Although a number of mutations or copy number variants have been described, it remains unclear which of these drives the cancer and represents a point of vulnerability. The first unifying hypothesis suggests that deregulation of chromatin modulation is responsible for induction of these tumors [63], which is supported by the recent finding that mixed lineage leukemia gene mutations occur across medulloblastoma subtypes [48]. It remains unclear whether a chromatin remodeling event that initiates tumors represents a vulnerable driver for established tumors. Histone deacetylase inhibitors, such as vorinostat (Zolinza), broadly affect chromatin remodeling and show preclinical activity against medulloblastoma as single agents and in combination therapy [16,64] and are being evaluated in human clinical trials [65]. A commendable collaborative effort involving each of the international groups that performed these studies has resulted in a working consensus to attempt to incorporate a && && 36 This is particularly true for those patient groups in which modest improvements in outcome are possible or for efficacy equivalency studies, both of which require more patients to achieve statistically relevant endpoints. Molecular classification of all medulloblastoma using a gene expression-based approach will improve current clinical risk stratification, but will require significant coordination and centralization of testing [66,67]. Use of novel technology to measure gene expression using paraffin-embedded tissue may significantly improve feasibility in national consortium clinical trials [68]. Because driver mutations are not well understood, there are no published transgenic mouse models of this disease. An alternative strategy for mouse model development is the patient-derived xenograft in which human tumor samples obtained at the time of therapeutic surgery are transplanted into animal models. This method, developed by the laboratory of Li, provides resources for study and therapeutic evaluation for rare and incompletely understood subtypes of disease for which there are no transgenic models [69]. Key opportunities are provided by the wealth of genome-based data now available and novel preclinical patient-derived tumor models. The molecular classification of medulloblastoma represents a modern paradigm shift in the diagnosis and treatment of malignancy. Similar shifts toward biologic stratification are likely to apply to an increasing number of tumors, perhaps all cancers, in the future. Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. Results of treatment of children with recurrent medulloblastoma/primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): longterm results from a prospective, multicentre trial. Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma. Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure. Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma. Pediatric medulloblastoma: toxicity of current treatment and potential role of protontherapy. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

Both the primary tumor and subsequent recurrence heart attack causes order cardizem 120 mg visa, as well as the treatments thereof blood pressure 14080 discount cardizem 60 mg with visa, can also cause significant physical morbidity or psychosocial dysfunction [8] pre hypertension low pulse buy 60mg cardizem. The introduction of novel blood pressure normal newborn quality cardizem 60mg, targeted therapeutics could therefore be of significant benefit in treating this tumor of the childhood brain, especially since, in contrast to most other tumor entities, it can become in effect a chronic disease which might require long-term and/or repeated cycles of adjuvant therapy. Classic presentation includes a biphasic architecture, with areas of densely packed, fibrillary tissue interspersed with looser microcystic compartments. Tumor cells usually display an elongated morphology with hair-like (piloid) tendrils that give the tumor its name. Rosenthal fibres (strongly eosinophilic structures of unknown composition) and granular bodies are also frequently observed, but are neither necessary nor sufficient for diagnosis. Until recently, very little was known about the genetic alterations underlying this disease. Functionally, this signaling pathway has been implicated in various neurological processes like memory formation and pain perception (reviewed in [16, 17]) but also in the induction of cortical neurogenesis [18] and development of the midbrain and cerebellum [19]. The underlying aberrations, however, are different in most of these entities when compared with the common mechanisms in pilocytic astrocytoma outlined below. Loss of neurofibromin activity leads to an increase in the active form of Ras, thereby contributing to tumor formation [40]. The frequency of this change stated in the literature varies from 50 to 100% depending on the demographics of the patients investigated, and a total of five different exonic combinations of the two genes have been described (see Fig 1). The gene fusions with their indicated fusion partners and break points in all cases result in a loss of the amino-terminal autoregulatory domain. This, as well as the V600E point mutation and the Ins598T insertion in the full length protein, results in constitutive activity of the kinase domain independent of upstream Ras status. Several reports looking at various additional low and high malignancy grade pediatric brain tumors have found no evidence for the fusion gene in these additional entities [65, 67, 68, 73]. Indeed, there are reports of primary pilomyxoid astrocytomas diagnosed early in life recurring later as prototypic pilocytic tumors [74]. Elucidation of the exact processes through which the 7q34 duplication arises may help to shed light on the question of its specificity. Whilst the mechanism is still not entirely clear, a recent study looking at the mapping of genomic breakpoints suggested a possible recombination mechanism. This mutation has been extensively characterized and is a welldocumented oncogenic lesion [78, 79]. The elucidation of the exact downstream pathways involved is therefore a key target for future research. Further mutations in the hotspot codons 12, 13, and 61 have subsequently been found in several larger, independent tumor series, but only at low frequency (5%) [61, 62, 84, 85]. The fusion protein has also been shown to possess constitutive kinase activity and transforming ability [81]. However, these findings have not been replicated in more recent cohorts, and these genes are currently not thought to play a major role in the development of pilocytic astrocytoma. The number of cases involved is currently too small to assess whether patients with multiple hits in the pathway generally show a worse clinical outcome. The question of which alterations are responsible for the remaining cases remains unclear, but is the subject of ongoing investigation in largescale genomics projects such as the International Cancer Genome Consortium, and elsewhere [91]. The reason for this discrepancy, and its potential impact on tumor behavior, is not currently clear, but the fact that a similar propensity has been observed in multiple independent studies suggests a genuine phenomenon. An influence of age on genetic alterations has also been previously reported for larger-scale changes, with wholechromosome gains (particularly chromosomes 5 and 7) being significantly more common in adult patients and almost absent in the youngest patients [9]. This feature, however, will require careful assessment in larger, well-characterized series. In contrast, looking solely at pilocytic astrocytomas and in all tumor locations, Cin et al. They did, however, report both an age of B1 year and incomplete tumor resection as independent factors of poor prognosis upon multivariate analysis of 93 cases. Because of the long-term survival of the vast majority of patients, pilocytic astrocytoma is viewed as a chronic disease by many pediatric neurooncologists. Treatment approaches should therefore aim for efficacy not only in terms of tumor growth control but also in terms of managing tumor- and treatment-related acute and long-term toxicity, and quality of life. For example, patients with supratentorial midline tumors frequently present with visual symptoms including nystagmus and loss of visual acuity. In addition, disruption of the hypothalamic region can result in endocrine problems such as growth failure, delayed onset of puberty, or pituitary gland dysfunction. Infants with supratentorial midline tumors may also suffer from diencephalic syndrome, which is associated with failure to thrive, weight loss, and cachexia. Tumors located in the cerebral hemispheres are associated with epileptic seizures or hemiplegia, whilst those arising in the brain stem can produce cranial nerve palsies including oculomotor or facial nerve palsy, swallowing difficulties, and tongue atrophy. Although outcome after surgery is generally good, complete surgical resection can only be achieved in around half of all cases, when the tumor is located in surgically accessible sites such as the posterior fossa. If the tumor involves the optic pathway, or the hypothalamic or thalamic regions, complete removal is impossible in a majority of patients. In the case of tumor progression, nonsurgical treatment strategies including chemotherapy and radiation therapy are usually implemented. Older children will typically receive local radiation therapy in the event of tumor progression. These additional treatments increase the risk of patients experiencing more severe side effects. In contrast to older children, small infants below 1 year of age have a poor prognosis and even succumb to their disease in a large proportion of cases. Furthermore, the biological factors determining spinal or leptomenigneal dissemination are not known, nor are any predictors of 123 D. All these are areas which would benefit from additional research and are currently under intensive investigation. Summary In conclusion, recent results in this field have proven highly significant both in terms of dramatically increasing our understanding of the basic biology behind pilocytic astrocytoma, and providing opportunities for rapid translation into clinical benefit for patients. And can we identify clinically relevant subgroups (such as very young patients) with inferior prognosis Open Access this article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. Schrock E et al (1996) Recurrent gain of chromosome arm 7q in low-grade astrocytic tumors studied by comparative genomic hybridization. Walker C et al (2001) Characterisation of molecular alterations in microdissected archival gliomas. Liu C et al (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Bouvier C et al (2003) Shared oligodendrocyte lineage gene expression in gliomas and oligodendrocyte progenitor cells. Colin C et al (2006) In vitro identification and functional characterization of glial precursor cells in human gliomas. Colin C et al (2007) Relevance of combinatorial profiles of intermediate filaments and transcription factors for glioma histogenesis. Potter N et al (2008) Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma. Shoshan Y et al (1999) Expression of oligodendrocyte progenitor cell antigens by gliomas: implications for the histogenesis of brain tumors. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

Delivery of drugs across the blood-brain barrier can be a substantial hurdle blood pressure medication sleepy purchase cardizem 60 mg fast delivery, and even agents with appropriate size and lipophilicity may be eliminated by efflux pumps located in the blood-brain barrier pulse pressure 39 cardizem 60mg otc. Otherwise the formation of double strand breaks is prohibited blood pressure medication starting with z generic cardizem 180mg with amex, and apoptosis is prevented blood pressure medication starting with x trusted cardizem 180 mg. Temozolomide treatment also produces N7-methylguanine and N3methyladenine, which are substrates for the cellular base excision repair pathway. With marked upregulation of proliferation markers, the proliferative type resembles stem cells, whereas the mesenchymal subtype expresses mesenchymal and angiogenic signatures. Proneural tumors share characteristics of slowly proliferating neuroblasts, proliferating tumors resemble neural stem cells and/or transit amplifying cells, and mesenchymal tumors resemble neural stem cells. Its expression profile includes neural, particularly oligodendrocytic and proneural marker genes. Considerations such as target presence, drug access to the target, downstream effects of target inactivation, optimal dose, patient selection, and possible multitarget and multimodality approaches, need to be addressed. Example outline for an 8-arm 2 2 2 factorial trial featuring drug A as the "backbone" used alone or in doublet, triplet, or quadruplet combinations with drugs B, C, and D. Patients with a response continue treatment; patients with progression discontinue treatment; patients with stable disease are randomized in a blinded fashion to either continued study treatment or placebo, with the option of crossover for patients who progress on placebo. This design is not only useful for the evaluation of monotherapy candidates, but could be used to evaluate the efficacy of each agent of a combination approach. Adaptive randomization designs (Figure 1C),6 in which patient allocation to various arms of a multi-arm study is informed by ongoing evaluation of potential treatment success, benefit patients while being cost-effective by decreasing inefficient arms, and allow for the incorporation of novel findings, such as stratification for new biomarkers, into ongoing trials. For example, one biomarker-based adaptive study conducted in the setting of non-small cell lung cancer has shown promising correlations of biomarkers and drug responses. Although still emerging in the field of neuro-oncology, new concepts being adapted include the incorporation of novel trial designs, specific targets, and molecular stratification of tumors. The synthetic peptide cilengitide competitively blocks ligand binding to the v 3 and v 5 integrins, affecting pathways associated with angiogenesis and invasion. A recent study assessing the combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine in patients with recurrent malignant glioma used a scheme in which dose-intense thioguanine was administered prior to addition of temozolomide or lomustine to potentiate the cytotoxic effects of the alkylating agent. The increasing number of candidate agents allows for a large number of permutations on potentially effective combination strategies. Due to potential changes in tumor characteristics at recurrence, such approaches will have to include the analysis of additional biopsies. Survival and functional status after resection of recurrent glioblastoma multiforme. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. Pharmacologic disruption of base excision repair sensitizes mismatch repair-deficient and -proficient colon cancer cells to methylating agents. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Poly(adp-ribose) polymerase inhibitors: a novel drug class with a promising future. Integrated arraycomparative genomic hybridization and expression array profiles identify clinically relevant molecular S32 M. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Neurooncology clinical trial design for targeted therapies: lessons learned from the North American Brain Tumor Consortium. A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma. Bevacizumab versus bevacizumab plus vorinostat in adults with recurrent glioblastoma. An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. Molecular heterogeneity in glioblastoma: therapeutic opportunities and challenges. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Cilengitide and sunitinib malate in treating patients with advanced solid tumors or glioblas- Recurrent glioblastoma treatment S33 96. Cediranib maleate and cilengitide in treating patients with progressive or recurrent glioblastoma. Updated response assessment criteria for high-grade gliomas: response assessment in Neuro-oncology Working Group. Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. The new england journal of medicine original article Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma Roger Stupp, M. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. The new england journal of medicine g lioblastoma is the most frequent primary malignant brain tumor in adults. Median survival is generally less than one year from the time of diagnosis, and even in the most favorable situations, most patients die within two years. Temozolomide, an oral alkylating agent, has demonstrated antitumor activity as a single agent in the treatment of recurrent glioma. Patients who were receiving corticosteroids had to receive a stable or decreasing dose for at least 14 days before randomization. All patients provided written informed consent, and the study was approved by the ethics committees of the participating centers.

It may be worse after a period of lying down because of distension of the epidural venous plexus blood pressure medication you can take while pregnant generic cardizem 180 mg mastercard, and may be more persistent with intradural lesions arrhythmia blog discount 180 mg cardizem otc. Over time heart attack american generic 180mg cardizem fast delivery, pain may become more radicular blood pressure normal low high discount 180 mg cardizem with mastercard, especially with involvement of the lumbosacral spine; thoracic epidural lesions can lead to bilateral, gripping girdle discomfort. Although sensory loss can lead to ataxia, gait ataxia without substantial sensory impairment indicates disruption of spinocerebellar pathways. Corticosteroids Anecdotal reports47 first suggested that corticosteroids could benefit patients with spinal-cord compression, which have been shown to reduce oedema, inhibit inflammatory responses, stabilise vascular membranes, and delay the onset of neurological deficit in spinal-cord compression. However, consensus ends with the agreement on the efficacy of steroids on spinal-cord compression: there is no agreement on the optimum dose to be used. High doses in the range of 100 mg dexamethasone have been compared with low doses (about 10 mg), and single bolus doses with continuous therapy without clear evidence of the benefit of one over the other. Indeed, in patients with no neurological dysfunction corticosteriods might be avoided altogether. Radiotherapy Although presence of metastatic disease in the spine makes all subsequent therapy palliative, most researchers regard the reversal of spinal compression as invaluable to restoring quality of life, and as an indication for therapy with curative intent in those with limited disease elsewhere. Presence of the spinal cord in immediate proximity limits the dose that can be delivered if toxic effects are to be avoided (unless sophisticated techniques are available to spare the cord). Because of the frequency of several levels of compression, imaging of the entire spine is recommended, although not always practical. See Review on page 51 for a discussion of dose delivery in radiotherapy Conventional external-beam fractionated radiotherapy Dose and fractionation Various dose schedules have been tried for pain relief and reversal of compression, from 8 Gy in one fraction, 20 Gy in five fractions, 30 Gy in ten fractions, to 40 Gy in 20 fractions. The most commonly used prescriptions are 30 Gy in 10 fractions and 8 Gy in one fraction. A systematic review of various dose schedules by Sze and colleagues50 found no difference in pain relief between single fraction and multifraction radiotherapy. Since fractionation helps lower the risk of spinal-cord injury, single fraction radiation is reserved for very sick patients. A randomised trial51 on different dosefractionation regimens for bone metastases generally did not identify any substantial difference between schedules that ranged from 30 Gy in five fractions to 27 Gy in 15 fractions. However, reanalysis51 suggested that more fractions was associated with improved pain control-a conclusion supported by a non-randomised single centre study by Hoskin. There was no reported difference of improvement in motor dysfunction with three different fractionation schedules that ranged from 30 Gy in ten fractions to 40 Gy in 20 fractions. When large portions of the gastrointestinal tract are included in the treatment area, mucositis with dysphagia or diarrhoea may occur. The spinal column has a substantial number of blood-cell precursors, and patients who have had much of their spine irradiated may develop cytopenia; however, substantial fatigue and nausea are uncommon with standard treatment schedules. Absolute 320 Gy 300 Gy 280 Gy 250 Gy 150 Gy Figure 3: Intensity-modulated radiotherapy dose plan by use of helical tomotherapy for treatment of thoracic spinal metastasis from lung cancer the high-dose zone (red) is shaped in a concave way to avoid the spinal cord. Intensity-modulated radiotherapy this technique is a specialised form of highly conformal three-dimensional radiotherapy that is planned by use of sophisticated computer-based methods and leads to a high degree of control by irradiation of different anatomical regions (figure 3). The possibility of differential doses means that curative rather than palliative radiotherapy can be given. With retreatment of vertebral metastases, intensitymodulated radiotherapy can minimise further doses to the cord while delivering therapeutic doses to the disease. Heidelberg55 studied 18 patients with 19 lesions who were retreated for recurrent spinal metastases by use of conformal radiation or intensity-modulated radiotherapy. All patients had previously undergone conventional radiotherapy and the indication for reirradiation was tumour progression associated with pain or neurological symptoms. After retreatment, overall local control was 947% and 81% of patients had significant pain relief; 42% of patients had neurological improvement and tumour size was unchanged in 84%. No clinically substantial late toxic effects were seen after conformal radiotherapy or intensity-modulated radiotherapy. Up to 25% of patients develop recurrent spinal-cord compression after irradiation, and 64% of patients with early recurrence (ie, within 3 months) have disease within two vertebral bodies of the site of initial compression. They may, however, be extended laterally to include paraspinal masses associated with the compression. Issacson and colleagues56 reported that the dose delivered to the compressing mass could be increased to 68 Gy compared 19 Courtesy of Chester Ramsey Review 737 Gy 702 Gy 632 Gy 562 Gy 491 Gy 421 Gy 351 Gy 281 Gy 211 Gy 70 Gy Radiosurgery this technique refers to the use of a single high dose of radiation delivered by use of stereotactic guidance to a well-defined target volume. Moreover, a steep gradient of radiation is introduced into the surrounding tissue with high biological effectiveness. Radiosurgery is commonly done in two to three courses and needs use of a localisation and immobilisation appliance such as a stereotactic frame. The poor tolerance of the spinal cord to radiation compared with the brain has meant that development of spinal radiosurgery has been slow. Definition of neurological status before treatment is an important predictor of outcome, which depends on: the extent of functional limitation when radiotherapy is started; the tumour type, and the rapidity of onset of neurological deficits. Rades and colleagues62 found that rapid onset of neurological deficits within 48 h in 14 of 57 patients was associated with a worse outcome. No patients showed improvement, 43% had no change, and 57% of patients showed deterioration. The importance of tumour type in determination of treatment outcome is intuitive because some tumours (eg, lymphoma, myeloma, and cancers of the breast, prostate, and small-cell lung) are more sensitive to radiation than others (eg, melanoma and renal-cell carcinoma). The maroon contour outside and to the right of the isodose colour wash is the left kidney. Both methods delivered 40 Gy to the spinal cord with a complication probability of 1% or less. Although particle accelerators are not readily available at most treatment facilities, they represent the role of developing technology in this area. Brachytherapy the implantation of radioactive seeds near to the region of spinal-cord compression is limited to a very small group of patients who have good performance status and expected long-term survival. Rogers and colleagues57 reported on brachytherapy combined with surgical resection of involved bony elements. The source of compression in all patients was malignant disease and seven patients had radioresistant disease (sarcoma in four patients, renal cancer in one, and colon cancer in two). Permanent iodine-125 seeds in absorbable suture were placed open to exposure after resection. The spinal cord needs only a few millimetres of protection from close proximity to brachytherapy sources, which can be done by wrapping the spinal cord in several layers of gold foil. Surgery Surgery remains the only method that leads to immediate relief of spinal compression and direct mechanical stabilisation of a diseased and weakened vertebral column. Results of a multicentre comparison70 of surgical decompression and radiation with radiotherapy alone concluded that patients with spinal-cord compression who were treated with radical, direct decompressive surgery and postoperative radiotherapy regained the ability to walk more often and maintained it longer than did patients treated with radiation alone. Surgery permits most patients to remain ambulatory and continent for the remainder of their lives whereas patients given radiation alone spend about two-thirds of their remaining time unable to walk and incontinent. This multicentre study may change practice and allow patients to be considered for procedures that they are often denied on the basis of their general condition, permitting better quality of life with aggressive surgical management in those patients who meet eligibility criteria for surgery. In anterior spinal-cord compression (the more common form) there is loss of spinal stability when posterior elements are removed, leading to neurological deterioration. Findlay71 noted that 51% of patients with spinal-cord compression had vertebral collapse (defined as over 50% loss of vertebral height) and that 25% of patients treated with laminectomy sustained major neurological deterioration associated with surgery. Therefore, this procedure should be reserved for the removal of posterior lesions. Anterior decompression Thoracotomy or retroperitoneal dissection-methods of anterior decompression-allows total removal of the pathological vertebral body and the tumour mass. Yen and co-workers74 found that 24 of 26 patients (92%) who died before completion of the study had a stable spine as a reuslt of surgery (mean postoperative survival 271 days). During accrual of these patients, 20 others were not enrolled because they were in poor general condition, which highlights that even when the surgeon is willing, only half the patients are actually candidates for this extensive procedure. A retrospective study of neoplastic spinal-cord compression by Sundaresan and colleagues75 to define the effectiveness of surgical treatment and the quality of life in patients with potential morbidity who were undergoing extensive procedures found that, over a 5-year period, 110 patients had surgery, 43% of which did not respond to previous radiotherapy. Apart from the nature of primary tumour, presence of paraparesis before surgery had the most substantial effect on survival.

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References

• Morgan WP, Leicester G: The role of depilation and deodorants in hidradenitis suppurativa. Arch Dermatol 118:101-102, 1982.
• Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54(8):1121-1125.
• Frost JK, Ball WC Jr, Levin ML, et al. Sputum cytopathology: use and potential in monitoring the workplace environment by screening for biological effects of exposure. J Occup Med 1986;28:692-703.
• Carter BS, Bova GS, Beaty TH, et al: Hereditary prostate cancer: epidemiologic and clinical features, J Urol 150:797n802, 1993.
• Oelke M, Giuliano F, Mirone V, et al: Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebocontrolled clinical trial, Eur Urol 61(5):917n925, 2012.
• Zimmerman MA, Goumnerova LC, Proctor M, et al. Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor. J Neurooncol 2005; 72:77-84.
• Goland S, Loutaty G, Arditi A, et al: Improvement in mitral regurgitation after aortic valve replacement, Isr Med Assoc J 5:12, 2003.
• Gelet A, Chapelon JY, Poissonnier L, et al: Local recurrence of prostate cancer after external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography, Urology 63(4):625n629, 2004.