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SYMPOSIUM
Year = :=20 2009  |  Volume : 46  | =20 Issue : 2  |  Page : = 127-131
 

Therapy for glioma: Indian=20 perspective

A = Munshi, R=20 Jalali
 Department of = Radiation=20 Oncology, Tata Memorial Hospital, Parel, Mumbai,=20 India

Correspondence = Address:
R=20 Jalali
Department of Radiation Oncology, Tata Memorial = Hospital,=20 Parel, Mumbai
India

Source of Support: None, Conflict of = Interest:=20 None

DOI: 10.4103/0019-509X.49150

 =BB Abstract  

Central nervous system (CNS) are rare = neoplasms with=20 considerable heterogeneity and variation. The most common = primary=20 lesions of CNS are gliomas. A majority of the data about the = demography and management of gliomas has emerged from the = west.=20 However, there may be considerable variation in the = presentation,=20 behavior, and response to treatment between patients in the = western=20 world and the Asian population. This article discusses = gliomas with=20 special reference to data from oncology centers in = India.


Keywords: Central nervous = system, gliomas,=20 treatment


How to cite this = article:
Munshi A,=20 Jalali R. Therapy for glioma: Indian perspective. = Indian J=20 Cancer 2009;46:127-31

=
How to cite this URL:
Munshi = A,=20 Jalali R. Therapy for glioma: Indian perspective. = Indian J=20 Cancer [serial online] 2009 [cited 2009 May = 9];46:127-31.=20 Available from: http:/= /www.indianjcancer.com/text.asp?2009/46/2/127/49150



 =BB Introduction   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 = border=3D0>


Tumors of the central=20 nervous system (CNS) are rare neoplasms constituting 1-2% of = all=20 malignancies. [1] Depending upon the age, histology, = and site=20 in the CNS, these tumors have varied presentations and = contrasting=20 clinical outcomes. [2],[3] Among CNS neoplasms, gliomas are = the most=20 common tumors. These tumors include astrocytomas,=20 oligodendrogliomas, and ependymomas. Most of the literature = in=20 epidemiology, molecular features, and management of gliomas = has=20 emerged from the west. However, it is well known that = geographical,=20 genetic, and phenotype differences in populations can alter = the=20 incidence, natural history, behavior, and response to = treatment of=20 cancers. [4]

Hence, the=20 interpretation and results from developed countries cannot = be=20 applied directly to developing countries. This article = addresses=20 this issue with the available evidence from the oncology = centers in=20 India.


 =BB Epidemiological=20 aspects   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 border=3D0>


The = cancer=20 registration system of developing and developed countries is = different. There are dedicated cancer registries in most of = the=20 developed world to document all cases and thus a prospective = database is available for comparison. [5],[6] In contrast, most of the = epidemiological data=20 in India is based on population-based cancer registries, = which=20 represent only a small proportion of the population. The = situation=20 is even more difficult for the less common CNS tumors.=20 Epidemiological information about these tumors in India, = therefore,=20 has mainly been based on reports from individual = centers.

A=20 prospective study from the Tata Memorial Hospital provided a = one-year demographic data and relevant tumor-related = information on=20 all 656 patients registered in the Neuro-oncology = Clinic. [7] Astrocytomas were the most common = primary=20 tumors. Gliomas constituted 38.7% (254 cases) of CNS tumors, = with=20 high-grade gliomas comprising 151 (59.5%) and low-grade = gliomas 79=20 (33.1%) cases. Pilocytic astrocytoma was seen commonly in = children.=20 Among the 19 oligodendrogliomas, 12 cases were grade-II and = seven=20 were anaplastic. Most of these tumors were seen in = middle-aged=20 males. Ependymomas presented either with posterior fossa = mass or as=20 a spinal tumor. Most of the cases were below 18 years of age = (43.5%). All spinal ependymomas were grade-II, whereas, = eight=20 intracranial ependymomas were of anaplastic histology. = Eighteen=20 patients presented with clinical and radiological signs of = brain=20 stem glioma. To be specific, the median age of presentation = of=20 pilocytic, fibrillary and, anaplastic astrocytomas, and=20 glioblastomas were 16, 35, 36, and 50 years as compared to = the=20 corresponding values of 23, 33, 49, 62 years recorded in = developed=20 countries. [8] One reason for this could be that = the average=20 life span of people in developing countries is generally = shorter=20 than those living in the developed countries. For instance, = the=20 average life expectancy in India is 62 years for men and 63 = years=20 for women, whereas, it is 73 and 79 years, respectively, in=20 developed countries. [9] This can explain the relatively = lower=20 proportions of high-grade gliomas when compared to the = western data=20 (16 vs. 23%).


 =BB Molecular studies   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 border=3D0>


The = concept of=20 different genetic pathways leading to glioblastoma = multiforme (GBM)=20 has gained considerable acceptance. Two major groups are now = described - primary or de novo GBM and secondary GBM. = Primary=20 GBMs occur in elderly patients and are characterized by = mutation in=20 the phosphate and tensin homolog gene (PTEN) and the = epidermal=20 growth factor receptor (EGFR). Secondary GBMs are a feature = of a=20 younger population and have p53 and platelet-derived = growth=20 factor (PDGF) mutations. A study evaluated the genetic=20 alterations in 30 pediatric GBM cases (age ≤ 18 years) = with=20 immunohistochemical staining for p53, p16, and p27 protein=20 expression, EGFR alterations, and PTEN deletion. [10] Although EGFR protein = overexpression was=20 noted in 23% of the cases, the corresponding amplification = of the=20 EGFR gene was rare (5.5%). Deletion of the PTEN gene was = also=20 equally rare (5.5%). One case showed polysomy (chromosomal = gains) of=20 chromosomes 7 and 10. Loss of p16 and p27 immunoexpression = was=20 observed in 68 and 54% of the cases, respectively. In = pediatric=20 de novo / primary GBMs, deletion of PTEN and EGFR=20 amplification were rare, while p53 alterations were more = frequent as=20 compared to primary adult GBMs. Frequency of loss of p16 and = p27=20 immunoexpression was similar to their adult counterparts. = This=20 suggested that pediatric malignant gliomas were distinctly = different=20 from adult GBMs, highlighting the need for the = identification of=20 molecular targets that could be adopted for future novel = therapeutic=20 strategies.

Another study assessed for the possible = existence=20 of molecular pathways, to determine whether there was any=20 correlation between these different variants and clinical=20 parameters, such as, age, duration of symptoms, and = outcome. [11] Immunophenotyping was performed = to study=20 the simultaneous expression of the p53 protein and EGFR in = 58 cases=20 of adult supratentorial GBMs. By this method, four variants = of GBM=20 could be distinguished: 34% were p53 positive only, 38% were = EGFR=20 positive only, 14% were double negative (p53 negative / EGFR = negative), and 14% were double positive (p53 positive / EGFR = positive). Interestingly, all nine cases of secondary GBM, = in which=20 there was clinical and histological evidence of progression = from a=20 pre-existing low-grade lesion, were p53 positive. = Differences were=20 observed with regard to the age distribution of the four = variants,=20 in that the p53 negative / EGFR negative tumors occurred = most=20 frequently in the younger age group (21 - 40 years). In the = elderly=20 group (61 - 80 years), two-thirds of the tumors were p53 = negative /=20 EGFR positive primary GBMs, and no case of a double positive = or=20 double negative variant was encountered. The differences in = duration=20 of symptoms and symptom-free survival according to age group = and=20 genetic subset were not statistically significant. There = were no=20 differences in outcome within each age category for any GBM = variant,=20 although the longest mean symptom-free survival was noted = among=20 patients aged between 41 and 60 years, with a p53 positive / = EGFR=20 negative variant.


 =BB Clinical = data   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 border=3D0>


No = study regarding=20 the long-term clinical outcome of low-grade gliomas has been = published from an Indian center. There, however, exist many = reports=20 about the outcome of patients with GBM. As established from = western=20 data, the cornerstone of the management of these tumors has = been=20 surgery, followed by postoperative radiotherapy. = Temozolomide (TMZ)=20 is an oral alkylating agent with considerable antitumor = activity in=20 brain tumors. Concomitant TMZ along with radiotherapy (RT) = followed=20 by six cycles of adjuvant TMZ has become the standard = treatment in=20 such patients, following a randomized European and Canadian = trial,=20 which demonstrated a significant improvement in the median = and=20 two-year survival in patients receiving or not receiving = TMZ.=20 [12] However, it is of interest to = assess if the=20 same results can be replicated in clinical practice in the = Indian=20 context.

A study reported the experience with = concomitant=20 and adjuvant TMZ with RT in patients with newly diagnosed = GBM.=20 [13] Forty-two newly diagnosed=20 histopathologically proven patients with GBM underwent = treatment as=20 per the Stupp's protocol. The patients were 13 - 69 years of = age=20 with a median age of 49.5 years (31 males, 11 females). = Fifty=20 percent of the patients underwent a gross total resection of = tumor,=20 43% had partial resection, and 7% an open or stereotactic = biopsy=20 only. Fifty-three percent of the patients had a = postoperative=20 Karnofsky Performance Score (KPS) of 60 - 80%. All patients = received=20 concomitant radiation and TMZ, with 74% of the patients = completing=20 six cycles of adjuvant TMZ. At a median follow-up of 12.5 = months,=20 the one- and two-year survival was 67 and 29%, respectively. = The=20 median overall and progression-free survivals were 16.4 and = 14.9=20 months, respectively. Patients with pretreatment KPS of 480% = had=20 significantly better overall survival as compared with those = having=20 KPS of 80% (median survival 22.12 vs. 11.97 months; = p=BC0.026).=20 Treatment was generally well tolerated with 9% of the = patients=20 developing grade 3 anemia, 2% grade 3 leucopoenia, and 7% = grade 3 or=20 4 thrombocytopenia, respectively, during the treatment. This = analysis confirmed the good overall tolerability to TMZ in = the=20 Indian population, both in the concomitant and adjuvant = settings and=20 concurs well with that in the published = literature.

In=20 another study, patients with a histopathological diagnosis = of GBM,=20 treated at a single institution, were analyzed. [14] After surgery, pts were planned = for=20 postoperative RT to a dose of 60 Gray (Gy) in 30 fractions, = in six=20 weeks, with concurrent chemotherapy (CT) ,with either TMZ 75 = mg/m 2 PO daily for six weeks or Paclitaxel (PT) = 60=20 mg/m 2 i/v weekly with RT or Carboplatin (CB) 150 = mg i/v=20 weekly with RT. Patients treated with TMZ were planned for = further=20 adjuvant TMZ as per Stupp protocol. 110 patients were = included in the analysis. Two patients receiving TMZ had = grade 4=20 thrombocytopenia. Both recovered and there were no = treatment-related=20 mortalities. At a median follow up of 31 weeks (range 7-157, = mean 38=20 weeks), 72 (66%) patients were evaluated for response. Of = these, 43=20 patients had progressive disease, 18 had complete response, = 10 had=20 partial response, and 1 patient had stable disease. The = median time=20 to progression was 32 weeks (range 11-90 weeks)

In = yet=20 another trial, 47 patients with newly diagnosed GBM, treated = with=20 Stupp regimen, were assessed. [15] The median overall survival was = 17 months.=20 Multivariate analysis revealed that an age of 60 years or = older (p=20 < 0.03), a postoperative performance score ≤ 70 (p = =3D 0.04),=20 non-total tumor resection (p =3D 0.03), tumor size > 4 cm = (p =3D=20 0.01), time interval between surgery and RT (p =3D 0.03), = and=20 proliferation index overexpression (p =3D 0.001) were = associated with=20 a worse prognosis.

Nimotuzumab is a Humanized = Monoclonal=20 Antibody with Anti EGFR Activity. [16] A multicentric trial is assessing = the=20 safety and efficacy of Nimotuzumab "An open Label, = Prospective,=20 Multicentric Study to Evaluate the Safety and Efficacy of = BIOMAb -=20 EGFRTM (Nimotuzumab) as Induction and Maintenance Therapy in = Combination with Radiotherapy Plus Temozolamide (concomitant = and=20 adjuvant)." This study is presently being conducted in = various=20 oncology centers in India and the results are awaited.=20

Lonidamine (LND) is an indazole carboxylic acid that = has=20 been shown to be synergistic with RT in tissue culture and = animal=20 models. Clinical experience has shown that LND is = well-tolerated=20 drug. A study assessed the combination treatment of TMZ and = LND to=20 see the increase in radiation response of malignant human = brain=20 tumour cells in vitro . [17] The effects of continuous = treatment for two=20 days on proliferation response and cytotoxicity were studied = after=20 trypsinization, by cell count and uptake of trypan blue dye = (0.5%).=20 For the study of radiation ((60)Co-Gamma-rays, 2 Gy) = response, the=20 drugs were removed 4 hours after irradiation and cultures = were grown=20 further in a drug-free, normal growth medium for another 20 = hours or=20 44 hours. The continuous presence of TMZ or LND for two days = significantly inhibited cell proliferation in a=20 concentration-dependent manner. Post-irradiation presence of = either=20 of these drugs for 4 hours significantly reduced the = proliferation=20 response, 24 and 48 hours after treatments. This suggested = that=20 combination of TMZ and LND at clinically achievable, = low-plasma=20 concentrations could inhibit tumor growth, and LND could = reduce the=20 dose of the temozolomide required for radiosensitization of = brain=20 tumors. This study is important for developing countries in = view of=20 its potential as a resource sparing, low-cost option in=20 GBMs.

Recurrent gliomas bear an even more dismal = outcome than=20 primary lesions. Of late, however, newer agents such as = Bevacuzimab=20 (Aniti VEGF) and Irinotecan have been tested in recurrent = gliomas. A=20 study tested Bevacizumab (Avastin) Plus Irinotecan in a = Phase II=20 setting, in recurrent GBM patients. Seventeen patients = received=20 Avastin 10 mg/kg plus CPT -11 125mg/m 2 q for two = weeks.=20 Four patients had a complete response (CR), seven had = partial=20 response (PR) / stable disease, and six patients progressed. = Based=20 on the promise shown by Bevacuzimab in the western data, it = is soon=20 going to be tested in a Phase III trial in GBM, upfront = along with=20 RT + TMZ (RTOG)

Brainstem tumors represent 10% of the = CNS=20 tumors, accounting for 30% of the pediatric posterior fossa = tumors.=20 These tumors are intractable, with most patients having = relentless=20 progression of the disease, and therefore, a dismal outcome. = In view=20 of their location, most of the lesions are not operable and = RT=20 remains the cornerstone of therapy. Various approaches tried = in=20 these tumors include use of chemotherapy and altered RT = schedules,=20 but all have reported uniformly dismal outcomes. [18]

A study performed the=20 clinicopathological correlation of 45 cases of brain stem = gliomas=20 and determined the occurrence and prognostic significance of = p53=20 expression. [19] Thirty patients were diagnosed by = surgical=20 biopsy and 15 at autopsy. In 25 cases p53 = immunohistochemistry=20 (Avidin Biotinylated technique) was performed. Fifty-one = percent of=20 the gliomas were observed in the first decade of life. = Diffuse=20 astrocytomas were seen in 40 cases (5% were Grade I, 47.5% = Grade II,=20 32.5% Grade III, and 15% Grade IV) and pilocytic = astrocytomas in=20 five cases. Grade IV patients had 2-3 mitoses /10 high-power = fields=20 and had a poorer survival rate. Grade II astrocytomas were = treated=20 with excision and RT, while grade III and IV tumors were = treated=20 with RT and chemotherapy (CCNU). Improvement was noted in = 20% of the=20 patients, postoperatively. The outcome was better in = patients who=20 were treated surgically.

In a prospective study, = pediatric=20 patients with newly diagnosed pontine gliomas were treated = with=20 focal RT to a dose of 54 Gy / 30 fractions, along with = concurrent=20 daily TMZ (75 mg/m 2 , day 1 - day 42). Four = weeks after=20 completing the initial RT + TMZ schedule, adjuvant TMZ (200=20 mg/m 2 , days 1-5) was given every 28 days, to a = maximum=20 of 12 cycles. Response was evaluated clinically and = radiologically=20 with magnetic resonance imaging (MRI) and positron emission=20 tomography (PET) scans. At the time of analysis, 19 patients = died=20 due to disease progression and one patient was alive with=20 progressive disease. The median overall survival and=20 progression-free survival was 9.15 months and 6.93 months,=20 respectively. As admitted by the authors themselves, this = was not=20 better than the results generally known historically and = through=20 previous experiences. [20],[21]


 =BB Quality of life=20 issues   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 border=3D0>


With = improving=20 treatment modalities, the survival of patients has improved. = Issues=20 such as quality of life have therefore become more important = in=20 contemporary neuro-oncology practice. [22] However, deterioration in the = quality of=20 life can be because of surgery, radiotherapy, medication, = and tumor=20 itself. A study prospectively assessed the activities of = daily=20 living (ADL) in young patients with low-grade gliomas = treated with=20 stereotactic conformal radiotherapy (SCRT), in 38 children = and young=20 adults (age 5-25 years, median 12.5 years) with low-grade=20 gliomas. [23] The mean of the total modified = Barthel's=20 ADL score (Barthel's Index, BI) at baseline, before staring = SCRT,=20 was 94.5 (standard deviation 14.8, range 45-100). At the = two-year=20 and three-year follow-up, mean BI was 97.1 and 99, = respectively. On=20 follow-up, maximum improvement in individual BI was seen in = the=20 ambulation-related domain in patients with impaired visual = function=20 (P =3D 0.027), low KPS (P =3D 0.015), and age less than 13 = years (P =3D=20 0.103). The mean pre-radiotherapy baseline BI of three = patients, who=20 eventually developed local recurrence, was only 64 (SD 32.1) = as=20 compared with a baseline score of 97.18 seen in patients = whose tumor=20 remained controlled at follow-up (P B 0.001). Young patients = with=20 low-grade gliomas after surgical intervention had a lower = than=20 normal BI before starting RT, suggesting a decrease in ADL = possibly=20 due to tumor- and surgery-related factors. At the two-year = and=20 three-year follow-up after SCRT, there was no further = decrease in=20 mean BI. A significant improvement in BI was seen in = visually=20 handicapped patients, patients with poor performance status, = and=20 younger patients.

To summarize, there are limited = studies=20 addressing the demography, clinical features, and outcome in = gliomas, in the Indian context. For gliomas, the demographic = trend=20 in Indian data as compared to the west is revealing. = However, as far=20 as disease management and outcome is concerned, the results = are in=20 close concurrence with the reported western data in terms of = disease-free and overall survival outcomes.

 
 =BB References   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 border=3D0>

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solid; FONT-FAMILY: Arial, = Verdana, Helvetica, sans-serif; BACKGROUND-COLOR: #eaead7 } .w3c { FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #000000; FONT-FAMILY: Arial, = Verdana, Helvetica, sans-serif } .vld { FONT-WEIGHT: normal; FONT-SIZE: 10px; COLOR: #000000; FONT-FAMILY: = Arial, Verdana, Helvetica, sans-serif } .ftl { CURSOR: hand } .bl { FONT-WEIGHT: normal; FONT-SIZE: 10px; COLOR: #000000; FONT-FAMILY: = Arial, Verdana, Helvetica, sans-serif; BACKGROUND-COLOR: #ffffff } .spl { BORDER-RIGHT: #ffffff 3px dotted; BORDER-TOP: #ffffff 3px dotted; = FONT-SIZE: 12px; MARGIN-LEFT: 2px; BORDER-LEFT: #ffffff 3px dotted; = COLOR: #000000; MARGIN-RIGHT: 2px; BORDER-BOTTOM: #ffffff 3px dotted; = FONT-STYLE: italic; FONT-FAMILY: Arial, verdana Helvetica, sans-serif; = BACKGROUND-COLOR: #cdd8ba } .splnote { BORDER-RIGHT: #a6adc4 1px solid; BORDER-TOP: #a6adc4 1px solid; = FONT-SIZE: 11px; BORDER-LEFT: #a6adc4 1px solid; LINE-HEIGHT: 135%; = BORDER-BOTTOM: #a6adc4 1px solid; FONT-FAMILY: Arial, Verdana, = Helvetica, sans-serif; BACKGROUND-COLOR: #e1f3ef } .jh { BACKGROUND-COLOR: #ffffff } .btm { BORDER-TOP: #eaead7 1px solid; BACKGROUND: = url(http://www.indianjcancer.com/images/btm.gif) #eaead7 no-repeat right = top; COLOR: #555555 } .ft { BACKGROUND: url(http://www.indianjcancer.com/images/ft.gif) } ------=_NextPart_000_0000_01C9D0C6.29C57C00 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.indianjcancer.com/templates/layer.js var link=3Dnew Array() var delay_hide=3D500 var menuobj; var menu; var default_menu_item; function lib_bwcheck(){ //Browsercheck (needed) this.ver=3Dnavigator.appVersion this.agent=3Dnavigator.userAgent this.dom=3Ddocument.getElementById?1:0 this.opera5=3Dthis.agent.indexOf("Opera 5")>-1 this.ie5=3D(this.ver.indexOf("MSIE 5")>-1 && this.dom && = !this.opera5)?1:0;=20 this.ie6=3D(this.ver.indexOf("MSIE 6")>-1 && this.dom && = !this.opera5)?1:0; this.ie4=3D(document.all && !this.dom && !this.opera5)?1:0; this.ie=3Dthis.ie4||this.ie5||this.ie6 this.mac=3Dthis.agent.indexOf("Mac")>-1 this.ns6=3D(this.dom && parseInt(this.ver) >=3D 5) ?1:0;=20 this.ns4=3D(document.layers && !this.dom)?1:0; this.bw=3D(this.ie6 || this.ie5 || this.ie4 || this.ns4 || this.ns6 || = this.opera5) return this } var bw=3Dnew lib_bwcheck(); function x(obj,visible) { this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 this.css.visibility =3D visible; this.css.width=3D'100%'; } function showHideLayer(obj,visible){ =09 this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 this.css.visibility =3D visible; this.css.top=3D'94px'; bw.ns4||bw.ns6?this.css.left=3D'-8px': this.css.left=3D'0px'; this.css.width=3D'100%'; this.css.position=3D"absolute"; } function writeSubmenu(obj,item){ =09 /* this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 thecontent=3D(item=3D=3D-1)? "" : link[item] this.wref.innerHTML=3Dthecontent;*/ } function clearContent(obj){=09 =09 this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 thecontent=3D(item=3D=3D-1)? "" : link[item] this.wref.innerHTML=3D""; } function clear_delayhide() { alert("asdASD"); if (window.delayhide) {onlpgld(default_menu_item) clearTimeout(delayhide) } } function contains_ns6(a, b)=20 { while (b.parentNode) if ((b =3D b.parentNode) =3D=3D a) return true; return false; } //// function navleftMouseOver(src) {=20 src.className=3D"leftnavcellover" }=20 function navleftMouseOut(src) {=20 src.className=3D"leftnavcell" } function navtabMouseOver(src) {=20 src.className=3D"topBand1MO" }=20 function navtabMouseOut(src) {=20 src.className=3D"topBand2" } //// function navMouseOver(src,item) {=20 src.className=3D"topBand1MO" //writeSubmenu("submenu",item); //showHideLayer("submenu","visible");=09 =09 }=20 function navMouseOut(src,lyr) {=20 src.className=3D"topBand1"; // onlpgld(default_menu_item); =09 } function onload(item) { // writeSubmenu("submenu",item); // showHideLayer("submenu","visible"); =09 } function onlpgld(item) { default_menu_item=3Ditem;=09 writeSubmenu("submenu",item); showHideLayer("submenu","visible"); =09 } function navMouseOversUB(src) {=20 src.className=3D"topBand2MO" }=20 function navMouseOutsUB(src) {=20 src.className=3D"topBand2" } function navMouseBotOut(src) { src.className=3D"leftnavcell" } function navMouseBotOver(src) { src.className=3D"leftnavcellover" } function loadMenu(index) { writeMenu("menu",item); showHideLayer("menu","visible");=09 if (index >=3D 0) { onload(index) =09 } } function showMenu(e,f) { var ie4=3Ddocument.all&&navigator.userAgent.indexOf("Opera")=3D=3D-1 var ns6=3Ddocument.getElementById&&!document.all var ns4=3Ddocument.layers eventX=3Die4? event.clientX : ns6? e.clientX : e.x eventY=3Die4? event.clientY : ns6? e.clientY : e.y var rightedge=3Die4? document.body.clientWidth-eventX : = window.innerWidth-eventX var bottomedge=3Die4? document.body.clientHeight-eventY : = window.innerHeight-eventY var obj=3D"floatmenu"; this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 this.css.visibility =3D "visible"; this.css.left=3Die4? document.body.scrollLeft+eventX : ns6? = window.pageXOffset+eventX : eventX if (bottomedge=3D 0 || pg.indexOf('changeaddress') >=3D 0 ) { var attributes =3D 'toolbar=3D0,location=3D0,directories=3D0,status=3D0, = menubar=3D0,scrollbars=3DYes,resizable=3D1,width=3D800,height=3D600,left=3D= 0,top=3D0'; } else { var attributes =3D 'toolbar=3D0,location=3D0,directories=3D0,status=3D0, = menubar=3D0,scrollbars=3D1,resizable=3D1,width=3D600,height=3D400,left=3D= 0,top=3D0'; } sealWin=3Dwindow.open(pg ,'',attributes);=20 self.name =3D pg;=20 } function valfld(field) { var valid =3D "0123456789"; // these are allowed values var ok =3D "yes"; var temp; if (field.value.length =3D=3D 0 ) { //alert("Invalid entry! please enter number"); field.value =3D "" field.focus(); field.select(); return false;=09 } for (var i=3D0; i'; t+=3D''; for(i=3D0;i'; } t+=3D''; document.write(t); var = bA=3D(ie)?document.all['blocks'+N]:document.getElementById('blocks'+N); bA.bar=3D(ie)?document.all['_xpbar'+N]:document.getElementById('_xpbar'+N= ); bA.blocks=3Dblocks; bA.N=3DN; bA.w=3Dw; bA.h=3Dh; bA.speed=3Dspeed; bA.ctr=3D0; bA.count=3Dcount; bA.action=3Daction; bA.togglePause=3DtogglePause; bA.showBar=3Dfunction(){ this.bar.style.visibility=3D"visible"; } bA.hideBar=3Dfunction(){ this.bar.style.visibility=3D"hidden"; } bA.tid=3DsetInterval('startBar('+N+')',speed); return bA; }} function startBar(bn){ var = t=3D(ie)?document.all['blocks'+bn]:document.getElementById('blocks'+bn); if(parseInt(t.style.left)+t.h+1-(t.blocks*t.h+t.blocks)>t.w){ t.style.left=3D-(t.h*2+1)+'px'; t.ctr++; if(t.ctr>=3Dt.count){ eval(t.action); t.ctr=3D0; }}else t.style.left=3D(parseInt(t.style.left)+t.h+1)+'px'; } function togglePause(){ if(this.tid=3D=3D0){ this.tid=3DsetInterval('startBar('+this.N+')',this.speed); }else{ clearInterval(this.tid); this.tid=3D0; }} function togglePause(){ if(this.tid=3D=3D0){ this.tid=3DsetInterval('startBar('+this.N+')',this.speed); }else{ clearInterval(this.tid); this.tid=3D0; }} document.write('