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The y-axis plots the inverse of the log of the association P value for each typed SNP ( 500 000 SNPs interrogated per patient) as it relates to MTX clearance; the x-axis sorts SNPs based on chromosomal position order alfuzosin us. The peak of P values corresponds to SNPs that localize to SLCO1B1 buy alfuzosin with paypal, indicating that variation in this gene identified genetic variation associated with interpatient variability in MTX clearance among 1279 children with ALL buy alfuzosin 10mg without a prescription. The strongest association was for features that have been repeatedly associated with low clearance cheap alfuzosin express, the C-allele at rs7142143 (in the PYGL gene) and a 3. We found that 14 The GWAS showed that MTX clearance was associated with SNPs of the 134 SNPs associated with relapse, including variants in in SLCO1B1 at a genome-wide level of significance (P 2. Therefore, we replicated findings using different schedules medication pharmacokinetics, thereby suggesting a mechanism by of high-dose MTX from the St. The which some germline SNPs may affect response to therapy in ALL. SLCO1B1 SNP rs4149056 has now been replicated for 5 different treatment regimens of MTX. Variants associated with MTX efficacy and pharmacokinetics We further evaluated the influence of rare versus common variants MTXPG accumulation differs among leukemic subtypes, with on MTX clearance in analyses that included all clinical covariates higher accumulation often corresponding to better subtype re- on clearance. After sequencing SLCO1B1 in 699 children, we identified 93 SNPs and, of these, 15 were nonsynonymous (NS). We applied a genome-wide approach to identify genomic determinants of MTXPG accumulation in primary ALL blasts and Three of these 15 NS SNPs were common, with an allele fre- normal lymphoid cell lines using gene expression, somatic copy quency 5%, one had a low minor allele frequency (MAF; number variation, and inherited SNP genotypes. We found that, regardless of 3 types of genomic variation in 7 genes (FHOD3, IMPA2, ME2, their MAF, NS SNPs that were predicted to be functionally RASSF4, SLC39A6, SMAD2, and SMAD4) were associated with damaging by computational algorithms were more frequent among MTXPG in blasts. To begin to assess the relative importance of the patients in the lowest decile for MTX clearance than among those 3 types of variation, we found that expression of the top 7 genes in with the highest clearance. By expressing variants in mammalian primary ALL cells accounted for more variation in MTXPGs than cell lines, we verified that 4 SLCO1B1 haplotypes that were did expression of the top 7 genes in normal lymphoid cell lines and associated with reduced MTX clearance in patients indeed had that the top 7 inherited SNP variants in children with ALL patients reduced MTX transport capacity in vitro. Quantitatively, after accounted for approximately the same degree of variation in adjusting for other genetic and nongenetic covariates, SLCO1B1 MTXPGs as did the top 7 SNP genotypes in HapMap cell lines. Rare variants had larger acquired genetic variation in the ALL cells themselves had a effect sizes than common NS variants, as is true for some nonpharmacogenetic traits. MTX effectiveness is also influenced by interindividual variation in its plasma clearance, which then results in heterogeneous systemic Variants associated with asparaginase efficacy and exposure. In a GWAS of children with ALL who received high-dose allergy MTX in St. Jude frontline trials, multiple common polymorphisms Asparaginase is an important drug for ALL, and overall response in SLCO1B1 were associated with MTX clearance. After adjusting for all (IC50) after exposure to native E coli asparaginase. At a threshold of relevant clinical covariates, we found that polymorphisms of ACP1 P. We then combined the germline SNP data with involved in the regulation of lipid levels. The ACP1 SNPs that were genes for which expression was associated with IC50 at the P. Testing for pathways overrepresented by the 94 lower albumin and higher cholesterol. The features of older age ( top-ranked genes (329 SNPs), we found that the top ranked pathway 10 years of age), lower albumin, higher lipid levels, and dexametha- was that of aspartate metabolism, which may be linked directly to sone exposure were associated with osteonecrosis and may be the mechanism of action of asparaginase. The 2 most highly ranked linked by common inherited genomic variation, suggesting a genes (ADSL and DARS) in this pathway encompassed 7 SNPs. Moreover, several of Overall, approximately one-third of the variability in asparaginase these features (lower albumin, higher lipids, and higher dexametha- IC50 among the lymphoid cell lines could be accounted for by these sone plasma levels) may reflect higher asparaginase exposure and 7 SNPs. Moreover, we found that more sensitive ALL subtypes its possible contribution to osteonecrosis. Asparaginase has been (hyperdiploid and TEL-AML1) had lower ADSL expression than shown to increase the frequency of dexamethasone-induced osteone- more resistant subtypes (T-ALL), which is consistent with higher crosis in our murine model of the disorder. Therefore, we found larger cohorts and in cohorts of differing age groups are ongoing. We and others incorporate genetic testing of TPMT before initiation of thiopurines1 to minimize acute myelosuppression. This is the One of the most common adverse effects of asparaginase is allergy, only antileukemic agent for which the evidence is sufficient to with up to 40% of patients developing hypersensitivity to the most warrant clinical use of germline genetic variation at this time. Allergy to the drug is problematic because it often results in lower serum asparaginase concentrations and thus less-than-optimal asparagine Conclusions depletion. We performed a GWAS to determine whether there were Although GWAS have been effective for the discovery of multiple variants affecting de novo disease risk,28 the number of adequately inherited variations associated with allergy to Elspar (native E coli powered GWAS for pharmacogenomics is far fewer. Of the relatively small in sample size and are rarely precisely replicated, it top-ranked 100 SNPs associated with allergy in the discovery is not surprising that the conduct of adequately powered pharmacog- cohort, chromosome 5 was overrepresented, with 10 SNPs anno- enomic studies is challenging. Among these 10 SNPs, we replicated the association cohorts of patients who receive uniform chemotherapy via clinical of one SNP (rs4958381), in GRIA1 on chromosome 5q33, in the trials, so is well suited to continued genome-wide pharmacog- validation cohort. GRIA1 had an additional 4 SNPs that were enomic studies. We are continuing to perform GWAS in additional associated with asparaginase allergy (P. These data contribute to the growing clinical phenotypes. Whether different variants will be important for Acknowledgments allergy to alternative forms of asparaginase and in additional This work was supported by the National Institutes of Health (grants clinical settings is under investigation. U01 GM092666, CA142665, CA21765, CA36401, CA98543, and CA156449), the Leukemia & Lymphoma Society (grant 6168-12), Variants associated with osteonecrosis and the American Lebanese Syrian Associated Charities. Osteonecrosis is caused by glucocorticoids, but additional treat- ment- and host-related factors also play a role. To detect both Disclosures symptomatic and asymptomatic osteonecrosis, we prospectively Conflict-of-interest disclosure: M. We found that the cumulative incidence of declares no competing financial interests. Off-label drug use: None any (grade 1-4) or of symptomatic (grade 2-4) osteonecrosis was 26 disclosed. The covariates that we evaluated included age, race, sex, ALL treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinet- Correspondence ics, and genome-wide germline genetic polymorphisms. As ex- Mary Relling, PharmD, Pharmaceutical Sciences, MS313, Room pected, age 10 years (odds ratio: 4. We also found that the more intensive Place, Memphis, TN 38105; Phone: 901-595-2348; Fax: 901-525- treatment arm, which included more asparaginase and higher doses 8869; e-mail: mary. Hematology 2013 129 References genomics of relapse in acute lymphoblastic leukemia. Genome-wide association rine methyltransferase genotype and thiopurine dosing: 2013 study identifies germline polymorphisms associated with re- update. Germline genomic methotrexate polyglutamate accumulation in leukemia. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on variation in an organic anion transporter polypeptide associated 7p12. Healy J, Richer C, Bourgey M, Kritikou EA, Sinnett D. Excess of rare evaluated by Bayesian network based Bayesian multilevel variants in genes identified by genome-wide association study analysis of relevance. Novel susceptibility resistance and prognosis in newly diagnosed childhood acute variants at 10p12. Pharmacokinetic, pharma- with risk of acute lymphoblastic leukaemia in adults: a Group codynamic, and pharmacogenetic determinants of osteonecro- for Research on Adult Acute Lymphoblastic Leukaemia sis in children with acute lymphoblastic leukemia. Yang L, Boyd K, Kaste SC, Kamdem Kamdem L, Rahija RJ, phisms contribute to racial disparities in the incidence and Relling MV. A mouse model for glucocorticoid-induced osteo- treatment outcome of childhood acute lymphoblastic leukemia. Genomewide association studies and assessment of germline genetic variation associated with treatment re- of the risk of disease. The management of elderly patients with CLL is more complex than that of younger patients due to the greater frequency of comorbidities and functional impairment as well as reduced organ function.

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A correlation between improved sexual life and a quality-of-life questionnaire was also reported in this study order alfuzosin australia. These findings were supported by another trial of transdermal E2 that indicated improvement in 76 sexual problems and dysfunction as measured with the McCoy Sex Scale compared to placebo discount alfuzosin 10mg without prescription. Another trial of transdermal E2 indicated improvement in vaginal dryness cheap alfuzosin 10mg with visa, but not dyspareunia cheap alfuzosin american express, 96 frequent urination, dysuria, stress incontinence, and nocturia, compared to placebo. Another trial comparing transdermal E2 and placebo indicated no differences between groups for 73 symptoms of vaginal discomfort, loss of libido, and incontinence. There are two brief reports from one head-to-head study that measured sexual functioning and sexual quality-of-life in 186 women randomized to transdermal E2 or oral E2. One of these 97 98 is an abstract and the other a poster presentation. On some, but not all, measures of sexual function and sexual quality of life, there was more improvement in women who used transdermal E2 compared with oral E2. This study is not published in full-text form and the brief reports do not provide sufficient detail to assess quality. A trial of CEE reported significantly improved vaginal dryness and urinary frequency, but no significant improvement on six other items related to sexual function on a General Health 61 Questionnaire compared to placebo. The HERS trial found that women with at least one episode of incontinence per week at baseline who received CEE/MPA had worsening 99 incontinence after approximately 4 years of follow up compared to women taking placebo. The WHI reported on genital symptoms, as noted above under the section ‘Hot 81 flashes/flushes’. In Update #3, the ULTRA study found no differences between treatment with low-dose 30 39 transdermal estradiol on vaginal dryness or on urinary incontinence. There was a reduction in Hormone therapy Page 38 of 110 Final Report Update 3 Drug Effectiveness Review Project investigator-assessed vaginal atrophy, dryness, and friability for estradiol acetate compared with 37 placebo (p<0. A Cochrane systematic review compared efficacy and safety of intra-vaginal estrogen preparations (creams, pessaries, tablets, and estradiol-releasing ring) for the relief of symptoms 100 of vaginal atrophy (vaginal dryness, itching, discomfort, and painful sexual intercourse). Overall, the author concluded that the preparations appear to be equally effective for the symptoms of vaginal atrophy. CEE cream caused more side effects compared to estradiol tablets (uterine bleeding, breast pain, and perineal pain) or estradiol vaginal ring (endometrial overstimulation). For the comparison of the estradiol ring to CEE vaginal cream, there was no difference between groups in patient assessment of vaginal dryness or withdrawals due to adverse events, but there was more improvement in pruritis with the ring. For the comparison of estradiol ring versus estradiol tablet, vaginal dryness was improved more with tablets, but there was no difference between groups in genital pruritis or withdrawals due to adverse events. Symptom improvement was similar for tablet versus cream, but there were fewer withdrawals due to adverse effects with tablets compared with cream. There was no difference among all treatment comparisons for dysuria, nocturia, urgency, urge incontinence, participant symptom improvement in dryness, soreness, and irritation, loss of libido, and vaginitis. Quality-of-life A head-to-head comparison of CEE vs. A trial comparing oral E2 and intravaginal ring E2 found significant improvement on the Greene Climacteric Scale among 102 both treatment groups but no between-group differences. One trial of oral E2 conducted in HRT-naive women in Thailand observed no difference in mean Greene score 83 improvement compared with placebo after 12 months of treatment. A trial of low-dose oral E2 103 (1 mg per day) reported significant improvement from baseline at 6 and 12 weeks on six of nine domains of the Women’s Health Questionnaire (vasomotor symptoms, sexual behavior, depressed mood, somatic symptoms, anxiety/fear, and sleep problems). There was no difference between control and treatment groups on the memory concentration, menstrual symptoms, and attractiveness items of the scale. Seven trials of transdermal E2 and placebo indicated improved health related quality-of- life and well-being measured by various instruments: Nottingham Health Profile, Psychological General Well-Being Index, Women Health Questionnaire, Kupperman’s index, McCoy Sex 68, 70, 73, 74, 76, 96, 104 Scale, and psychological general well-being index. One trial indicated that women with high well-being and no vasomotor symptoms at baseline had no improvement with 105 treatment as measured by the Psychological General Well-Being Index. The HERS trial (CEE), using non-validated quality of life instruments (Duke Activity Status Index, RAND Mental Health Inventory, among others), found that quality of life scores were significantly lower among women who were older, had diabetes, hypertension, chest pain, 91 or heart failure, and that use of CEE had little effect. One trial found a significant decrease in 59 Kupperman’s index among women treated with E2V compared with placebo. A trial of Hormone therapy Page 39 of 110 Final Report Update 3 Drug Effectiveness Review Project esterified estrogens reported improvement in the Quality of Life Menopause Scale compared to 106 placebo. Health-related quality of life (HRQL) measures were collected on a subgroup of women 85 enrolled in the WHI randomized to CEE plus MPA or to placebo (n=16,608). Quality of life and functional status were assessed using the RAND 36-item Health Survey, which includes items about general health, physical functioning, limitations on usual role-related activities due to physical health problems, bodily pain, energy and fatigue, limitations on usual role-related activities due to emotional or mental problems, social function, and emotional or mental health. At 1-year follow-up, there were small but statistically significant positive effects of CEE/MPA on physical functioning (0. There were no differences from placebo in any other HRQL measure and by 3 years of follow-up (n=1511) there were no significant differences from placebo on any HRQL measure. Subgroup analyses detected no statistically significant interactions between baseline age, race, ethnicity, body mass index, or menopausal symptoms and HRQL. In a post hoc analysis of women 50 to 54 years of age who reported moderate-to-severe vasomotor symptoms at baseline, there was a positive effect on sleep disturbance, but no effect on other HRQL measures, despite significant improvement in vasomotor symptoms. At 1-year follow-up, there was a small positive effect of CEE on sleep disturbance (0. At 1- year follow-up of women who had moderate-to-severe vasomotor symptoms at baseline, 72. In a subsample (n=1,189) examined at 3-year follow-up there were no significant differences in any HRQL measure between treatment groups. For Update #3, none of the three new studies reporting HRQL or related outcomes showed significant effects between the treatment and placebo groups. The ULTRA study of 78 low-dose transdermal estrogen reported no significant improvements in the SF-36 subscales of 29 physical and mental function. The findings of Dayal and colleagues were similar in that conjugated equine estrogen did not improve vitality, general health status, or quality of life at 12- week follow-up. A third study of women over 70 years randomized to oral estradiol or placebo 26 also did not report significant changes in a “SF-36 score. What is the comparative effectiveness of different hormone therapy preparations when used by postmenopausal women or women in the menopausal transition stage for preventing low bone density and fractures? Outcomes include bone density measurements at lumbar spine, forearm, and hip sites and/or fracture data from one or more sites. Numbers of included studies are summarized in Table 7 below; trials are described in Evidence Tables 5 (head-to-head trials) and 6 (placebo- controlled trials), and quality ratings are presented in Appendix F. Quality ratings of studies added for Update #3 are shown in Appendix G. Hormone therapy Page 40 of 110 Final Report Update 3 Drug Effectiveness Review Project Table 7. Number of studies of estrogens with bone density or fracture outcomes Total Bone Density Fractures Head-to-head comparisons CEE and transdermal estradiol (E2) 3 3 0 Transdermal estradiol (E2) and estradiol 1 1 0 valerate (E2V) Placebo comparisons Estradiol (E2) Oral 16 16 1 Transdermal 15 15 2 Estradiol valerate (E2V) 5 5 1 Conjugated equine estrogen (CEE) 29 26 8 Conjugated synthetic estrogen 1 1 0 Esterified estrogen (EE) 1 1 0 Estropipate 0 0 0 Characteristics of the trials included: • Three trials with bone density outcomes compared estrogens head-to-head. Treatment refers to studies of women with pre-existing fractures or a diagnosis of osteoporosis at baseline. Bone density Head-to-head comparisons We identified no new head-to-head trials with bone density or fracture outcomes in this update. Four head-to-head trials compared different estrogen preparations, including three trials 108-110 of CEE compared to transdermal E2, and one trial of transdermal E2 compared to estradiol 111 valerate (Table 8 and Evidence Table 5). Hormone therapy Page 41 of 110 Final Report Update 3 Drug Effectiveness Review Project Table 8. Head-to-head trials with bone density outcomes Population Study/year Study design characteristics Interventions Main outcomes/results Oral CEE compared with transdermal E2 Castelo- Open label Postmenopausal CEE: 0. Oral CEE compared oral E2 Castelo- Blinding unclear Postmenopausal CEE: 0. N=73 Mean age 51 (45- days); E2V: 2 mg/day No significant differences between treatment 2 years 54 years) (11 days); groups at any site. In one trial, women using either CEE for 30 days or transdermal E2 for 25 days/month had an increase in lumbar spine 108 bone mineral content compared to placebo (CEE: +4. Use of CEE for 25 days/month did not show a significant change (+1. Similar results were 109 found when using these regimens in 118 women with prior hysterectomies. Increases in bone mineral density (BMD) occurred in all treatment groups after one year, and the increases did not differ significantly between the CEE and E2 groups. The addition of alendronate to either form of hormone therapy increased BMD significantly more than did 110 hormone therapy alone. One study of 73 healthy postmenopausal women age 45 to 54 years compared the effects 111 of oral E2 and E2V on forearm and spinal BMD.

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In recent years buy alfuzosin 10 mg with visa, 5-HT2a inhibitors and/or serotonin receptor antagonists have been proposed for PML treatment discount 10mg alfuzosin. It has been shown that the serotonergic receptor 5HT2AR could act as the cellular receptor for JCV on human glial cells (Elphick 2004); the blockade could represent a therapeutic goal order genuine alfuzosin. Case studies for some agents such as risperidone and mirtazapine buy generic alfuzosin 10mg on line, which block serotonergic receptors, exist already (Verma 2007, Focosi 2007+2008, Cettomai 2009). On the basis of in vitro efficacy (Brickelmeier 2009), mefloquine (a drug that has been used extensively for prophylaxis and treatment of malaria) was tested in a Opportunistic Infections (OIs) 379 clinical trial. In this study on 37 patients with PML, no evidence of anti-JCV activ- ity by mefloquine was found (Clifford 2013). Thus, it should be an absolute priority to optimize ART in cases of PML. Improvement of the JC virus-specific immune response which is often observed within immune reconstitution determines the patient’s further progress to a large extent (Khanna 2009, Marzocchetti 2007+2009, Gasnault 2011). Our early observation that prog- nosis significantly improved on ART (Albrecht 1998) was confirmed by several other groups (Clifford 1999, Dworkin 1999, Gasnault 1999+2008, Berenguer 2003, Khanna 2009). Since synergy between HIV and JCV has been demonstrated in vitro, maximal HIV suppression should be the goal. Although progression of disease has been described with sufficient antiretroviral therapy, ART often remains the only real hope for patients. There is also some evidence that intracerebral penetrating antiretrovi- ral agents such as AZT, FTC, abacavir, nevirapine and lopinavir are more efficient regarding survival of patients with PML (Gasnault 2008). There is one small pilot trial suggesting that an intensive 5-drug ART may improve survival of patients with PML (Gasnault 2011). Treatment/prophylaxis of PML Acute therapy Treatment of choice ART The most important goal is maximal HIV suppression and immune reconstitution! Use intracerebral penetrating agents such as AZT, FTC, abacavir, nevirapine and lopinavir Experimental Only within clinical trials (risperidone? HAART significantly improves the prognosis of patients with HIV-asso- ciated progressive multifocal leukoencephalopathy. Epidemiology and prognosis of AIDS-associated progressive multi- focal leukoencephalopathy in the HAART era. Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51 Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoen- cephalopathy in patients treated with highly active antiretroviral therapy. Predictive factors for prolonged survival in AIDS-associated progressive multifocal leukoencephalopathy. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Identification and characterization of mefloquine efficacy against JC virus in vitro. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. Human Herpesvirus 6 Infection of the Central Nervous System. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. HAART improves prognosis in HIV-associated progressive multi- focal leukoen-cephalopathy. A study of mefloquine treatment for progressive multifocal leukoen- cephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 2013 [Epub ahead of print] De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? Quantification of JC virus DNA in the cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy – a longitudinal study. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Incidence, clinical presentation, and outcome of progressive multifo- cal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nation- wide cohort study. Influence of HAART on the clinical course of HIV-1-infected patients with pro- gressive multifocal leukoencephalopathy: results of an observational multicenter study. Garcia De Viedma D, Diaz Infantes M, Miralles P, et al. JC virus load in progressive multifocal leukoencephalopathy: analysis of the correlation between the viral burden in cerebrospinal fluid, patient survival, and the volume of neurological lesions. Intracerebral penetrating ART are more efficient on survival of HIV+ patients with progressive multifocal leucoencephalopathy (ANRS CO4 – FHDH). Prolonged survival without neurological improvement in patients with AIDS-related PML on potent combined antiretroviral therapy. Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy. Failure of cytarabine in progressive multifocal leukoencephalopathy associ- ated with HIV infection. Progressive multifocal leucoencephalopathy with unusual inflam- matory response during antiretroviral treatment. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy. J Virol 2009, 83:4404-11 Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive mul- tifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Marzocchetti A, Sanguinetti M, Giambenedetto SD, et al. Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis. Determinants of survival in progressive multifocal leukoen- cephalopathy. Clinical manifestations and treatment with steroids. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. Evaluation of patients treated with natalizumab for progressive mul- tifocal leu-koencephalopathy. Opportunistic Infections (OIs) 381 Bacterial pneumonia Bacterial pneumonia occurs even with a relatively good immune status (>200 CD4 T cells/µl). It is not as closely associated with immunodeficiency. Furthermore, the decrease in incidence since the HAART era has been more moderate than for other opportunistic infections. Only recurring, radiologically and culturally detected acute pneumonia (more than one episode in the last 12 months) is considered AIDS-defin- ing. As with HIV-negative patients, community-acquired pneumonia should be distinguished from nosocomial pneumonia.

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Pre-malignant lesions of the cervix can be treated • If PID is suspected buy 10mg alfuzosin overnight delivery, a full course of appropriate with either cryotherapy buy alfuzosin 10 mg low cost, LEEP of cold knife coni- antibiotic treatment should be completed prior zation cheap alfuzosin 10 mg visa. In this chapter we describe them with indi- to any treatment (see Chapter 17 on STI) order generic alfuzosin on-line. If you want thorough • Whenever a woman is treated for a cervical in- knowledge about the subject you can download fection, with or without PID, her partner also the following publications for free: http://screen- needs to be fully treated to prevent reinfection. Condoms and instructions on their Indications for treatment use need to be provided to all such patients. All biopsy-confirmed CIN 2 and 3 lesions should The woman is HIV infected be treated, because the majority of them persist and may eventually progress to invasive cancer. CIN 1 HIV-positive women should be managed in the is more likely to resolve spontaneously; these same manner as uninfected women. However, 326 Cervical Cancer Prevention and Treatment HIV-positive women are known to have higher 1. Explain the procedure, and why it is important rates of persistence, progression and recurrence of to return for further management as requested. Women with HIV infection Ensure that the woman has understood and should therefore be monitored every 6 months obtain informed consent. Show her the cryotherapy equipment and ent, progressive or recurrent high-grade lesions are explain how you will use it to freeze the detected. At present there is no clear evidence on abnormal areas on the cervix. Prepare the patient for a gynecological exami- drugs modifies regression or progression of cervical nation, and perform a speculum. If there is no evidence of infection, proceed Before any treatment, HIV-positive women with cryotherapy. If there is a cervical infection, provide treat- understand the need for close follow-up, and the ment (see Chapter 17 about STIs). You may possibility of need for repeat treatments, as well as proceed with the cryotherapy, or you may give the potential for increased transmission and acquisi- the patient an appointment to return once the tion of STIs and HIV during healing. Wipe the cervix with a saline-soaked cotton swab and wait a few minutes. Apply acetic acid to outline the abnormality Treatment and wait a further few minutes. Tell the woman she might feel some discom- fort or cramping while you are freezing the Cryotherapy eliminates pre-cancerous areas on the cervix. Wipe the cryoprobe surface with saline to en- cedure takes about 15 min and can be performed sure optimum effectiveness. Apply the cryoprobe tip in the center of the os cooled metal disc (cryoprobe) to the cervix, and and make sure the probe adequately covers the freezing its surface using carbon dioxide (CO2) or lesion (Figure 9). The cryoprobe is applied beyond the probe, discontinue the procedure. Ensure that the vaginal wall is not in contact gas is preferred, but industrial-grade gas can be used with the cryoprobe or you may cause a freez- if that is what is locally available and affordable. Cryotherapy is highly effective for the treatment of 12. Set the timer and release the gas trigger to cool small lesions, but for larger lesions the cure rate is the probe. You will observe the ice forming on the tip of has very few nerve endings, cryosurgery is gener- the cryoprobe and on the cervix (Figure 9). Cryotherapy can be performed at all levels of the In some cases, the patient may have a vasovagal healthcare system by a variety of trained providers reaction, with fainting and plummeting blood (doctors, nurses, midwives) skilled in pelvic exami- pressure. If this happens, stop the treatment nation, and trained in cryotherapy as an outpatient immediately and raise the patient’s legs as much procedure. Allow two cycles of freezing and thawing: Performing cryotherapy 3 min freezing, followed by 5 min thawing, Before the procedure: followed by a further 3 min freezing. Once the second freezing is complete, allow (a) time for thawing before attempting to remove the probe from the cervix. Removing it before it is fully thawed will pull tissue off the cervix. Instruct the woman to abstain from intercourse and not to use vaginal tampons for 4 weeks, until the discharge stops completely. Provide condoms for use if she cannot abstain from intercourse as instructed. Teach her how Figure 9 (a) Position of cryoprobe on the cervix and ice to use them. Source: Compre- hensive cervical cancer control: a guide to essential 23. Invite her to return in 2–6 weeks to be checked 39 practice. Geneva: WHO, 2006 for healing, and again in 6 months for a repeat VIA, Pap smear and possible colposcopy. Either use a rubber cap to seal off the hol- her to return immediately if she notes: low part of the cryoprobe during process- a. Clean and disinfect the cryoprobe and de- air-dry and then reassemble. Perform a pelvic examination to check for and regulator by wiping them with alcohol healing 2–6 weeks after the cryotherapy. At 6 and 12 months, do a VIA, Pap test or a soap and water until visibly clean colposcopy and take a biopsy if necessary. Rinse the cryotip and plastic sleeve Indications and exclusion criteria for cryotherapy thoroughly with clean water are shown in Table 1. High-level disinfect the cryotip and plastic sleeve by one of the following methods: Loop electrosurgical excision procedure (1) boil in water for 20 min; or (2) steam for 20 min; or (3) soak in chemical disin- LEEP, also called large loop excision of the trans- fectant (0. It is critical that the hollow part of the cryo- produces a constant low voltage and transmits it to tip is completely dry when next used, other- a wire loop device, which is used to remove the wise the water will freeze and the probe abnormal tissue. The loops are of very fine stainless could crack or the treatment not work steel or tungsten wire and come in different sizes 328 Cervical Cancer Prevention and Treatment Table 1 Indications and exclusion criteria for cryotherapy Eligibility criteria Exclusion criteria Positive screening test for cervical precancer Evidence or suspicion of invasive disease or glandular dysplasia Lesion small enough to be covered by the cryoprobe with The lesion extends more than 2 mm beyond the cryoprobe no more than 2 mm beyond its edges edge The lesion and all edges fully visible with no extension into Pregnancy the endocervix or onto the vaginal wall PID (until treated) Active menstruation PID, pelvic inflammatory disease Table 2 Indications and exclusion criteria for loop electrosurgical excision procedure (LEEP) Eligibility criteria Exclusion criteria A positive diagnostic test for precancer Suspicion of invasive cancer or glandular dysplasia Lesion extending <1 cm into the endocervical canal Lesion extending >1 cm into the endocervical canal, or whose distal or upper extent is not visible (these lesions are treated by cold knife conization) Cervical infection or PID (until treated or resolved) Pregnancy or delivery within the last 12 weeks Bleeding disorders PID, pelvic inflammatory disease and shapes. LEEP aims to remove both the lesion and the entire transformation zone. The tissue re- moved can be sent for examination to the histo- pathology laboratory, allowing the extent of the lesion to be assessed. Thus, LEEP serves a double purpose: it treats the lesion, and at the same time, produces a specimen for pathological examination. The procedure also has the advantage that it can be Figure 10 Excision of an ectocervical lesion with one performed under local anesthesia on an out-patient pass. Source: Comprehensive cervical cancer control: a basis. It is successful in eradicating pre-cancer in guide to essential practice. LEEP is a relatively simple surgical procedure, Indications and exclusion criteria for LEEP are but it should be performed only by a well-trained given in Table 2. LEEP is best carried out in facilities Cold knife conization is the removal of a cone- where back-up is available for management of shaped area from the cervix, including portions of potential problems. In most resource-poor coun- the outer (ectocervix) and inner cervix (endo- tries, this will limit LEEP to second-level (district cervix). Conization is recommended for the treat- hospital) facilities. Videos of LEEP can be seen at ment of dysplasia when out-patient treatment is not 329 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS feasible or not accessible, and to rule out invasive pack and bladder catheter may be applied for cervical cancer. It takes less Management of complications of conization After cold than one hour. The patient may be discharged from knife conization, bleeding is the most common hospital the same or the next day. Because of pos- complication; it can occur immediately (primary sible side-effects, cold knife conization should be bleeding) or up to 14 days after the procedure reserved for cases that cannot be resolved with cry- (secondary bleeding). In either case, the patient otherapy or LEEP excision. The extent of the needs to return to the surgical facility. Secondary conization will depend on the size of the lesion and hemorrhage is usually related to local infection and, the likelihood of finding invasive cancer. The along with measures to stop the bleeding (like woman’s desire to have more children also has to suturing, vaginal packing, cauterization), treatment be taken into account, as conization may result in with antibiotics should be prescribed.

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