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However calcitriol 0.25 mcg without a prescription, these combinations will have to Hematology 2013 145 Figure 3 cheap 0.25mcg calcitriol otc. For this treatment approach order 0.25mcg calcitriol fast delivery, I propose the term “sequential triple-T” (tailored, targeted, total eradication of MRD) to illustrate that this future approach should be a sequence of tailored measures (according to the risk of the leukemia, the tumor burden, and the fitness of the patients), should use targeted agents (ie, using the novel nonchemotherapeutic agents with a mechanism of action targeting pathogenic signaling events of CLL cells and their microenvironment), and aim at the total eradication of the leukemic clone (as assessed by MRD negativity as a clinical end point). Please note that the drugs or classes of drugs in this figure are shown as examples. Similar agents of the same class or additional classes of drugs (see Table 1) may be used as well. Because most of the new agents either induce a be available for a few years. Moreover, such a treatment strategy compartment shift of malignant lymphocytes (eg, ibrutinib, idelal- will not be without toxicity and therefore will be tolerated only by isib), they transiently increase peripheral blood lymphocyte counts. This often causes concern in patients and physicians and prevents combination with some other drugs. Other agents (ABT-199, A second possibility would be to use sequential monotherapies of obinutuzumab, lenalidomide) often cause severe reactions during new or old agents. Each agent would be given until maximal the first treatment phase (cytokine release syndrome, tumor lysis response was achieved. Therefore, in cases with elevated lymphocyte counts could be repeated with the same agent, whereas alternative agents (above 30 000/ l) or large lymph nodes, a short debulking therapy would be used in case of short remissions. This strategy might be (eg, with 1 or 2 courses of bendamustine or fludarabine) might be an applied in elderly or nonfit patients (“slow go”), in whom the goal of optional first treatment element. Alternatively, nonchemotherapeu- treatment is symptom control rather than disease control. This step would be performed to rapidly clear the peripheral blood of CLL cells in the majority of patients. A third strategy would combine the best agents in a sequence that This treatment period would last 1 to 2 months. After reducing peripheral blood lymphocytes to This strategy would have the goal of preventing the outgrowth of levels below a certain threshold (eg, below 30 000 peripheral blood adverse leukemic subclones94 and minimizing the use of chemo- lymphocytes/ l), induction therapies could be initiated. These therapy, thereby reducing the risk for secondary mutations of the therapies would contain nonchemotherapy combinations of drugs. CLL clone(s) and for secondary malignancies that are frequent and To avoid infusion-related reactions, antibodies such as obinutu- prognostically unfavorable events in CLL. For this treatment zumab would be given first, followed a few days later by a third approach, I propose the term “sequential TTT (triple-T)” (tailored, class of drugs, such as a tyrosine kinase inhibitor or Bcl-2 inhibitor targeted, total eradication of MRD; Figure 3). This treatment period would typically last 4 to 6 months triple-T approach will make use of all of the currently available and the patient would be monitored at the end by MRD assessment 3 options in a nonaggressive, nontoxic way and will aim at the months after a CR is achieved. In general, this combination complete elimination or control of the malignant clone. The treatment during induction would last as long as the remission advantage of such an approach would be as follows: (1) it would be continues to improve or until a CR is achieved. At the end of this induction period, the third (3) it would use the current treatment options in a tailored and sequential element of the triple-T strategy will ensure that a very response-adjusted manner and therefore use the drugs in a cost- good remission is maintained. This could be achieved by giving effective, resource-saving way (Figure 3). It might also be used to single agents, either oral drugs (eg, kinase inhibitors, Bcl-2 inhibi- monitor the evolution of new genetic subclones in CLL that may tors, or lenalidomide) or repetitive infusions of antibodies (eg, have clinical and prognostic impact. This therapeutic approach would be monitored by MRD assessment The proposed sequential triple-T strategy might consist of the and treatment could be stopped 3 months after an MRD-negative following 3 steps (Figure 3): remission has been achieved and restarted in case of MRD 146 American Society of Hematology positivity. This treatment phase would last at least 1 year, but chronic lymphocytic leukemia. The Although I am fully aware that the proposed sequential triple-T microenvironment in mature B-cell malignancies: a target for strategy needs to be validated by clinical research, it may help to new treatment strategies. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. Finally, at a time when new and exciting therapeu- B-cell receptor signaling in chronic lymphocytic leukemia. CLL, hematologists and oncologists have the obligation to include 10. Emerging role of kinase-targeted strategies in their patients in clinical trials to ensure that maximal progress is chronic lymphocytic leukemia. Hematology Am Soc Hematol achieved in the shortest possible time. Targeting pathological B cell receptor so-far incurable disease such as CLL. Chemotherapeutic options This work is supported by the Deutsche Krebshilfe (German Cancer in chronic lymphocytic leukemia. Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil schaft (grants KFO 286 and SFB 832 and Center of Excellence grant R. Purine antagonists for chronic lymphocytic leukaemia. Multicentre prospective for carefully reading the manuscript; the team of the GCLLSG study randomised trial of fludarabine versus cyclophosphamide, office for giving important suggestions; Dr Gu¨nter Krause for doxorubicin, and prednisone (CAP) for treatment of advanced- generating Figure 2; and all of the patients and physicians participat- stage chronic lymphocytic leukaemia. The French Coopera- ing in the studies of the GCLLSG for their continuing support and tive Group on CLL [see comments]. Fludarabine compared with chlorambucil as primary therapy for chronic Disclosures lymphocytic leukemia.

If you unintended pregnancies including HIV-positive 11 integrate PMTCT activities and maternal health women generic calcitriol 0.25mcg visa. Here are some more examples of service inte- These services do not only share their clients cheap 0.25mcg calcitriol with mastercard, they gration from practical experience that merit a have common objectives as well: further look: • Safe delivery with knowledgeable generic calcitriol 0.25 mcg online, skilled • Infection prevention and control in the hospital. For • Involvement of the public and of patients (tradi- example, the weak point of many PMTCT pro- tional healers/birth attendants, religious leaders, grams is that the focus was put initially on the child, male partners). As a consequence referral of • Safe blood provision (from opportunistic dona- HIV-positive mothers to a CTC after delivery or tions to voluntary donations). ART often didn’t take place and the women were • Family planning services. Given the fact that, as mentioned above, the mortality of HIV-negative infants is higher when the mother is sick, this will diminish REFERENCES the benefits from PMTCT for the HIV-exposed 1. Nature 2001;410:868–73 facility you should assess additional activities you 3. For example, if you are planning HIV-infected mothers in Africa: a pooled analysis. Gynäko- living with HIV/AIDS and their children in resource- loge 1999;32:540–51 constrained settings. Sero-discordant couples in five African incidence of cervical cancer in women with HIV. Cancer countries: implications for prevention strategies. Int J Gyn Obst 2006; tion for HIV-1 serodiscordant couples. Curr Opin HIV AIDS 2009;4:52–6 Rakai Project Study Group. Medical Eligibility Criteria for N Engl J Med 2000;342:921–9 Contraceptive Use, 2010: Revised Recommendations 15. Probability of HIV-1 transmission Women at High Risk for HIV Infection or Infected per coital act in monogamous, heterosexual, HIV-1- with HIV. MMWR Morb Mortal Wkly Rep 2012;61: discordant couples in Rakai, Uganda. Global and encing complications of miscarriage and unsafe abor- regional burden of disease and risk factors, 2001: sys- tion: USAID’s postabortion care program. J Midwifery tematic analysis of population health data. Lancet 2006; Womens Health 2007;52:368–75 367:1747–57 10. Infect Dis Clin North Am 2008;22:709–39, vii HIV for surveillance and revised clinical staging and 11. Sexual and re- immunological classification of HIV-related disease in productive health of women living with HIV/AIDS. Geneva: WHO, 2007 Guidelines on care, treatment and support for women 211 . They affect 20–40% of those women1 but are found in contain receptors for female reproductive hor- 75% of hysterectomy specimens2. This is due to the mones (estrogen and progesterone) and other fact that most fibroids are asymptomatic. A true enzyme receptors related to estrogen production estimate of prevalence would need to be based (aromatase receptors). From ultrasound-based present in the fibroid, the growth of the fibroid will screening studies in the USA and Europe it is esti- be stimulated by these hormones. The cause of mated that women have a risk of 50–70% of suffer- fibroid development is not fully understood. Onset under cells of one fibroid are the same and different to the the age of 30 years is rare although not impossible3. Classification of fibroids fibroids tend to decrease in size or remain stable. They can A genetic pre-condition for developing fibroids grow to the interior part of the wall or completely seems to exist that differs by ethnicity. From studies under the serosa and become pedunculated with in the USA it is known that women of African only a thin bridge to the myometrium (Figure 1). They onset, bigger tumors and earlier symptoms than 3 are situated in the middle layer of the uterine caucasian or Asian women. Like the subserous fibroids, they can Fibroids can cause high morbidity and suffering become pedunculated and protrude into the when they grow and cause symptoms. As a matter of ureters, vessels and nerves and should only be fact every doctor will encounter patients with attempted by experienced surgeons. From ultrasound-based screening studies some risk factors could be established (level of evidence 2): • Age • African ancestry • Early age at menarche (first period) • Parity. These risk factors all deal with the already men- tioned exposure to female reproductive hormones and the duration of exposure. However, they don’t explain why some women with the same risk fac- tors which are fairly common, develop fibroids and others not, and why some fibroids start to grow and Figure 1 Locations of uterine fibroids others not. Observational studies from environ- mental health registers (level of evidence 3) have MAGNITUDE OF THE PROBLEM IN LOW- found some interesting new associations or absence RESOURCE SETTINGS of association: Not much is known about the true prevalence of • No association between smoking and fibroids. First, this is due to • No association between contraceptive pills and the above-mentioned fact that most fibroids are fibroids unless used before the age of 17 years. Second, some women may have sympto- • The association with raised body mass index matic fibroids but as a result of limited availability of (BMI) was inconsistent; no association was financial resources and healthcare they never reach found for caucasian women, but a slight but a healthcare provider for examination.

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Twenty-five years’ the parent protein; PEGylation may block potential inhibitory experience of prophylactic treatment in severe haemophilia A and B quality calcitriol 0.25mcg. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemo- new product discount calcitriol 0.25mcg with mastercard, there is the risk of higher rates of developing philia calcitriol 0.25 mcg cheap. These issues will only be resolved by planned clinical 6. White GC 2nd, Courter S, Bray GL, Lee M, Gomperts ED. The Recombinate Previously Recombinant FVIIa has not produced neutralizing antibodies in Treated Patient Study Group. Feldman BM, Pai M, Rivard GE, et al; Association of Hemophilia do not recognize the infused FVIIa as a foreign protein. Tailored prophy- pharmaceutical companies have development programs to generate laxis in severe hemophilia A: interim results from the first 5 years of the molecularly modified FVIIa proteins with either longer t1/2 or Canadian Hemophilia Primary Prophylaxis Study. The 2 programs with the most clinical trial data 2006;4(6):1228-1236. Magnetic resonance imaging and vative amino acid substitutions into native FVIIa. After no problems joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada. Musculoskeletal health of of neutralizing inhibitors. These results will need further investiga- subjects with hemophilia A treated with tailored prophylaxis: Canadian tion, but serve as a potential warning for programs based on Hemophilia Primary Prophylaxis (CHPS) Study. Barriers to compliance and the development of extended t1/2 factor products with promise to with prophylaxis therapy in haemophilia. Its marked increase in t1/2 for FIX is expected to allow less 12. Advances in care of children frequent infusions of factor, to allow higher factor trough levels so with hemophilia. Prophylactic dosing of factor VIII and factor IX from a on patients and economic burden of disease. A 6-year follow-up of associated virus vector-mediated gene transfer in hemophilia B. N Engl dosing, coagulation factor levels and bleedings in relation to joint status J Med. Weimer T, Wormsba¨cher W, Kronthaler U, Lang W, Liebing U, Schulte a first human dose trial in patients with hemophilia B. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Innovative coagulation factors: albumin fusion technology of IB1001, an investigational recombinant factor IX, in patients with and recombinant single-chain factor VIII. PROLONG-9FP clinical development program–phase I 17. Recombinant factor IX-Fc results of recombinant fusion protein linking coagulation factor IX with fusion protein (rFIXFc) demonstrates safety and prolonged activity in a recombinant albumin (rIX-FP). Safety and prolonged activity netic half-life of coagulation factors by fusion to recombinant albumin. Mahlangu J, Powell JS, Ragni MV, et al; A-LONG Investigators. Circulating and binding characteristics of with albumin (rIX-FP) in hemophilia B patients. Receptor-Fc fusion therapeutics, traps, and MIMETIBODY ment of polyethylene glycol. The tertiary structure and insights for longer-lasting and more effective therapeutics. Crit Rev domain organization of coagulation factor VIII. Strategies for extended serum half-life of protein 47. Lusson J, Vieau D, Hamelin J, Day R, Chre´tien M, Seidah NG. Rational design of a fully active, proprotein convertase expressed in endocrine and nonendocrine cells. Certolizumab pegol for the treatment of recombinant factor IX. Powell JS, Pasi KJ, Ragni MV, et al; B-LONG Investigators. FDA-approved poly(ethylene study of recombinant factor IX Fc fusion protein in hemophilia B. Ivens IA, Baumann A, McDonald TA, Humphries TJ, Michaels LA, efficacy and safety in previously treated patients with moderately severe Mathew P. PEGylated therapeutic proteins for haemophilia treatment: a to severe haemophilia B. Roth DA, Kessler CM, Pasi KJ, Rup B, Courter SG, Tubridy KL; 52. VWF contributes to longer half-life of Recombinant Factor IX Study Group. Human recombinant factor IX: PEGylated factor VIII in vivo. BAX 855, a PEGylated with plasma-derived factor IX concentrates.

If chemotherapy is indicated discount 0.25 mcg calcitriol mastercard, patients with non-small cell lung carcinoma (NSCLC) in otherwise good condition should receive standard therapy beginning with cis- or carboplatin plus either taxane (paclitaxel) cheap calcitriol 0.25mcg line, gemcitabine or navelbine purchase calcitriol 0.25 mcg on line. Carboplatin/ gemcitabine seem to be tolerated well (Bridges 2008). A second choice is pemetrexed or erlotinib, an inhibitor of epidermal growth factor receptor (EGFR) kinase. Preliminary data suggest an EGFR mutation status similar to that of the general pop- ulation (Okuma 2015). A large study recently found no significant difference in clinical outcome between HIV+ patients and uninfected controls with lung cancer. Survival after curative sur- gical resection in early-stage patients was similar. Thus, HIV status should not affect therapeutic decision making in lung cancer (Rengan 2012). HIV doctors should talk with and convince the oncologist not to expect the worst just because HIV-infection is involved and that HIV is not a contraindication for any drug. If general condition is poor, however, a well-tolerated combination of gemcitabine and navelbine can be given, which has been known to stop progression for a short time. References Alfa-Wali M, Allen-Mersh T, Antoniou A, et al. Chemoradiotherapy for anal cancer in HIV patients causes pro- longed CD4 cell count suppression. Colorectal cancer in HIV positive individuals: the immunological effects of treatment. A randomized, placebo-controlled, dose-escalation study to determine the safety, tolerability, and immunogenicity of an HPV-16 therapeutic vaccine in HIV-positive participants with onco- genic HPV infection of the anus. Risk factors for anal cancer in persons infected with HIV: a nested case- control study in the Swiss HIV Cohort Study. Screening colonoscopy for the detection of neoplastic lesions in asymptomatic HIV- infected subjects. Blazy A, Hennequin C, Gornet JM, Furco A, Gerard L, Lemann M, Maylin C. Anal carcinomas in HIV-positive patients: high-dose chemoradiotherapy is feasible in the era of HAART. High Rates of Endoscopic Findings and Histologic Abnormalities in Routine Colonoscopy of HIV Patients: German HIV Cohort. Changes in cancer mortality among HIV-infected patients: the Mortalité 2005 Survey. Phase II trial of gemcitabine/carboplatin followed by paclitaxel in patients with performance status=2,3 or other significant co-morbidity (HIV infection or s/p organ transplantation) in advanced non-small cell lung cancer. Lung Cancer 2008; 61:61-6 Bruyand M, Ryom L, Shepherd L, et al. Cancer risk and use of protease inhibitor or nonnucleoside reverse tran- scriptase inhibitor-based combination antiretroviral therapy: the D: A: D study. Cadranel J, Garfield D, Lavole A, Wislez M, Milleron B, Mayaud C. Lung cancer in HIV infected patients: facts, questions and challenges. Human immunodeficiency virus-associated adenocarci- noma of the colon: clinicopathologic findings and outcome. Chaturvedi AK, Pfeiffer RM, Chang L, Goedert JJ, Biggar RJ, Engels EA. Elevated risk of lung cancer among people with AIDS. HIV-associated squamous cell cancer of the anus: epidemiol- ogy and outcomes in the highly active antiretroviral therapy era. The impact of HIV viral control on the incidence of HIV-asso- ciated anal cancer. Lung cancer in the Swiss HIV Cohort Study: role of smoking, immun- odeficiency and pulmonary infection. Pattern of cancer risk in persons with AIDS in Italy in the HAART era. HAART slows progression to anal cancer in HIV-infected MSM. Causes of death in HIV-infected patients from the Cologne-Bonn cohort. Elevated incidence of lung cancer among HIV-infected individuals. Non-AIDS-defining Malignancies 451 Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980- 2002. Lung cancer in HIV patients and their parents: a Danish cohort study. Germ cell tumors in patients infected by the human immunodeficiency virus. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Association of cancer with AIDS-related immunosuppression in adults. HIV-associated bladder cancer: a case series evaluating difficulties in diagnosis and management. Goedert JJ, Purdue MP, McNeel TS, McGlynn KA, Engels EA.

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