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By I. Runak. Baylor University. 2019.

Pantoprazole versus omeprazole in one-week low-dose triple therapy for curve of H buy triamterene 75mg with mastercard blood pressure 9870. Effects of genetic differences in CYP2C19 status on cure rates of Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in comparison with dual omeprazole/amoxicillin therapy discount triamterene 75mg with amex blood pressure chart by weight. Comparison of rabeprazole-based four- and seven-day triple therapy and omeprazole-based seven-day triple therapy for Helicobacter pylori infection in patients with peptic ulcer generic 75 mg triamterene with visa arrhythmia upon exertion. A meta-analysis: comparison of esomeprazole and other proton pump inhibitors in eradicating Helicobacter pylori cheap 75mg triamterene with amex blood pressure diet. Systematic review: direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease Aliment Pharmacol Ther. Tindberg Y, Casswall TH, Blennow M, Bengtsson C, Granstrom M, Sorberg M. Helicobacter pylori eradication in children and adolescents by a once daily 6-day treatment with or without a proton pump inhibitor in a double-blind randomized trial. Effective maintenance treatment of reflux esophagitis with low dose lansoprazole. A randomized, double blind, placebo controlled trial. Daily omeprazole surpasses intermittent dosing in preventing relapse of oesophagitis: a US multi-centre double-blind study. Proton pump inhibitors Page 87 of 121 Final Report Update 5 Drug Effectiveness Review Project 209. Prevention of relapse of gastro-oesophageal reflux disease by lansoprazole: 30 mg every other day or 15 mg daily? Sontag SJ, Kogut DG, Fleischmann R, Campbell DR, Richter J, Haber M. Lansoprazole prevents recurrence of erosive reflux esophagitis previously resistant to H2-RA therapy. Omeprazole 10 mg or 20 mg once daily in the prevention of recurrence of reflux oesophagitis. Omeprazole in the long-term treatment of gastro-oesophageal reflux disease. Escourrou J, Deprez P, Saggioro A, Geldof H, Fischer R, Maier C. Maintenance therapy with pantoprazole 20 mg prevents relapse of reflux oesophagitis. Long-term prevention of erosive or ulcerative gastro-oesophageal reflux disease relapse with rabeprazole 10 or 20 mg vs. Caos A, Moskovitz M, Dayal Y, Perdomo C, Niecestro R, Barth J. Rabeprazole for the prevention of pathologic and symptomatic relapse of erosive or ulcerative gastroesophageal reflux disease. Esomeprazole once daily for 6 months is effective therapy for maintaining healed erosive esophagitis and for controlling gastroesophageal reflux disease symptoms: a randomized, double-blind, placebo- controlled study of efficacy and safety. The new proton pump inhibitor esomeprazole is effective as a maintenance therapy in GERD patients with healed erosive oesophagitis: A 6-month, randomized, double-blind, placebo-controlled study of efficacy and safety. Zacny J, Zamakhshary M, Sketris I, Veldhuyzen van Zanten S. Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients. Maintenance treatment of gastroesophageal reflux disease: an evaluation of continuous and on-demand therapy with rabeprazole 20 mg. Daily treatment with esomeprazole is superior to that taken on-demand for maintenance of healed erosive oesophagitis. Proton pump inhibitors Page 88 of 121 Final Report Update 5 Drug Effectiveness Review Project 222. Cibor D, Ciecko-Michalska I, Owczarek D, Szczepanek M. Optimal maintenance therapy in patients with non-erosive reflux disease reporting mild reflux symptoms--a pilot study. Six-month management of patients following treatment for gastroesophageal reflux disease symptoms -- a Norwegian randomized, prospective study comparing the costs and effectiveness of esomeprazole and ranitidine treatment strategies in a general medical practitioners setting. Long-term treatment of gastro-oesophageal reflux disease patients with frequent symptomatic relapses using rabeprazole: on-demand treatment compared with continuous treatment. Omeprazole vs ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Effects of pantoprazole 20 mg in mild gastroesophageal reflux disease: once-daily treatment in the acute phase, and comparison of on-demand versus continuous treatment in the long term. Current Therapeutic Research, Clinical & Experimental. Hansen AN, Bergheim R, Fagertun H, Lund H, Wiklund I, Moum B. Long-term management of patients with symptoms of gastro-oesophageal reflux disease -- a Norwegian randomised prospective study comparing the effects of esomeprazole and ranitidine treatment strategies on health-related quality of life in a general practitioners setting. A randomised prospective study comparing the effectiveness of esomeprazole treatment strategies in clinical practice for 6 months in the management of patients with symptoms of gastroesophageal reflux disease. Therapy for gastroesophageal reflux disease: more is not necessarily better. Richter JE, Fraga P, Mack M, Sabesin SM, Bochenek W, Pantoprazole USGSG. Prevention of erosive oesophagitis relapse with pantoprazole. Management of symptoms in step- down therapy of gastroesophageal reflux disease. Esomeprazole 40 mg administered intravenously has similar safety and efficacy profiles to the oral formulation in patients with erosive esophagitis. Boccia G, Manguso F, Miele E, Buonavolonta R, Staiano A. Maintenance therapy for erosive esophagitis in children after healing by omeprazole: is it advisable? Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial. Proton pump inhibitors Page 89 of 121 Final Report Update 5 Drug Effectiveness Review Project 235. Esomeprazole 20 mg compared with lansoprazole 15 mg for maintenance therapy in patients with healed reflux oesophagitis [abstract]. Pantoprazole therapy in the long-term management of severe acid peptic disease: clinical efficacy, safety, serum gastrin, gastric histology, and endocrine cell studies. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of lansoprazole: The US clinical trial experience. Leufkens H, Claessens A, Heerdink E, van Eijk J, Lamers CB. A prospective follow-up study of 5669 users of lansoprazole in daily practice. Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety.

General themes within the consensus guidelines include the role for radiation treatment as a monotherapy for early-stage disease order 75mg triamterene otc blood pressure near death, the value of large B-cell lymphoma–directed regimens for transformed disease purchase triamterene 75 mg overnight delivery heart attack protocol, the utility of rituximab for treatment of relapsed disease triamterene 75mg line blood pressure bottom number high, and triamterene 75mg cheap pulse pressure cardiovascular risk, in the pediatric setting, the role of surgical management alone for patients with early-stage disease. This the pathogenesis of NLPHL by establishing a method of microdis- pathologic entity was first described in 1944 by Jackson and Parker section of L&H cells from frozen tissue, which allowed for RNA as a paragranuloma histologic variant of HL. The disease was then later renamed by the World diffuse large B-cell lymphoma (DLBCL), and cHL, despite having Health Organization (WHO) in 2001 as NLPHL, which remains the differences in immunohistochemical expression from these diagno- diagnostic term used today. Contrary to previously held viewpoints, NLPHL was not found to have substantial gene expression profiling overlap with follicular Evolution of understanding of pathogenesis lymphoma. Supervised analysis confirmed these results and 49 Given the typical clinical behavior pattern of NLPHL as an indolent distinctive genes were identified as being reliably up-regulated in lymphoma, as well as the characteristic CD20 positivity of L&H L&H cells, allowing for the generation of a comparative profile of cells (Figure 1) with a lack of CD30 or CD15 positivity seen in cHL, NLPHL compared with cHL, normal B cells, and indolent B-cell it was long commonly viewed that NLPHL likely would have the non-Hodgkin lymphoma. L&H cells had overlap with germinal closest pathogenesis overlap with indolent B-cell non-Hodgkin center B cells as the point of transition to memory B cells. L&H cells also showed high- tumor mass, making up 1% of the overall tumor cells. It was level expression of NF- B activity and ERK activation. These known that both HRS and L&H cells arise from germinal center insights into the pathogenesis of NLPHL opened up future methods B cells, but determining the key differences in CD20, CD30, and that could be used for molecular diagnosis and therapeutic develop- CD15 expression was often challenging. We now know that, ment and highlighted that, although there can be clinical behavior compared with HRS cells, L&H cells express IgV genes, BCL6, and overlap between 2 lymphoma diagnoses, their underlying driving activation-induced cytidine deaminase; however, CD10 and CD19 biologic factors for growth can be very divergent. Images courtesy of Jeffrey Medeiros, MD, University of Texas MD Anderson Cancer Center. Additional distinguishing pathologic features of NLPHL have also indolent course with delayed relapses. SOCS1, which is known to control JAK2 activity, Group (GHSG) conducted a large, retrospective study of nearly 400 has been found to undergo somatic hypermutation (SHM) in patients and, as anticipated, the majority 79% had early-stage NLPHL, which can result in the activation of JAK2 in nearly 40% of disease. With a median follow-up of 50 months, the freedom from NLPHL cases via activation of the JAK2/STAT6 pathway. The mechanism NLPHL compared with cHL at, respectively, 88% versus 82% and leading to high NF- B activity in NLPHL has also been found to be 96% versus 92%, with early-stage patients having better outcomes different from that in cHL. In cHL, inactivating mutations occur compared with those with advanced-stage disease. In a small study, 80% of NLPHLs had mutations in 1 or knowledge of the pathogenic processes that drive NLPHL will open more of SHM targets, with PAX5 being the most frequently up further development of biologically targeted therapeutic options, affected. In addition, because this population of T cells was rarely seen in cHL or reactive lymphoid hyperplasia Early-stage disease without progressively transformed germinal centers, the presence of Although radiation as a single modality for treatment would be CD4 CD8 T cells might be useful in supporting a diagnosis of 15 considered inferior treatment for patients with early-stage cHL, NLPHL in cases in which there is limited tissue. More recent data from the British Columbia Cancer Agency described in siblings and now a total of 4 familial-associated cases (BCCA) suggests potentially improved outcomes for combined have been reported. CM treatment is typically considered for based review of data was reported and involved data collection of patients with stage IB or IIB disease, although the preferred regimen first-degree relatives from nearly 700 patients with NLPHL. This suggests benefit for the CD20-targeted monoclonal antibody rituximab, that potential as-yet unknown genetic or environmental factors are which was initially evaluated in relapsed NLPHL disease for influencing this familial incidence ratio and potentially could be patients with stage IA disease. Pediatric trials have shown excellent used to further develop and select therapies through improved results from surgical excisional biopsy-alone management for knowledge of the disease process. Multiple large, cooperative groups such as the The rarity of the diagnosis of NLPHL makes it very challenging to Australasian Radiation Oncology Lymphoma Group and the GHSG, accrue the numbers of patients needed to complete the same types of as well as smaller single-institution series including the Harvard large randomized trials that are done in cHL. Therefore, most of the Hospital group and our center, The University of Texas MD data that support management decisions comes from single-arm Anderson Cancer Center (UTMDACC), have reported excellent phase 2 and retrospective trials. Furthermore, overall NLPHL outcomes from radiation therapy (RT) alone. The Australasian compared with HL is generally characterized as having a more group described the potential of RT alone to cure NLPHL stage I Hematology 2013 407 Table 1. Comparative outcomes for early-stage NLPHL treatments Treatment Response rate Long-term outcomes Reference RT alone Median dose 36 Gy, mantle-field in 52% N/R 15-y FFP: 84% Stage I, 73% Stage II 26 15-y OS: 83% Median dose 40 Gy, LF in 78% N/R 5-y RFS: 95% Stage IA 27 5-y OS: 100% Stage IA Median dose 32 Gy, LF in 22%; median dose 36 Gy, regional-field N/R 10-y PFS: 89% Stage I, 72% Stage II 28 in 31%; median dose 38 Gy, EFRT in 41% 10-y OS: 96% Stage I, 100% Stage II EFRT dose of 30-40 Gy in 35%; IFRT dose of 20-40 Gy in 35% CR/CRu: 98% EFRT, 2-y FFTF: 100% EFRT, 92% IFRT 29 100% IFRT 2-y OS: 100% CM Median of 3 cycles of MOPP or NOVP 40 Gy N/R 10-y RFS: 68% 30 10-y OS: 100% ABVD or EBMV for 1-3 cycles followed by RT 30-40 Gy CR 97% 15-y FFP: 80% 32 15-y OS: 86% ABVD-like chemotherapy for 2 cycles followed by RT N/R 10-y PFS: 91% 24 10-y OS: 93% Chemotherapy alone CVP for 3 cycles CR: 94% Median follow-up: 12 mo 31 EFS: 94% OS: 100% Rituximab monotherapy Rituximab weekly for 4 wk ORR: 100% Median follow-up: 43 mo 35 CR: 86% OS: 100% 3-y PFS: 81% Rituximab weekly for 4 wk maintenance therapy every 6 mo ORR: 100% 10-y PFS: 35% 36 for2y CR/CRu: 63% 10-y OS: 76% Surgical excision alone Surgery alone CR: 86% Median follow-up: 43 mo 38 FFP: 67% OS: 100% Surgery alone CR: 100% Median follow-up: 26 mo 39 2-y EFS: 80% 2-y OS: 100% N/Rindicatesnotreported;andRFS,relapse-freesurvival. Complete remissions (CRs) occurred in 98% of patients received full mantle field irradiation. At 15 years of follow-up, the and outcomes were equivalent across the 3 treatment arms with the freedom from progression (FFP) was 84% in stage I and 73% in exception of patients included from the HD7 trial. Limited-field RT (LFRT) was delivered treated with EFRT plus IFRT alone, at 96% versus 83%, to 78% of the patients with a median dose of 40 Gy. The best outcomes were described in stage IA adding nonanthracycline chemotherapy to RT for early-stage pa- patients, who had a 5-year relapse-free survival of 95%. This study evaluated a large number were treated with RT alone versus CM therapy. The 23% of patients of patients relative to the incidence of this diagnosis and had a long who received the CM approach were treated with a median of 3 median follow-up of 11 years. A total of 93 patients received RT cycles of mechlorethamine, vincristine, procarbazine, and predni- alone, with 27% receiving LFRT, defined as IFRT or less than sone (MOPP) or with mitoxantrone, vincristine, vinblastine, and mantle or mini-mantle RT. A median dose of 40 Gy was given to both (PFS) was 85% for stage I and 61% for stage II with OS ratesof 94% treatment groups. Overall, MOPP or NOVP chemotherapy did not and 97%, respectively. PFS and OS were not statistically different improve relapse-free survival, with similar outcomes at 10 years of for those treated with LFRT, regional-field, or EFRT. However, by 77% and 68% for RT alone and CM treatments, respectively. Comparative outcomes for advanced-stage NLPHL treatments Treatment Response rate Long-term outcomes Reference cHL regimens HD6: COPP/ABVD 4 versus COPP/ABV/IMEP 4, CR/CRu: 78% Median follow-up: 50 mo; FFTF: 77%; 22 both 30–40 Gy RT; HD9: COPP/ABVD 4 versus OS: 96% baseline BEACOPP 8 versus escalated BEACOPP 8, all 30–40 Gy RT; HD12: escalated BEACOPP 8 versus escalated BEACOPP 4 baseline BEACOPP 4, all no RT versus 30 Gy RT ABVD or EVA vs MOPP or MOPP/ABVD N/R Relapse rate: 75% in ABVD or EVA versus 40 32% in MOPP or MOPP/ABVD B-cell lymphoma–directed chemotherapy R-CHOP ORR: 100%; CR: 92% Median follow-up: 43 mo; PFS: 100%; 42 OS: 100% N/R indicates not reported; COPP, cyclophosphamide, vincristine, procarbazine, prednisone; IMEP, ifosfamide, methotrexate, etoposide, prednisone; and BEACOPP, bleomycin,etoposide,doxorubicin,cyclophosphamide,vincristine,procarbazine,prednisone. From 2004 to 2006, 18 patients with stage IA or IIA maintenance therapy. Ten patients overall had relapse with 60% having biopsy- nisolone (CVP) with a CR rate of 94%. At a short follow-up of 12 documented transformation to DLBCL or TCR-BCL. Four of the 6 months, the event-free survival was 94%. The overwhelming majority of the data Leuce`mies et Autres Maladies du Sang (GOEL-AMS). Patients for this approach comes from the pediatric setting, where it is especially within their H81 and H90 trials received ABVD or epirubicin, desired to minimize exposure to RT and/or chemotherapy. Two initial bleomycin, vinblastine, methotrexate (EBVM) for 1 or 3 cycles reports were published for 19 children treated with surgical resection followed by RT. Of the 500 stage IA and IIA HL patients, 8% had alone in 2003, highlighting the potential benefits of this approach. Overall outcomes, including 15-year mortality rates, were Subsequent multicenter trials have confirmed the benefit of this very low at 2. The EuroNet-Paediatric Hodgkin Lymphoma Group (PHL) without mediastinal adenopathy; however, it is difficult to conclude evaluated outcomes for 57 pediatric patients. CR was achieved after superiority for CM over RT alone treatment in NLPHL patients surgery in 86% of patients, all with stage IA disease. At a median follow-up of 43 months, the this retrospective trial, stage IA/B or IIA patients who received RT estimated overall FFP was 67%. More than 60% had stage I disease and the 10-year of 52 patients with stage IA disease without bulky disease with surgical PFS showed favorable outcomes for CM treatment at 91% versus total resection alone. These investigators found a 17% relapse rate at a 65% and raised the question of whether all early-stage HL patients median of 10 months, with a 2-year estimated event-free survival of should be treated similarly. Although follow-up overall for both of these trials was relatively short, if these Rituximab monotherapy. Given the high levels of activity seen results remain durable, with longer follow-up, this would add further for the anti-CD20 antibody rituximab from trials conducted in the evidence to this as a potential curable treatment modality.

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In vivo vitro model of action and in vivo antithrombotic benefit triamterene 75 mg mastercard hypertension 15090. Thromb evidence for a role of factor XI as an anti-fibrinolytic factor order triamterene 75 mg on-line blood pressure eyes. Inhibition of warfarin in patients with mechanical heart valves discount 75mg triamterene blood pressure higher in one arm. Dabigatran and mechanical heart valves–not as easy as we 464-470 discount 75 mg triamterene with amex pulse pressure rate. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2–TIMI 51 biological evaluation of aryl boronic acids as potential inhibitors of Investigators. Rivaroxaban in patients with a recent acute coronary factor XIa. Tricoci P, Huang Z, Held C, et al; TRACER Investigators. Thrombin- product with selective recognition and irreversible inhibition of factor receptor antagonist vorapaxar in acute coronary syndromes. Morrow DA, Braunwald E, Bonaca MP, et al; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary XIa anticoagulant from the salivary gland of the vampire bat (Desmodus prevention of atherothrombotic events. Baeriswyl V, Calzavarini S, Gerschheimer C, Diderich P, Angelillo- formation following FeCl3-induced injury of the carotid artery in the Scherrer A, Heinis C. Development of a selective peptide macrocycle mouse. Effects of factor IX or factor XI antithrombotic therapy. Woodruff RS, Xu Y, Layzer J, Wu W, Ogletree ML, Sullenger BA. Inhibiting the intrinsic pathway of coagulation with a factor XII- 41. XII provides protection from pathological thrombosis in cerebral 59. Location of the disulfide bonds ischemia without interfering with hemostasis. Key1 1Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC Currently available evidence supports the contention that elevated levels of factor XI (fXI) are associated with a greater risk of venous thromboembolism and ischemic stroke, but, less convincingly, with myocardial infarction. Conversely, reduced plasma levels of fXI seem to offer some protection from venous thromboembolism and stroke, but not myocardial infarction. Factor XI-deficient patients are at risk for certain types of bleeding, particularly posttraumatic hemorrhage on mucosal surfaces where there is a high endogenous fibrinolytic activity. In contrast, the situation with fXII in human thrombosis remains enigmatic. Deficiency of fXII is clearly not associated with any bleeding risk, but neither does it seem to be protective against thrombosis. The longstanding debate as to whether partial fXII deficiency represents a risk factor for thrombosis remains unresolved, with seemingly conflicting results depending on study design, type of assay used, and analyte evaluated. The possibility that elevated fXII levels represent a risk factor for thrombosis is not borne out in the literature. The fact ● To understand that high levels of factor XI are associated with that even severe fXII deficiency is not associated with bleeding, thrombosis, but that the relationship between factor XII and whereas fXI deficiency of a more moderate degree is, provides thrombosis is not established compelling evidence for the existence of an alternative mechanism by which fXI is activated during physiological hemostasis. The discovery Introduction that thrombin fulfills this role was a milestone observation and led to a 1953 was a landmark year in the history of the intrinsic pathway of revised coagulation schematic in which hemostasis is initiated by tissue factor/fVIIa, with thrombin providing feedback activation of fXI. Rosenthal et al described a factor that, when deficient, was associated with a familial bleeding disorder. He noted Such a revised model adequately addresses the dichotomous bleeding that both sexes could be affected and that the abnormal clotting phenotypes in fXI and fXII deficiencies. In the In addition to its procoagulant function in the activation of fIX, fXIa same year, Brinkhous et al invented the partial thromboplastin time contributes to hemostasis by down-regulating fibrinolysis. This role (PTT) test,2 which was later modified by Rapaport to include a is mediated by activation of thrombin-activatable fibrinolysis inhib- kaolin activation step, which became the basis of today’s activated itor (TAFI), also known as plasma carboxypeptidase U. It makes intuitive sense, Rosenthal’s cases, these individuals had no abnormal bleeding therefore, that the typical bleeding manifestations in fXI-deficient history and the discovery of their defect was entirely serendipitous patients tend to be more pronounced at sites of enhanced fibrinolytic during presurgical screening. This defect was also shown to be activity, such as in the nasopharyngeal or genitourinary tracts. Further milestones, including the ous intraarticular or intramuscular bleeding that is seen in patients discovery of the last remaining “major” procoagulant, namely fX with hemophilia. Factor XII also participates in fibrinolysis; fXIIa, (“Stuart Prower factor”) in 1956,5 laid the groundwork for the via activation of pre-kallikrein, activates plasminogen and pro- waterfall or cascade models of blood coagulation proposed by 2 urokinase, and thus has a seemingly paradoxical role in promoting groups on either side of the Atlantic. The autoactivation of fXII after several other case reports and series of thrombotic events in contact with negatively charged surfaces was proposed to be the fXII-deficient subjects,11 led to a view that fXII deficiency is a initiating event that preceded activation of fXI, thereby providing an hypercoagulable state in humans. However, it was recognized quite early In addition to their roles in coagulation, the contact factors that deficiencies of fXII, high-molecular-weight kininogen or collaborate to generate bradykinin from high-molecular-weight 66 American Society of Hematology embolus, fXII / (heterozygote) animals were not. It also suggests that, in population studies, the phenotype of interest may only be manifest in severely deficient subjects. This distinction between outcomes in severe and moderate deficiency is indeed illustrated in epidemiologic studies of survival in subjects with fXII deficiency. In a large Austrian cohort of almost 9000 individuals who were initially screened for thrombophilia, all-cause mortality on follow-up was analyzed according to fXII activity (fXII:c) levels. Individuals with 100% fXII:c had an overall survival that was similar to the Austrian population; however, mortality increased with stepwise decreases in fXII levels, Figure 1. Protean roles of fXII and other contact factors in such that those with fXII:c levels in the 10%–30% range had more coagulation, inflammation, and fibrinolysis. Interestingly, however, the group with molecular-weight kininogen; and PK, prekallikrein. Many of these effects are further augmented by fXIIa-mediated activation of the classic complement pathway Furthermore, many factor deficiency states are clearly associated with (Figure 1). Recent animal studies have shown that not only fXI, but the predicted outcome(s); for example, although fVIII deficiency leads also fXII, may have a role in stabilizing platelet thrombi (reviewed by to bleeding, excessively high fVIII levels are a risk factor for van Montfoort and Meijers in a separate chapter in this publication). This is true regardless of the mutation causing the other words, separate from its formerly proposed role as an initiator of deficiency or excess. Conversely, the relationship between plasma coagulation, fXII may have a newly discovered function in propagating levels and phenotype for some coagulation factor defects are much less thrombus formation in vivo. Conceptually, because fXII is apparently predictable, as is the case with fibrinogen deficiency, in which severely dispensable for normal hemostasis, this paradigm challenges McFar- reduced levels may be associated with thrombosis as well as bleeding. These studies have included case- data and early human trials addressing this novel concept will be control and prospective cohort designs and are summarized in addressed by Gailani in a separate chapter in this publication. Relevance of animal data to humans Although recent data generated in animal models are intriguing, the VTE possibility exists that animal data fail to predict the situation in FXII humans. For example, although fXII / animals were protected John Hageman’s death from pulmonary embolism occurred 12 days from thrombosis in experimental models of stroke and pulmonary after he sustained pelvic fractures, during which time he was largely Table 1. Epidemiologic studies examining associations between fXII and VTE, ischemic stroke, and MI/coronary heart disease Association Study Subjects (n) Variable (assay) Outcome (yes/no) Comment Viennese15 51% male (8936) Low fXII (fXII:c) All-cause Yes “U”-Shaped curve mortality LETS19 Age 70 y (350) Low fXII (fXII:c) DVT No LITE20 Age 45 y (462) Low fXII (fXII:Ag) VTE No VTE also not associated with high fXII NPHS-II24 Males age 50-63 y at intake (2997) Low fXII (fXIIa-C1-INH) IS Yes RATIO25 Females age 18-50 y with IS (175) High fXII (fXIIa-C1-INH) IS Yes Risk further increased by OCPs RATIO34 Females age 18-50 y with IS (175) High fXII (fXII:Ag) IS No fXII:Ag not correlated with fXIIa-C1-INH ARIC26 Age 45-54 y at intake (15 792) High fXII (fXII:c) IS No Case-control within ARIC cohort NPHS-II29 Males age 50-63 y at intake (2997) High fXII (fXIIa:Ag) CHD Yes NPHS-II24 Males age 50-63 y at intake (2997) High fXII (fXIIa-C1-INH) CHD No RATIO25 Females age 18-50 y with MI (205) High fXII (fXIIa-C1-INH) MI No Low fXII-CI INH also not associated with MI RATIO34 Females age 18-50 y with MI (205) High fXII (fXII:Ag) MI No fXII:Ag not correlated with fXIIa-C1 INH SMILE30 Males age 70 y with MI (560) Low fXII (fXII:c) MI Yes Increased risk with high fXI:c ARIC33 Age 45-54 y at intake (15 792) High fXII (fXII:c) CHD No Case-control within ARIC cohort Thefulltitlesanddescriptionsofeachstudyareprovidedinthemaintext. Epidemiologic studies examining associations between fXI and VTE, ischemic stroke, and MI/coronary heart disease Association Study Subjects (n) Variable (assay) Outcome (yes/no) Comment Israeli22 Inherited fXI deficiency fXI:c 15% Protection against DVT Yes LITE20 Age 45 y (462) High fXI (fXI:Ag) VTE Yes LETS23 Age 70 y (350) High fXI (fXI:c) DVT Yes Israeli27 Inherited fXI deficiency fXI:c 15% Protection against IS Yes ARIC26 Age 45-54 y at intake (15 792) High fXI (fXII:c) IS Yes Case-control within ARIC cohort Yang28 Age 55 y with IS High fXI (fXI:c) IS Yes Retrospective study RATIO25 Females age 18-50 y with IS High fXI (fXIa-C1-INH; fXIa-AT INH) IS Yes Risk further increased by (175) OCPs RATIO34 Females age 18-50 y with IS High fXI (fXI:Ag) IS Yes (175) Israeli32 Inherited fXI deficiency fXI:c 15% Protection against MI No ARIC33 Age 45-54 y at intake (15 792) High fXI (fXI:c) CHD No Case-control within ARIC cohort SMILE30 Males age 70 y with MI High fXI (fXI:c) MI Yes Increased risk with low (560) fXII:c NPHS-II24 Males age 50-63 y at intake High fXI (fXIa-C1-INH; fXIa-AT INH) CHD No (2997) RATIO25 Females age 18-50, with MI High fXI (fXIa-C1-INH; fXIa-AT INH) MI No (205) RATIO31 Females age 18-50, with MI High fXI (fXI:c) MI No (205) RATIO34 Females age 18-50, with MI High fXI (fXI:Ag) MI No (205) The full titles and descriptions of each study are provided in the main text. C1-INH indicates C1 esterase inhibitor; AT-INH, 1-antitrypsin; CHD, coronary heart disease; and OCPs,oralcontraceptivepills.

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Second cheap triamterene 75 mg online blood pressure classification, there is a paucity of versus 61% purchase triamterene 75 mg visa arrhythmia in 5 year old, respectively cheap triamterene 75mg on-line blood pressure medication insomnia. The 2-year PFS for negative and positive data regarding the impact of epidemiologic variations on outcome cheap 75 mg triamterene fast delivery heart attack 25, end-of-treatment PET was 87% versus 51%, respectively. Although PFS Response to therapy as a means of risk stratification varied by the induction regimen (R-CHOP vs R-CVP), the investiga- Once a patient starts treatment, there are fewer data regarding risk tors proposed that a positive end-of-treatment PET portends an stratification. Intuitively, patients with a complete remission have aggressive disease because the median PFS, even in R-CHOP– better outcomes than those with partial remissions, stable disease, or treated patients, was only 22 months. While interesting, it should be progressive disease. A recently reported study of 536 patients noted that routine PET at the end of treatment in FL is not currently recommended by published guidelines. Prognosis is instead based on a clinical synthesis of study, including the era in which patients were treated (1980s- several factors, including number of prior regimens, assessment of 1990s) and the possibility that depth of response is simply a kinetic failure, and progressive decline of BM reserve. Nevertheless, because OS as a a long response duration from their frontline treatment and a lack of clinical trial end point in FL is not practical, long-term follow-up symptoms are often observed even with radiographic progression, 564 American Society of Hematology making the relevance of PFS results in clinical trials challenging in treatment and this issue remains unresolved in the current treatment practice. In terms of decision making, patients with a long time from era. On a positive note, FL remains a clinical challenge, with several parameters influencing the number of prior regimens is increasingly less useful in light of the overall disease course. A major challenge with risk stratification today’s armamentarium of biologic and targeted agents. The old in FL is that many of the above-mentioned biologic tools are paradigm is that increasing number of regimens is a surrogate for generally not validated in prospective settings and are not yet outcome, with duration of response progressively decreasing with commercially available. Furthermore, there is no instrument address- each line of therapy. However, this has changed in the current era in a comprehensive manner. As newer therapies emerge, older of targeted and biologic agents, when response to a second or third prognostic factors may become less relevant, and this review does treatment may actually exceed prior response durations. Therefore, not discuss predictive factors in the context of specific therapies. For the number of prior regimens in and of itself is a poor predictor of now, risk stratification at an individual level relies heavily on outcome. Instead of assessing the number of prior regimens, a more useful designation might be “rituximab-refractory,” which has crept into Disclosures the eligibility criteria of numerous recent and ongoing trials. This is Conflict-of-interest disclosure: The author has consulted for Mi- variably defined as lack of response or progression on rituximab cromet, Seattle Genetics, Celgene, Allos, Genentech, and Onyx. Regard- (including but not limited to BTK inhibitors and PI3K inhibitors) less of the precise definition, it is clear that as frontline management and approved agents in unapproved indications (including but not options improve, patients with relapsed disease or short response limited to lenalidomide). Examples include newer monoclonal antibodies that are promising in relapsed settings Correspondence but cannot overcome rituximab-refractory states as single agents. Smith, MD, Associate Professor, Section of Hematology/ Oncology, Department of Medicine, The University of Risk stratification in the relapsed setting has an unmet need for hard Chicago, 5841 S Maryland Avenue MC2115, Chicago, IL 60637; data to aid the clinician and to standardize evaluation of published Phone: 773-702-4400; Fax: 773-702-0963; e-mail: smsmith@ clinical trial results. Many of the genetic and epigenetic features medicine. Transformed FL (TFL) is variably defined but clinically refers to a 2. Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman shift from an indolent to a more aggressive lymphoma, with VL, Chrischilles E, Link BK. Improved survival of follicular histologic evidence of either DLBCL or other high-grade morphol- lymphoma patients in the United States. Swerdlow S, Campo E, Harris NL, eds; International Agency genase, and new onset of B symptoms being some of the prominent for Research on Cancer. Geneva, Switzerland: median survival between patients with a clinical versus biopsy- World Health Organization; 2008. The overall risk of TFL is approximately 3% per year, with a 5. Follicular lymphoma grade lifetime cumulative risk of 30% for patients with FL in excess of 10 3B is a distinct neoplasm according to cytogenetic and immuno- to 15 years. Predicting risk of transformation in individual patients histochemical profiles. Clinical significance of the unfavorable genetic and epigenetic events (BCL6 rearrangements, WHO grades of follicular lymphoma in a population-based TP53 loss, del 1p36, DNA copy number alterations),51-53 which, if cohort of 505 patients with long follow-up times. Br J present, raise suspicion and at the very least warrant closer Haematol. Transformation of found only advanced stage to be predictive, although all patients follicular lymphoma to diffuse large-cell lymphoma: alternative were from a pre-rituximab era. Similarly, a United Kingdom study patterns with increased or decreased expression of c-myc and found that, among 88 TFL patients (of 325 FL patients), advanced- its regulated genes. Acquired TNFRSF14 patients who were initially observed had a higher rate of transforma- mutations in follicular lymphoma are associated with worse tion than patients who were treated. High rate of TNFRSF14 Hematology 2013 565 gene alterations related to 1p36 region in de novo follicular for follicular lymphoma developed by the international follicu- lymphoma and impact on prognosis. Genome-wide profiling of ment for patients with indolent and mantle-cell lymphomas: an follicular lymphoma by array comparative genomic hybridiza- open-label, multicentre, randomised, phase 3 non-inferiority tion reveals prognostically significant DNA copy number trial. Frequent effective therapy in patients with rituximab-refractory, indolent mutation of histone-modifying genes in non-Hodgkin lym- B-cell non-Hodgkin lymphoma: results from a Multicenter phoma. Bendamustine in patients methylation profiling in follicular lymphoma. Hodgkin’s lymphoma: results from a phase II multicenter, 14. EZH2 codon 641 mutations a phase II study [abstract]. Blood (ASH Annual Meeting are common in BCL2-rearranged germinal center B cell Abstracts). Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, 16. The Follicular Lymphoma International Prog- follicular lymphoma based on molecular features of tumor- nostic Index (FLIPI) separates high-risk from intermediate- or infiltrating immune cells. Gene expression treated front-line with rituximab and the combination of profiling in follicular lymphoma to assess clinical aggressive- cyclophosphamide, doxorubicin, vincristine, and prednisone ness and to guide the choice of treatment. Phase II trial of immunohistochemical study of specific T-cell subsets and galiximab (anti-CD80 monoclonal antibody) plus rituximab accessory cell types in the transformation and prognosis of (CALGB 50402): Follicular Lymphoma International Prognos- follicular lymphoma. Implications of the tumor microenvironment on responsiveness. Taskinen M, Valo E, Karjalainen-Lindsberg ML, Hautaniemi usefulness of the Follicular Lymphoma International Prognos- S, Meri S, Leppa S. Signal transducers and activators of tic Index to predict the outcome of patients. Examination of the of patients with improved outcome after R-CHOP. Clin Cancer follicular lymphoma international prognostic index (FLIPI) in Res. Prognostic patient cohort treated predominantly in community practices. R-CHOP Versus R-FM for the Initial Treatment of Patients 22. Impact of the tumor With Advanced-Stage Follicular Lymphoma: Results of the microenvironment on prognosis in follicular lymphoma is FOLL05 Trial Conducted by the Fondazione Italiana Linfomi. The composition of the for 2 years in patients with high tumour burden follicular microenvironment in follicular lymphoma is associated with lymphoma responding to rituximab plus chemotherapy the stage of the disease.

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Otherwise order triamterene 75mg on-line prehypertension risks, for adverse event withdrawals and insomnia triamterene 75mg lowest price pulse pressure 63, differences between methylphenidate OROS and placebo did not consistently reach statistical significance cheap triamterene 75 mg with visa blood pressure medication edarbyclor. Adverse events in placebo-controlled trials of methylphenidate OROS Author Adverse event Decreased Year Weeks Mean dose withdrawals appetite Insomnia Reimherr 228 18-90 mg daily 12% vs discount 75 mg triamterene with amex pulse pressure 2013. Attention deficit hyperactivity disorder 82 of 200 Final Update 4 Report Drug Effectiveness Review Project Sustained-release methylphenidate 231-234 We included 4 fair-quality trials of sustained-release methylphenidate. Three of the trials 233 231 focused on subgroups of adults who were methadone-maintained cocaine-dependent or 234 amphetamine abusers and results from these will be discussed in Key Question 3. Methylphenidate transdermal system No data was available regarding the adverse event profile of methylphenidate transdermal 235 system, as the single included placebo-controlled trial was rated poor quality. Modafinil No data was available regarding the adverse event profile of modafinil in adults with ADHD, as 236 analysis of harms was not reported in the single included placebo-controlled trial. What is the evidence of serious adverse effects associated with use of pharmacologic treatments for attention deficit disorders? Evidence on the long-term safety of drugs used to treat ADHD 210, 245-275 We included observational studies for analysis of long-term safety parameters. Suicide Atomoxetine Two analyses indicate an increased risk of suicidal ideation and behaviors with use of atomoxetine in the short term, and a third analysis indicates a potential for this risk to be increased with longer duration of therapy. Using data on file from all clinical trials of atomoxetine in children, the manufacturer conducted an independent meta-analysis of suicidal-related behavior in response to requests from 245 the US Food and Drug Administration and other organizations. Based on 12 short-term clinical trials in children with ADHD or enuresis, 1357 children taking atomoxetine were compared with 851 taking placebo (6 to 18 week trials), finding an increased risk of suicidal ideation (n=5) or suicidal behaviors (n=1) in those taking atomoxetine; 0. No suicidal-behavior events occurred in the placebo groups, such that the risk difference between the groups was statistically significant (Mantel-Haenszel Incidence Difference, 0. Time to onset of suicidal-related behavior was 9 to 32 days. All children experiencing suicidal-related behaviors were boys, ages 7-12, and 2 of 6 (33%) were African American – whereas the proportion of African American children in these studies was 12%. Analysis of data from 2 trials comparing atomoxetine to methylphenidate found 1 case of suicidal ideation in each group (atomoxetine or methylphenidate), with no significant difference. Prior to this analysis, a US Food and Drug Administration analysis of the same data also found an increased risk, but identified 1 case as a suicide attempt and identified 1 fewer case of suicidal behavior overall. Atomoxetine was associated with significantly higher risk of suicidal ideation than placebo: 0. Suicide attempts were slightly higher Attention deficit hyperactivity disorder 83 of 200 Final Update 4 Report Drug Effectiveness Review Project 245 with atomoxetine; 0. A subsequent black box warning is included in Appendix B. A higher rate was found in an analysis of children taking atomoxetine for at least 3 148 years. Based on data from 2 extension studies and 3 open label studies, 2% (14 of 714) experienced suicide-related outcomes (11 suicidal ideation, 2 suicide attempts, and 1 suicidal behavior). These events occurred as early as 234 days and as late as 5. Because there was no control group for this analysis, and because much of these data came from extension studies where some level of selection bias exists, these findings must be viewed as suggestive only. Other drugs A single before-after study followed 8 adult males (mean age of 27. A retrospective cohort study based on the GPRD database in the United Kingdom (N=5351) found an increased risk of suicide among children and teens taking methylphenidate or 273 amphetamine in comparison with population normative data. The standardized mortality ratios were for children age 11 to 14, 161. This finding was based on a post-hoc analysis, a very small number of events, was not able to adjust for potential confounding, and should be interpreted with caution. Cardiovascular deaths and events Three retrospective cohort studies evaluated cardiovascular cardiac death (e. The largest study evaluating cardiac death in children included 241 417 incident (new) users of ADHD medications (specifically, amphetamines, methylphenidate, and atomoxetine) 274 and evaluated only validated cases of sudden death or ventricular arrhythmia. Estimates for risk of sudden death or ventricular arrhythmia associated with methylphenidate current use compared with never use was elevated but not statistically significant, with a wide confidence interval (hazard ratio, 2. Risk with use of any of the 3 types of medication was lower but also not found to be statistically significantly elevated (hazard ratio, 1. Unfortunately, this study did not make direct comparisons among the different drugs, but the crude incidence rates per 10 000 person years was higher in methylphenidate users (hazard ratio, 0. This study also examined cardiovascular outcomes such as stroke, myocardial infarction and composite outcomes. For all of these outcomes the hazard ratios were less than 1, indicated a reduced risk with exposure to the ADHD medication, but again the confidence intervals indicated a nonstatistically significant finding. Only “nonaccidental death” resulted in a (barely) statistically significant lower risk among users of any ADHD medication compared with nonusers (hazard ratio, 0. In a much smaller study based on the GPRD database in the United Kingdom, 5321 patients (age 2 to 21 years) who had received at least 1 Attention deficit hyperactivity disorder 84 of 200 Final Update 4 Report Drug Effectiveness Review Project prescription for methylphenidate, dexamphetamine, or atomoxetine, 7 deaths occurred and none 273 were deemed to be caused by “sudden death”. A good-quality retrospective cohort study based on 10 years of Florida Medicaid claims data and the Vital Statistics Death Registry data identified 55 383 patients with newly diagnosed 251, 275 ADHD. Of these, 32 807 had used a stimulant (either currently or formerly) and 22 576 had never used a stimulant medication. Of 73 children who died over the study period, 5 died of circulatory causes (4 per 100 000 person-years); none of these were sudden cardiac death and numbers were too small to make reliable comparisons among groups. Emergency department and physician office visits due to cardiac causes occurred significantly more often in the group currently using a stimulant compared with non-users (hazard ratio, 1. Former use of stimulants was not significantly associated. Comparison of current users of methylphenidate products to those currently using amphetamine products showed no statistically significant difference in the rate of emergency department visits for cardiac reasons (hazard ratio, 1. Comparison of former use of these products also resulted in a nonsignificant finding. In a good-quality case-control study, children (ages 7 to 19) who had died from “sudden unexplained death” during the years of 1985 to 1996 were identified from state vital statistics 276 from each of the 50 United States. A control group was selected from children who died from motor vehicle traffic accidents, with 1:1 matching resulting in 564 in each group. The exposure was defined as stimulant use immediately prior to death, based on survey of parents. Sensitivity analyses altering the way exposure was identified or removing children also taking a tricyclic antidepressant did not meaningfully alter the results. Recall bias is the greatest risk in this study, as the time since the child’s death to the survey of the parent was longer in the sudden death group (13 years) compared with the motor vehicle death group (10 years). In a fair-quality retrospective cohort database study, the risk of stroke or transient ischemic attack was compared in adults taking initiating atomoxetine or stimulant therapy for ADHD/ADD (N=42 993). Using propensity score matching and only validated cases of stroke or transient ischemic attack, no statistically significant difference was found between the drugs for either outcome (relative risks, 1. Overall the numbers of cases were small, limiting the ability to determine statistically significant differences if they were to exist. Blood pressure, pulse, electrocardiographic changes Lisdexamfetamine. Three trials of lisdexamfetamine 30, 50, or 70 mg daily compared with placebo reported various intermediate outcome measures of cardiovascular function. Small increases in blood pressure and heart rate were seen in all 3 studies, with none being deemed clinically important. A small, open-label, uncontrolled 11-month study of lisdexamfetamine in 272 children did not find any cases of “clinically relevant” changes in blood pressure or 277 electrocardiographic parameters.

It is itself crossed here by the left superior intercostal (T5–10) effective 75 mg triamterene blood pressure numbers what do they mean, lesser splanchnic (T10–11) and lowest splanchnic (T12) purchase triamterene 75mg without a prescription arteria en ingles. Below 75mg triamterene free shipping hypertension hereditary, it descends behind the lung root to reach the oesophagus They lie medial to the sympathetic trunk on the bodies of the thoracic where it contributes to the oesophageal plexus mentioned above (see vertebrae and are quite easily visible through the parietal pleura buy 75mg triamterene with visa blood pressure medication how long to take effect. The cardiac plexus Vagal branches This plexus is for descriptive purposes divided into superficial and deep • The left recurrent laryngeal nerve arises from the left vagus below parts. It consists of sympathetic and parasympathetic efferents as well the arch of the aorta. It hooks around the ligamentum arteriosum and as afferents. The nerves of the thorax 25 10 Surface anatomy of the thorax Cervical plexus 2 2 4 4 Cardiac notch of lung Transverse fissure 6 6 Oblique fissure Costodiaphragmatic recess 8 8 10 10 Apex of lower lung Oblique fissure 6 Beginning of transverse fissure 8 Costodiaphragmatic recess Fig. The areas of auscultation for the aortic, pulmonary, mitral and tricuspid valves are indicated by letters 26 Thorax The anterior thorax pleura passes laterally for a small distance at the 4th costal cartilage and Landmarks of the anterior thorax include: descends vertically lateral to the sternal border to the 6th costal cartil- • The angle of Louis (sternal angle): formed by the joint between the age. From these points both pleurae pass posteriorly and in so doing manubrium and body of the sternum. It is an important landmark as the cross the 8th rib in the mid-clavicular line, the 10th rib in the mid- 2nd costal cartilages articulate on either side and by following this line axillary line and finally reach the level of the 12th rib posteriorly. The sternal angle corresponds to a horizontal point level with the inter- The lungs (Fig. The apex and mediastinal border of the right lung follow the pleural • The suprasternal notch: situated in the midline between the medial outline. In mid-inspiration the right lung lower border crosses the 6th ends of the clavicles and above the upper edge of the manubrium. The left lung borders are the 7th, 8th, 9th and 10th ribs and the ends of the 11th and 12th ribs. The oblique fissures separate the lungs into upper • The first palpable spinous process is that of C7 (vertebra prominens). C1–6 vertebrae are covered by the thick ligamentum nuchae. The • The transverse fissure: is represented by a line drawn horizontally spinous processes of the thoracic vertebrae can be palpated and counted from the 4th costal cartilage to a point where it intersects the oblique in the midline posteriorly. The fissure separates the upper and middle lobes of the right • The scapula is located on the upper posterior chest wall. The heart • The borders of the heart are illustrated by joining the four points Lines of orientation shown (Fig. These are imaginary vertical lines used to describe locations on the • The apex of the left ventricle corresponds to where the apex beat is chest wall. The surface marking for the apex beat is in the 5th intercostal • The mid-clavicular line: a vertical line from the midpoint of the clav- space in the mid-clavicular line. The great vessels •Themid-axillary line: from the midpoint between anterior and poster- • The aortic arch: arches antero-posteriorly behind the manubrium. The highest point of the arch reaches the midpoint of the manubrium. Palpable bony prominences can be used to identify the location of • The brachiocephalic veins: are formed by the confluence of the inter- important underlying structures. The following bony landmarks and nal jugular and subclavian veins. This occurs posterior to the sterno- their corresponding vertebral levels are given: clavicular joints. The breast • Subcostal plane (lowest part of the costal margin): L3. The position of the nipple is variable The trachea in the female but in the man it is usually in the 4th intercostal space in The trachea commences at the lower border of the cricoid cartilage (C6 the mid-clavicular line. It runs downwards in the midline and ends slightly to the right by bifurcating into the left and right main bronchi. The bifurca- The internal thoracic vessels tion occurs at the level of the sternal angle (T4/5). These arteries and veins descend 1 cm lateral to the edge of the sternum. The lines of pleural reflection pass behind the sternoclavicu- In mid-inspiration the highest part of the right dome reaches as far as lar joints to meet in the midline at the level of the sternal angle. The the upper border of the 5th rib in the mid-clavicular line. The left dome right pleura then passes downwards to the 6th costal cartilage. The left reaches only the lower border of the 5th rib. Surface anatomy of the thorax 27 11 The abdominal wall Serratus anterior Cut edge of external oblique Linea alba Linea semilunaris Cut edge of external oblique Internal oblique Fig. Internal oblique A: above the costal margin Inferior B: above the umbilicus epigastric Transversus abdominis C: above the pubic symphysis artery Peritoneum 28 Abdomen and pelvis (a) External oblique aponeurosis Superficial ring Ilioinguinal nerve Femoral artery and vein in Spermatic cord femoral sheath Femoral canal (b) Testicular artery and Transversus pampiniform plexus of veins Position of deep ring Vas deferens Lymphatics Internal oblique Transversalis fascia Internal spermatic Position of fascia superficial ring Cremasteric fascia and Femoral artery and vein in muscle (striated) femoral sheath Femoral canal External spermatic fascia Fig. A schematic cross section through the spermatic cord (a) The superficial inguinal ring. The external spermatic fascia has been removed (b) After removal of the external oblique Internal thoracic Anterior cutaneous branches of Musculophrenic intercostal nerves T7 Superior epigastric T10 T12 Lumbar Iliohypogastric (lateral branch) Para-umbilical veins Iliohypogastric anastomose with (anterior cutaneous) epigastric veins Ilioinguinal Fig. The two lower intercostal and four lumbar arteries supply the extraperitoneal fat, and parietal peritoneum. The lateral lower six thoracic intercostal and iliohypogastric (L1) nerves. The canal passes obliquely from the deep inguinal ring brane. The fibrous fascial layer is in a medial direction to the superficial inguinal ring. It lies half- way between the anterior superior iliac spine and the pubic tubercle. These comprise: external oblique, internal oblique, transversus abdo- • The superficial ring: is not a ring but a triangular-shaped defect in minis, rectus abdominis and pyramidalis (see Muscle index, p. It contains also the super- • Superior: internal oblique arches posteriorly to form the roof of the ior and inferior epigastric vessels and anterior rami of the lower six canal. The conjoint tendon (the combined common insertion of the inter- anterior abdominal wall. The linea alba represents the fusion of the nal oblique and transversus into the pectineal line) forms the medial aponeuroses in the midline. Throughout the major part of the length of part of the posterior wall. The composition of the sheath Contents of the inguinal canal is, however, different above the costal margin and above the pubic • The spermatic cord (or round ligament in the female). These are the: rectus muscle, leaving only the transversalis fascia. The lateral border of the rectusathe linea semilunarisacan usually • Cremasteric fascia and muscle: from the internal oblique be identified in thin subjects. It crosses the costal margin in the trans- aponeurosis. Three tendinous intersections firmly attach the anterior sheath wall The contents of the spermatic cord include the: to the muscle itself. They are situated at the level of the xiphoid, the • Ductus (vas) deferens (or round ligament). These give the abdominal ‘six- • Testicular artery: a branch of the abdominal aorta.

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Blood (ASH Annual Meeting Ab- Annual Meeting Abstracts) buy triamterene 75mg line pulse pressure stroke volume. The specific definitions of high-risk ALL vary across cooperative groups purchase 75 mg triamterene blood pressure healthy range, but the themes are consistent buy triamterene 75 mg lowest price arterial stenosis, being largely based on leukemia biology and disease response discount triamterene 75mg amex 5 fu arrhythmia. Intensification of conventional chemotherapy for those with high-risk disease has led to improved outcomes. It is anticipated that the development of rational targeted therapy for specific biologically unique subsets of children with leukemia will contribute to ongoing progress in improving the outcomes for children with acute lymphoblastic anemia. Learning Objectives History of risk stratification in ALL The importance of understanding why certain patients are cured of ● To understand current criteria used to identify children with their disease and others are not has been an integral part of the high-risk ALL development of ALL therapy. Reporting in the Journal of the ● To understand therapeutic strategies for children with high- American Medical Association in 1966, Sidney Farber described 15 risk ALL long-term survivors from the initial group of 1445 pediatric patients with ALL treated with chemotherapy. He notes, “it is still impos- Introduction sible to differentiate, at the time of diagnosis, the 99% whose lives The chance of successful treatment for a child or adolescent with will be prolonged by months or one or 2 years and the 1% who acute lymphoblastic leukemia (ALL) has improved dramatically will survive 5 years of longer. In the early 1990s, the 4 cooperative 75% by the 1980s. The majority of the improvement in groups running clinical trials in pediatric ALL in North America all outcomes in the last several decades can be attributed to used risk definitions that included age and WBC, but all used modifications of the use of these original components and, to different cutoff points for these continuous variables. The need to be some extent, to intensifying therapy for those patients identified as having disease that is more difficult to cure. In this brief able to compare and apply results across studies lead to a consensus review, contemporary criteria used to identify patients at higher conference in 1993 leading to the creation of the National Cancer risk of relapse and the utility of intensification of therapy based Institute (NCI) criteria defining high-risk patients with B-precursor on this risk are reviewed. ALL as those 10 years of age or older or those having a presenting WBC count of 50 000/ L or greater. For the purposes of care of a risk groups in contemporary trials can be divided into 3 child with newly diagnosed ALL, the future event is relapse of categories: the patient’s clinical features at the time of diagnosis, disease and past experience is largely generated from data from cooperative clinical trials. Risk classification is important for the disease characteristics, and measurements of initial response determining the average outcome for a group and for determining to therapy. Risk classification is not the same as being able to predict an individual’s experience. Within the Children’s Oncology Group (COG), patients with ALL are currently classified into 7 different groups including infants, For the care of patients with ALL, the ideal risk classification those with Philadelphia chromosome-positive (Ph ) disease, and system uses factors that are simple to measure and therefore easily those with T-ALL. The classification of the remainder of children generalizable and are able to be determined at the time of diagnosis with precursor B-ALL into 4 additional groups is described in Table or early on during the treatment course. Factors used to define the risk group of children with ALL by for risk-adapted therapy with treatment modifications made that other cooperative groups in contemporary clinical trials are similar may affect the likelihood of success. COG classification of newly diagnosed B-precursor ALL (adapted from the COG classification system for B precursor ALL, AALL08B1)86 Low risk Average risk High risk Very high risk NCI risk (age/WBC) SR SR SR SR SR HR (age 13 y) SR HR HR (age 13 y) SR or HR Favorable genetics Yes Yes No Yes No Any No Any Any Any Unfavorable None None None None None None None None None Yes characteristics d8PBMRD 0. Unfavorable characteristics: CNS2, induction failure, age 13 y and older, hypodiploid( 44chromosomesorDNAindex 0. Clinical features Patients meeting the criteria of CNS 3 (having 5 WBCs/ Linthe Age at diagnosis remains an important predictor of risk of relapse. CSF with blasts in the cytospin) and, at least within the context of Excluding infants, older age is consistently associated with a worse some studies, those with initial traumatic lumbar punctures with outcome, which can be explained in large part by variations in the blasts ( 10 RBCs/ L) have an inferior event-free survival (EFS). A smaller proportion of older Presence of CNS disease at the time of diagnosis is associated with children and adolescents with ALL have favorable cytogenetic other adverse prognostic factors. MLL gene rearrangement, found in 75% and in the majority of younger infants. In addition, months of age at the time of diagnosis, Gender and ethnicity have not been used in the allocation of treatment with those 3 or 6 months fairing worse and high presenting WBC intensity in clinical trials, except for the use of prolonged maintenance ( 100 000 or 300 000) are important prognostic factors within therapy for boys in some cooperative group protocols. Risk classification strategies used by cooperative groups in recent or ongoing clinical trials for children with ALL BFM Risk assignment to standard-, intermediate-, and high-risk groups based on MRD assessment postinduction (week 5) and postconsolidation (week 12). In addition, prednisone poor response and the presence of unfavorable genetics, such as t(9:22, t(4:11) allocate the patient to high risk. DFCI Risk assignment at diagnosis to standard- or high-risk groups based on age, WBC count, and CNS status. Assessment of MRD postinduction (week 4) with allocation to very-high-risk group for those with high MRD. Patients with MLL translocation or hypodiploidy ( 44) are allocated to very-high-risk group. T-cell disease patients are allocated to the high-risk group. Patients with Ph disease and infants are treated on alternative protocols. SJCRH Risk assignment to low-, standard-, or high-risk groups at completion of induction therapy based on age, WBC count, CNS status, evidence of testicular disease, immunophenotype, cytogenetics, and response. High-risk patients include those with t(9:22), infants with MLL gene rearrangement, those with induction failure or evidence of persistent disease by MRD, or early T-cell precursor ALL phenotype. MRC-UK-ALL Risk assignment at diagnosis to standard- or high-risk groups based on age and WBC count. Patients with MLL rearrangements, hypodiploidy ( 39), or iAMP are assigned to the high-risk group. Disease response at d 8 and 15 by morphologic assessment of BM, MRD assessment done postinduction and pre-interim maintenance, and age 16 y are used to further allocate to standard-, intermediate-, or high-risk groups. Infants and those with Ph disease are treated on alternative protocols. BFM, Berlin Frankfurt Munster; DFCI, Dana Farber Cancer Institute; SJCRH, St. Jude Children’s Research Hospital; and MRC-UK-ALL, Medical Research Council-United Kingdom. Failure to obtain remission after 4-6 precursor B-ALL, prognostic factors for patients with T-cell ALL weeks on induction therapy is a relatively rare event, occurring in are less clear. A subset of T-cell ALL patients with a unique 50 2%-3% of patients with ALL, and is associated with a poor OS. Some of these factors are Prednisone response as measured in peripheral blood after 7 days of well established as predictive of outcomes, whereas others remain to monotherapy and day 8 and day 15 of induction therapy assessments be validated. These response tools remain valuable, Patients with hypodiploid leukemic cells have an unfavorable including their use in contemporary trials in countries with variable prognosis; those with fewer than 44 chromosomes are at the highest 37 resources in which minimal residual disease (MRD) measurements risk. A significant portion of ALL samples with low hypodiploidy are not routinely feasible. Several recent large clinical trials have cemented this response to therapy. Of the high-risk patients that of Ph disease but without the presence of the BCR-ABL included in this study treated on the POG 9905 regimen, those who translocation. The AIEOP-BFM 2000 study used PCR-based MRD measurements In infants with ALL, in whom translocations involving the MLL at the end of induction (day 33) and the end of consolidation (day gene are very common, any MLL rearrangement confers a signifi- 78) in 3184 patients with precursor B-ALL to prospectively risk 15 stratify patients. In older children, the prognostic impor- tance of MLL is somewhat less clear and may be affected by age and well as those with a prednisone poor response, induction failure, or translocation partner. High-risk patients received intensi- to higher-risk therapy. Even in the context of allocation of more intensive therapy, in multivariate analysis, MRD Initial descriptions of patients with intrachromosomal amplification at the end of induction was the most important factor, although of RUNX1 (iAMP) described very poor outcomes. By MRD risk assignment alone, the EFS at 5 years abrogate this risk. With the availability of newer genomic techniques, multiple recur- rent submicroscopic genetic alterations, including gene deletions, In the UKALL 2003 trial, patients were risk stratified based on mutations, and amplifications, have been identified. One of the more common of these abnormalities is IKZF1 altera- MRD risk status, with high risk defined by the presence of 0.

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