Pooled analysis of these trials suggested significantly higher rates of injection site reaction purchase suhagra 100mg with visa erectile dysfunction pumps buy, abnormal liver function tests suhagra 100 mg with mastercard young husband erectile dysfunction, and withdrawal due to adverse events with ® interferon beta-1a SC (Rebif ) 22 µg and flu-like syndrome and withdrawal due to adverse ® events with interferon beta-1b SC (Betaseron ) compared with placebo (Table 25). Adverse events in trials of beta interferons in patients with secondary progressive multiple sclerosis (beta interferon compared with placebo) Withdrawal due to Flu-like Injection site Elevated adverse Study syndrome reactions Depression LFTs Myalgia events ® Interferon beta-1a IM (Avonex ) vs. A systematic review for the Cochrane collaboration reviewed the 2 placebo-controlled trials in primary progressive multiple sclerosis and although pooling did not allow interpretation for comparative effectiveness, it did find that for the interferons, the most significant adverse events were flu-like reactions (relative risk, 2. There was no difference in the frequency of fatigue (relative risk, 1. Of the 5 observational studies in patients with relapsing-remitting multiple sclerosis, 3 met inclusion criteria for both effectiveness and harms analysis, and the best of these was a retrospective cohort study based on data from patients in Austria, Switzerland, and Germany, 49 with 4754 patients exposed to 1 of the 3 interferons. An analysis of the reasons for discontinuation of treatment indicated that discontinuations due to injection site reactions were ® significantly lower in the interferon beta-1a (Avonex ) 30 µg IM weekly group compared with ® either the interferon beta-1a SC (Rebif ) 22 mcg SC 3 times weekly or interferon beta-1b ® (Betaseron ) 250 µg SC every other day groups, but no different than the interferon beta-1a SC ® (Rebif ) 44µg SC twice weekly group. Differences in frequency of flu-like syndrome was ® statistically significant only for interferon beta-1a SC (Rebif ) 22 mcg group compared with the ® ® interferon beta-1b (Betaseron ) group with the interferon beta-1a SC (Rebif ) 22 mcg being ® lower. Discontinuations due to lack of efficacy was greatest in the interferon beta-1a SC (Rebif ) ® 22 mcg group, compared with the interferon beta-1a IM (Avonex ) group or the interferon beta- ® 1b (Betaseron ) group (Table 26). The other 2 studies were of patients being treated at large multiple sclerosis specialty centers (1 in Spain, 1 in Italy), enrolled and followed every 3 46, 47 months. These studies had a high risk of bias due to clinically important differences among ® groups at baseline, and because at the outset of data collection only Betaseron was marketed in ® ® those countries, while Avonex and Rebif were approved during the time period of the study. Disease-modifying drugs for multiple sclerosis Page 61 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 26. Discontinuation due to adverse events: Observational evidence in 51 patients with relapsing-remitting multiple sclerosis Adverse event Rates of discontinuation due to adverse events, adjusted analysis ® ® Flu-like Interferon β-1a SC (Rebif ) 22 mcg< Interferon β-1b (Betaseron ) syndrome 0. Other non-trial evidence was limited and low quality, with 4 open-label studies of ® 133-138 interferon beta-1b (Betaseron ), 3 open-label studies of interferon beta-1a IM ® 114, 139, 140 ® 141, 142, 142 (Avonex ), 3 open label studies of interferon beta-1a SC (Rebif ), , 3 studies 143-147 (1 with 3 publications) reporting adverse event data for more than 1 beta interferon, 1 study ® 148 comparing open-label use of interferon beta-1b SC (Betaseron ) to an untreated control group, ® and 1 study comparing interferon beta-1a IM (Avonex ) to alemtuzumab, a drug not available in 149 the United States (Investigators 2008). The observational study by Rio et al provided a median of 60 months of follow-up (range 12-115 months) on 146 patients receiving interferon beta-1b ® 150 (Betaseron ). They observed 4 deaths (3 sepsis and 1 pulmonary hemorrhage), 1 intracerebral hemorrhage, and 1 gastrointestinal hemorrhage, all of which were unexpected adverse events. The rest of the studies were not longer in duration than the trials, nor did they provide data on rare but serious adverse events. Because of the limitations of these designs and lack of controlling for potential confounding, these studies did not provide better information on tolerability than the trial data. In a study of patient perceptions of adverse events associated with beta interferon ® therapy, 40 patients taking interferon beta-1b SC (Betaseron ) or interferon beta-1a IM ® 151 (Avonex ) were questioned on the impact of adverse effects on their lives. Results of this study indicated that most adverse effects were mild and did not have a strong impact on the lives of patients, although fatigue was rated moderate or severe. The study found wide variation in patient response to both systemic and local adverse events, but did not make comparisons between the products. Synthesis of direct and indirect evidence Pooled rates of tolerability of adverse effects and discontinuation for each of the beta interferons, based on all head-to-head and placebo-controlled trial rates and controlling for study effects, are presented in Table 27 below. Given the differences in events reported with the different doses of ® interferon beta-1a SC (Rebif ), only data using the 44 µg dose was pooled. This analysis indicated higher rates of injection site reactions, fever, and overall or adverse event-related ® ® discontinuation with interferon beta-1b SC (Betaseron ). Interferon beta-1a IM (Avonex ) led to higher rates of flu-like syndrome than the others, but the lowest rates of fatigue, fever, injection- site reaction and overall or adverse event-related discontinuations. Interferon beta-1a SC Disease-modifying drugs for multiple sclerosis Page 62 of 120 Final Report Update 1 Drug Effectiveness Review Project ® (Rebif ) 44 µg had slightly higher rates of fatigue, but lower rates of depression than the others. Although a small observational study of 225 patients with relapsing-remitting multiple sclerosis ® did not agree with the pooled evidence, suggesting that interferon beta-1a SC (Rebif ) 44 µg had the lowest overall rates of withdrawal due to adverse event or perceived lack of efficacy, the 152 lower quality of the evidence precludes making any conclusion on its results. Interferon beta-1b and 1a: pooled adverse event rates Interferon beta-1b Interferon beta-1a Interferon beta-1a SC ® ® ® Adverse event SC (Betaseron ) IM (Avonex ) (Rebif ) 44µg Rate (95% CI) Rate (95% CI) Rate (95% CI) Injection site reaction 58. One retrospective observational study comparing the 3 different interferons (N=4754) found that ® flu-like syndrome was higher in the interferon beta-1b (Betaseron ) group (1. A small observational study of patients with relapsing-remitting multiple sclerosis (N=454) compared injection site pain and injection site reactions in patients receiving interferon beta-1b SC ® ® (Betaseron ) with interferon beta-1b SC (Rebif ) 44 µg and found that interferon beta-1b SC ® (Betaseron ) had fewer injection site reactions (48. In reviewing the 4 placebo-controlled trials in patients with relapsing-remitting multiple sclerosis and 2 systematic reviews of the 4 ® trials, only the 3 times weekly interferon beta-1a SC (Rebif ) was not associated with significantly increased rates of flu-like syndrome, fever, and myalgias while leukopenia was 52-56 significantly higher with this drug. This was contrary to pooled analysis from the 5 trials of the beta interferons compared with placebo in secondary progressive multiple sclerosis which suggested that significantly higher rates of injection site reactions, abnormal liver function tests, ® and withdrawal due to adverse events with interferon beta-1a SC (Rebif ) and flu-like syndrome ® and withdrawal due to adverse events with interferon beta-1b SC (Betaseron ) compared with placebo. Our pooled analysis of all head-to-head and placebo-controlled trial data indicated that Disease-modifying drugs for multiple sclerosis Page 63 of 120 Final Report Update 1 Drug Effectiveness Review Project ® interferon beta-1b SC (Betaseron ) had higher rates of injection site reactions, fever, overall withdrawal, and discontinuation rates due to adverse events (Table 27). The ® 16-month EVIDENCE trial (N=677) compared interferon beta-1a IM (Avonex ) 30 µg SC once ® weekly to interferon beta-1a SC (Rebif ) 44 µg SC 3 times weekly and found that significantly ® more patients taking interferon beta-1a SC (Rebif ) experienced injection site reactions (85% compared with 33%; P<0. Significantly more ® patients taking interferon beta-1a IM (Avonex ) experienced flu-like symptoms (53% compared with 45%; P=0. Differences in withdrawal or early discontinuation overall or due to adverse events were not found. Data on compliance or patient satisfaction with treatment were not recorded. This study then had a crossover phase in which patients initially receiving weekly ® ® interferon beta-1a IM (Avonex ) once weekly were switched to interferon beta-1a SC (Rebif ) 3 ® 45 times weekly while those taking interferon beta-1a SC (Rebif ) continued to do so. For those ® transitioning to the interferon beta-1a SC (Rebif ) there was a significant increase in injection site reactions (10% compared with 23%), liver function abnormalities (3% to 6%), and white blood cell abnormality (1. Similarly, there was a significant decrease ® in flu-like symptoms with the interferon beta-1a SC (Rebif ) (16% to 4%). One large retrospective observational study in patients with relapsing-remitting multiple sclerosis (N=4754) compared the 3 different interferons and found that discontinuations due to ® injection site reactions and lack of efficacy were higher in the interferon beta-1a (Rebif ) 22 µg ® group compared with the interferon beta-1a IM (Avonex ) group (2% compared with 0. A short-term, 6-month, ® ® observational study compared interferon beta-1a IM (Avonex ) to interferon beta-1a (Rebif ) 44 µg and found that there were no notable differences between the 2 treatment groups regarding ® any of the adverse responses, with 1 patient in the interferon beta-1a (Rebif ) 44 µg group ® discontinuing due to an adverse event while 78. In reviewing the 4 placebo-controlled trials and 2 systematic reviews of the 4 trials in patients with ® relapsing-remitting multiple sclerosis, interferon beta-1a IM (Avonex ) was associated with ® increased rates of flu-like syndrome, fever, and myalgias while interferon beta-1a (Rebif ) was 52-56 associated with higher rates of leukocyte and liver enzyme abnormalities. Our pooled analysis of all head-to-head and placebo-controlled trial data indicated that interferon beta-1a SC ® (Rebif ) had higher rates of injection site reactions and withdrawal due to adverse events (Table ® 27). Interferon beta-1a IM (Avonex ) was associated with higher rates of flu-like syndrome, fatigue, fever, and depression. Disease-modifying drugs for multiple sclerosis Page 64 of 120 Final Report Update 1 Drug Effectiveness Review Project The 1 retrospective observational study in patients with relapsing-remitting multiple sclerosis that compared the 3 different interferons (N=4754) found that discontinuation rates due ® to injection site reactions were higher in the interferon beta-1b (Betaseron ) group compared ® 49 with the interferon beta-1a IM (Avonex ) group (2. In reviewing the 4 placebo-controlled trials and 2 systematic reviews of the 4 trials in ® patients with relapsing-remitting multiple sclerosis, interferon beta-1b SC (Betaseron ) was associated with higher flu-like syndromes, injection site reactions, leukopenia, and abnormal ® 52-56 liver tests compared with interferon beta-1a IM (Avonex ). Our pooled analysis of all head- ® to-head and placebo-controlled trial data indicates that interferon beta-1b SC (Betaseron ) had higher rates of injection site reactions, fever, and rates of overall withdrawal and discontinuation ® due to an adverse event (Table 27). Interferon beta-1a IM (Avonex ) was associated with higher rates of flu-like syndrome. Additional evidence of safety for beta interferon drugs Thyroid function The effect of beta interferons on thyroid function in relapsing-remitting multiple sclerosis 153 patients was assessed in 2 observational studies (Table 28). The larger study found that thyroid autoimmunity was common at baseline in relapsing-remitting multiple sclerosis patients (8.

The median CD4 T cell counts were between 300 and 350/µl at time of diagnosis generic suhagra 100mg impotence emotional causes, although with great vari- ation buy discount suhagra 100mg erectile dysfunction studies. Overall prognosis was good and a matched-pair analysis did not prove worse with HIV+ patients (Powles 2004). Other studies confirm the positive course (Fizazi 2001). Patients should be treated with the standard regimens that are also recom- mended for negative patients. Depending on histology and stage of cancer, the regimen consists of orchiectomy, lymph node extirpation or radiation, and or a platinum-based chemotherapy. High dose therapies are also possible (Hentrich 2009). Treatment should be performed in cooperation with a urologist experienced in oncology and an HIV specialist. Lung cancer In the general population, lung cancer is the most frequent cancer disease that leads to death in male patients. This tendency is increasing in women and already ranks third. More recent studies from France show that lung carcinoma accounts for 5% of all causes of death and leads more fre- quently to death than Kaposi’s sarcoma (Bonnet 2009). In a British cohort, the rel- ative risk in the early years of the HIV epidemic was similar to that of the normal population and has now risen by a factor of 8 (Bower 2003). In other cohorts, rela- tive risk remained constant between 3–10 (Engels 2006, Cadranel 2006, Dal Maso 2009). Overall risk seems to rise as immunodeficiency increases (Guiguet 2009, Reekie 2011). In our own retrospective study of 72 patients developing lung cancer during the last decade, most cases occurred in the setting of limited immune deficiency and a long-lasting sufficient viral suppression (Hoffmann 2011). This increase can partly be explained by simple reasons: first, HIV+ patients live longer and have more time to develop lung cancer and second, HIV+ patients smoke more than non-infected patients. In some HIV outpatient clinics, up to 60–70% of the patients are smokers. Smoking remains the main risk factor for developing lung cancer (Hoffmann 2011, Clifford 2012). Thus, one should discuss the issue of smoking: “It’s time to quit” – there are possibilities to cease smoking (Niaura 2000). Apart from age and nicotine abuse, other factors also seem determine an increased risk (Kirk 2007, Chaturvedi 2007). This is underlined by the fact that the most fre- quent subtype found in HIV+ patients, adenocarcinoma, is the subtype that is least associated with nicotine consumption (Cadranel 2006). Because often immune defi- ciency is not present, other factors, such as specific lung infections and a resulting scarring, are assumed, but also increased proinflammatory cytokines in the lungs or reduced glutathione levels are found frequently in HIV+ individuals. These factors can worsen the damage caused by smoking. Generally, HIV+ patients seem to be more sensitive towards carcinogenesis (Engels 2006, Kirk 2007, Chaturvedi 2007). In the US veterans cohort, an increased risk for HIV+ patients remained significant, even after adjusting for smoking, age, ethnicity and COPD (Sigel 2010). There is also some evidence for a genetic predisposition (Engsig 2011). From a diagnostic-therapeutic view, patients always stand a better chance when the lung cancer has been diagnosed early. Symptoms are unspecific and when they present, it is often too late. In the case of HIV+ patients, diagnosis is seldom early enough. In our own cohort of 72 cases of lung cancer diagnosed 2000-2010, only 34% of the patients were in stages I-IIIa which are considered to be curable (Hoffmann 2011). Patients in early tumor stages should undergo surgery with curative intention since chemotherapy only suspends further progression for a few months (Cadranel 2006, Lavolé 2009). In our own cohort, median estimated overall survival (OS) was 450 AIDS 1. Clinical stage was highly predictive and long-term OS could only be achieved in very limited disease stages (Hoffmann 2011). If chemotherapy is indicated, 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), gemcitabine or navelbine. 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.

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Normalization of 156 American Society of Hematology pre-ASCT 100 mg suhagra overnight delivery erectile dysfunction nclex, FDG-PET imaging with second-line cheap suhagra generic impotence medication, non-cross-resistant, 38. A phase 1/2 single-arm, chemotherapy programs improves event-free survival in patients with open-label study to evaluate the safety and efficacy of brentuximab Hodgkin lymphoma. Brentuximab vedotin as first line lymphoma in the first salvage setting: interim results [abstract]. Biol salvage therapy in relapsed/refractory HL [abstract]. FDG-PET adapted administered to platinum-refractory transplant naive Hodgkin lym- sequential therapy with brentuximab vedotin and augmented ICE phoma patients can increase the proportion achieving FDG-PET nega- followed by autologous stem cell transplant for relapsed and refractory tive status [abstract]. Highlights in lymphoma from the 2013 American Society of Hematol- dosing study of brentuximab vedotin in patients with relapsed/refractory ogy Annual Meeting and Exposition. Both normal GCs and neoplastic follicles of FL also contain non-neoplastic cells (microenvironment) that influence and are influenced by the GC and FL B cells and are likely important for tumor cell survival. Many insights into the nature of the GC/FL microenvironment have come from morphologic and immunophenotypic analysis, both before and after the discoveries from gene expression profiling. This chapter reviews what we have learned from the microscope and highlights the pitfalls involved in trying to enumerate cells in the microenvironment for clinical prognostication. The long processes ● To perceive the strong interconnections revealed by micro- are not usually visible on routine sections. FDC processes have scopic observation between immune system and stromal cells surface complement receptors (CD21) and Fc receptors (CD23) in the microenvironment and neoplastic cells in the develop- and bind both free antigen and antigen–antibody complexes for ment and progression of FL presentation to B cells. In GCs, the FDCs express both CD21 and CD23, whereas in primary follicles and mantle zones, typically only CD21 is detected. Macrophages present in the GC (CD68 ) Introduction are typically phagocytic (tingible body macrophages), containing Follicular lymphomas (FLs) are neoplasms of germinal center (GC) apoptotic debris from B cells that have failed to reexpress a B cells, which retain many of the morphologic, immunophenotypic, surface Ig molecule (SIg), also known as the BCR, after genetic, and functional features of normal GC B cells. FL (FL) is undergoing somatic hypermutation (SHM) of the Ig variable defined in the fourth edition of the World Health Organization 1 region genes (IGV) (see Centroblasts below). The exact role of (WHO) classification as “a neoplasm composed of follicle centre macrophages in the GC has not been extensively studied, but (germinal centre) B-cells (typically both centrocytes and centro- evidence suggests that they both facilitate and regulate GC blasts), which usually has at least a partially follicular pattern. Lymphomas composed of centrocytes and centroblasts with an entirely diffuse pattern in the sampled tissue may be included in this GC T cells category. The majority of GC T cells are TFH cells dendritic cells that comprise the FL microenvironment. Many of the (CD3 CD4 CD57 PD1 CXCL13 CXCR5 BCL6 ), which are components of the FL microenvironment mimic those present in important for selection of B cells for entry into and proliferation normal GCs, but there are important differences that may contribute within the GC. Follicular Treg cells (Foxp3 Blimp-1 CD4 CXCR5 to tumor cell survival. This chapter begins with a summary of what high highPD-1 ) exert negative regulatory effects on both immunoreac- morphology and immunophenotyping can tell us about the GC tive T cells and B cells and are required to shut off the GC reaction reaction, both the B-cell component and the microenvironment, and and prevent excessive immune responses and autoimmunity; these then provides a discussion of similar issues in FL. Microenvironment of the GC reaction GC B cells The GC reaction occurs within a few days of primary antigen B cells home to lymph nodes via receptors on the endothelial cells of exposure and with subsequent antigen challenges. Each GC is the high endothelial venules10 and within the lymph node via formed from between 3 and 10 naive B cells, and ultimately interactions with stromal cells. FDCs and macrophages FDC are large cells with nuclei that are similar in size to Centroblasts centroblast nuclei, but have delicate nuclear membranes and The proliferating GC B cells, known as centroblasts, are large cells central, small, eosinophilic nucleoli. FDCs are often binucleate with vesicular nuclei, 1-3 prominent, peripheral nucleoli, and a 158 American Society of Hematology narrow rim of basophilic cytoplasm. Centroblasts express SIg at low mechanisms of IGV region mutation and class switching, the GC levels2,15,16 and also switch off the gene that encodes the BCL2 reaction gives rise to the better-fitting IgG or IgA antibody of the protein; therefore, they and their progeny are susceptible to death late primary or secondary immune response,42 as well as B-cell through apoptosis. Perhaps not surprisingly, the gene expression profile of undergoes SHM of the 5 noncoding promoter region at a lower FL is similar to that of the light zone, with up-regulation of frequency than is seen in the IGV genes. GC cells in the light Like normal GC B cells, FL B cells have undergone SHM of the zone express antigens associated with activation, most of which are IGV genes and almost always express SIg. The lymphoma cells involved with interaction with T cells, including CD23, CD71, CD40, have undergone Ig class switch in 20%–50% of the cases. An important property of the SIg produced by zone As shown by in vivo imaging and flow cytometry, expression FL is the acquisition during SHM of sequence motifs for the of CXCR4 and CD83 can be used to distinguish between cells in the high low addition of unusual mannosylated glycans not seen in normal B dark zone (CXCR4 CD83 ) and those in the light zone low high 23 cells to the mutated IGV regions (for review, see Stevenson and (CXCR4 CD83 ). These glycans bind to lectins (mannose-binding lectin and DC-SIGN) on dendritic cells and macrophages of the Centrocytes express a BCR/SIg that has an altered antibody- 3 innate immune system, allowing them to survive in the GC combining site because of the somatic mutations in the IGV region. Consistent with Centrocytes with IGV gene mutations that have resulted in decreased this observation is the old observation that FDCs in FL do not affinity for antigen rapidly die by apoptosis (programmed cell have surface deposits of Ig on their processes, in contrast to death); the prominent “starry sky” pattern of phagocytic macro- 48 FDCs of normal GCs. Neoplastic follicles contain many phages seen in GCs at this stage is a result of the apoptosis of 49 elements of the GC microenvironment. Centrocytes with IGV gene mutations that have resulted in increased affinity process the antigen and present it to CD4 T cells in the light zone of the GC. T cells FH FH Non-neoplastic B cells (CD3 CD4 CD57 PD1 CXCL13 CXCR5 BCL6 ) are pres- Neoplastic follicles usually lack mantle zones, but in some cases, ent in large numbers in the light zone and express CD40 ligand partial or complete mantle zones composed of non-neoplastic naive (CD40L), which can engage CD40 on the B cell. Both ligation of B cells may be present around all or some of the follicles. The fact that reenter the dark zone, where clonal expansion occurs; cells may the majority of the neoplastic follicles lack mantle zones suggests cycle between the dark and light zones multiple times. FH FDCs Centrocytes then go on to become either Ig-secreting plasma cells or Nodular meshworks of FDCs invest the neoplastic follicles, as demon- memory B cells. Interaction with surface molecules expressed by strated by monoclonal antibodies to CD21 or CD23. In diffuse areas of FLs, FDCs are absent, from IgM to IgG or IgA. Hematology 2014 159 FL-associated T cells tion with advanced disease or a poor prognosis. Although PD1 T FH FH cells in FL appear to be similar to those in tonsil GCs,53 Treg cells Why the discrepancies? These include the use of different patient populations and in follicular than diffuse areas, and are decreased in areas of different treatment regimens (particularly the use of rituximab). One study confirmed this variability and sug- conspicuous than in reactive GCs and are typically not phagocytic, gested that automated microscopy analysis may be more reproduc- correlating with the relatively low proliferation fraction and lack of ible and accurate. Macrophages in FL and other of cutoff numbers of cells to define “low” versus “high” levels of cancers are thought to show M2 polarization, a phenotype associ- immune cells and the consideration of pattern (where the immune ated with tissue remodeling and tumor progression. Unfortunately, until and type can be associated with up-regulated mannose receptors and unless these issues can be resolved, the utility of such testing in could facilitate survival of neoplastic B cells via binding of the clinical practice remains dubious. This GC, including elements of the microenvironment, such as FDCs, may take the form of so-called “FL in situ/intrafollicular 57 50 macrophages, and T cells. Understanding the similarities and neoplasia” or partial nodal involvement by FL. This phenomenon differences between normal and neoplastic follicles, including likely reflects the ability of preexisting reactive GCs to be entered 58 elements of the microenvironment, has led to insights into lym- by newly antigen-reactive B cells. Interestingly, FL B cells within phoma development and progression. Understanding the relation- preexisting GCs often exhibit stronger staining for BCL2 than the ship of the neoplastic cells to the microenvironment (ie, which cells typical neoplastic follicles of the same lymphoma (personal are needed for lymphoma growth and which are involved in observation). Techniques for enumerating FL microenvironment and prognosis such cells will be of limited value in lymphoma management until After the landmark study from the Lymphoma/Leukemia/Molecular these issues are understood and better standardization of immunohis- Profiling Project demonstrated the prognostic importance of genes tochemistry is possible.

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