Modification Of Treatment Regimen Research Articles

Body Composition of Adults Living with HIV in Two Cities in Ghana

Background: Human immunodeficiency virus (HIV) infection affects nutrition through increases in resting energy expenditure, reduction in food intake, nutrient malabsorption and loss, and complex metabolic alterations that culminates in weight loss and wasting common in acquired immune deficiency syndrome. This study sought to assess body composition of adults living with HIV. Methods: This cross-sectional study involved 63 adults living with HIV in two cities in Ghana. Socio-demographic information was obtained with a questionnaire. Body composition was measured with the deuterium dilution method and with anthropometry. Data analysis was done by SPSS version 16.0. Descriptive statistics and frequencies and percentages were calculated. The independent sample t-test was used for comparisons between groups. Differences were considered significant at p < 0.05. Results: Median (interquartile range) body mass index was within normal for both males (20.6, (18.9, 21.6 kg/m 2 )) and females (21.6; (19.8, 24.9 kg/m 2 )). Underweight (7.9%) and overweight (19.0%) were however prevalent. Males have significantly higher median fat free mass than females (52.7 kg versus 40.1 kg; p<0.0001) kg whereas females have a significantly higher fat mass (27.5% versus 12.2%; p<0.0001), and high abdominal obesity (49.0%). Almost 21% and 8% of participants have depleted fat free mass and fat mass respectively. Conclusion: The study demonstrates some level of malnutrition among the study participants. This underscores the importance of monitoring body composition in people living with HIV. Measurements of waist and hip circumferences should form part of the assessment tools. This will help in identifying those on antiretroviral treatment that are at risk of developing abdominal obesity and thereby supporting the need for modifying treatment regimens when necessary. In addition, regular screening for hypertension, diabetes and other indicators of metabolic abnormalities is recommended.

Comparison of Outcomes from a Phase 3 Study of Age-Related Macular Degeneration with a Matched, Observational Cohort

To compare outcomes of intravitreal therapy from an observational study cohort with those of participants receiving treatment in the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (MARINA) for the treatment of neovascular age-related macular degeneration (wet AMD). Database observational study. Participants in the observational cohort were chosen to match demographic features and entry criteria of the treatment group from MARINA. Outcomes over 12 months were compared. Eight hundred twenty-one anti-vascular endothelial growth factor (anti-VEGF)-naïve eyes treated with ranibizumab with 12 months or more of follow-up were included in the total Fight Retinal Blindness! (FRB-All) cohort, whereas a subset of this cohort of 401 eyes who were matched to the MARINA treatment group were included as the FRB-MARINA cohort. Intravitreal ranibizumab therapy of 0.5 mg for wet AMD. Visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters and treatments given were recorded continuously and anonymously in an electronic database for 12 months. Locally weighted scatterplot smoothing (LOESS) regression was used to plot change in visual acuity data over the course of 12 months for both the FRB-All cohort and the FRB-MARINA cohort, whereas results from the MARINA trial were taken from the published study report. Change in VA in logMAR letters over 12 months, treatment, and visit intensity. Mean visual acuity improvement after 12 months in FRB-MARINA (+5.5 letters) was similar to that of the 0.5-mg group from MARINA (+7.2 letters). Improvement in FRB-ALL was slightly less (+4.9 letters). Mean treatment effect compared with the MARINA control group was similar for the MARINA treated group (+17.6 letters) and the FRB-MARINA cohort (+15.9 letters). A mean of 7.3 injections in 12 months was received by the observational cohorts. Similarity of mean VA improvement in the matched observational cohort with that of the phase 3 clinical trial suggests that these results can be achieved in real-world clinical practice with a modified treatment regimen.

Living-Donor Liver Transplantation and Hepatitis C

Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompression. In areas with low deceased-donor organ availability like Japan, living-donor liver transplantation (LDLT) is similarly indicated for HCV cirrhosis as deceased-donor liver transplantation (DDLT) in Western countries and accepted as an established treatment for HCV-cirrhosis, and the results are equivalent to those of DDLT. To prevent graft failure due to recurrent hepatitis C, antiviral treatment with pegylated-interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. In contrast to DDLT, many Japanese LDLT centers have reported modified treatment regimens as best efforts to secure first graft, such as aggressive preemptive antiviral treatment, escalation of dosages, and elongation of treatment duration.

Combinatorial Resistance: The Best Defense is a Good Offense

In drug development, specificity and the avoidance of off-target effects are the initial holy grails, with the ultimate goal of obtaining maximal in vivo efficacy coupled with minimal toxicity. Tumors, however, can be very efficient at nullifying the benefits of what could otherwise be good drugs. Tumors achieve these effects through a variety of mechanisms, one of which is drug resistance. Acquired resistance to cancer therapies remains a major health problem in oncology (1). Targeted therapies inhibit tumor growth but success is often short-lived as tumors rapidly evolve a way to bypass the pharmacologic block via re-activation of the targeted or parallel pathways. So, what can be done to overcome acquired resistance and achieve desired outcomes in the clinic? Perhaps the best defense against acquired resistance is to come out swinging and deal with it up front, rather than waiting for the inevitable to occur and subsequently modifying treatment regimens on the fly. Two recent papers (2, 3) shed light on a novel combination therapy strategy to circumvent acquired resistance in BRAFV600E-positive melanomas. One is a mechanistic study (3) that shows why combination therapy may be promising for BRAFV600E-positive melanomas and that it can work in xenograft mouse models, while the other, a clinical study (2), indicates improved outcome when patients are treated with a combination of both a BRAFV600E-specific inhibitor and a MEK inhibitor. The BRAFV600E mutation is present in ∼50% of human melanomas (4, 5). Prior to its discovery as a causal mutation in melanoma, prognosis for melanoma patients was grim as melanoma is notoriously unresponsive to chemo- and radiotherapies. Following BRAFV600E identification, there was a flurry of activity that culminated in Plexxikon’s development of vemurafenib (Zelboraf) (6), which was approved by the FDA in 2011 and the following year saw approval in Canada and Europe. Moreover, while vemurafenib has been a boon, promoting tumor regression and improved survival, acquired resistance frequently occurs after several months of vemurafenib treatment leading to MAP kinase pathway re-activation (6) that is not blocked by vemurafenib. How was the resistance happening and what can be done to minimize resistance up front? Now, recent work from the Rosen lab at Memorial Sloan-Kettering Cancer Center has uncovered data that vemurafenib reduces feedback inhibition in BRAFV600E-expressing cells such that these cells become sensitized to extracellular growth factors like hepatocyte and epidermal growth factors. Unlike canonical receptor-mediated RAF signaling, which utilizes RAF-RAF dimers, BRAFV600E functions as a monomer that is sensitive to RAF inhibition. Vemurafenib and other BRAFV600E inhibitors like dabrafenib (GlaxoSmithKline, currently in Phase III trials) inhibit the BRAFV600E monomer but are unable to block ligand-mediated RAF-RAF dimers. Thus, in the context of persistent vemurafenib, feedback inhibition wanes permitting extracellular mitogens to bypass vemurafenib-mediated inhibition since they promote RAF-RAF dimers. Importantly, the authors go on to show using four different BRAFV600E melanoma xenograft mouse models that an effective dose of Plexxikon’s vemurafenib analog PLX4720, when combined with a low dose of the MEK inhibitor PD0325901 promotes tumor regression in 25/26 tumors. Either PLX4720 or PD0325901 alone also inhibited tumor growth but less potently that when combined. Concurrently, in a recent study published in the New England Journal of Medicine, Flaherty and colleagues provide promising data from an open-label trial (2) involving over 400 patients that a combination of the BRAFV600E inhibitor, dabrafenib, and a MEK inhibitor trametinib (GlaxoSmithKline), which is near approval (7), significantly increased progression-free survival when compared to monotherapy. These studies validate the rationale to try to anticipate acquired resistance at the onset of therapy, rather than dealing with it once it has already occurred. Going forward, how might targeted therapies be best designed to overcome acquired resistance, especially when parallel pathways become activated? Recent work (8) published in Nature from the Cagan and Shokat labs at Mt. Sinai School of Medicine and University of California, San Francisco, CA, USA respectively, suggests a systems-based strategy to do just that. In a Drosophila model of Ret-induced multiple endocrine neoplasia, the authors show using a rationally designed single small molecule that balanced inhibition of multiple targets (Raf, Src, and S6K) was the most efficacious especially when the molecule was designed to avoid a so-called “anti-target,” Tor in this case, to minimize toxicity and relief from feedback inhibition. There is cautious optimism that such strategies will have success in the clinic (1). Finally, these data raise questions for the possible future therapies (9) for the developmental disorders caused by MAP kinase pathway mutations, collectively referred to as the RASopathies, and in particular cardio-facio-cutaneous (CFC) syndrome in which the majority of cases are caused by gain-of-function BRAF mutations.

Hepatitis C Virus: A Critical Appraisal of New Approaches to Therapy

The HCV council 2011 convened 11 leading clinicians and researchers in hepatitis C virus from academic medical centers in the United States to provide a forum for the practical and comprehensive evaluation of current data regarding best practices for integrating new direct-acting antiviral agents into existing treatment paradigms. The council investigated 10 clinical practice statements related to HCV treatment that reflect key topical areas. Faculty members reviewed and discussed the data related to each statement, and voted on the nature of the evidence and their level of support for each statement. In this new era of DAAs, a comprehensive and critical analysis of the literature is needed to equip clinicians with the knowledge necessary to design, monitor, and modify treatment regimens in order to optimize patient outcomes.

Current Treatment Options for Pediatric and Adult Patients With Ependymoma

Survival rates for patients with ependymoma, a glial tumor arising from the ependymal cells lining the ventricles of the brain and spinal cord canal, have changed little during the past decade. Contemporary "standard" therapy for children and adults with ependymoma consists of maximal surgical resection followed by focal irradiation except in cases of disseminated disease. Despite refinements in radiotherapy techniques and improvements in survival for patients with gross totally resected, nonanaplastic disease, many therapeutic challenges remain, especially for patients with unresectable, macroscopic, metastatic, or anaplastic disease. Moreover, radiotherapy to the developing central nervous system, especially in patients younger than age 5 years, can have potential long-term neurocognitive and neuroendocrine sequelae. Chemotherapy has not played a role in most treatment regimens for ependymoma to date, but due to the ongoing therapeutic challenges for a subset of patients, this modality is being reinvestigated in a few ongoing studies. Early recognition of patients who will not respond to primary therapy is imperative to modify treatment regimens, such as intensification with the addition of adjuvant chemotherapy, the use of novel experimental therapies, or their combination. Refinements in patient stratification schemes that are based on a combination of clinical variables and molecular profiles also require improved knowledge of tumor biology. Several molecular alterations have been identified already, some of which may be of prognostic significance. Furthermore, disruption of molecular alterations in signaling pathways involved in the development and maintenance of ependymoma by using novel molecularly targeted therapies may improve outcomes and reduce toxicity for patients with ependymoma.

Treatment of relapsing-remitting multiple sclerosis

The aim of this review is to summarize unmet needs for patients with multiple sclerosis (MS). It is important to understand the current status of these patients and both the benefits and limitations of the most commonly used MS treatments as new medications with the potential to simplify therapy and improve outcomes may soon be available. Current treatments for MS decrease the frequency of relapses and slow progressive disability. However, nearly all of these medications require frequent administration, and some patients also experience side effects. In some patients, adherence to MS treatment may be less than optimal. This may be associated with increased risk for relapses and hospitalizations and higher cost of care. Healthcare providers involved in the treatment of MS must be aware of the unmet needs of their patients and intervene as needed to improve adherence and/or modify treatment regimens to optimize outcomes.

Neisseria gonorrhoeae Antimicrobial Susceptibility in Lilongwe, Malawi, 2007

Malawi adopted syndromic management of sexually transmitted infections in 1993. Based on clinical efficacy and cost, gentamicin 240 mg intramuscularly, and doxycycline 100 mg twice daily x 7 days was selected as the first line regimen to treat urethritis. We sought to establish current laboratory-based Neisseria gonorrhoeae antibiotic susceptibility patterns for Malawi and describe the pattern of susceptibility since syndromic management began. Between May 15 and August 10, 2007, 126 men with urethritis attending the STD clinic at Kamuzu Central Hospital in Lilongwe had history, genital exam, and urethral swabs taken. All were treated with gentamicin and doxycycline in accordance with Malawi guidelines. Gonorrhea was diagnosed by Gram stain and culture. Antimicrobial susceptibility patterns in gonococcal isolates were determined by disk diffusion and E-test minimum inhibitory concentration (MIC) determination and agar dilution MIC determination. One hundred six isolates were cultured, and MICs were determined for 100. High levels of resistance to tetracycline and penicillin were observed, but isolates were uniformly susceptible to both gentamicin and ciprofloxacin. Susceptibility patterns identified by the agar dilution MIC and E-test MIC agreed. The most recent study continues the trend of high susceptibility of gonococcal isolates to gentamicin in Malawi after 14 years of use and suggests agar dilution MICs may be substituted with the simpler E-test methods in future susceptibility testing. However because of the lack of susceptibility criteria for aminoglycosides for N. gonorrhoeae and the difficulty obtaining clinical/in vitro correlates in this setting, caution should be exercised in using these data for modifying treatment regimens.

Culture result of smear-positive sputum samples after 2 months of antituberculous treatment

To the Editors: The correlation between sputum smear for acid-fast bacilli (AFB) and culture for Mycobacterium tuberculosis is usually good before antituberculous treatment (ATT), but it is not so good after treatment has started. In previous studies, up to 23.5% of patients had sputum that remained smear positive after 2 months of ATT 1. Old age, high bacillary load, presence of pulmonary cavitary lesions, treatment interruption and emergence of resistant strains are risk factors of persistent smear positivity. Determining whether these sputum samples contain viable tuberculosis (TB) bacilli is crucial because it indicates higher rates of relapse 2, 3. Meanwhile, for patients without viable TB bacilli, modifying treatment regimens and isolation appears to be redundant. However, the results of mycobacterial culture are only available after 2 weeks, even when using fluorometric liquid culture technique. Despite having good sensitivity and specificity, commercialised nucleic acid amplification tests are expensive and do not discriminate between viable and dead bacilli and, therefore, are not recommended for TB patients receiving ATT. Thus, we conducted a study to identify clinical factors for predicting the culture results of the persistent smear-positive sputum samples in a 2,100 bed, tertiary-care referral centre in northern Taiwan and an 800 bed local teaching hospital in southern Taiwan. In the two hospitals, all sputum specimens were processed by adding NaOH-citrate- N -acetyl-l-cysteine at room temperature for 15 min. After centrifugation, the precipitate was resuspended 4. Before October 2006, smears for AFB of the processed samples were stained using the Kinyoun method. From November 2006, the smear was stained with auramine-rhodamine fluorochrome 5. Smears were graded according to guidelines established by the American Thoracic Society 6 and the highest smear grading was recorded. All collected …

Overcoming Resistance to Conventional Drugs in Ewing Sarcoma and Identification of Molecular Predictors of Outcome

The improvement of Ewing sarcoma (EWS) therapy is currently linked to the discovery of strategies to select patients with poor and good prognosis and of modified treatment regimens. In this study, we analyzed the molecular factors governing EWS response to chemotherapy to identify genetic signatures to be used for risk-adapted therapy. Microarray technology was used for profiling 30 primary tumors and seven metastases of patients who were classified according to event-free survival. For selected genes, real-time polymerase chain reaction was applied in 42 EWS primary tumors as validation assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test was used to evaluate in vitro drug sensitivity. We identified molecular signatures that reflect tumor resistance to chemotherapy. Annotation analysis was applied to reveal the biologic functions that critically influenced clinical outcome. The prognostic relevance of glutathione metabolism pathway was validated. The expression of MGST1, the microsomal glutathione S-transferase (GST), was found to clearly predict EWS prognosis. MGST1 expression was associated with doxorubicin chemosensitivity. This prompted us to assess the in vitro effectiveness of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a new anticancer agent that efficiently inhibits GST enzymes. Six cell lines were found to be sensitive to this new drug. Classification of EWS patients into high- and low-risk groups is feasible with restricted molecular signatures that may have practical value at diagnosis for selecting patients with EWS who are unresponsive to current treatments. Glutathione metabolism pathway emerged as one of the most significantly altered prognosis-associated pathway. NBDHEX is proposed as a new potential therapeutic possibility.

Prediction of virologic response in difficult-to-treat chronic hepatitis C patients during high-dose interferon induction therapy

Objective. To determine (i) whether early viral kinetics or other markers during a modified treatment regimen are predictors of treatment outcome and (ii) whether fast responders can be treated for 24 weeks, without compromising the sustained virologic response (SVR) rate. Material and methods. One hundred “difficult-to-treat” chronic hepatitis C patients (46 previous non-responders/relapsers (any genotype), 54 treatment-naive patients genotypes 1 and 4) were treated with triple antiviral induction therapy: amantadine hydrochloride and ribavirin, combined with 6 weeks interferon alfa-2b induction (weeks 1–2: 18 MU/day, weeks 3–4: 9 MU/day, weeks 5–6: 6 MU/day), thereafter combined with weekly peginterferon alfa-2b. Fast responders (≥3 log10 HCV RNA decline at week 4) were randomized to 24 or 48 weeks. Slow responders (<3 log10 HCV RNA decline at week 4) were treated for 48 weeks. Treatment was stopped in patients with detectable HCV RNA at week 24. Results. Thirty-six patients achieved SVR: 28 of 60 fast responders (47%) versus 8 of 32 slow responders (25%, p<0.05). Relapse rates among fast responders treated for 24 or 48 weeks were 27% and 20%, respectively (p=NS). SVR in fast responders was independent of baseline HCV RNA ≥ or <600,000 IU/mL. All treatment-naive patients with HCV RNA <5 IU/mL at week 1 or 2 achieved SVR; all treatment-naive patients with HCV RNA ≥5 IU/mL at week 16 became non-SVR. In previous non-responders/relapsers, the predictive value for SVR was 83% if HCV RNA was <5 IU/mL at week 2; all previous non-responders/relapsers with HCV RNA ≥5 IU/mL at week 8 became non-SVR. Conclusions. With high-dose interferon induction, SVR and non-SVR can be predicted reliably within 16 weeks. Fast responders can be treated for 24 weeks, and SVR is independent of baseline viral load in fast responders.

Multispectral quantification of tissue types in a RIF‐1 tumor model with histological validation. Part I

Accurate assessments of therapeutic efficacy are confounded by intra- and intertumor heterogeneity. To address this issue we employed multispectral (MS) analysis using the apparent diffusion coefficient (ADC), T(2), proton density (M(0)), and k-means (KM) clustering algorithm to identify multiple compartments within both viable and necrotic tissue in a radiation-induced fibrosarcoma (RIF-1) tumor model receiving single-dose (1000 cGy) radiotherapy. Optimization of the KM method was achieved through histological validation by hematoxylin-eosin (H& and E) staining and hypoxia-inducible factor-1alpha (HIF-1alpha) immunohistochemistry. The optimum KM method was determined to be a two-feature (ADC, T(2)) and four-cluster (two clusters each of viable tissue and necrosis) segmentation. KM volume estimates for both viable (r = 0.94, P < 0.01) and necrotic (r = 0.69, P = 0.07) tissue were highly correlated with their H&E counterparts. HIF-1alpha immunohistochemistry showed that the intensity of HIF-1alpha expression tended to be concentrated in perinecrotic regions, supporting the subdivision of the viable tissue into well-oxygenated and hypoxic regions. Since both necrosis and hypoxia have been implicated in poor treatment response and reduced patient survival, the ability to quantify the degree of necrosis and the severity of hypoxia with this method may aid in the planning and modification of treatment regimens.

Ovarian hyperstimulation syndrome: Aetiology, prevention and management

Ovarian hyperstimulation syndrome is a serious and potentially life-threatening complication of infertility treatment. The symptoms are generally triggered by human chorionic gonadotrophin (hCG) following ovulation induction in an in vitro fertilisation cycle. It is believed that the underlying pathology is a shift of protein-rich fluid from the intravascular space to extravascular compartments. The exact aetiology has not been established however it is felt that vascular permeability plays a key role which may be mediated by the immune system, VEGF and the ovarian rennin–angiotensin system. Prevention of the syndrome is important and involves monitoring of patients undergoing ovulation induction, modifying treatment regimens and pharmacological interventions. The management of patients depends upon the severity of the condition. There should be a low threshold for hospital admission where close monitoring, replacement of intravascular volume, thromboprophylaxis and paracentesis (if required) can be effected.

A Preliminary Report of a Phase I Study of Zevalin® Using a Modified Treatment Regimen for Relapsed or Refractory CD20+ B-Cell Follicular or Transformed Non-Hodgkin's Lymphoma (NHL).

Rationale Escalation of the Zevalin dose is limited by hematologic toxicity associated with marrow B-cells ± tumor cells. Rituxan treatment before Zevalin may reverse marrow infiltration with malignant and normal B-cells allowing an increase in the dosage of Zevalin with enhanced radiation delivery to lymphoma tumor sites. Since NHL is radiation sensitive, a substantial increase in radiation dose delivered should increase the ORR and CR rates.Design Low-grade follicular/transformed NHL patients receive 4 weekly dose of Rituxan (375mg/m2) before the corresponding Zevalin dose. Bilateral bone marrow biopsies/aspirates as well as biodistribution and dosimetry studies using 111In-2B8 were obtained before and after Rituxan. The trial was schedule to escalate the Zevalin dose (from 0.4 to 0.7 mCi/Kg). After completion of the 0.4 mCi/kg cohort an additional cohort of Rituxan sensitive patients using 0.3 mCi/kg was completed. Safety, pharmacokinetics, dosimetry and preliminary responses are presented.Results 5 pts were enrolled in the 0.4mCi/kg cohort and 6 pts in the 0.3 mCi/kg cohort. In the 10 Rituxan sensitive patients the plasma T ½ and the AUC of 111In-2B8 increased after the administration of Rituxan, with a reduction in the plasma clearance (T½ from 45 ± 4.5 hours to 54 ± 1.9 hours, AUC from 60 ± 10 hrs/μCi/ml to 85 ± 14 hrs/μCi/ml, and the clearance from 1.4 ± 0.3 ml/hrs/kg to 0.9 ± 0.2 ml/hrs/kg). Dosimetry showed no differences in the radiation-absorbed dose for major normal organs (whole body, liver, kidneys) except for the spleen in which a reduction was observed in 7 out of 10 patients. The radiation-absorbed dose to the marrow increased after Rituxan; from 3.6 rads/mCi to 4.28 rads/mCi. In the 0.4 mCi/kg cohort 3 out of 4 evaluable patients for response had a complete response, and 1 patient had progression documented at initial evaluation six weeks post-Zevalin (patient refractory to previous Rituxan). No non-hematological toxicity was observed. One patient had a grade 4 thrombocytopenia, 3 patients had grade 3 thrombocytopenia, and 4 patients had grade 4 WBC and ANC. All patients recovered within two weeks after the nadir. Two out of 6 patients treated in the 0.3 mCi/kg cohort had complete response by physical evaluation, and 4 had partial response; no early progressions were seen in this cohort. No non-hematological toxicity was observed. Only one patient had a grade 4 WBC and ANC, and 2 patients had a grade 3; 3 patients had grade 3 thrombocytopenia; all patients recovered.Conclusions The administration of high doses of Rituxan before Zevalin prolongs the circulation time of the radiolabeled antibody and increases the bone marrow exposure to the radioisotope. Additionally, the increased amount of the radiolabeled antibody available after Rituxan therapy with the prolonged circulation time may explain the unusual high complete response rate observed in this small number of patients despite extensive chemotherapy failures. Although this is very provocative data, the number of patients is very limited to generate a strong conclusion. The trial continues at this time.

Lupus Nephritis: Induction Therapy

Effective induction therapy is of pivotal importance in minimizing renal parenchymal damage by the active immune-mediated inflammatory processes in severe proliferative lupus nephritis. Preservation of nephron mass is prerequisite to long-term renal survival. Data from US-based studies have shown improved efficacy with induction treatment comprising corticosteroid and cyclophosphamide, compared with corticosteroid treatment alone. Data from European studies have shown similar efficacy with a modified treatment regimen, in which smaller doses of cyclophosphamide were given at weekly or fortnightly intervals over a shortened treatment duration, and the treatment related adverse effects appeared less frequent with the reduced-dose regimen. We have also reported that sequential immunosuppression with prednisolone and oral cyclophosphamide as induction followed by azathioprine maintenance was associated with a high incidence of remission and relatively favourable long-term renal outcome in Chinese patients. However, cyclophosphamide treatment is associated with considerable adverse effects, which could be potentially fatal. Mycophenolate mofetil selectively inhibits lymphocyte proliferation, and thus targets an instrumental step in the pathogenesis of systemic lupus erythematosus. There is accumulating evidence that the combined use of mycophenolate mofetil and corticosteroid presents an effective treatment for severe proliferative lupus nephritis in different ethnic groups, and is associated with much fewer adverse effects compared with cyclophosphamide-based regimens. Recent data from our group also demonstrate the long-term efficacy of mycophenolate mofetil in preserving renal survival, when used continuously as both induction and maintenance therapy.

Lupus Nephritis: Induction Therapy

Effective induction therapy is of pivotal importance in minimizing renal parenchymal damage by the active immune-mediated inflammatory processes in severe proliferative lupus nephritis. Preservation of nephron mass is prerequisite to long-term renal survival. Data from US-based studies have shown improved efficacy with induction treatment comprising corticosteroid and cyclophosphamide, compared with corticosteroid treatment alone. Data from European studies have shown similar efficacy with a modified treatment regimen, in which smaller doses of cyclophosphamide were given at weekly or fortnightly intervals over a shortened treatment duration, and the treatment related adverse effects appeared less frequent with the reduced-dose regimen. We have also reported that sequential immunosuppression with prednisolone and oral cyclophosphamide as induction followed by azathioprine maintenance was associated with a high incidence of remission and relatively favourable long-term renal outcome in Chinese patients. However, cyclophosphamide treatment is associated with considerable adverse effects, which could be potentially fatal. Mycophenolate mofetil selectively inhibits lymphocyte proliferation, and thus targets an instrumental step in the pathogenesis of systemic lupus erythematosus. There is accumulating evidence that the combined use of mycophenolate mofetil and corticosteroid presents an effective treatment for severe proliferative lupus nephritis in different ethnic groups, and is associated with much fewer adverse effects compared with cyclophosphamide-based regimens. Recent data from our group also demonstrate the long-term efficacy of mycophenolate mofetil in preserving renal survival, when used continuously as both induction and maintenance therapy.

The association between compliance with antihypertensive drugs and modification of antihypertensive drug regimen.

Non-compliance is an important factor in lack of control of blood pressure. Uncontrolled blood pressure, as well as patients' complaints about the prescribed medication, may lead to modification of the initially prescribed antihypertensive drug regimen. The objective of this study was to assess the association between non-compliance and change in medication regimen. A nested case-control study within a cohort of new users of antihypertensive drugs between 1 January 1999 and 31 December 2002. We used data from the PHARMO database, a record linkage system containing drug-dispensing records from community pharmacies and linked hospital discharge records of approximately 950,000 subjects. Cases were subjects whose initial drug regimen was modified. Controls did not undergo such a modification. Conditional logistic regression was used to calculate odds ratios (OR) and their 95% confidence intervals (CI), and to adjust for confounders. In a cohort of 39,714 new users of antihypertensive drugs, we identified 11,937 cases and 11,937 matched controls. The percentage of non-compliant patients (compliance < 80%) among cases and controls was 5.1 and 3.6%, respectively [OR 1.39 (95% CI: 1.22-1.58)]. The association is stronger in females [OR 1.64 (95%CI: 1.37-1.94)] than in males [OR 1.14 (95% CI: 0.94-1.40)] and stronger if the duration of episode of use is longer than 6 months. Non-compliance is significantly associated with the occurrence of change in antihypertensive medication regimen. Pharmacists and physicians can use pharmacy data, although data tend to overestimate actual compliance, to assess and improve compliance with antihypertensive drugs, before modifying treatment regimens.

Chemo-radiotherapy for stage III unresectable non-small cell lung cancer—long-term results of a prospective study

Introduction: Combined-modality treatment is considered standard of care in the treatment of stage III non-small-cell lung cancer (NSCLC). This study was designed to assess the efficacy and tolerability of induction paclitaxel/carboplatin followed by concurrent thoracic radiotherapy and weekly paclitaxel. Materials and methods: Patients with unresectable stage III NSCLC were treated prospectively with two cycles of paclitaxel (175 mg/m 2) and carboplatin (area under the curve of 6) followed by radiotherapy (60–66 Gy) concurrent with 6 weekly doses of paclitaxel (60 mg/m 2). Response was determined 8 weeks after the completion of treatment and treatment-related toxicities were assessed at each visit during treatment and follow-up. Results: Sixty-three patients were treated, 5 had complete response and 33 had partial response, giving a response rate of 60%. Thirty-seven percent of patients developed grade 3 or 4 neutropenia; 48% had significant esophagitis requiring the use of narcotic analgesics. Two patients developed esophageal stricture subsequently. The median survival was 51 months and 12 months for stage IIIA and IIIB patients, respectively. Progression-free survival was 16months and 11months respectively. Conclusions: The response rate was encouraging. Esophagitis was a significant morbidity and should prompt modification of treatment regimen, either in the chemotherapy schedule or by adjusting the radiotherapy treatment planning.

Modified Magrath Regimens for Adults with Burkitt and Burkitt-Like Lymphomas: Preserved Efficacy with Decreased Toxicity

Burkitt and Burkitt-like lymphomas are rapidly growing tumors which require specialized therapy. Although intensive, multi-agent regimens have been effective in children, results are more variable in adults. Magrath et al. previously described a regimen that was highly effective in children and young adults. This phase II study of a modified Magrath regimen was designed to assess its efficacy in older adults and reduce treatment-related toxicity. Fourteen patients with Burkitt/Burkitt-like lymphoma and median age of 47 years were stratified into two categories: low-risk (normal LDH and a single focus of disease measuring less than 10 cm, 3 patients) and high risk (all other, 11 patients). Low-risk patients received three cycles of modified CODOX-M (cyclophosphamide, doxorubicin, adriamycin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate, regimen A). High-risk patients received four alternating cycles of regimens A and B (A-B-A-B). Regimen B consisted of ifosfamide, cytarabine, etoposide and intrathecal methotrexate (IVAC). The modified treatment regimen was associated with no grade 3/4 neuropathy and only one episode of grade 3/4 mucositis. All patients completed protocol therapy and there were no treatment-related deaths. Twelve patients (86%, 90% CI: 61 – 97%) achieved a complete response; 1 patient achieved a PR and 1 patient died of progressive disease. Nine patients (64%) are alive and disease free at a median follow-up of 29 months. This modified Magrath regimen is effective and well-tolerated in a representative group of older adult patients.

Alemtuzumab and tolerance: the university of wisconsin experience

H istorically, the transplantation program at the University of Wisconsin, Madison, WI, has used induction agents followed by steroid-based maintenance therapy in solid organ transplantation. Nonhuman primate experiments showed the usefulness of an antibody that could effectively deplete 2 to 3 logs of lymphocytes from the recipient at the time of renal transplantation.1 Experience in humans has accumulated with virtually all of the commonly used antibodies including Minnesota antilymphocyte globulin, OKT3 (muromonab-CD3), Thymoglobulin (rabbit antithymocyte globulin; SangStat Medical Corporation, Fremont, CA), Simulect (basiliximab; Novartis AG, Basel, Switzerland), Zenapax (daclizumab; Hoffmann-La Roche Inc, Nutley, NJ), and, most recently, alemtuzumab (CAMPATH 1H; ILEXTM Oncology, Inc [ILEX], San Antonio, TX). Our protocol is modified on the basis of results and clinical experience in one of the largest renal transplant programs in the United States. Because of the published results observed in renal transplant recipients treated with alemtuzumab as an induction agent followed by cyclosporine maintenance therapy,2,3 physicians at Wisconsin designed an immunosuppressive protocol in which 29 low-risk patients were treated with alemtuzumab 20 mg intravenously and methylprednisolone 500 mg intravenously on days 0 and 1 and maintenance therapy with rapamycin (sirolimus) 2 mg/d orally starting on day 1 (Fig 1). Rapamycin was substituted for cyclosporine because it predisposes alloreactive cells to apoptosis whereas cyclosporine inhibits their apoptosis and because rapamycin is antifibrogenic and is not nephrotoxic. The dose of rapamycin was adjusted to achieve target levels in blood of 8 to 12 ng/dL.4 Eight of the 29 patients (28%) experienced a rejection episode, with all but 2 occurring within 30 days after transplantation, and most of which (5/8) were shown histologically to include humoral responses. These 5 patients had evidence of C4d deposition in the peritubular capillaries. Results from flow cytometry studies performed retrospectively on patients who experienced rejection episodes confirmed that the episodes were humoral responses directed at major histocompatibility complex class I antigen, but these responses were not because of pretransplant recipient sensitization. Treatment of rejection with steroids, Thymoglobulin, plasmapheresis, and rituximab was well tolerated, indicating that the treatment regimen did not induce overimmunosuppression. Interestingly, the occurrence of early rejection was clustered around younger patients, with 7 of 13 patients younger than 45 years experiencing rejection compared with 1 of 16 patients older than 45 years. To date, no incidents of biopsy-proven chronic rejection have been detected. Other notable complications included 2 operations for lymphoceles and 1 case of hepatotoxicity with anemia, all of which were considered as secondary effects of the rapamycin therapy. There were no systemic or opportunistic infections. The treatment regimen was modified as a result of the unexpected increased incidence of aggressive humoral rejection and because flow cytometry results showed that patients who experienced these rejection episodes had CD52-negative cells in the blood within 1 month after transplantation. Physicians theorized that CD52-negative cells may be involved in the rejection process. Therefore Thymoglobulin was added to the treatment to target the CD52-negative cells, and steroids were included to deter nonspecific activation of the immune response (Table 1). Five patients were treated with the modified treatment regimen of alemtuzumab 20 mg intravenously on days 1 and 0 followed by Thymoglobulin 1.5 mg/kg on day 1, maintenance therapy with sirolimus 2 mg/d starting on day 1, and steroid therapy 500 mg starting on day 1 tapered to 30 mg and discontinued on day 14. Three of the patients have From the Division of Organ Transplantation, University of Wisconsin, Madison, WI. Address reprint requests to Stuart Knechtle, MD, Division of Organ Transplantation, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792-7375. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/S0955-470X(03)00079-X