Terms Of Clinical Response Research Articles

The impact of different fluence rates on pain and clinical outcome in patients with actinic keratoses treated with photodynamic therapy

Literature data suggest that lower fluence rates are preferable in terms of clinical response and tolerability for treating patients with actinic keratoses (AKs). We aimed to clarify the impact of different fluence rates on pain during photodynamic therapy (PDT) for AKs, as well as on treatment outcome. Individuals with at least three discrete AKs were recruited. Each lesion was randomly allocated to 25, 50 or 75 mW/cm2 of topical 5-aminolevulinic acid (5-ALA) PDT, using non-coherent light source. Primary end point was pain during illumination, evaluated using a visual analogue scale (VAS). Secondary end points were clinical outcome and adverse events. Fifty adults, with 150 AKs lesions were recruited in the study. Mean VAS score did not significantly differ between the groups of 25 and 50 mW/cm2 (P=0.714). However, mean VAS was significantly higher at the group of 75 mW/cm2 in comparison to the former ones (P=0.000). With respect to the clinical outcome and adverse events during the first year of follow-up, no differences were observed between the three groups. Comparison between the 25 and the 50 mW/cm2 (P=0.749), as well as between the former and the 75 mW/cm2, did not show a dependence of complete response rate on fluence (P=0.749 and P=1.000, respectively). According to our observations a fluence rate between 25 and 50 mW/cm2 is effective and better tolerated by patients treated with topical 5-ALA PDT for AKs.

"Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07).

BackgroundSchedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression).MethodsThirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations.ResultsPathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or “in situ”) on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 “minimal” responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%).ConclusionsA “short course” of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this “short course” schedule, the result in term of clinical responses didn't turn into complete pathological responses.

Safety and Efficacy of Panitumumab Therapy After Progression With Cetuximab: Experience at Two Institutions

Cetuximab therapy has been effectively combined with cytotoxic chemotherapy in the first-, second-, and third-line treatment settings. In general, treatment with cetuximab is well tolerated, though it has been associated with the development of hypersensitivity reactions (HSRs). In the case of severe HSRs, further therapy with cetuximab is not possible. In contrast with cetuximab, HSRs have been rarely observed with panitumumab therapy. Currently, panitumumab is indicated for patients with metastatic colorectal cancer (mCRC) with progressive refractory disease, and there is recent evidence documenting its clinical efficacy with cytotoxic chemotherapy in the first-line and second-line settings. However, the safety and efficacy of panitumumab after progression with cetuximab has not been well documented. We present a retrospective review of our experience in treating 15 patients with mCRC who tolerated panitumumab with clinical benefit after failure on cetuximab therapy from November 2006 through September 2008 at the Yale Cancer Center in New Haven, CT and at the Saint Francis Cancer Treatment Center in Grand Island, NE. KRAS status was retrospectively assessed in patients with readily available tumor tissue. All 15 patients were treated with a standard dose of panitumumab 6 mg/kg intravenously every 2 weeks. No patient received premedication therapy. Of the 15 patients treated, 4 received only 2 doses of panitumumab but stopped further therapy because of deterioration in performance status. Of the 11 evaluable patients, we noted minor radiographic responses (Response Evaluation Criteria in Solid Tumors) in 3 patients and stable disease (SD) in 3 other patients after 8 weeks of therapy. Five patients had evidence for progressive disease, and further therapy was stopped. The median duration of SD was 4 months (range, 2-8 months). Among the 11 evaluable patients, 1 patient achieved > 50% reduction in carcinoembryonic antigen (CEA; 112 to 49 U/L), 3 patients had a 25% reduction (59 to 43 U/L, 84 to 61 U/L, and 67 to 42 U/L), and 1 patient had minor reduction in CEA (98 to 83 U/L). All patients tolerated panitumumab well with no occurrence of hypersensitivity reactions. Grade 3/4 toxicities were skin rash in 5 patients and asthenia in 1 patient. The other adverse events observed included grade 1-2 skin rash in 2 patients, grade 2 paronychia in 4 patients, grade 2 hypomagnesemia in 2 patients, and fatigue in 3 patients. One patient had wild-type KRAS, and this individual experienced a minor response to antibody therapy with > 50% reduction in CEA. A second patient was found to have mutant KRAS and, in terms of clinical response, this patient experienced SD for 6 months. The third patient evaluated had mutant KRAS, and this individual was unable to tolerate more than 2 doses and was therefore not evaluable for response. Panitumumab may represent an alternative treatment strategy for patients with refractory mCRC who have experienced failure with standard therapy including cetuximab-based regimens. Our relatively small clinical experience suggests that cetuximab and panitumumab may exert their antitumor activity through different mechanisms; however, further work is required to investigate this potentially interesting issue.

Traitement de la tuberculose ganglionnaire : des recommandations à la pratique

Purpose Lymph node infection is the most frequent localization of extrapulmonary tuberculosis. However, there is still no consensus on the length of antimicrobial treatment. Methods We conducted a retrospective study in the Department of infectious diseases and internal medicine in the Amiens Teaching Hospital, France. All patients diagnosed with lymph node tuberculosis between 1998 and 2007 were included; some patients presented with bi- or multifocal tuberculosis. The aim of the study was a practice analysis. Results We studied 48 medical records, 16 were excluded for lack of more than 40% of data or because lymph node tuberculosis was non-active. The mean age of the 32 patients included was 49 years. The mean duration of treatment was 10.9 months (standard deviation 2.6, median 11, range 6–18). There was no statistical age difference between subgroups (lymph node tuberculosis versus multifocal tuberculosis). There was no significant difference between the 6-month treatment group and the 9-month treatment group in term of clinical response. One relapse was diagnosed, eight patients (25%) were lost to follow-up at 1 year after treatment. Discussion and review No reliable published data was found as to the optimal duration of treatment. A high quality clinical trial should be carried out to suggest a consensus.

Long Term Clinical Outcomes, Toxicity, and Immunologic Response of Patients Treated on a Phase II Trial with Definitive Radiation in Combination with a Viral Vaccine to Prostate-specific Antigen

Long Term Clinical Outcomes, Toxicity, and Immunologic Response of Patients Treated on a Phase II Trial with Definitive Radiation in Combination with a Viral Vaccine to Prostate-specific Antigen

Liposome-encapsulated doxorubicin plus paclitaxel and trastuzumab as neoadjuvant chemotherapy for operable and locally advanced breast cancer.

e11069 Background: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, liposome- encapsulated doxorubicin (Myocet) has been widely used in advanced breast cancer with high response rates (92% in Cortes study). The aim of our study was to assess clinical and pathological responses with liposome-encapsulated doxorubicin plus paclitaxel (and trastuzumab in pts with Her2 overexpression). Methods: 30 patients entered the study: 8 locally advanced and 22 operable. Median age was 57 years (range: 31-73). 23 pts without Her-2 3+ expression (or FISH not amplified) were treated with liposome-encapsulated doxorubicin 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 (Taxol) for 8 courses. 7 pts with Her-2 3+ expression or FISH amplified were treated with the same schedule plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/Kg for the following 7 weekly administrations. Results: Objective clinical responses were documented in 18 out of 24 evaluable pts (75%): 7 complete (29%), 7 partial (29%) and 4 minimal responses (17%). Pathological complete response was not documented in any pts. Clinical response in pts with HER-2 pverexpression treated with trastuzumab and chemotherapy was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 out of 14 operable pts (57%) and mastectomy in 11 pts. Main toxicity was neutropenia: febrile in 3 pts (10%) and gr. 3-4 in 10 (34%). Other grade 3 toxicities were as follows: vomiting in 2 pts, asthenia in 1 pt. Conclusions: Paclitaxel and liposome-encapsulated doxorubicin was active in terms of clinical response and conservative surgery for pts with potentially operable and locally advanced breast cancer. Our study confirmed high activity of the combination with trastuzumab in pts with Her2 overexpression. However, these results in terms of clinical responses didn't turn into pathological responses. No significant financial relationships to disclose.

Moxifloxacin is non-inferior to combination therapy with ceftriaxone plus metronidazole in patients with community-origin complicated intra-abdominal infections

Management of community-origin complicated intra-abdominal infections (cIAIs) requires surgical intervention and antimicrobial therapy. This multinational, randomised, double-blind clinical trial carried out in Asia compared the efficacy and safety of moxifloxacin monotherapy and ceftriaxone/metronidazole combination therapy in adults with confirmed or suspected cIAI. Patients received surgical intervention and either intravenous (i.v.) moxifloxacin 400 mg once daily or i.v. ceftriaxone 2 g once daily plus i.v. metronidazole 500 mg twice daily. A total of 364 patients were randomised [intent-to-treat (ITT), moxifloxacin N = 180, comparator N = 181; per-protocol (PP), moxifloxacin N = 174, comparator N = 171]. The most common cIAI diagnosis was complicated appendicitis. Moxifloxacin was non-inferior to ceftriaxone/metronidazole in terms of clinical response at test-of-cure in the PP population [clinical cure, 90.2% for moxifloxacin vs. 96.5% for ceftriaxone/metronidazole; 95% confidence interval (CI) of the difference −11.7 to −1.7] and in the ITT population (87.2% for moxifloxacin vs. 91.2% for ceftriaxone/metronidazole; 95% CI −10.7 to 1.9). Bacteriological cure rates in the microbiologically evaluable population support the clinical results (89.4% for moxifloxacin vs. 95.9% for ceftriaxone/metronidazole; 95% CI −13.3 to −0.6). The incidence of treatment-emergent adverse events was similar for both treatment groups (moxifloxacin 31.7% vs. comparator 24.3%). These results confirm previous findings that moxifloxacin plus adequate source control is an appropriate treatment of cIAI.

Role of circulating angiogenin TGF-β1, VEGF-R1, and VEGF-R2 in metastatic malignant melanoma patients

9048 Background: Malignant melanoma is a disease capable of rapid progression and is associated with high angiogenesis. Thus, investigation of mechanisms involved in metastasis is essential to control this tumor. However, the angiogenesis regulators that are biologically relevant for melanoma are still unknown. We have previously reported that high levels of soluble VEGF in metastatic malignant melanoma (MMM) patients may represent a useful biomarker to predict the effect of biochemotherapy in terms of clinical response. In this study, we evaluate whether soluble levels of angiogenin, transforming growth factor-β1 and VEGFR-1 and -2 play a role in metastatic malignant melanoma patients and to determine if they have any relationship with clinicopathological parameters. Methods: Using a sensitive enzyme-linked immunosorbent assays, angiogenin TGF-β1, VEGF-R1 and VEGF-R2 were measured in sera of 70 patients with a fully documented history of metastatic malignant melanoma in comparison with 30 healthy controls. Results: Pretreatment circulating angiogenin, TGF- β1 VEGF-R1 and VEGF-R2 were detectable, variable in all samples from either melanoma patients or healthy donors Only serum transforming growth factor- β1 levels was significantly higher (p=0.005) in patients compared to healthy controls. No relationship was observed between sex, age or LDH level and all studied parameters. When tumor burden has been taken into consideration, a significant relationship was established between high circulating serum TGF-β1 (p= 0.001) levels and tumor burden were found, Similarly, higher serum VEGFR1 levels were correlated with tumor burden (P = 0.02). Conclusions: The presence of high circulating TGF-β1 and VEGF-R1 in metastatic malignant melanoma patients may prospectively identify high-risk patients with a worse prognosis. In addition, these two parameters may be promising targets for new therapeutic strategies in this pathology. No significant financial relationships to disclose.

Economic Burden of High Risk Acute Lymphoblastic Leukemia (ALL) in Adults and Children

Background: Acute lymphoblastic leukemia is a hematological malignancy, characterized by overproduction of immature white blood cells in the bone marrow. Highrisk forms of ALL are typically characterized by poor treatment response, short remission duration, poor survival with conventional chemotherapy and incur high disease-related costs. The most common form of high-risk acute lymphoblastic leukemia in adults is Philadelphia chromosome positive (Ph+) ALL.Objectives: This study investigated the treatment costs of high-risk ALL from a Canadian perspective.Methods: Costs for the induction phase of ALL treatment (inpatient costs and length of stay in hospital) were obtained from the Ontario Case Costing Initiative (OCCI) acute inpatient databases. Drug costs for outpatient treatment were obtained from the Ontario Drug Benefit Program and the medical literature. Since no published Canadian guidelines were available treatment pathways and costs for consolidation and maintenance phases of chemotherapy, broken down by age and risk level of disease, were based on the medical literature and expert opinion.Results: The average total cost of inpatient ALL treatement (induction phase) was $31,694 for both adults and children. The cost for consolidation therapy was $29,244 and $12,753 in adults and children, respectively. The maintenance therapy cost was $7,288 and $3,452 in adults and children, respectively. The high-risk therapy following relapse was $17,100 and $12,000 in adults and children, respectively. The total treatment cost for ALL is estimated at $85,326 in adults and $59,899 in children.Conclusions: In canada, high-risk ALL exacts a substantial economic burden as a result of rapid disease progression and decreased survival duration. Imatinib (Gleevec®) in Ph+ALL has produced superior results in terms of clinical response, disease-free survival, and overall survival with a good safety and tolerability profile. More comprehensive research is recommended to investigate the economic and humanistic benefits of imatinib as compared to the current therapies in the treatment of Ph+ ALL.

Fotemustine, Etoposide, Aracytin and Melphalan (FEAM), a Different Conditioning Regimen for Lymphoma Treatment with Autologous Hemopoietic Stem-Cell Transplantation

Introduction. BEAM (carmustine, etoposide, aracytin, melphalan) is a conditioning regimen used in autologous hemopoietic stem cell transplantation for Hodgkin Lymphoma and non Hodgkin Lymphoma, with acceptable toxicity and high efficacy. In our study we replaced the carmustine with fotemustine, an analogous chloroethylnitrosourea. Primary end-point was to valuate the feasibility of this modified conditioning regimen.Patients and Methods. 86 patients were consecutively conditioned in seven BM-Units with FEAM before receiving aHSCT. 44 patients (63%) were male, 32 (37%) female. Median age was 51 years (range, 18–77). 23 patients (27%) had HL, 60 (70%) had NHL (2 SLL, 1 LPL, 1 MZL, 2 FL, 6 MCL, 37 DLBCL, 3 BL, 1 B-LBL, 1 T-LBL, 4 u-PTCL, 2 AIL), 1 patient had a B-CLL, 1 a B-ALL FAB L3 and 1 an aggressive NK-cell leukemia. In the lymphoma group, 22 patients (27%) were in stage II (10 with bulky disease), 20 (24%) in stage III and 41 (49%) in stage IV. Among lymphoma patients, 19 (23%) had a bone marrow involvement, 5 (6%) a central nervous system involvement, including 2 primary central nervous system lymphoma. At the time of transplantation, 41 patients (48%) were in CR, 3 (3%) in VGPR, 32 (37%) in PR, 10 (12%) had a resistant-progressive disease (R/PD); 30 patients (35%) were at first line of therapy, 56 (65%) had received more than one line of therapy. Patients received fotemustine 150 mg/m2 on days -7, -6, etoposide 200 mg/m2 and aracytin 400 mg/m2 on day -5, -4, -3, -2, and melphalan 140 mg/m2 on day -1. The median number of CD34+ cells infused was 3.8 × 106/Kg recipient body weight (range, 1–21.8).Results. Only 2 patients were not evaluated for engraftment and toxicity. Among evaluable patients, all engrafted. The median time to neutrophil (N >0.5 × 106/L) and platelet (PLT >20 × 109/L) recovery was 11 (range, 9–19) and 13 days (range, 6–105) respectively. 55 patients (65%) received trasfusions of red blood cell units, with a median of 2 units (range, 1–8). All patients received platelet trasfusions with a median of 2 units (range, 1–15).Toxicity. No chemotherapy-induced nausea and vomiting (CINV) was observed in 17 patients (20%), 53 patients (63%) had CINV grade I–II, 14 patients (17%) grade III, no grade IV was observed. No mucositis was observed in 16 patients (19%), 45 patients (54%) had mucositis grade I–II, 17 patients (20%) grade III, 6 patients (7%) grade IV. No diarrhea was observed in 50 patients (60%), 29 patients (34%) had diarrhea grade I–II, 5 patients (6%) grade III, no grade IV was observed. No epatic toxicity was observed in 80 pts (95%), 1 patient had epatic toxicity grade I, 1 patient grade II and 2 patients grade III, no grade IV was reported. Only one patient had a transient renal toxicity grade II. No pulmonary toxicity was observed. Fever >38, 5°C was documented in 68 patients (81%) with a median duration of 4 days (range 1–25). GRAM-were identified in 15 patients, GRAM+ in 14 patients, yeasts were isolated in 3 patients and there was only one infection by Pneumocystis Carinii. In the other 35 patients (51%) no organism was identified as the source of the fever which was classified as FUO.Outcome. At a median follow-up of 5 months (range, 1–16), 79 patients (92%) are alive. On 75 evaluated patients, fifty-nine (79%) are alive and free from disease. Among the seven deceased patients, three died for PD at day +111, +110 and +75 from transplantation respectively, one died for bacterial meningitis at day +45 from transplantation, after a complete hematologic recovery, one in PR died for gastric haemmorrhage from tumor site, and two (1 CR, 1 VGPR) died for comorbidity, respectively at day +150 and +240 from transplantation. TRM at 100 days was 1%. Among the 75 patients who were evaluated after aHSCT, thirty-five patients, out of thirty-six who were in CR before aHSCT, maintained the CR after, for the other thirty-nine, twenty-seven (69%) achieved the CR (three of these had a CNS involvement before aHSCT), one achieved a VGPR, two a PR (ORR 77%), four had a stable disease and five progressed. Considering as treatment failure the relapse, the progression or the death for any cause, in our study the treatment failure was assessed on 16%.Conclusions. Our study demonstrated the feasibility and the safety of the FEAM, regard its toxicity it was not superior with respect to BEAM. However, a longer follow-up is needed to valuate the efficacy of this modified conditioning regimen in term of clinical response.

Therapeutic Strategy for Treatment of Metastatic Non-Small Cell Lung Cancer

To review the current practices for metastatic non-small cell lung cancer (NSCLC) management and highlight the latest progress. A literature review using HighWire Press (1960-May 2008) was conducted using the following key words: non-small cell lung cancer, chemotherapy, supportive care, therapeutic strategy, quality of life (QOL), and targeted therapies. Review articles, clinical trials, and case reports, as well as the references of those articles, were reviewed. Statistical significance and number of patients included in the studies were some of the aspects that were considered seriously. Response rates, overall survival, and progression-free survival were the major data considered. The therapeutic management of metastatic NSCLC has undergone a profound evolution over the past 10 years. The positive impact of chemotherapy on survival compared with supportive care alone has been demonstrated by several meta-analyses. The development of third-generation agents with better efficacy/toxicity ratios, such as vinorelbine, paclitaxel, docetaxel, gemcitabine, and pemetrexed, has led to improved therapeutic management of NSCLC, especially when tailored to patients' comorbidities and performance status. First-line platinum-based combinations remain the standard of care, with median survival 8 months and 1-year survival 35%, but no particular combination has yet shown superiority. First-line platinum regimens in combination with bevacizumab, a targeted inhibitor of vascular endothelial growth factor, have further improved NSCLC median survival. Moreover, second- and third-line treatments have evolved. The addition of small-molecule epidermal growth factor inhibitors and other targeted therapies has modified the pattern of NSCLC treatment. Specific management of the elderly and patients with poor performance status should be applied. Although there has been progress in the treatment of NSCLC, the gain in terms of clinical response and survival is still modest. Maintaining QOL and tailoring therapy for patients based on age, performance status, comorbidities, and toxicities, remain the first priority for clinicians.

Study of IL-2 receptor expression after chemoimmunotherapy in patients treated for metastatic malignant melanoma.

Using flow cytometry, cellular IL-2 receptors were studied before and following chemoimmunotherapy combination in 20 patients with metastatic malignant melanoma (MMM). Patients received cisplatin (100 mg/m2) at days 1 and 28, recombinant IL-2 by continuous infusion from days 3 to 6, 17 to 21, 31 to 34, and 45 to 49. Interferon-alpha (IFN-alpha) was given subcutaneously three times weekly. In terms of clinical response, we observed 55% objective response (complete: 15%). When pretreatment blood samples were compared with those of healthy donors, we did not observe any change in low (alpha chain) and high affinity receptor (alpha + beta) expression. In contrast, intermediate affinity p75 (beta chain) expression was decreased significantly (P < or = 0.0001) in MMM patients. During treatment, we found a dramatic increase of beta chain as well as high affinity (alpha + beta) expression in responding patients, as soon as IL-2 therapy began. Furthermore, the increase of beta chain expression was limited to natural killer (NK) cells (CD56+). In non-responding patients, on the other hand, increase of both receptors was seen only at day 31. These data suggest the involvement of beta chain expression in the mechanism of cell activation after chemoimmunotherapy. Moreover, this early beta chain expression is correlated with the clinical response to chemoimmunotherapy.

Use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections

Background: The ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. Ketolides bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the FDA in 2004 for treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) and sinusitis. However, in 2006, after reports of serious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of AECB and sinusitis were removed from the labeling. Cethromycin (ABT-773) is the only other ketolide currently under clinical development. Objective: To review currently available data on cethromycin, including chemistry, in vitro activity, pharmacokinetics, pharmacodynamics, in vivo activity and results of treatment studies in humans. Methods: A search was made in PubMed, pharmaceutical databases and meeting abstracts using the terms ketolides, ABT-773 and cethromycin. Results/conclusions: Cethromycin has comparable tissue penetration, pharmacokinetics and in vitro activity compared with telithromycin to Streptococcus pneumoniae, including multidrug-resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. There is only one published CAP treatment study that compared cethromycin 150 mg q.d. with 150 mg b.i.d. One Phase II and a Phase II/III study have been presented in abstract form, both were non-comparative, dose-ranging studies, which suggested that 150 mg q.d. or 300 mg q.d. were comparable in terms of clinical response and bacterial eradication, although data on the latter are limited. Data on side effects are limited and appear to be mainly gastrointestinal. There have been no reports of serious hepatotoxicity at the time of this writing. Cethromycin may have other uses in addition to treatment of CAP respiratory infections, including treatment of infections due to Neisseria gonorrhoeae and Chlamydia trachomatis and bioterrorism agents including Bacillus anthracis, Yersinia pestis and Francisella tularensis.

Pemphigus

Pemphigus is an uncommon but potentially life-threatening chronic autoimmune bullous disorder. Antibodies are directed against antigens (desmoglein 1 and 3) in the desmosomes linking keratinocytes and against acetylcholine receptors. Conventional treatment with high-dose corticosteroids, sometimes with adjuvant immunosuppressive agents, may be associated with very serious adverse effects. There is an urgent need to establish the evidence for the safest and most effective form of treatment. A literature review has revealed 11 controlled (9 randomized) trials of treatment for pemphigus. The numbers of participants in the individual trials are small and the data cannot be pooled as they evaluate different forms of treatment. The results of these trials suggest that very high doses of corticosteroids, either as pulse therapy or in daily dosage, are not superior to moderate daily doses. Based on evidence from the available trials, addition of an immunosuppressive agent generally does not appear to offer substantial benefit in terms of clinical response. However, a recent study demonstrated a significant reduction in corticosteroid requirements among patients receiving immunosuppressive agents. Newer therapies, such as biologic agents (in particular rituximab), calcineurin inhibitors, or immunoadsorption appear promising but there are inadequate controlled trials to establish their role clearly. Initial open-label studies suggest that specific peptide immunotherapy may offer a safe and novel approach to the treatment of pemphigus in the future. At present, treatment of an individual patient with pemphigus requires clinical judgment and should not be based purely on guidelines or on the inadequate available evidence alone. There is an urgent need for large randomized, controlled, multicenter trials of treatment in patients with pemphigus.

What Have We Learned from Measuring Health-Related Quality of Life in Patients with Chronic Lymphocytic Leukemia? A Systematic Review of Published Studies from 1990 to 2007.

While a large amount of health-related quality of life (HRQOL) studies has been conducted in patients with solid tumors, no data are available for patients with CLL. The aim of the present work was therefore to quantify and evaluate the quality of studies investigating patient's self-reported HRQOL in CLL patients. A systematic literature search for studies meeting the criteria, published from 1990 to 2007, was undertaken on a number of databases. Candidate articles were mainly searched in PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL). Meeting abstracts at ASCO and ASH conferences were also assessed. We used the following key terms to identify candidate articles “quality of life” and “CLL” or “lymphocytic leukemia” or “chronic leukemia”. All articles included in the review were independently evaluated based on a pre-defined set of methodological issues and criteria by two reviewers (SM and FE). These included a number of methodological and statistical quality criteria such as HRQOL missing data documentation, timing of assessment, rationale for instrument selection and discussion of outcomes in terms of clinical significance. In addition, HRQOL and traditional clinical outcomes were extracted and analyzed. More than 200 candidate articles were evaluated, but only 5 studies met the inclusion criteria for the review. The majority of articles were excluded as HRQOL was not measured by patient's reported tools. Overall, some 1019 patients were involved in these studies. HRQOL was assessed in 3 prospective randomized controlled trials (RCTs) and 2 longitudinal non-randomized studies. Two of these 5 studies were only published as abstracts. The EORTC QLQ-C30 was the most frequently used measure being utilized in 4 out of 5 studies. Some methodological constraints were identified, mainly in terms of handling of HRQOL missing data and possible lack of sensitivity of the measure being used. The most robust evidence stemmed from a prospective RCT comparing Fludarabine (F) vs. Fludarabine + Cyclophopsphamide (FC) where HRQOL was assessed as a secondary endpoint. While there was no significant HRQOL difference between treatment arms over time, this study showed nonetheless that the newer FC combination had no detrimental effect on patient's HRQOL compared with the standard F arm. This information definitely reinforces concomitant clinical findings which favor the more intensive FC treatment (e.g. in terms of clinical response and progression-free survival). Taken together, very limited conclusions can to date be drawn with regard to HRQOL issues in patients with CLL in view of the paucity of data in this area. There is urgent need of implementing HRQOL research in patients with CLL and of providing the scientific community with robust evidence-based data on the impact of new treatment approaches in these patients.

MRI activity and neutralising antibody as predictors of response to interferon β treatment in multiple sclerosis

Objective:To prospectively validate MRI activity and neutralising anti-interferon antibody (NAb) during the first 6 months of interferon β treatment as response indicators in multiple sclerosis (MS).Methods:Patients with relapsing–remitting MS were...

Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) has increased longevity. Currently, women comprise >50% of HIV-infected individuals worldwide. It is not known if there are differences between the sexes in the immunological and virological responses to HAART across the age strata. Immunological reconstitution and virological response in the first 6 months of a first HAART regimen in two observational clinical HIV-infected cohorts were compared by both sex and age (>or=50 vs. <50 years old). A total of 246 individuals (28% women) were included in the study; 63 cases (>or=50 years old) and 183 controls (<50 years old). Over two-thirds of patients had HIV RNA levels <400 HIV-1 RNA copies/mL and CD4 count increases >or=50 cells/microL at 6 months from therapy initiation. There were no differences in immunological reconstitution across age and sex strata (P=0.81) and no differences in virological suppression, even after adjusting for type of HAART (P=0.68) or restricting the analysis to women only (P=0.81). These results suggest that younger and older women and men may have similar short-term initial HAART outcomes. Further evaluation of longer term clinical response to initial HAART regimen based on sex and age is indicated, especially with more efficacious and simplified antiretroviral regimens and the associated decrease in mortality.

Topoisomerase I expression in locally advanced rectal cancer as predictive marker for response to preoperative chemoradiation

14566 Background: In locally advanced rectal cancer combined modality treatment has become the standard therapeutical intervention. Preoperative downstaging is known as a predictor concerning lower local recurrence rate and probably better overall-survival. However, efficacy of neoadjuvant chemoradiation is compromised in some patients by so far unknown factors. The aim of the present study was to investigate topoisomerase I expression as a potential parameter for predicting response to irinotecan-based chemoradiation. Methods: 15 patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive weekly neoadjuvant irinotecan (1 hour before radiation) and capecitabine as well as cetuximab with a concurrent RT dose of 50.4 Gy (45+5.4 Gy). Surgery was scheduled 4–6 weeks after the completion of chemoradiation. Samples of normal and tumor tissues of all patients were collected before neoadjuvant treatment. Initially, RNA-oligonucleotid-array of three patients (one good responder and two non-responders) was accomplished to show qualitatively different gene expression. To quantify the differences, real-time PCR of topoisomerase I was performed. Results: The differences of gene expression in the RNA-oligonucletoidarray were correlated to the clinical response to neoadjuvant chemoradiation as topoisomerase I showed a significant higher expression in the tumor tissue of the good responder before treatment (p&lt;0.0001). PCR-analysis showed a relatively higher median expression of topoisomerase I in normal tissue (1.7 vs. 0.9; p=0.85) and in tumor tissue (1.5 vs. 1.3; p=0.36) of the subsequent good responding patients (n=10). Conclusion: Patients respond differentially to chemoradiation in terms of clinical response and gene expression shifts. The oligonucleotidarray results leads us to assume that response may be predictable. The preliminary results of PCR demonstrate that TopoI expression describes a valuable parameter for prediction of efficiency of irinotecan in advanced rectal cancer. The small number of patients may have caused the missing of the statistical significance. We are intending an extension of the PCR analysis to more powerful series based on the achievements of the current investigation results. No significant financial relationships to disclose.

Cytomegalovirus as a Cause of Anterior Uveitis in Immunocompetent Patients

To describe 7 cases of unilateral, chronic and/or recurrent anterior uveitis caused by cytomegalovirus (CMV) in immunocompetent patients; to identify specific ophthalmologic characteristics; and to evaluate the clinical effect of valganciclovir treatment. Retrospective observational case series. Immunocompetent patients (n = 7) with a history of chronic and/or recurrent unilateral anterior uveitis and a positive analysis for either CMV-DNA and/or antibodies against CMV in their aqueous humor (Goldmann-Witmer coefficient > 3). Full ophthalmologic examination, anterior chamber fluid analysis, serologic examination, and systemic evaluation. Treatment modalities included topical steroids, topical and/or systemic antiglaucoma medications, glaucoma surgery, and systemic valganciclovir. Visual acuity, inflammation, and intraocular pressure (IOP). Chronic unilateral anterior uveitis was seen in 6 patients, whereas recurrent uveitis was observed in 1. Additional findings consisted of slight iris atrophy and secondary glaucoma (n = 3), secondary glaucoma without iris abnormalities (n = 3), and a slightly elevated IOP without iris abnormalities (n = 1). Examinations of the aqueous humor by polymerase chain reaction demonstrated CMV-DNA in 6 patients and were negative for other herpes viruses in all. Goldmann-Witmer coefficients were strongly positive in 4 out of 5 patients. Other laboratory investigations were within normal limits. No other causes for uveitis were identified. Because of the insufficient effect of topical steroids and antiglaucoma medications, 5 patients were treated with additional oral valganciclovir with good clinical response in terms of uveitis activity and IOP. Discontinuation of valganciclovir in 1 patient resulted in a prompt recurrence of uveitis activity. Cytomegalovirus may cause a chronic and/or recurrent anterior uveitis in otherwise healthy patients. Iris atrophy and glaucoma may accompany it, but an inflammatory reaction in the anterior chamber may be the only sign. Aqueous humor analysis is of the utmost importance in differentiating between CMV and other herpes viruses and in making a definite diagnosis in chronic anterior uveitis. Valganciclovir may be very effective in treating CMV anterior uveitis, but its exact role can only be determined in larger studies with a longer follow-up.

Antidepressants for the negative symptoms of schizophrenia.

Negative symptoms are common in people with schizophrenia and are often difficult to treat with antipsychotic drugs. Treatment often involves the use of various add-on medications such as antidepressants. To review the effects of the combination of antipsychotic and antidepressant drug treatment for management of negative symptoms in schizophrenia and schizophrenia-like psychoses. We searched the Cochrane Schizophrenia Group's register (January 2004). We also contacted authors of included studies in order to identify further trials. We included all randomised controlled trials comparing antipsychotic and antidepressant combinations with antipsychotics alone for the treatment of prominent negative symptoms in schizophrenia and/or schizophrenia-like psychoses. Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated the relative risk RR) and their 95% confidence intervals (CI), with the number needed to treat (NNT). We included five studies (all short-term, total N=190). We found no significant difference for 'leaving the study early for any reason' between the antipsychotic plus antidepressant combination and the control group (n=90, 3 RCTs, RR 3.0 CI 0.35 to 26.04). Leaving early due to adverse events (n=64, 2 RCTs, RR 5.0 CI 0.26 to 97.0) and leaving the study early due to inefficacy (n=34, 1 RCT, RR 3.0 CI 0.13 to 68.84) also showed no significant difference between the two treatment groups. In terms of clinical response, participants treated with the antipsychotic plus antidepressant medications showed a statistically significant greater improvement (n=30, 1 RCT, WMD -1.0 CI -1.61 to -0.39) and showed a significantly lower severity at endpoint (n=30, 1 RCT, WMD -0.9 CI -1.55 to -0.25) on the Clinical Global Impression Scale than those treated with antipsychotics alone. More people allocated to combination therapy had a clinically significant improvement in negative symptoms compared with those given antipsychotics and placebo (n=60, 2 RCTs, RR 0.56 CI 0.32 to 0.97, NNT 3 CI 3 to 34). Significant differences in favour of the combination therapy were seen in different aspects of negative symptoms: 'affective flattening' (n=30, 1 RCT, WMD -7.0 CI -10.37 to -3.63), 'alogia' (n=26, 1 RCT, WMD -3.00 CI -5.14 to -0.86) and 'avolition' (n=30, 1 RCT, WMD -3.0 CI -5.04 to -0.96). No statistically significant difference was found between treatment groups in regards to the outcome 'at least one adverse event' (n=84, 2 RCTs, RR 1.80 CI 0.66 to 4.90). For movement disorders and other adverse effects, no statistically significant differences were found in any of the studies that provided usable data on these outcomes. There are no data at all on outcomes such as compliance, cost, social and cognitive functioning, relapse, recurrence of negative symptoms, rehospitalisation or quality of life. There are no medium or long term data. The combination of antipsychotics and antidepressants may be effective in treating negative symptoms of schizophrenia, but the amount of information is currently too limited to allow any firm conclusions. Large, pragmatic, well-designed and reported long term trials are justified.