Sustained Treatment Response Research Articles

High‐Grade Salivary Duct Carcinoma of the Parotid Gland: Clinicopathologic Features and Treatment Outcomes

Objectives: (1) Analyze the treatment approach for these rare salivary gland neoplasms at our institution. (2) Demonstrate observed patterns of failure and survival for high-grade salivary duct carcinoma (HGSDC) involving the parotid glands. Methods: Clinical data on 17 patients with nonmetastatic HGSDC involving parotid salivary glands from 1998 to 2012 were abstracted from our institutional database. Inclusion required surgical resection with postoperative radiotherapy (n = 8) or concurrent chemoradiotherapy (n = 9). Demographics, histopathologic features, treatment course, and clinical outcomes were recorded. Specimens were re-reviewed by a dedicated head and neck pathologist. Overall survival (OS) and disease-free survival (DFS) were estimated via Kaplan-Meier method, and comparisons were made with the log-rank test. Results: Median patient age was 65 years (range, 52-83 years) with a male:female ratio of 7.5:1 and median follow-up of 37 months. Most commonly, these cases presented as pT4a (n = 14) with adverse clinical features, including perineural invasion (76.5%), positive lymph nodes (76.5%), and vascular invasion (58.8%). Three-year DFS and OS were 35.7% and 61.4%, respectively. The pattern of treatment failure was predominately distant (n = 11) versus locoregional (n = 3). Univariate analysis of demographic, histopathologic, and treatment characteristics did not reveal a significant association with OS or DFS. Median survival after metastasis was 13 months, with only a single patient having a sustained treatment response >2 years after disease dissemination. Conclusions: In this series, we highlight the aggressive nature of high-grade salivary duct carcinoma, which has a significant risk of distant recurrence and poor overall survival.

Rituximab For The Treatment Of Hepatitis C Associated IgM Mediated Cold Hemolytic Anemia – Case Report and Literature Review

In April 2007 a 48-year-old woman with a history of hepatitis C and anti-phospholipid antibody syndrome presented with a hemoglobin (Hb) of 5.3g/dL. Lactate dehydrogenase and bilirubin were elevated at 582U/L and 66µmol/L respectively. Severe autoimmune hemolytic anemia due to cold agglutinins was diagnosed based on a positive DAT (C3B and C3D positive, IgG negative) and detection of cold agglutinins. The patient was discharged 4 days later with a Hb of 8.3g/dL after plasma exchange and transfusion of 3 units of RBCs. Immunosuppressive therapy was initially avoided due to the risk of hepatitis C activation. Treatment over the next 12 months consisted of as needed RBC transfusions and IVIg infusions. Treatment with corticosteroids occurred only during 1 of 2 hospital admissions for severe anemia – the patient otherwise refused corticosteroid treatment. Although responses to IVIg were consistently favorable they were short lived. Rituximab was administered in an effort to achieve a more sustained treatment response. The dose of 375mg/m2weekly for 4 weeks was administered in August 2008. A dramatic but transient decrease in IVIg requirements was observed. Periodic treatment with IVIg was continued over the next 19 months until a second rituximab course was administered in June 2010. IVIg has been required on only 6 occasions in the almost three years since the second rituximab course (see Figure 1). To determine the efficacy of rituximab in this condition, we searched the MEDLINE and EMBASE databases. Articles citing the use of rituximab to treat mixed-type or cold autoimmune hemolytic anemia (CAIHA) were identified. Ten studies (summarized in Table 1) and 43 case reports/series (48 total cases) met our criteria for inclusion. A complete response (CR) required Hb>12g/dL and the sustained absence of hemolysis. Disappearance of cold agglutinins was not required for a CR. A partial response (PR) required an improvement of symptoms, transfusion independency, and either: Hb>10g/dL or at least 2.0g/dL above pre-treatment levels, or a decrease in serum IgM concentration by at least 50%. Non-responders met neither CR nor PR criteria. Ages of the 26 male and 22 female patients ranged from 1-85 years with a median of 62 years. Diagnoses of CAIHA were reported in 40 cases, and mixed-type in 8. On average, patients had received 3 modes of treatment prior to rituximab. CRs were observed in 34 patients (70.8%), PRs in 7 (14.6%), and NRs in 7 (14.6%). Three of the 7 non-responders experienced an improvement in condition despite not meeting response criteria. Adverse effects were reported in only 3 cases and included a post-infusion low-grade fever, transient lymphopenia, and agranulocytosis (possibly due to CMV reactivation and not rituximab therapy).Table 1Studies employing rituximab to treat cold or mixed autoimmune hemolytic anemia.CitationStudy typeNumber of participants, Age rangeAIHA typeOutcome (CR, PR, NR)Barcellini et al, 2012prospective multicenter9, 30-71cold16.6%, 33.3%, 0Berentsen et al, 2010prospective multicenter29, 39-87cold21%, 55%, 24%Berentsen et al, 2001prospective6, 54-80cold14%, 57%, 29%Berentsen et al, 2004prospective27, 51-91cold3%, 51%, 46%Berentsen et al, 2006retrospective multicenter52, 51-96*coldsingle agent: 5%, 53%, 42%in combination: 25%, 42%, 33%Cholankeril et al, 2012retrospective single institution6, 62-894 cold, 2 mixedOR 100%, median Hb rise of 1.8g/dLPeñalver et al, 2010retrospective multicenter9, 20-86*coldCR and MR 66.7%Schöllkopf et al, 2006prospective multicenter20, 54-86cold5%, 40%, 55%Dierickx et al, 2009retrospective multicenter14, 1-87*cold28.6%, 35.7%, 35.7%Zecca et al, 2003prospective1, 1.3coldresponderZaja et al, 2003not specified1, 72coldcomplete responder*age range reflects entire study population, not CAIHA subgroupOR=overall response, MR=maintained response In summary, we report a case of CAIHA. A literature summary supported the efficacy of rituximab for this condition. Based on our observations we recommend the use of rituximab over alternative therapies for patients with CAIHA to reduce symptoms, need for transfusion and reduce exposure to immunosuppressive drugs (Grade 2C Recommendation). Disclosures: Off Label Use: Rituximab was used to treat cold autoimmune hemolytic anemia. Crowther:Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck: Consultancy; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

123I-Iodobenzamide SPECT Is Not an Independent Predictor of Dopaminergic Responsiveness in Patients with Suspected Atypical Parkinsonian Syndromes

The prediction of dopaminergic responsiveness in patients with parkinsonism is desirable for effective treatment strategies. We investigated whether striatal dopamine D2/D3 receptor (D2R) binding assessed by (123)I-iodobenzamide SPECT is an independent predictor of dopaminergic responsiveness in patients with parkinsonism. Seventy-eight patients with clinically suspected atypical parkinsonian syndrome (APS) were prospectively recruited for imaging. To quantify striatal D2R binding, (123)I-iodobenzamide SPECT datasets were subjected to an observer-independent, regions-of-interest analysis. A final clinical diagnosis of Lewy-body disease (LBD) or APS was made after a mean follow-up of 12 mo. On the basis of follow-up data, dopaminergic responsiveness was classified as 0 (none), 1 (transient), 2 (sustained mild), or 3 (sustained strong). Uni- and multivariate analyses of the relationship between treatment response, D2R binding, and confounding variables were conducted. Sixty patients with clinically verified LBD (n = 28; 22/28 with Parkinson disease) or APS (n = 32), in whom dopaminergic responsiveness could be assessed (n = 19/13/15/13 in categories 0/1/2/3; 18 were excluded because of insufficient dosing), were included in the statistical analysis. Univariate analyses revealed that a sustained treatment response was significantly associated with higher D2R binding, clinical diagnosis of LBD, lower Hoehn and Yahr scores, and younger age. After multivariate correction of D2R binding for diagnosis, age, symptom duration, Hoehn and Yahr score, and dopaminergic pretreatment, no association was found between D2R binding and treatment response, either in the pooled group or in LBD or APS subgroups. Striatal D2R binding assessed by (123)I-iodobenzamide SPECT does not provide additional predictive information about treatment response beyond other clinical variables, most notably the clinical diagnosis.

Hepatocyte growth factor in neovascular age related macular degeneration: In vitro study of its effects on choroidal endothelial cells

AbstractPurpose Intraocular angiogenesis is associated with a number of common blinding conditions including neovascular age‐related macular degeneration (nAMD). The growth factor vascular endothelial growth factor (VEGF) is reported as being central in driving choroidal neovascularisation in nAMD. Many clinical nAMD therapies target VEGF with anti‐VEGF drugs such as ranibizumab, bevacizumab and Aflibercept. These however have limited efficacy and require repeated, prolonged treatment. Other cytokines are known to be involved in nAMD including hepatocyte growth factor (HGF) which has been shown to have a role in the early stages of nAMD. Our aim was to elucidate the effect of HGF and its cooperation with VEGF on human choroidal endothelial cells (CEC).Methods The expression of HGF and related molecules in CEC was investigated using western blotting and flow cytometry. In vitro assays for proliferation, tubule formation and transendothelial permeability were used to assess the role of HGF in nAMD.Results Expression of HGF, VEGF and their receptors c‐met and VEGFR2 and co‐receptor CD44v6 was found in primary human CEC. Stimulation with HGF increased CEC proliferation and tube formation but did not increase permeability, the increased proliferation was additive with VEGF.Conclusion This study provides insight into the interactions or cross‐talk in CEC signalling and indicates that a more efficient approach to regulate intraocular angiogenesis would aim to simultaneously block the actions of multiple growth factors, or the common downstream site in the angiogenesis pathway and this may provide a more sustained treatment response in order to enhance treatment protocols in nAMD. Commercial interest

Efficacy of Infliximab in Intestinal Behçet’s Disease

Although infliximab is widely accepted as a therapeutic option for inflammatory bowel disease, its therapeutic efficacy for the treatment of intestinal Behçet's disease (BD) is unknown. We investigated the short-term and long-term response rates to infliximab in intestinal BD and predictive factors of sustained treatment response following infliximab treatment. This study was conducted using a retrospective noncontrolled review of medical records from 8 tertiary hospitals in Korea. We collected clinical, demographic, and laboratory data for patients with 28 patients with intestinal BD who received at least 1 dose of infliximab. Response rates of infliximab at 2, 4, 30, and 54 weeks for each patient and factors predictive of sustained response were investigated. Adverse events were also identified. The median duration of follow-up after initial infliximab infusion was of 29.5 months. The clinical response rates at 2, 4, 30, and 54 weeks were 75%, 64.3%, 50%, and 39.1%, respectively, with clinical remission rates of 32.1%, 28.6%, 46.2%, and 39.1%, respectively. After multivariate analysis, older age at diagnosis (≥40 yr), female sex, a longer disease duration (≥5 yr), concomitant immunomodulator use, and achievement of remission at week 4 were found to be predictive factors of sustained response. There was 1 serious infection but no malignancies or deaths in this study. Infliximab was a well-tolerated and effective therapy for patients with moderate-to-severe intestinal BD. Moreover, we found 5 predictive factors associated with sustained response, which might assist in optimal patient selection for infliximab treatment.

Formal hepatitis C education enhances HCV care coordination, expedites HCV treatment and improves antiviral response

Formal Hepatitis C virus (HCV) education improves HCV knowledge but the impact on treatment uptake and outcome is not well described. We aimed to evaluate the impact of formal HCV patient education on primary provider-specialist HCV comanagement and treatment. Primary care providers within the San Francisco safety-net health care system were surveyed and the records of HCV-infected patients before and after institution of a formal HCV education class by liver specialty (2006-2011) were reviewed retrospectively. Characteristics of 118 patients who received anti-HCV therapy were: mean age 51, 73% males and ~50% White and uninsured. The time to initiation of HCV treatment was shorter among those who received formal education (median 136 vs 284 days, P < 0.0001). When controlling for age, gender, race and HCV viral load, non-1 genotype (OR 6.17, 95% CI 2.3-12.7, P = 0.0003) and receipt of HCV education (OR 3.0, 95% CI 1.1-7.9, P = 0.03) were associated with sustained virologic treatment response. Among 94 provider respondents (response rate = 38%), mean age was 42, 62% were White, and 63% female. Most providers agreed that the HCV education class increased patients' HCV knowledge (70%), interest in HCV treatment (52%), and provider-patient communication (56%). A positive provider attitude (Coef 1.5, 95% CI 0.1-2.9 percent, P = 0.039) was independently associated with referral rate to education class. Formal HCV education expedites HCV therapy and improves virologic response rates. As primary care provider attitude plays a significant role in referral to HCV education class, improving provider knowledge will likely enhance access to HCV specialty services in the vulnerable population.

Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections

Acute bacterial skin and skin structure infections (ABSSSIs), including cellulitis or erysipelas, major cutaneous abscesses, and wound infections, can be life-threatening and may require surgery and hospitalization. Increasingly, ABSSSIs are associated with drug-resistant pathogens, and many antimicrobial agents have adverse effects restricting their use. Tedizolid phosphate is a novel oxazolidinone in development for the treatment of ABSSSIs. To establish the noninferiority of tedizolid phosphate vs linezolid in treating ABSSSIs and compare the safety of the 2 agents. The Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs 10-day Oral Linezolid Therapy (ESTABLISH-1) was a phase 3, randomized, double-blind, noninferiority trial that was conducted from August 2010 through September 2011 at 81 study centers in North America, Latin America, and Europe. The intent-to-treat analysis set consisted of data from 667 adults aged 18 years or older with ABSSSIs treated with tedizolid phosphate (n = 332) or linezolid (n = 335). A 200 mg once daily dose of oral tedizolid phosphate for 6 days or 600 mg of oral linezolid every 12 hours for 10 days. The primary efficacy outcome was early clinical response at the 48- to 72-hour assessment (no increase in lesion surface area from baseline and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours). A 10% noninferiority margin was predefined. In the intent-to-treat analysis set, the early clinical treatment response rates were 79.5% (95% CI, 74.8% to 83.7%) of 332 patients in the tedizolid phosphate group and 79.4% (95% CI, 74.7% to 83.6%) of 335 patients in the linezolid group (a treatment difference of 0.1% [95% CI, -6.1% to 6.2%]). The sustained clinical treatment response rates at the end of treatment (day 11) were 69.3% (95% CI, 64.0% to 74.2%) in the tedizolid phosphate group and 71.9% (95% CI, 66.8% to 76.7%) in the linezolid group (a treatment difference of -2.6% [95% CI, -9.6% to 4.2%]). Results of investigator-assessed clinical treatment success rates at a posttherapy evaluation visit (1-2 weeks after the end-of-treatment visit) were 85.5% (95% CI, 81.3% to 89.1%) in the tedizolid phosphate group and 86.0% (95% CI, 81.8% to 89.5%) in the linezolid group (a treatment difference of -0.5% [95% CI, -5.8% to 4.9%), and were similar for 178 patients with methicillin-resistant Staphylococcus aureus isolated from the primary lesion. Tedizolid phosphate was a statistically noninferior treatment to linezolid in early clinical response at 48 to 72 hours after initiating therapy for an ABSSSI. Tedizolid phosphate may be a reasonable alternative to linezolid for treating ABSSSI. clinicaltrials.gov Identifier: NCT01170221.

Rituximab in the treatment of refractory or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

IntroductionEosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear.MethodsWe report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment.ResultsAll patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded.ConclusionsIn our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an efficient and safe treatment for ANCA-positive and ANCA-negative patients. Preemptive retreatment with RTX, combined with standard maintenance immunosuppressants, resulted in a sustained treatment response. Prospective, randomized trials evaluating the use of RTX in EGPA are warranted.

Population-Based Sequencing of the V3-loop Can Predict the Virological Response to Maraviroc in Treatment-Naive Patients of the MERIT Trial

MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing. HIV env V3-loop was amplified in triplicate using reverse transcriptase-polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876). Approximately 8% of patients screened as having R5 virus by OTA were classified as having non-R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar. The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.

Baseline Serum Cholesterol Is Associated with a Response to Pegylated Interferon Alfa-2b and Ribavirin Therapy for Chronic Hepatitis C Genotype 2

Background. HCV infection is associated with lipid disorders because this virus utilizes the host lipid metabolism to sustain its life cycle. Several studies have indicated that higher concentrations of serum cholesterol and LDL before treatment are important predictors of higher rates of sustained virological response (SVR). However, most of these studies involved patients infected with HCV genotype 1. Thus, we performed a multi-institutional clinical study to evaluate the impact of lipid profiles on SVR rates in patients with HCV genotype 2. Methods. A total of 100 chronic hepatitis C patients with HCV genotype 2 who received peg-IFN alfa-2b and ribavirin therapy were consecutively enrolled. The significance of age, sex, BMI, AST level, ALT level, WBC, hemoglobin, platelet count, gamma-glutamyltransferase, total cholesterol level (TC), LDL level, HCV RNA, and histological evaluation was examined for SVR using logistic regression analysis. Results. The 100 patients infected with HCV genotype 2 were divided into 2 groups, an SVR group and a non-SVR group. Characteristics of each group were subsequently compared. There was no significant difference in the level of HCV RNA, BMI, platelet, TG, or stage of fibrosis between the groups. However, there were significant differences in the levels of TC and LDL-C. In multivariate logistic regression analysis using baseline characteristics, high TC level was an independent and significant risk factor (relative risk 18.59, P = 0.015) for SVR. Conclusion. Baseline serum total cholesterol levels should be considered when assessing the likelihood of sustained treatment response following the course of peg-IFN and ribavirin therapy in patients with chronic HCV genotype 2 infection.

Complete Barrett’s excision by stepwise endoscopic resection in short-segment disease: long term outcomes and predictors of stricture

Complete Barrett's excision (CBE) of short-segment Barrett's high grade dysplasia (HGD) and early esophageal adenocarcinoma by stepwise endoscopic resection is a precise staging tool, detects covert synchronous disease, and may produce a sustained treatment response. Esophageal stricture is the most commonly reported complication of CBE although risk factors have not yet been clearly defined. Data were recorded prospectively on patients with limited co-morbidity and age ≤ 80 years undergoing CBE for histologically proven HGD or esophageal adenocarcinoma within ≤ C3M5 segments. Endoscopic resection was performed by standardized protocol every 6 - 8 weeks until CBE was achieved. Esophageal dilation was performed when patients reported dysphagia. Dysphagia scores were recorded at scheduled endoscopic surveillance or by telephone interview. By intention-to-treat analysis, complete eradication of neoplasia and intestinal metaplasia was achieved in 95 % and 82 %, respectively, in 77 patients undergoing a median of 2 resection sessions (interquartile range [IQR] 1 - 3). Esophageal dilation was required in 33 % (median 3 dilations, IQR 1 - 3.5) at median follow-up of 20 months (IQR 6 - 40). Independent risk factors for dilation requirement were the number of mucosal resections at the index procedure (odds ratio [OR] 1.3 per resection, 95 % confidence interval [CI] 1.0 - 1.9; P = 0.043) and maximal extent of the Barrett's segment (OR 2.2 per cm, 95 %CI 1.2 - 3.9; P = 0.009). Although CBE is highly effective in the treatment of Barrett's HGD and esophageal adenocarcinoma, the risk of post-CBE dysphagia increases with the maximal extent of the Barrett's segment and the number of mucosal resections at the index procedure. These data could be used to inform treatment decisions and identify those patients who may benefit from prophylactic therapies such as dilation.

P.3.c.039 Sustained treatment response in schizophrenia to JNJ-37822681 can be predicted within three days

P.3.c.039 Sustained treatment response in schizophrenia to JNJ-37822681 can be predicted within three days

Secondary resistance to imatinib mesylate 70months after initiation of therapy in a patient with a metastatic gastric gastrointestinal stromal tumor.

It is unknown how long the risk of developing secondary resistance to imatinib persists in patients with gastrointestinal stromal tumors (GISTs). Here we report a case of a patient with a metastatic gastric GIST who developed secondary resistance to imatinib 70months after initiation of imatinib therapy. A 62-year-old woman with a gastric GIST underwent total gastrectomy with pancreaticosplenectomy. Immunohistochemistry revealed a KIT-positive GIST. The mitotic index of the tumor was 13/50 high-power fields, indicating a high-risk malignancy. After surgery, the patient developed a solitary liver metastasis and underwent right hepatic lobectomy. Four months later, a metastatic tumor was found at the left adrenal gland, and imatinib therapy was initiated in December 2004. Imatinib therapy led to marked tumor shrinkage and complete clinical remission in the patient. However, in October 2010, computed tomography scans revealed a peritoneal metastasis in the ileocecal area. The tumor progression was clinically determined to be due to the development of secondary resistance to imatinib, and the patient's treatment was switched to sunitinib. This case illustrates secondary resistance to imatinib can develop even after a sustained and marked treatment response. Long-term therapy and close monitoring are recommended for the management of patients with metastatic GISTs.

Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation

BackgroundLeukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase....

Predictors of Sustained Response to Rivastigmine in Patients With Alzheimer’s Disease

The cholinesterase inhibitor rivastigmine is approved for the treatment of mild to moderate Alzheimer's disease. However, it is not possible to predict which individuals will benefit from treatment. This retrospective analysis of an international, 24-week, randomized, double-blind trial aimed to identify the percentage of persons with Alzheimer's disease who have a sustained response with rivastigmine patch, rivastigmine capsules, or placebo; to determine the magnitude of the sustained treatment response; and to investigate baseline patient characteristics predictive of the observed sustained response. Patients who improved on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL) at week 16 and maintained at least the week 16 improvement at week 24 were identified as sustained responders. Treatment differences and baseline predictive factors were assessed in patients demonstrating a 1-, 2-, 3-, 4-, or 5-point sustained improvement. The first patient was screened in November 2003 and the last patient completed the study in January 2006. More persons with Alzheimer's disease had sustained improvements on the ADAS-cog and ADCS-ADL with rivastigmine versus placebo. Sustained improvements of 4 or 5 points on the ADAS-cog or ADCS-ADL were demonstrated in the 9.5-mg/24-h rivastigmine patch (24% and 36% of patients, respectively) and 12-mg/d capsule groups (28% on both outcome measures). Factors predictive of a sustained response to treatment included baseline Mini-Mental State Examination, ADAS-cog, and ADCS-ADL scores and treatment, country of treatment, and time since first symptom was diagnosed by a physician. Understanding factors predictive of sustained cholinesterase inhibitor treatment response should help to optimize Alzheimer's disease management and encourage compliance by allowing more realistic expectations of treatment effects.

Early‐onset L‐dopa‐responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations

Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome.

Indications for treatment: Whom to treat and whom not to treat!

Despite the development of an effective vaccine, Hepatitis B virus (HBV) infection remains a major public health problem worldwide with a significant proportion of chronic HBV infected patients developing liver cirrhosis, liver failure, and primary hepatocellular carcinoma (HCC). Chronic hepatitis B is one of the 10 major causes of death worldwide. Although a number of antiviral agents against HBV are now available, proper selection of patients who would be ideal candidates for therapy is essential. The rationale for treatment is to reduce the risk of progressive chronic liver disease, transmission to others, and other long-term complications from chronic HBV such as hepatocellular carcinoma. The decision to commence treatment must balance the likelihood of a sustained treatment response, with the future risk of liver-related morbidity and mortality. Consideration of further factors, including patient age, concurrent illness, medication compliance, liver disease activity, likelihood of long-term benefit, and potential therapeutic risks such as side effects, must be included as part of a risk-benefit analysis. A large amount of new data have become available in recent years, suggesting that conventional criteria for treatment initiation based on existing disease progression do not necessarily correlate with the future risk of disease complications. This review summarizes the various factors which have to be considered before selecting the patient for treatment.

Sustained treatment response of metastatic hepatocellular carcinoma with bevacizumab and sorafenib

The overall survival for patients with advanced hepatocellular carcinoma (HCC) is still limited. Although the multi-kinase inhibitor sorafenib has recently been approved for this disease, response rates are still low and patients often face dose-limiting toxicities which lead to a reduction in prognosis and treatment success. We here report a patient with metastasized HCC who shows a sustained response for more than 30 mo to sorafenib therapy after failure of a first line therapy with gemcitabine, oxaliplatin and bevacizumab.

AA-Amyloidosis Caused by Visceral Leishmaniasis in a Human Immunodeficiency Virus-Infected Patient

AA-amyloidosis in the setting of chronic visceral leishmaniasis (VL) has been reported in animal models but documentation in humans is unavailable. Here, we report on a Portuguese man who in 1996 was diagnosed with both human immunodeficiency virus (HIV)-infection and VL. Antiretroviral treatment led to sustained suppression of HIV viremia but CD4+ lymphocytes rose from 8 to only 160 cells/mL. Several courses of antimony treatment did not prevent VL relapses. Renal failure developed in 2006 and renal biopsy revealed AA-amyloidosis. The patient had cryoglobulinemia and serum immune complexes containing antibodies directed against seven leishmanial antigens. Antimony plus amphotericin B, followed by oral miltefosine resulted in a sustained VL treatment response with elimination of circulating Leishmania infantum DNA and CD4+ recovery. The concomitant reduction of serum AA levels and disappearance of circulating leishmanial immune complexes suggests that prolonged VL may lead to AA-amyloidosis in immunocompromised humans.

Innovative child and adolescent treatment research for anxiety and depressive disorders

‘‘Taking it to the Streets: Advancing the Dissemination of CBT’’ was the theme of the annual meeting of the Association for Behavioral and Cognitive Therapies (ABCT) held in Orlando, Florida in November 2008. ABCT is an interdisciplinary organization comprising researchers, clinicians, and trainees who are committed to development, implementation, and dissemination of behavioral, cognitive, and other evidence-based interventions. Historically, the ABCT annual meetings have had a preponderance of presentations focused on the treatment of anxiety and depressive disorders, and the 2008 meeting was no exception. Below are some of the highlights of this year’s convention. Treatments for childhood anxiety were evaluated in the Child/Adolescent Anxiety Multimodal Treatment Study (CAMS), a multisite National Institute of Mental Health (NIMH)-supported trial comparing the efficacy of cognitive-behavior therapy (CBT), sertraline, pill placebo, and a combination of CBT and sertraline for treating children and adolescents with Generalized Anxiety Disorder, Social Phobia, and/or Separation Anxiety Disorder. Study investigators presented a symposium focused on the primary outcomes of CAMS, the largest (n5 488) and first ever randomized clinical trial for childhood anxiety. Results indicated that the combined intervention led to significantly better response rates than CBT alone or sertraline alone (81% versus 60% and 55%, Po.001), whereas the monotherapies were not significantly different from each other. All three active conditions were superior to pill placebo (23.7% response rate, Po.001). John Walkup, M.D. and colleagues emphasized that clinicians can recommend three options for treating child and adolescent anxiety based on treatment availability and family preferences. Paul Rohde, Ph.D. from the Oregon Research Institute presented the findings of the continuation and maintenance treatments provided in the multisite Treatments of Adolescents with Depression Study (TADS). TADS examined the impact of psychosocial and psychopharmacological interventions on the achievement and maintenance of sustained treatment response for depression, comparing the effectiveness of fluoxetine (FLX), CBT, combination therapy (COMB), and pill placebo with clinical management (PBO). Following 12 weeks of acute treatment, patients in the FLX, CBT, and COMB conditions received 6 weeks of continuation treatment (intensity based on degree of response to acute treatment) followed by three maintenance treatment sessions scheduled over 18 weeks. Patients continued in the same treatment conditions assigned during acute treatment. Among the 39% (n5 95) of patients who had not achieved a sustained response (two consecutive ratings of a full response in assessments conducted 6 weeks apart) at the end of the acute treatment, sustained response rates during continuation and maintenance treatments were as follows: 80% COMB, 62% FLX, and 77% CBT (difference not significant). These results indicate that for most depressed adolescents who do not achieve a sustained response during acute treatment, extra time and treatment will result in the desired treatment effect. Although CAMS and TADS studied treatments for either anxiety or depression, respectively, Robin Weersing, Ph.D. from San Diego State University and University of California, San Diego presented the results of a pilot effectiveness study of a brief, integrated cognitive-behavioral approach to treat children with anxiety and/or depressive disorders in a primary-care setting. The eight-session treatment adapted and combined two CBT protocols, one for anxiety and one for depression, with a focus on ‘‘graded engagement’’ (a combination of exposure and behavioral activation). Children aged 8–17 (n5 60) with diagnoses of depression and/or anxiety were randomized to receive either the brief behavioral treatment or outside referral. Results at 12 weeks indicated that children in the brief CBT condition demonstrated significantly greater clinical global improvement and symptom reduction than children in the control group. Children with comorbid diagnoses demonstrated significant reductions in both anxious and depressive symptoms, suggesting the feasibility of a