High-dose therapy and autologous hematopoietic stem cell transplant in T-cell lymphoma: a single center experience.

Abstract We report here the long-term outcome of autologous stem cell transplant in peripheral T-cell lymphoma (PTCL). Forty-three consecutive patients with PTCL diagnosed between 2000 and 2011 were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) in our center. Diagnoses included PTCL-not otherwise specified (n = 19), anaplastic large cell lymphoma (n = 11), angioimmunoblastic T-cell lymphoma (n = 5), enteropathy-associated T-cell lymphoma (n = 5) and other rare subtypes (n = 3). Thirty-six patients with a median age of 50 years (range 22-65) were transplanted in first response and seven after relapse. After a median follow-up of 63 months, estimated overall survival at 12 years was 40%, progression-free survival at 12 years was 34% and event-free survival at 12 years was 30%. On univariate analysis, age less than 50 years and no B symptoms at diagnosis were significantly associated with prolonged overall and progression-free-survival. HDCT/ASCT for peripheral T-cell lymphoma can lead to long-term survival for patients responding to induction chemotherapy.

Statistical Modeling of the Eye for Multimodal Treatment Planning for External Beam Radiation Therapy of Intraocular Tumors.

PURPOSE: Ocular anatomy and radiation-associated toxicities provide unique challenges for external beam radiation therapy. For treatment planning, precise modeling of organs at risk and tumor volume are crucial. Development of a precise eye model and automatic adaptation of this model to patients' anatomy remain problematic because of organ shape variability. This work introduces the application of a 3-dimensional (3D) statistical shape model as a novel method for precise eye modeling for external beam radiation therapy of intraocular tumors. METHODS AND MATERIALS: Manual and automatic segmentations were compared for 17 patients, based on head computed tomography (CT) volume scans. A 3D statistical shape model of the cornea, lens, and sclera as well as of the optic disc position was developed. Furthermore, an active shape model was built to enable automatic fitting of the eye model to CT slice stacks. Cross-validation was performed based on leave-one-out tests for all training shapes by measuring dice coefficients and mean segmentation errors between automatic segmentation and manual segmentation by an expert. RESULTS: Cross-validation revealed a dice similarity of 95% ± 2% for the sclera and cornea and 91% ± 2% for the lens. Overall, mean segmentation error was found to be 0.3 ± 0.1 mm. Average segmentation time was 14 ± 2 s on a standard personal computer. CONCLUSIONS: Our results show that the solution presented outperforms state-of-the-art methods in terms of accuracy, reliability, and robustness. Moreover, the eye model shape as well as its variability is learned from a training set rather than by making shape assumptions (eg, as with the spherical or elliptical model). Therefore, the model appears to be capable of modeling nonspherically and nonelliptically shaped eyes.

Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemoirradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter.

Background: Preclinical data indicate activity of mammalian target of rapamycin inhibitors and synergistic activity together with radiotherapy in glioblastoma. The aim of this trial is to assess the therapeutic activity of temsirolimus (CCI-779), an intravenous mTOR inhibitor, in patients with newly diagnosed glioblastoma with unmethylated O6 methlyguanine-DNA-methlytransferase (MGMT)promoter. Methods: Patients (n=257) with newly diagnosed glioblastoma after open surgical biopsy or resection fulfilling basic eligibility criteria underwent a central MGMT promoter analysis using quantitative methylation specific PCR. Patients with glioblastoma harboring an unmethylated MGMT promoter (n=111) were randomized 1:1 between radiotherapy (60 Gy; 5 times 2 Gy per week) plus concomitant and six cycles of maintenance temozolomide or radiotherapy plus weekly temsirolimus at 25 mg flat dose to be continued until progression or undue toxicity. Primary endpoint was overall survival at 12 months (OS12). Sample size of the investigational treatment arm required 54 patients to assess adequacy of temsirolimus activity set at 80%. More than 38 patients alive at 12 months in the per protocol population was considered a positive signal. A control arm of 54 patients treated with the standard of care was implemented to evaluate the assumptions on OS12. Results: Between December 2009 and October 2012, 111 pts in 14 centers were randomized and treated. Median age was 55 and 58 years in the temsirolimus and standard arm, respectively. Most patients (95.5%) had a WHO performance status of 0 or 1. Both therapies were properly administered with a median of 13 cycles of maintenance temsirolimus. In the per protocolpopulation, exactly 38 patients treated with temsirolimus (out of 54 eligible) reached OS12. In the intention to treat population OS12 was 72.2% [95% CI (58.2, 82.2)] in the temozolomide arm and 69.6% [95% CI (55.8, 79.9) in the temsirolimus arm [HR=1.16 95% CI (0.77, 1.76), p=0.47]. Conclusions: The therapeutic activity of temsirolimus in patients with newly diagnosed glioblastoma with an unmethylated MGMT promoter is too low.

Positional therapy for obstructive sleep apnea: an objective measurement of patients' usage and efficacy at home.

BACKGROUND: Positional therapy that prevents patients from sleeping supine has been used for many years to manage positional obstructive sleep apnea (OSA). However, patients' usage at home and the long term efficacy of this therapy have never been objectively assessed. METHODS: Sixteen patients with positional OSA who refused or could not tolerate continuous positive airway pressure (CPAP) were enrolled after a test night study (T0) to test the efficacy of the positional therapy device. The patients who had a successful test night were instructed to use the device every night for three months. Nightly usage was monitored by an actigraphic recorder placed inside the positional device. A follow-up night study (T3) was performed after three months of positional therapy. RESULTS: Patients used the device on average 73.7 ± 29.3% (mean ± SD) of the nights for 8.0 ± 2.0 h/night. 10/16 patients used the device more than 80% of the nights. Compared to the baseline (diagnostic) night, mean apnea-hypopnea index (AHI) decreased from 26.7 ± 17.5 to 6.0 ± 3.4 with the positional device (p<0.0001) during T0 night. Oxygen desaturation (3%) index also fell from 18.4 ± 11.1 to 7.1 ± 5.7 (p = 0.001). Time spent supine fell from 42.8 ± 26.2% to 5.8 ± 7.2% (p < 0.0001). At three months (T3), the benefits persisted with no difference in AHI (p = 0.58) or in time spent supine (p = 0.98) compared to T0 night. The Epworth sleepiness scale showed a significant decrease from 9.4 ± 4.5 to 6.6 ± 4.7 (p = 0.02) after three months. CONCLUSIONS: Selected patients with positional OSA can be effectively treated by a positional therapy with an objective compliance of 73.7% of the nights and a persistent efficacy after three months.

First explicit criteria to decide on the appropriateness of therapy of ulcerative colitis: the European EPATUC panel

Background: Ulcerative colitis (UC) is a chronic disease with a wide variety of treatment options many of which are not evidence based. Supplementing available guidelines, which are often broadly defined, consensus-based and generally not tailored to specifically reflect the individual patient situation, we developed explicit appropriateness criteria to assist, and improve treatment decisions. Methods: We used the RAND appropriateness method which does not force consensus. An extensive literature review was compiled based on and supplementing, where necessary, the ECCO UC 2011 guidelines. EPATUC (endorsed by ECCO) was formed by 7 gastroenterologists, 2 surgeons and 2 general practitioners from throughout Europe. Clinical scenarios reflecting practice were rated on a 9-point scale from 1 (extremely inappropriate) to 9 (extremely appropriate), based on the expert's experience and the available literature. After extensive discussion, all scenarios were re-rated at a two-day panel meeting. Median and disagreement (D) were used to categorize ratings into 3 categories: appropriate (A), uncertain (U) and inappropriate (I). Results: 718 clinical scenarios were rated, structured in 13 main clinical presentations: not refractory (n = 64) or refractory (n = 33) proctitis, mild to moderate left-sided (n = 72) or extensive (n = 48) colitis, severe colitis (n = 36), steroid- dependant colitis (n = 36), steroid-refractory colitis (n = 55), acute pouchitis (n = 96), maintenance of remission (n = 248), colorectal cancer prevention (n = 9) and fulminant colitis (n = 9). Overall, 100 indications were judged appropriate (14%), 129 uncertain (18%) and 489 inappropriate (68%). Disagreement between experts was very low (6%). Conclusions: For the very first time, explicit appropriateness criteria for therapy of UC were developed that allow both specific and rapid therapeutic decision making and prospective assessment of treatment appropriateness. Comparison of these detailed scenarios with patient profiles encountered in the Swiss IBD cohort study indicates good concordance. EPATUC criteria will be freely accessible on the internet (epatuc.ch)

Optimization and regeneration kinetics of lymphatic-specific photodynamic therapy in the mouse dermis.

Lymphatic vessels transport fluid, antigens, and immune cells to the lymph nodes to orchestrate adaptive immunity and maintain peripheral tolerance. Lymphangiogenesis has been associated with inflammation, cancer metastasis, autoimmunity, tolerance and transplant rejection, and thus, targeted lymphatic ablation is a potential therapeutic strategy for treating or preventing such events. Here we define conditions that lead to specific and local closure of the lymphatic vasculature using photodynamic therapy (PDT). Lymphatic-specific PDT was performed by irradiation of the photosensitizer verteporfin that effectively accumulates within collecting lymphatic vessels after local intradermal injection. We found that anti-lymphatic PDT induced necrosis of endothelial cells and pericytes, which preceded the functional occlusion of lymphatic collectors. This was specific to lymphatic vessels at low verteporfin dose, while higher doses also affected local blood vessels. In contrast, light dose (fluence) did not affect blood vessel perfusion, but did affect regeneration time of occluded lymphatic vessels. Lymphatic vessels eventually regenerated by recanalization of blocked collectors, with a characteristic hyperplasia of peri-lymphatic smooth muscle cells. The restoration of lymphatic function occurred with minimal remodeling of non-lymphatic tissue. Thus, anti-lymphatic PDT allows control of lymphatic ablation and regeneration by alteration of light fluence and photosensitizer dose.

Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial.

BACKGROUND: Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC. METHODS/DESIGN: Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety. DISCUSSION: Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT01345669.

Busulphan-melphalan is the superior myeloablative therapy (mat) for high risk neuroblastoma: results from the hr-nbl1/siopen trial

Purpose: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens to demonstrate superiority based on event free survival (EFS).Method: Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) 3 4 2 courses of TVD (Cancer, 2003) included complete bone marrow remission andA ^ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4_150 mg/m2 in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140 mg/m__/day) and CEM (carboplatin ctn. infusion (4xAUC 4.1 mg/ml.min/day), etoposide ctn. infusion (4_338 mg/m__day or 4_200 mg/m__/ day*), melphalan (3_70 mg/m__/day or 3_60 mg/m__/day*. *reduced if GFR<100 ml/ min/1.73m__)). A minimum of 3_10E6 CD34/kgBW PBSC were requested. VOD prophylaxis included ursadiol, but not prophylactic defibrotide. Local control included surgery and radiotherapy of 21 Gy. A total of 598 high risk neuroblastoma patients were randomised (296 BuMel, 302 CEM). The median age at randomisation was 3 years (1-17.2).Results: A significant difference in EFS in favour of BuMel (3-years EFS 49% vs. 33%) was observed as well as for overall survival (3-years OS 60% vs. 48%, p¼0.004) with a median follow up of 3 years. This difference was mainly related to the relapse and progression incidence, which was significantly (p<0.001) lower with BuMel (48% vs. 60%). The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p¼0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute MAT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%). Based on these results and following advice from the DMC, the randomisation was closed early.

Efficacy, tolerability and risk factors for virological failure of darunavir-based therapy for treatment-experienced HIV-infected patients: the Swiss HIV Cohort Study.

OBJECTIVES: Darunavir was designed for activity against HIV resistant to other protease inhibitors (PIs). We assessed the efficacy, tolerability and risk factors for virological failure of darunavir for treatment-experienced patients seen in clinical practice. METHODS: We included all patients in the Swiss HIV Cohort Study starting darunavir after recording a viral load above 1000 HIV-1 RNA copies/mL given prior exposure to both PIs and nonnucleoside reverse transcriptase inhibitors. We followed these patients for up to 72 weeks, assessed virological failure using different loss of virological response algorithms and evaluated risk factors for virological failure using a Bayesian method to fit discrete Cox proportional hazard models. RESULTS: Among 130 treatment-experienced patients starting darunavir, the median age was 47 years, the median duration of HIV infection was 16 years, and 82% received mono or dual antiretroviral therapy before starting highly active antiretroviral therapy. During a median patient follow-up period of 45 weeks, 17% of patients stopped taking darunavir after a median exposure of 20 weeks. In patients followed beyond 48 weeks, the rate of virological failure at 48 weeks was at most 20%. Virological failure was more likely where patients had previously failed on both amprenavir and saquinavir and as the number of previously failed PI regimens increased. CONCLUSIONS: As a component of therapy for treatment-experienced patients, darunavir can achieve a similar efficacy and tolerability in clinical practice to that seen in clinical trials. Clinicians should consider whether a patient has failed on both amprenavir and saquinavir and the number of failed PI regimens before prescribing darunavir.

Intrahepatic mRNA levels of SOCS1 and SOCS3 are associated with cirrhosis but do not predict virological response to therapy in chronic hepatitis C.

BACKGROUND: Antiviral treatment of chronic hepatitis C is not invariably successful, costly and associated with serious side-effects, and therefore should be indicated only when the chances of benefitting patients exceed the potential risks. The suppressor of cytokine signalling (SOCS) family members have been suggested to affect the rate of virological response to therapy, but the published evidence is conflicting. METHODS: We measured the intrahepatic SOCS1, SOCS3 and SOCS7 mRNA levels in 107 chronic hepatitis C patients and assessed their clinical and histological correlates with the virological response to therapy and with some factors known for affecting treatment outcome. RESULTS: By multivariate analysis, SOCS1, SOCS3 and SOCS7 mRNA levels were not associated with rapid or sustained virological response. Similarly, no association was found between the levels of any intrahepatic SOCS mRNA and those of the homeostasis model assessment of insulin resistance. Conversely, SOCS1 (OR 2.185, 95% CI 1.223-3.906, P=0.0083) and SOCS3 (OR 40.601, 95% CI 2.357-699.25, P=0.0108) mRNA level (but not SOCS7), together with age (OR 1.156, 95% CI 1.049-1.275, P=0.0036), were independently associated with cirrhosis. CONCLUSIONS: Intrahepatic SOCS1, SOCS3 and SOCS7 mRNA levels do not predict virological response to therapy in chronic hepatitis C. The association between SOCS1, SOCS3 and cirrhosis warrants further study.

Iron Supplementation Therapy in a Large Swiss Cohort of Inflammatory Bowel Disease Patients: Shift from Oral to Intravenous Therapy over Time

Background a nd A ims: T he 2 007 ECCO g uidelines o nanemia in inflammatory bowel disease (IBD) favour intravenous(iv) over oral (po) i ron supplementation due to bettereffectiveness and tolerance. Application of guidelines in clinicalpractice m ay r equire time. We a imed to determine thepercentage of IBD patients under iron supplementation therapyand its application mode over time in a large IBD cohort.Methods: Helsana, a leading Swiss health insurance companyprovides c overage f or approximately 18% of t he Swisspopulation, corresponding to about 1.2 million enrollees.Patients with Crohn's disease (CD) and ulcerative colitis (UC)were identified b y keyword search from t he a nonymisedHelsana database.Results: I n total, 6 29 CD ( 61% female) a nd 4 03 UC ( 56%female) patients w ere identified, mean retrospectiveobservation time w as 2 0.4 m onths f or CD and 13 m onths f orUC patients. Of t he entire study population, 29.3% wereprescribed iron. O ccurrence of iron prescription was 21.3% inmales a nd 31.2% in f emales ( odds r atio [OR] 1 .69, 95%-confidence interval [CI] 1.26-2.28). The prescription of iv i ronincreased from 2006/2007 ( 48.8% w ith iv i ron) to 2 008/2009(65.2% with iv iron) by a factor of 1.89.Conclusions: One third of the IBD population was treated withiron supplementation. A gradual s hift from oral t o iv iron wasobserved over time in a large Swiss IBD cohort. This switch inprescription habits g oes a long with the implementation of theECCO consensus guidelines on anemia in IBD.

Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders.

There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders stemming from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to a "barbaric" form of placebo effect. Here we show differential, highly specific, spatially distributed effects of ECT on regional brain structure in two populations: patients with unipolar or bipolar disorder. Unipolar and bipolar disorders respond differentially to ECT and the associated local brain-volume changes, which occur in areas previously associated with these diseases, correlate with symptom severity and the therapeutic effect. Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.