Frontal, Parietal, and Temporal Brain Areas Are Differentially Activated When Disambiguating Potential Objects of Joint Attention.

Humans establish joint attention with others by following the other's gaze. Previous work has suggested that a cortical patch (gaze-following patch, GFP) close to the posterior superior temporal sulcus (pSTS) may serve as a link between the extraction of the other's gaze direction and the resulting shifts of attention, mediated by human lateral intraparietal area (hLIP). However, it is not clear how the brain copes with situations in which information on gaze direction alone is insufficient to identify the target object because more than one may lie along the gaze vector. In this fMRI study, we tested human subjects on a paradigm that allowed the identification of a target object based on the integration of the other's gaze direction and information provided by an auditory cue on the relevant object category. Whereas the GFP activity turned out to be fully determined by the use of gaze direction, activity in hLIP reflected the total information needed to pinpoint the target. Moreover, in an exploratory analysis, we found that a region in the inferior frontal junction (IFJ) was sensitive to the total information on the target. An examination of the BOLD time courses in the three identified areas suggests functionally complementary roles. Although the GFP seems to primarily process directional information stemming from the other's gaze, the IFJ may help to analyze the scene when gaze direction and auditory information are not sufficient to pinpoint the target. Finally, hLIP integrates both streams of information to shift attention to distinct spatial locations.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1).

BACKGROUND: Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for locally advanced head and neck cancer. This phase II study investigated the effectivity of a split-dose TPF ICT before surgery for locally advanced resectable (stage III/IVA) oral and oropharyngeal cancer. PATIENTS AND METHODS: Patients received TPF split on two dosages on days 1 and 8 per cycle (30 mg/m2 docetaxel, 40 mg/m2 cisplatin, 2000 mg/m2 fluorouracil per week). Responders (reduction tumor volume ≥30% after first cycle) received three 3-week cycles and non-responders only one cycle before surgery and postoperative radio(chemo)therapy (RCT). The primary endpoint was progression-free survival rate after 24 months. Secondary endpoints were amongst others overall survival, histopathological response to ICT, toxicity, quality of life and swallowing function. RESULTS: Fifty-four patients (91% stage IVA, 87% male, 72% oropharyngeal cancer, 70% responders) were eligible for a per-protocol analysis. The progression-free survival rate after 24 months was 88.5% for responders and 60.6% for non-responders (P = 0.005). The overall survival rate after 24 months was 97.3% for responders and 73.7% for non-responders (P = 0.032). The rate of histopathological complete remission of the primary tumor was higher in responders (P = 0.015). High-risk classification for postoperative RCT was lower in responders (P < 0.0001). The most common grade 3+ adverse event was neutropenia in 26% of patients during ICT and mucositis in 13% during postoperative RCT. During treatment and follow-up quality of life and swallowing function was not different between responders and non-responders. CONCLUSION: Patients with oral and oropharyngeal cancer responding to split-dose TPF before surgery and postoperative RCT show good oncological results. The tri-modal treatment regime was well tolerated. ICT using tumor response as criterion for duration of ICT before surgery of oral and oropharyngeal cancer merits additional investigation in a phase III study. CLINICAL TRIAL NUMBER: NCT01108042.

Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide.

Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia.

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse.

To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

The impact of allogeneic stem cell transplantation on the natural course of poor-risk chronic lymphocytic leukemia as defined by the EBMT consensus criteria: a retrospective donor versus no donor comparison.

BACKGROUND: In a single-center retrospective donor versus no-donor comparison, we investigated if allogeneic stem cell transplantation (alloSCT) can improve the dismal course of poor-risk chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: All patients with CLL who were referred for evaluation of alloSCT within a 7-year time frame and had a donor search indication according to the EBMT criteria or because of Richter's transformation were included. Patients for whom a matched donor could be found within 3 months (matches) were compared with patients without such a donor (controls). Primary end point was overall survival measured from the 3-month landmark after search initiation. RESULTS: Of 105 patients with donor search, 97 (matches 83; controls 14) were assessable at the 3-month landmark. Matches and controls were comparable for age, gender, time from diagnosis, number of previous regimens, and remission status. Disregarding if alloSCT was actually carried out or not, survival from the 3-month landmark was significantly better in matches versus controls [hazard ratio 0.38, 95% confidence interval (CI) 0.17-0.85; P = 0.014]. The survival benefit of matches remained significant on multivariate analysis. CONCLUSION: This study provides first comparative evidence that alloSCT may have the potential to improve the natural course of poor-risk CLL as defined by the EBMT criteria.

Multimodality treatment for poorly differentiated neuroendocrine head and neck carcinomas--a single institution experience.

Poorly differentiated head and neck neuroendocrine neoplasms are very rare. Surgical resection alone is insufficient to control the disease because of the high incidence of metastases. However, due to the lack of randomised clinical trials, treatment recommendations for this cancer vary considerably and are based on a limited number of small retrospective studies. We performed a retrospective analysis of all patients treated at our institution between 2003 and 2011. We assessed the stage of disease, type of therapy, toxicity, treatment response, time to progression and overall survival for all cases. Ten patients received combined modality treatment with chemotherapy in addition to surgery or radiation or both. According to Response Evaluation Criteria In Solid Tumours (RECIST) criteria, six of nine evaluable patients achieved complete remission and three patients had a partial remission. The mean duration of response was 358 days, with a range from 141 to 1080 days. The overall 1-year survival rate was 88%; however, only approximately 50% of patients were alive after 2 years. Multimodality treatment concepts induce high initial remission rates in poorly differentiated neuroendocrine head and neck carcinomas. However, the time to relapse is usually short, and therefore long-term prognosis of this rare head and neck tumour remains poor.

[Early-stage breast cancer - strategies for adjuvant systemic therapy]. / Mammakarzinom im lokalisierten Stadium - Strategien für die systemisch-adjuvante Therapie.

Systemic adjuvant treatment is an integral component in the treatment of women with early-stage breast cancer and contributes significantly to the reduction of breast cancer-specific mortality. Decisions regarding adjuvant treatment modalities are becoming increasingly complex and demand individualised risk assessments based not only on clinicopathological criteria such as tumour size and axillary lymph node status but also on molecular predictors of the biological behaviour of the cancer. In addition, with the development of targeted therapies targeting HER-2 and with the availability of third generation aromatase inhibitors, new therapeutic options are available and need to be integrated into the treatment algorithms. In this review, we discuss the guidelines and recommendations concerning adjuvant systemic treatment of early-stage breast cancer based on current risk classifications.

Adjuvant chemotherapy for colon cancer--analysis of treatment costs from the perspective of statutory sickness funds.

OBJECTIVE: The aim of this study was to calculate sickness funds' costs associated with the application of three different adjuvant chemotherapy regimens for patients with stage III colon cancer treated in different settings (inpatient/outpatient) in Germany. METHODS: Standard procedures according to national guidelines were defined for inpatient and outpatient diagnostics and treatment. Costs associated with the three commonly used standard treatment regimens were calculated from the perspective of statutory sickness funds. RESULTS: The highest costs are associated with the FOLFOX regimen in the outpatient (21530.00 euro) as well as in the inpatient setting (23170.00 euro). Of the two 5-FU bolus regimens, the monthly MAYO-Clinic protocol (inpatient 7070.00 euro vs. outpatient 6610.00 euro) is significantly less expensive than the weekly NSABP protocol (17569.00 euro vs. 12200.00 euro). Costs are remarkably lower in the outpatient setting as compared to inpatient application of the MAYO-Clinic protocol or the FOLFOX regimen. In the outpatient setting, medication costs are the major cost-driving factor, comprising 82% of the total costs of the MAYO-Clinic protocol, 94% of the total costs of the NSABP, and 91% of the total costs of FOLFOX-4 regimen. In the inpatient setting, costs for medications are less important with regard to total costs (10% MAYO-Clinic, 7% NSABP, 10% FOLFOX-4), whereas costs for staff and hotel-like services become more important. CONCLUSION: From a health insurance perspective, substantial cost savings may be realised through the use of established chemotherapy regimens, if most patients are treated in the outpatient setting. In the outpatient setting, costs for drug prices are the main cost driver, so further savings could be realised for third-party payers if prices of chemotherapeutic drugs are reduced. For economic reasons, patients who are candidates for bolus 5-FU regimens, should not be treated according to the NSABP protocol. The MAYO-Clinic protocol is a low cost regimen in both settings, but for medical reasons alternative therapies such as capecitabine or infusional 5 FU protocols must be preferred in patients unable to tolerate the new standard FOLFOX-4.

Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine.

Although reduced intensity conditioning (RIC) before allografting is associated with low treatment-related morbidity and mortality, graft-versus-host disease (GVHD) remains a significant complication of hematopoietic stem cell transplantation (HSCT). T cell depletion (TCD) has been successfully used in conventional allotransplantation to reduce the incidence of GVHD, but was associated with an increased rate of engraftment failure. In a small cohort of six patients at high risk of developing GVHD we have determined whether sustained engraftment could be achieved using reduced intensity conditioning and T cell depletion in combination. All patients engrafted and 5/6 developed high levels (i.e. > or =95%) of donor chimerism, even though mismatched related or matched unrelated donors were used. Only one patient developed acute GVHD, as he received donor lymphocyte infusions (DLI) for relapse. In summary, TCD might be a useful prophylactic tool in RIC allogeneic HSCT. Although TCD after RIC might be associated with high relapse rate, as 5/6 patients are not in remission, this combined strategy might be appropriate for patients with less aggressive malignant or non-malignant diseases in which high transplant-related morbidity and mortality is not acceptable.

Development of catalytic platinum-binder electrodes for glucose determination.

Compact catalytic platinum-binder glucose sensors were developed, provided for the artificial beta-cell. These consist of three electrodes: the working electrode, a 0.5 mm diameter glass-sheathed platinum wire, covered with a mixture of platinum black and binder (PMMA, PVC) at the face, the reference electrode and the rejuvenating or counter electrode. Measurements were carried out either by a non-equilibrium method within the anodic range or by determination of the current at the anodically directed peak during the cathodic scan. In the first case a periodical switching between rejuvenating and measuring potential takes place and, in the second case, the whole voltammogram is cycled between +1.2 V and -1.2 V (vs. Ag/AgCl). For measurements in phosphate-buffered saline at 37 degrees C the calibration curves exhibit an approximately linear dependence up to a glucose concentration of 30 mM; the sensitivity amounts to 0.3 microA mM-1 and the response times t90% are between 6 and 10 min. A urea concentration of 2.5 mM causes a decrease of the non-equilibrium current of 11.5%-3.0%, and a mixture of amino acids causes a current rise of 11.4%-2.7% with increasing glucose concentration. During the cathodic scan the amino acids affect the peak current negligibly, and the influence of urea reaches saturation for concentrations higher than 6.7 mM. Preliminary in vivo measurements permit the conclusions that after appropriate pretreatment the catalytic glucose sensors can be used for short-time blood glucose monitoring.