Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.

The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.

Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.

Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.

Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system.

Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.

Phase II study with docetaxel and cisplatin in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: Since the combination of cisplatin and docetaxel have demonstrated activity in squamous cell carcinomas of the lung and oesophagus before, promising results in recurrent metastatic head and neck cancer were expected. PATIENTS AND METHODS: Between September 1998 and October 2000, 40 patients entered this trial, 38 of whom were evaluable. Six patients were previously untreated, 24 had surgery and/or radiotherapy and 13 had received chemoradiation and/or surgery. Therapy consisted of 75 mg/m(2) docetaxel (1-hour infusion) and 75 mg/m(2) cisplatin (90-min infusion) on day 1, repeated every three weeks for a maximum of 6 courses. All patients received corticosteroids routinely, 5-HT3-antagonists, and hydration. RESULTS: The overall response rate was 52.5% (95% confidence interval, 36.1 to 68.5%) including 7 complete (17.5% complete response; CR) and 14 partial remissions (35% partial response; PR). The overall response rate in patients who had no prior treatment (n = 6) was 100%, including 3 CR and 3 PR. In patients who had prior surgery and/or radiotherapy (n = 21) an overall response rate of 42.8% was observed, including 2 CR and 7 PR; 8 patients (38.1%) had stable disease, while disease progressed in 3 (14.3%). Six of 13 patients (46.2%) who had prior chemoradiation +/- surgery responded, including 2 CR (15.4%) and 4 PR (30.8%), no change was seen in 4 patients (30.8%) and tumour progressed in 2 (15.4%). The median response duration for all patients was 10 months (range, 3-20), the median overall survival was 11 months (range, 1-30). Myelosuppression was commonly observed; WHO grade 3 or 4 neutropenia occurred in 12 patients (30%) each, and was complicated by septicaemia in 5 cases. WHO grade 3 anaemia was observed in only 3 patients (7.5%). Severe non-hematologic toxicity except for alopecia was rarely observed, and included diarrhea in 2 (5%), nausea/vomiting in 2 patients (5%) and stomatitis in 1 patient (2.5%). CONCLUSION: Our data suggest that docetaxel and cisplatin in combination is an effective and fairly well tolerated regimen for the treatment of head and neck cancer with an excellent response rate in previously untreated patients.

Comparison of six three-dimensional navigation systems during sinus surgery.

Three-dimensional (3D) navigation systems are routinely used in the fields of endoscopic skull base surgery, neurosurgery, maxillo-facial and endoscopic sinus surgery. The use of such systems is associated with the following advantages: a better 3D orientation: a more confident surgeon; a more precise surgical approach; and a reduced operation time. Six different brands of 3D navigation system were compared in order to find out if there are major differences in performance and whether the considerable financial investment required to purchase such a system would be justified by a noticeable improvement in surgical interventions and a realization of the above expectations. The 3D navigation systems were tested by performing endoscopic sinus surgery on 26 patients suffering from chronic sinusitis. The system accuracy, the confidence of the surgeon, the time of anaesthesia, the cost, the number of personnel required (and their skills), and the technical resources were compared. No major differences in performance of the different brands of 3D navigation system were noticed. All of the systems showed high, but varying, system precision, the surgeons felt more confident and the time of anaesthesia was prolonged by 5-15 min. A well-trained operating staff is required. Assuming that the initial costs are excluded and that data transfer occurs automatically, personnel costs and the extra time required still have to be considered.

Comparison of different 3D navigation systems by a clinical "user".

Three-dimensional navigation systems are routinely used in endoscopic skull base surgery, neurosurgery, maxillo-facial and endoscopic sinus surgery. Their precision can, however, change in the course of one experiment. We have compared five different 3D navigation systems and discuss here possible reasons for the limits of system precision. A plexiglass cube on which test points were marked served as a test-model. Two well-trained system users measured the distances between the test points in each of the five systems. The results were compared with reference data provided by the NUMEREX device at the Technical University of Vienna. The accuracy data shown by all these 3D navigation systems ranged from 0.0 mm to 6.67 mm. The accuracy data of a system calculated in advance did not always correspond with the system precision on the screen. The system precision in the center of the cube was higher than on its surface, which made us conclude that the angle between the tracker system and the pointing device touching the test point may be critical for system precision. Applying an automatic registration step did not result in greater system precision. Slice thickness and the angle of the pointing device seem to be responsible for system precision.

Neurofibroma of the auriculotemporal nerve.

Despite the extensive branching of the trigeminal nerve, solitary neurofibromas along its branches are a rare finding. We report our management of a neurofibroma of the right auriculotemporal nerve in a 46-year-old women. A chain of small nodules palpable in the right postauricular region was associated with increasing pain radiating into the postauricular and temporoparietal regions of her head. Magnetic resonance imaging and computed tomography showed several small ovoid lesions extending from the postauricular region to the infratemporal fossa. The lesions were removed surgically. The facial nerve adhered to the dorsal side of the largest nodule, but this could be removed without sequelae. The auriculotemporal nerve was identified as the nerve of origin and was removed together with the lesions. Histopathological examination was consistent with a neurofibroma with early plexiform cell formations. Clinical findings are discussed.

No relationship between leptin and cortisol in obese children and adolescents.

Recent findings have shown that leptin downregulates the steroid producing system in the adrenal. We studied the interactions of leptin, insulin and cortisol in obese children and adolescents at different stages of maturation. In 44 boys (age 11+/-3.1 yr, body mass index [BMI] 29+/-5.3 [mean +/- SD]) and 35 girls (age 11.4+/-2.6 yr, BMI 29+/-4.3), blood levels of leptin, insulin, cortisol, and glucose were determined. Fat mass (FM) was calculated by bioelectrical impedance. No significant differences were found between boys and girls with respect to humoral and anthropometric characteristics. When children were divided according to maturation stage (prepubertal, pubertal, and late/postpubertal) insulin was higher in the more mature groups (p<0.01) and leptin was higher in the pubertal group (p=0.03). In the prepubertal and pubertal groups, the expected positive relationship between adiposity and leptin was found although the magnitude of this association decreased with maturity. In none of the groups studied was cortisol significantly correlated to leptin. Insulin (p=0.03) and glucose (p=0.01) were positively associated with cortisol in the prepubertal group after adjustment for adiposity. However, in the pubertal group an inverse correlation was found between insulin and cortisol (p=0.03), and between insulin and glucose after control for adiposity. In the late/ postpubertal group, no significant correlations were found between estimates of adiposity and humoral parameters even after adjustment for gender. Stepwise multiple regression failed to detect a significant influence of cortisol to explain the variation in leptin, and vice versa. BMI contributed to the variation in leptin (adj. R2 =0.275, p<0.0001), and glucose added 5% to the variation in cortisol (p=0.03). The results do not confirm the inverse association between leptin and cortisol found in adults. Although BMI reflects levels of leptin, it is likely that several other factors in conjunction with fatness modulate the relationship with leptin. Whether leptin per se exerts an influence on the hypothalamic-adrenal-adipo axis remains to be investigated in longitudinal studies.

[Congenital and benign changes with regard to the pharynx]. / Kongenitale und benigne Veränderungen mit Bezug zum Pharynx.

DEVELOPMENT: The first part of this article is supposed to present a brief overview on the development of tissues and structures related to the pharynx, as far as they provide a better understanding of the most congenital lesions in this area of the body. BENIGN LESIONS: The second part of this article focuses on benign lesions originating in the pharynx or in neighbouring structures. Functional pharynx abnormalities are beyond the scope of this paper.

[Intraoperative navigation in paranasal sinus surgery with the Philips "Neuroguide" system]. / Intraoperative Navigation in der Nasennebenhöhlenchirurgie mit dem Philips "Neuroguide"-System.

OBJECTIVE: To investigate the feasibility, precision and usefulness of computer aided surgery in ENT-sinus surgery. MATERIAL AND METHODS: 5 Patients with chronic sinus pathology and an indication for sinus surgery were elected. For intraoperative navigation we used a Philips "NEUROGUIDE" system and surgical instruments with LED's. Navigation procedures are described in detail in the paper, the system's precision was measured by pointing at anatomical landmarks. The accuracy was measured as the distance in millimeter between the bony structures of the CT scan on screen and the haircross of the pointer's tip on the screen. Another parameter of the systems accuracy was calculated by the system itself as the root mean square error in millimeter (RMSE) between the registered markers position and the marker position in the CT data set. RESULTS: Axial 3/3/1 mm spiral CT provided sufficient resolution, data transfer via optical disk was practicable. Positioning of the navigation equipment required some experience and the registration of the patients head position needed attention, as the markers have to be pointed at precisely. During operation, the head tracking system must not change its position on the patients head to ensure a correct navigation display. The main advantage of the computed navigation system was the constant orientation during the sinus surgical procedure. Frontiers and critical anatomical structures could be identified in the corresponding CT data set, thus enabling the surgeon to decide on the further procedure. At present stage, the operation time was increased through the handling of the navigation system for at about 15 min, resulting in additional time of narcosis. CONCLUSION: We found the computed navigation system Philips "NEUROGUIDE" system to be an established technical aid, ready to use for ENT sinus surgery, in our cases with a precision between 1 and 3 mm. These results were similar to results obtained with a SPOCS Navigation System from Aesculap, as previously published by us [17].

No evidence for leptin as an independent associate of blood pressure in childhood and juvenile obesity.

We studied whether leptin is an independent associate of blood pressure in obese children and adolescence. 102 obese children (48 girls, age: 11.6 +/- 2.22 yr; body mass index [BMI]: 27.45 +/- 4.4; blood pressure: 122.5 +/- 11.1/64.7 +/- 10.6 mm Hg and 54 boys, age: 11.5 +/- 2.4 yr; BMI: 27.6 +/- 4.4; blood pressure: 122.5 +/- 13.2/60.9 +/- 8.1 mm Hg [mean +/- SD]) were investigated. Serum leptin and insulin were measured by RIA; glucose was determined enzymatically. Fat mass (FM) was calculated by bioelectrical impedance. Leptin was higher in girls than in boys (p=0.018) but no significant gender differences were found with respect to indices of adiposity and systolic blood pressure (SBP). Children were divided into three groups, according to pubertal stage (Group 1: prepubertal, 32 boys/13 girls; Group 2: pubertal, 17 boys/25 girls; Group 3: late/postpubertal, 5 boys/10 girls). SBP and DBP correlated with body weight in the whole group (r=0.49, p<0.0001, and r=0.27, p=0.004). In Group 1, BMI showed the highest correlation to SBP; in Group 3 no indices of adiposity were related to SBP. In no case was leptin significantly associated with SBP after adjustment for adiposity. In Group 2, glucose was significantly associated with SBP after adjustment for body weight. In Group 3, however, no correlations were found between SBP, DBP and metabolic characteristics, perhaps due to small sample size. Stepwise multiple regression revealed that body weight and glucose contributed to the variation in SBP in the whole group (R2=0.31, p<0.0001). Insulin accounted for almost 8% of the variation in DBP (R2=0.08, p=0.0034). Body weight contributed significantly to SBP in boys (R2=0.39, p<0.0001) and girls (R2=0.24, p< 0.001). The results imply that body weight contributes independently to the variation in blood pressure. Glucose and insulin contribute to mean blood pressure to some extent, but our data do not support the assumption that leptin per se serves as an independent predictor of blood pressure in obese children and adolescents.

Endoscopic sinus surgery using intraoperative computed tomography imaging for updating a three-dimensional navigation system.

OBJECTIVES: The use of three-dimensional navigation systems provides information on the structures surrounding the field of operation and thereby reduces the risk of iatrogenic damage. The computed tomography (CT) data conventionally used are provided by preoperative scanning procedures, which means that tissue changes coming about during surgery are not seen on the screen. An intraoperative CT scanning procedure being able to update the CT data could provide a solution. STUDY DESIGN: Endoscopic sinus operations using an intraoperative CT updating the three-dimensional navigation system were performed on six persons to find out, whether the above is true. METHODS: Different parameters, advantages, and disadvantages in the cases of these six patients were compared with a group of 22 patients who underwent conventional endoscopic sinus surgery with different three-dimensional navigation systems without updating the CT data set. RESULTS: The intraoperative CT for updating the three-dimensional navigation system provides useful information for the surgeon. CONCLUSION: Balancing its advantages against its disadvantages, the updating of the CT data set with intraoperative CT cannot be recommended for conventional standard endoscopic sinus surgery.

Experiences in intraoperative computer-aided navigation in ENT sinus surgery with the Aesculap navigation system.

Five patients with chronic sinus pathology and an indication for sinus surgery were selected. For intraoperative navigation, we used Surgical Planning and Orientation Computer Systems (SPOCS) Aesculap navigation software (ISG Technologies, Mississauga, Ontario, Canada) and surgical instruments fitted with light-emitting diodes. Navigation procedures are described in detail in the article. The system's precision was measured by pointing at anatomical landmarks. The accuracy was measured as the distance in millimeters between the bony structures of the computed tomographic (CT) scan on screen and the cross-hair of the pointer tip displayed on the screen. Another parameter of the system's accuracy was calculated by the system itself as the root mean square error in millimeters between the markers' position as registered and their position in the CT data set. Axial 3/3/1-mm spiral CT provided sufficient resolution, and data transfer via optical disk was practicable. Positioning of the navigation equipment required some experience, and the registration of the patient's head position also needed attention, as the markers have to be pointed at precisely. During the operation, the position of the head-tracking system on the patient's head must remain unchanged to ensure a correct navigation display. The main advantage of the computed navigation system was the constant orientation provided during the sinus surgical procedure. Borders and critical anatomical structures could be identified in the corresponding CT data set, thus enabling the surgeon to decide on subsequent procedures. Use of the navigation system was found to increase the operation time by about 1 h, resulting in additional time under anesthesia. We found the SPOCS Aesculap computed navigation system to be an established technical aid, ready for use in ENT sinus surgery. In the cases reported here, a precision between 1 and 3 mm was obtained.

[Soft tissue sarcomas of the ENT area. A report of experiences of the Vienna University ENT Clinic]. / Weichteilsarkome im HNO-Bereich. Ein Erfahrungsbericht der Univ.-HNO-Klinik Wien.

BACKGROUND: Soft-tissue sarcomas of the head and neck are rare. Local recurrence is common, and wide excision is thought to be the mainstay of treatment. Surgical radicality is limited by the vicinity of vital organs. Improvement of cure rates therefore is expected mainly from combined treatment modalities. METHOD: Retrospective analysis of 32 cases of soft-tissue sarcoma on file at the Department of Otorhinolaryngology of the University of Vienna between 1954 and 1994. RESULTS: The most frequent descriptive histological diagnosis was polymorphic cell sarcoma in 11 cases. An immunohistological verification was possible in seven cases. The larynx and the pharynx (16 percent each) were the most common sites of affection. Incidence peaks were noted in the third and seventh decade of age. Treatment during the 1950s consisted of surgery and/or irradiation and was supplemented from the 1960s on by polychemotherapy. The median survival was 29 months. Three patients are alive, two patients died free of disease and six patients were lost to follow-up. CONCLUSION: Permanent cure was rare but each therapeutic regimen seemed to provide prolongation of life. The most important prognostic factors were tumor size, histologic grade, and surgical margins.

Beneficial effect of acupuncture on adult patients with asthma bronchiale.

In a retrospective study 17 patients with long-standing history of asthma bronchiale were treated with acupuncture at the outpatient unit of the Department of Anaesthesia and Intensive Care in the University Hospital of Vienna. The subjective effectiveness of the treatment was determined using a standard questionnaire, which was sent to the patients' homes half a year after starting acupuncture treatment. Over 70% of our patients reported a significant improvement of their ailments after ten weeks of treatment as well as half a year after starting acupuncture.

Central projections from singular parts of the vestibular labyrinth in the guinea pig.

Primary afferent projections from singular parts of the vestibular labyrinth were studied in the guinea pig. The posterior ampullary nerve, the common trunk of the anterior and lateral ampullary nerves, as well as fibers innervating the macula sacculi or the macula utriculi were traced with crystals of horseradish peroxidase (HRP) lyophilisate. Posterior, as well as anterior and lateral ampullary fibers were found to project extensively to the superior vestibular nucleus, but also reached the other main vestibular nuclei. Saccular fibers projected mainly to the lateral parts of the lateral vestibular nucleus and to the adjoining descending and superior vestibular nuclei as well as to group y. Modest projections could be followed to the medial vestibular nucleus. Furthermore, a distinct saccular projection to the cochlear nuclei was evident. Utricular projections reached the four main vestibular nuclei with a denser accumulation of fibers within ventral parts of the lateral, descending and superior vestibular nuclei.

Acupuncture in gonarthrotic pain--"Bachmann's knee program".

In a retrospective study 35 patients with gonarthrotic pain were treated with acupuncture at the outpatient unit of the Department of Anaesthesia and Intensive Care in the University of Vienna. The subjective effectiveness of the treatment using a standard method on the knee demonstrated that patients reported an explicit improvement of their ailments. Therefore, we can unreservedly recommend this program, which was only augmented through additive "locus dolendi" treatment if indicated.