Silke Gronau

Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma

CD44v6 is a tumor associated antigen abundantly expressed in head and neck squamous cell carcinomas (HNSCC) and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. The maximum tolerated dose (MTD), safety and efficacy of BIWI 1 administered IV in patients with HNSCC has not been determined. In a clinical phase I trial, adult patients with recurrent or metastatic HNSCC were treated intravenously with BIWI 1. Starting with 25mg/m(2), the dose was escalated in steps of 25mg/m(2) until dose limiting toxicity was observed. Six women and 25 men were included. The MTD was 300 mg/m(2). Twelve patients were treated with at least the MTD. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Three patients had partial responses at doses of 200, 275 and 325 mg/m(2). The concept that bivatuzumab can direct mertansine activity to CD44v6 expressing tumors was confirmed. Although CD44v6 was abundantly expressed in all tumors, the response to BIWI 1 was variable. Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study.

Nasal toxicity of benzalkonium chloride.

Background Benzalkonium chloride (BAC) is added to nasal preparations to prevent microbial contamination. Adverse effects of BAC on human nasal mucosa should be evaluated. Methods The ciliotoxicity of BAC was assessed in isolated human nasal epithelia from 15 donors. The effects of nasal BAC 0.05% (4 X 200 μL/day for 8 days) on nasal saccharin transport time, inflammatory cells and cytokine levels in nasal secretions, and nasal symptom scores were assessed in a randomized, double-blind crossover trial in 16 healthy volunteers. Results In vitro, BAC was ciliotoxic (p < 0.0001). In vivo, BAC did not alter saccharin transport time in healthy individuals (p > 0.8). No BAC-associated proinflammatory effects were observed. The staining index for myeloperoxidase was 4.8% in the placebo period and 6.3% (p = 0.42) in the BAC period. Also, nasal secretion levels of cytokines and the neuropeptide substance P revealed no BAC-associated differences. Concentrations for interleukin (IL)-6 in the placebo period were 41.5 pg/mL (0.9–91.7 pg/mL) and in the BAC period were 17.6 pg/mL (3.2–65.9 pg/mL; p = 0.46), and concentrations for substance P were 119 pg/mL (58–293 pg/mL) and 131 pg/mL (80–330 pg/mL; p = 0.31), respectively. Immediately after application, BAC caused nasal irritation (p = 0.001), a burning sensation (p = 0.0003), and hypersecretion (p = 0.006). Moreover, BAC caused a persistent sensation of nasal irritation (p < 0.01). Conclusion BAC in concentrations used in nasal preparations is ciliotoxic. In healthy individuals, the ciliotoxic effect of BAC is neutralized, probably by components of nasal secretions. No BAC-related proinflammatory effects have been observed. At higher doses than normally used therapeutically, BAC caused significant nasal irritation. (American Journal of Rhinology 18, 291–299, 2004)

Immunohistomorphologic and molecular cytogenetic analysis of a carcinosarcoma of the urinary bladder

Abstract Carcinosarcomas of the urinary bladder are malignant biphasic tumors with an epithelial and a spindle cell component. For the histogenesis of the two components, a biclonal and a monoclonal origin are discussed. We present the immunomorphology and molecular cytogenetics of such a case. The immunohistology of biopsies of the urinary bladder revealed a poorly differentiated urothelial carcinoma (GIII) and a co-existing pleomorphic, spindle cell leiomyosarcoma (GIII). The two components were microdissected and further analyzed for gains and losses of chromosomal material using comparative genomic hybridization. In addition, loss of heterozygosity analyses were included. The tumor components revealed as overlapping core aberrations losses on the short arm of chromosome 9 and on the long arm of chromosome 11. However, both components showed additional aberrations exclusively detected in one of the components. The occurrence of overlapping aberrations strongly argues for a monoclonal origin of this tumor with a common ancestor. The additional aberrations of the components point to an independent and divergent course of tumor progression in both components.

Genotype and phenotype of glutathione-s-transferase in patients with head and neck carcinoma☆

OBJECTIVE: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and cancer has been demonstrated. Possible underlying mechanisms and genotype-phenotype correlations are not adequately investigated. The aim of this study was to investigate the influence of the GSTM1-null-genotype on the level of GSTM enzyme concentration and on the enzyme activity of GST in patients with head and neck cancer (HNC). METHODS: We investigated in 83 patients and 91 healthy controls the GSTM1 polymorphisms, GSTM1 protein concentration, GSTM1 protein in tumor tissues, and total GST enzyme activity. RESULTS: Total GST enzyme activity was significantly lower in patients with HNC (208 ± 9 μmol/min1) than in controls (264 ± 11 μmol/min1, P < 0.0001) but did not depend on GSTM1-genotype (P = 0.1). GSTM protein concentration in null-genotype patients (3.6 ± 2.5 μg/mL, mean ± SE) was significantly lower than in GSTM1 allele carriers (26.7 ± 9.6 μg/ml, P < 0.0001); GSTM protein expression did not depend on GSTM1-genotype (P > 0.5). CONCLUSION: GST enzyme activity in patients with HNC is suppressed, indicating impaired detoxification capacity of tobacco-smoke-related carcinogens. This suppression is not correlated with the GSTM1-genotype. (Otolaryngol Head Neck Surg 2004;130:718-25.)

TRIFUNCTIONAL BISPECIFIC ANTIBODY-INDUCED TUMOR CELL LYSIS OF SQUAMOUS CELL CARCINOMAS OF THE UPPER AERODIGESTIVE TRACT

The trifunctional bispecific antibody Removab (tbAB) bridges and activates CD3 positive T cells to EpCAM on carcinoma cells and simultaneously binds to an accessory immune‐cell inducing tumor cell lysis. tbAB‐induced tumor cytotoxicity was assessed in an autologous human ex vivo system.

Early radiation-induced malignant fibrous histiocytoma of the oral cavity.

With an incidence of less than 0.3 per cent, post-radiation sarcomas are rare malignant neoplasms with a very poor prognosis. On average, they occur after a latency period of at least 15 years following radiation therapy with doses ranging from 24 to 80 Gy. We present the case of a post-irradiation malignant fibrous histiocytoma (MFH) on the floor of the mouth in a 79-year-old male patient arising only five and a half years after radiation therapy. The primary tumour was classified as a well differentiated squamous cell carcinoma of the right rim of the tongue. Primary therapy was surgical resection of the tumour and post-operative radiation with 50 Gy. Five and a half years later, the patient developed a rapidly progressing MFH within the field of radiation.

Sekundär beschleunigte Fremdkörper als Gefahrenquelle bei Airbagauslösung

BACKGROUND The use of airbag systems in motor vehicle construction has led to a significant reduction in both the frequency and intensity of injuries during traffic accidents. However, recent reports have shown numerous cases in which it is assumed that the airbag was the major cause of serious injury. CASE REPORT In a collision with a wild boar, both airbags in the automobile deployed. The driver suffered facial abrasion and belt contusion to the left shoulder. The passenger held a glass bottle in her hands during the impact that, secondarily accelerated through the airbag, hit both eyes and the bridge of her nose. On clinical admission, the patient showed fractures of the nasal bridge, of both medial orbital walls on both sides and a massive periocular haematoma which required direct examination under narcosis. Both eyes showed an orbital contusion, a large area of corneal abrasion, traumatic mydriasis with sphincter tears such as bilateral 90% hyphema. During surveillance, a progressive reduction in visual acuity occurred. After posterior chamber vitrectomy with epiretinal peeling and posterior chamber lens implantation in the left eye, visual acuity was 0.05 in the left eye and 0.01 in the right. CONCLUSIONS A considerable danger emanates from objects which are situated between head and airbag in the moment of airbag deployment. This requires public education and, in addition, airbag systems which are adapted to the drivers height and weight, as well as to objects in its immediate vicinity.ZusammenfassungHintergrundDie Einführung des Airbags in den Automobilbau hat zu einer signifikanten Reduktion der Verletzungshäufigkeit und -schwere der Insassen bei Autounfällen geführt. Es gibt trotzdem in der Literatur mehrere Fälle, in denen wahrscheinlich der Airbag die Ursache für Personenschäden bei einem Unfall war.FallBeim Zusammenstoß mit einem Wildschwein lösten beide Airbags des Autos aus. Der Fahrer erlitt außer Gesichtsabschürfungen sowie einer Prellmarke keine Verletzungen. Die Beifahrerin hatte beim Aufprall eine Flasche in der Hand. Diese wurde durch den Airbag beschleunigt und traf Augen und Nase. Folge waren eine Nasenpyramidenfraktur, eine Fraktur der medialen Orbitawand beidseits sowie ein massives periorbitales Hämatom. Die Untersuchung der Augen in Narkose ergab eine Contusio bulbi, eine großflächige Erosio corneae, eine traumatische Mydriasis mit Sphinktereinrissen sowie ein 90%iges Vorderkammerhämatom beidseits. Im Verlauf trat eine progrediente Visusreduktion auf, sodass eine Vitrektomie und Hinterkammerlinsenimplantation am linken Auge durchgeführt wurde. Bei Entlassung betrug der Visus am linken Auge 0,05 und am rechten Auge 0,1.FazitÜber die potenzielle Gefahr von Objekten, die sich im Moment der Airbagauslösung zwischen Person und Airbag befinden, muss aufgeklärt werden. Die Automobilindustrie sollte ein System entwickeln, das Größe und Gewicht der betreffenden Person sowie etwaige sich im Radius des Airbags befindende Fremdkörper erkennt und daraufhin die Airbagauslösung modifiziert.AbstractBackgroundThe use of airbag systems in motor vehicle construction has led to a significant reduction in both the frequency and intensity of injuries during traffic accidents. However, recent reports have shown numerous cases in which it is assumed that the airbag was the major cause of serious injury.Case reportIn a collision with a wild boar, both airbags in the automobile deployed. The driver suffered facial abrasion and belt contusion to the left shoulder. The passenger held a glass bottle in her hands during the impact that, secondarily accelerated through the airbag, hit both eyes and the bridge of her nose. On clinical admission, the patient showed fractures of the nasal bridge, of both medial orbital walls on both sides and a massive periocular haematoma which required direct examination under narcosis. Both eyes showed an orbital contusion, a large area of corneal abrasion, traumatic mydriasis with sphincter tears such as bilateral 90% hyphema. During surveillance, a progressive reduction in visual acuity occurred. After posterior chamber vitrectomy with epiretinal peeling and posterior chamber lens implantation in the left eye, visual acuity was 0.05 in the left eye and 0.01 in the rightConclusionsA considerable danger emanates from objects which are situated between head and airbag in the moment of airbag deployment. This requires public education and, in addition, airbag systems which are adapted to the drivers height and weight, as well as to objects in its immediate vicinity.

Radiofrequency-induced thermotherapy on nasal polyps: preliminary results.

Background The aim of this study was to determine the effects of radiofrequency-induced thermotherapy (RFITT) in patients with nasal polyps. Methods A retrospective analysis was performed of prospectively collected data from 17 consecutive patients (11 men and 6 women; mean age, 51.7 ± 16.9 years) treated with RFITT from 2002 to 2003. The postoperative outcome was assessed using active anterior rhinomanometry, “sniffin’ stick” test, and endoscopic nasal examination preoperatively and 4 weeks postoperatively. Subjective complaints were assessed with Likert scales. Results Transnasal airflow increased by 40.3% 4 weeks postoperatively (p = 0.029). Endoscopic appearance of nasal polyps indicated a nonsignificant reduction of 37.1%. Subjective complaints such as impaired nasal ventilation (p = 0.014), nasal discharge (p = 0.0007), postnasal drip (p = 0.0002), and hyposmia (p = 0.048) improved significantly 4 weeks after surgery. Conclusion RFITT is well tolerated as a day case procedure under local anesthesia and might be a procedure for treating recurrence of NP after sinus surgery. It remains unclear at this point whether RFITT for nasal polyps results in a permanent reduction.

Secondarily accelerated foreign bodies as a source of danger from airbag deployment

BACKGROUND The use of airbag systems in motor vehicle construction has led to a significant reduction in both the frequency and intensity of injuries during traffic accidents. However, recent reports have shown numerous cases in which it is assumed that the airbag was the major cause of serious injury. CASE REPORT In a collision with a wild boar, both airbags in the automobile deployed. The driver suffered facial abrasion and belt contusion to the left shoulder. The passenger held a glass bottle in her hands during the impact that, secondarily accelerated through the airbag, hit both eyes and the bridge of her nose. On clinical admission, the patient showed fractures of the nasal bridge, of both medial orbital walls on both sides and a massive periocular haematoma which required direct examination under narcosis. Both eyes showed an orbital contusion, a large area of corneal abrasion, traumatic mydriasis with sphincter tears such as bilateral 90% hyphema. During surveillance, a progressive reduction in visual acuity occurred. After posterior chamber vitrectomy with epiretinal peeling and posterior chamber lens implantation in the left eye, visual acuity was 0.05 in the left eye and 0.01 in the right. CONCLUSIONS A considerable danger emanates from objects which are situated between head and airbag in the moment of airbag deployment. This requires public education and, in addition, airbag systems which are adapted to the drivers height and weight, as well as to objects in its immediate vicinity.ZusammenfassungHintergrundDie Einführung des Airbags in den Automobilbau hat zu einer signifikanten Reduktion der Verletzungshäufigkeit und -schwere der Insassen bei Autounfällen geführt. Es gibt trotzdem in der Literatur mehrere Fälle, in denen wahrscheinlich der Airbag die Ursache für Personenschäden bei einem Unfall war.FallBeim Zusammenstoß mit einem Wildschwein lösten beide Airbags des Autos aus. Der Fahrer erlitt außer Gesichtsabschürfungen sowie einer Prellmarke keine Verletzungen. Die Beifahrerin hatte beim Aufprall eine Flasche in der Hand. Diese wurde durch den Airbag beschleunigt und traf Augen und Nase. Folge waren eine Nasenpyramidenfraktur, eine Fraktur der medialen Orbitawand beidseits sowie ein massives periorbitales Hämatom. Die Untersuchung der Augen in Narkose ergab eine Contusio bulbi, eine großflächige Erosio corneae, eine traumatische Mydriasis mit Sphinktereinrissen sowie ein 90%iges Vorderkammerhämatom beidseits. Im Verlauf trat eine progrediente Visusreduktion auf, sodass eine Vitrektomie und Hinterkammerlinsenimplantation am linken Auge durchgeführt wurde. Bei Entlassung betrug der Visus am linken Auge 0,05 und am rechten Auge 0,1.FazitÜber die potenzielle Gefahr von Objekten, die sich im Moment der Airbagauslösung zwischen Person und Airbag befinden, muss aufgeklärt werden. Die Automobilindustrie sollte ein System entwickeln, das Größe und Gewicht der betreffenden Person sowie etwaige sich im Radius des Airbags befindende Fremdkörper erkennt und daraufhin die Airbagauslösung modifiziert.AbstractBackgroundThe use of airbag systems in motor vehicle construction has led to a significant reduction in both the frequency and intensity of injuries during traffic accidents. However, recent reports have shown numerous cases in which it is assumed that the airbag was the major cause of serious injury.Case reportIn a collision with a wild boar, both airbags in the automobile deployed. The driver suffered facial abrasion and belt contusion to the left shoulder. The passenger held a glass bottle in her hands during the impact that, secondarily accelerated through the airbag, hit both eyes and the bridge of her nose. On clinical admission, the patient showed fractures of the nasal bridge, of both medial orbital walls on both sides and a massive periocular haematoma which required direct examination under narcosis. Both eyes showed an orbital contusion, a large area of corneal abrasion, traumatic mydriasis with sphincter tears such as bilateral 90% hyphema. During surveillance, a progressive reduction in visual acuity occurred. After posterior chamber vitrectomy with epiretinal peeling and posterior chamber lens implantation in the left eye, visual acuity was 0.05 in the left eye and 0.01 in the rightConclusionsA considerable danger emanates from objects which are situated between head and airbag in the moment of airbag deployment. This requires public education and, in addition, airbag systems which are adapted to the drivers height and weight, as well as to objects in its immediate vicinity.

Dendritic cells pulsed with tumor-derived lysate augment t cell mediated tumor cell lysis

Abstract Problem: Immunotherapy of malignant diseases mediated by dendritic cells (DC) pulsed with tumor antigens is a promising new tool in the individual treatment of malignant diseases. Tumor-specific T cells should be generated by coincubation with DC pulsed with tumor-derived lysate (TL), and their cytolytic activity should be assessed in an autologous ex vivo system. Methods: DC were generated from peripheral blood monocytes using standard techniques and pulsed with autologous TL from patients with head and neck squamous cell carcinoma (HNSCC). Pulsed DC are able to induce the generation of cytotoxic T cells (CTL). CTL were then coincubated with autologous tumor cells on a chorioallantois membrane. Tumor cells coincubated with 200μl (0.5 mg/mL) Cisplatin; native T cells or cell culture medium served as controls. Results: Coincubation of HNSCC cells with CTL resulted in a decrease of viable cells at T24 and T48 when compared with the control containing only medium or native T cells. The coincubation of HNSCC with Cisplatin resulted in a decrease of about 50% at T24 and T48. Conclusion: DC pulsed with TL were able to present tumor antigens to lymphocytes resulting in the generation of tumor-specific CTL inducing tumor cell lysis. DC pulsed with TL may represent a method for inducing immune responses against squamous cell carcinomas of the upper aerodigestive tract. Significance: These results are encouraging for the possible application of pulsed DC in the therapy of HNSCC. Support: None reported.