[show abstract][hide abstract] ABSTRACT: Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas ICOS-L was expressed by a subset of RMSs and was inducible by tumor necrosis factor α in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag(-/-) mice with fetal acetylcholine receptor-specific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-cell-based therapy.
American Journal Of Pathology 04/2013; · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Induction chemotherapy followed by primary radiotherapy in responders is considered an alternative to surgery for advanced cancer of the larynx and hypopharynx (LHC). Comparison of therapeutic approaches is challenging and must respect oncological and functional outcome as well as quality of life during and after treatment. One aspect of primary radiochemotherapy is the option of salvage surgery in case of residual tumor. The outcome after salvage surgery following new organ-preserving strategies has to be examined. All patients undergoing induction chemotherapy with paclitaxel and cisplatin followed by radiotherapy from 01/96 to 07/05 were included. Salvage surgery was performed either for local recurrence or suspected persistent nodal disease. Complete tumor removal, perioperative morbidity, and overall survival were analyzed in a retrospective study. 28 out of 134 patients underwent salvage surgery after primary treatment with induction chemotherapy and radiotherapy for advanced LHC. 15 patients had laryngectomy (LE) with neck dissection (ND), while 1 patient had lasersurgical partial laryngeal resection with ND for local recurrences. Twelve patients had salvage ND for suspicion of persistent lymph node metastases. 73% of LE patients had major postoperative problems such as pharyngocutaneous fistulas. In 56% of the cases, tumor removal turned out to be microscopically incomplete. Eight out of 12 patients who underwent salvage ND because of suspicious lymph nodes (66%) were free of vital tumor. When metastatic disease was present in the neck (4/12), recurrences occurred in 75% during postoperative follow-up. Only 2 out of 20 patients undergoing surgery for histologically proven recurrence after radiochemotherapy (10%) are actually tumor-free and alive after a mean observation time of 43.9 months. Salvage surgery for local recurrence is associated with high morbidity and poor oncological and functional outcome. ND for suspicious persistent nodal disease after radiochemotherapy can be an over-treatment. In our patients, it was burdened with cervical recurrences and distant metastases in presence of histologically confirmed lymph node metastases. In the light of our results, unfavourable outcome after salvage surgery must be pointed out when initially informing patients about different therapeutic options for advanced LHC.
Archives of Oto-Rhino-Laryngology 04/2009; 266(11):1799-805. · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: A prospective multicenter phase-II trial (12 centers) was performed by the German larynx organ preservation group (DeLOS) to evaluate the effect of induction chemotherapy (ICHT) with paclitaxel/cisplatin (TP), followed by accelerated-hyperfractionated (concomitant boost) radiotherapy (RT) in responders. The trial was focused on larynx preservation, tumor control, survival, salvage surgery and late toxicity in patients with advanced larynx/hypopharynx carcinoma eligible for total laryngectomy (LE). Seventy-one patients (40 larynx, 87.5% St. III, IV; 31 hypopharynx, 93.4% St. III, IV) were enrolled into the study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22) according to the DeLOS protocol. Patients with complete or partial tumor response proceeded to RT (69.9 Gy in 5.5 weeks). Non-responders received a LE followed by postoperative RT (56-70 Gy in 5.5-7 weeks). The response rate to ICHT for larynx cancer was 69.6% (7.1% complete, 62.5% partial response) and for hypopharyngeal cancer was 84.3% (6.9% complete, 77.4% partial response). Overall survival after 36 months was 60.3% (95% CI, 48.4-72.2%), after 42 months was 56.5% (95% CI, 44.2-68.8%). Laryngectomy-free survival was as follows: after 36 months, 43.0% (95% CI, 30.9-55.0%); after 42 months, 41.3% (95% CI, 29.3-53.3%). Both parameters did not show different outcomes after distinguishing larynx from hypopharynx. LE was indicated in 15 non-responders after ICHT. Five of the 15 non-responders refused the laryngectomy. Two of the five received RT instead and had no evidence of disease 42 months after RT. Late toxicity (dysphagia III, IV LENT SOMA score in laryngectomy-free survivors: after 6 months, 1.8%; 12 months, 11.4%; 18 months, 14.5%; 24 months, 8.1%; 36 months, 16%) and salvage surgery (4 pharyngocutaneous fistulas in 27 operations) were tolerable. In a large portion of patients eligible for LE, the larynx could be preserved with satisfying functional outcome. Good responders after ICHT had also a good general outcome with relatively rare severe late toxicities. Due to a slight increase of relevant late dysphagia, functional outcome regarding swallowing and tracheotomy free breathing should be more focused in future larynx organ preservation trials.
Archives of Oto-Rhino-Laryngology 11/2008; 266(8):1291-300. · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Commonly used staging procedures often cannot predict the absence of lymphatic micro- metastases in squamous cell carcinoma (SCC) of the head and neck. Therefore in many cases an elective neck dissection (ND) is necessary. In the surgical therapy of melanoma or breast cancer the presence of metastases can be evaluated securely by identification and examination of the sentinel lymph node (SLN). The type of surgical procedure is usually chosen in regard to the histopathological result. The present study evaluates the applicability of this concept for SCC of the head and neck.
Radioactive labeled micro-albumin particles were injected preoperatively around the tumor in 38 patients without proven metastases. Following the excision of the primary tumor the sentinel lymph node/s were detected and dissected and ND was completed. Histological examination of the tissue was performed to evaluate whether the SLN reflected the lymphatic status.
In two cases (5.1 %) no SLN were detected. ND was completed in 32 cases. In nine cases (28.1 %) the SLN were infiltrated by the primary tumor. In 22 cases (68.8 %) SLN and ND revealed a N(0) stage. In one case (3.1 %) we could not identify a metastasis because of the anatomical closeness of the SLN to the primary. The negative predictive value was 96 %.
Predictive value regarding metastases to the neck was higher with the detection of SLN than with conventional staging procedures. Whether the detection of a tumor-free SLN is an indication not to perform an elective neck dissection is a matter of discussion, especially under the aspect of the effective reduction of postoperative morbidity.
[show abstract][hide abstract] ABSTRACT: The anti-neoplastic drug paclitaxel (taxol), which is known to block cells in the G2/M phase of the cell cycle through stabilization of microtubules, is meanwhile commonly used for chemotherapy of advanced head and neck cancer. Chemotherapy is primarily used in order to preserve laryngeal and/or pharyngeal structures. Although paclitaxel generally seems to be a powerful agent, it failed to reach a loco-regional tumor control in a sufficient percentage of patients. In order to investigate molecular resistance mechanisms, we have established a paclitaxel-resistant subline originating from the larynx carcinoma cell line HLaC79, which seemed to be partially dependent on taxol. The original and the descendant cell line were characterized by growth inhibition assays. We used western blotting and the cDNA subtraction (SSH) technique to identify genes differentially expressed in the taxol-resistant cell clone. cDNA subtraction revealed increased expression of six genes, including clathrin heavy chain, alpha3-tubulin, a neuroblastoma-specific Thymosin beta, the ribosomal protein L7a, HLA-B associated transcript 3 and collagen IIIalpha1 in the taxol-resistant cell line. Furthermore, western blots showed an overexpression of MDR-1 in the taxol-resistant clone, while alpha- and beta-tubulins and p48/IRF9 were expressed in equal amounts in both cell lines.
Archiv für Klinische und Experimentelle Ohren- Nasen- und Kehlkopfheilkunde 03/2006; 263(2):127-34. · 1.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.
European Journal of HumanGenetics 02/2006; 14(1):39-48. · 4.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Injuries of the head and neck with suicidal intention might create serious situations that require rapid and interdisciplinary treatment.
Twenty-seven patients with suicidal head and neck injuries were treated at the Department of oto-rhino-laryngology, head and neck surgery, University of Wurzburg/Germany, between 1991 and 2002. The medical histories were analyzed retrospectively.
Twenty-three of them were male, 4 female. Mean age at time of attempted suicidal was 48 years (18 - 90). One patient was already treated for a psychiatric disorder. None of the patients had a suicidal attempt in the history. Nine patients suffered from a pharynx or larynx trauma after strangulation. Four out of seven patients with cutting or stabbing injuries showed a perforation of the upper airways. Nine patients had gunshot traumas, one of them with perforation of the pharynx. Thirteen patients underwent immediate endoscopy under general anaesthesia followed by a neck exploration in 3 patients. Six patients received a temporary tracheotomy. All patients were considered suicidal for the duration of stay in the ENT-department resulting in a permanent supervision. All patients were transferred to a psychiatric unit as soon as possible for further treatment. A statistically significant accumulation was observed during the last third of a year. Over the period of 11 years, suicidal injuries of the head and neck tend to occur more frequently.
The presented study emphasizes the need of immediate surgical and intensive care treatment of patients with head and neck injuries due to suicide attempts as well as an adequate psychiatric supervision during as well as after the surgical treatment.
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to determine the feasibility and efficacy of hyperfractionated accelerated radiotherapy (HFRCB) combined with simultaneous chemotherapy with weekly cisplatin (CDDP) in locally advanced inoperable head and neck cancer.
From August 1999 to December 2002, 37 patients (median age, 59 years) with Union Internationale Contre le Cancer stage III (n = 2) and stage IV (n = 35) squamous cell cancer of the oropharynx and hypopharynx were treated in a prospective phase I/II trial. Concomitant boost radiotherapy (1.8 Gy, days 1-38 and 1.5 Gy boost, days 22-38, twice daily with at least a 6-hour interval; total dose 69.9 Gy) and simultaneous cisplatin, 40 mg/m2 weekly, were given.
The median treatment duration was 42 days (range, 38-46 days). Toxicity was manageable, with neutropenia grade III/IV and thrombocytopenia grade IV in seven and one patients, and mucositis grade III/ IV in 27 and five patients, respectively. Chemotherapy was restricted to four weekly applications in 29 patients mainly because of mucosal toxicity with a median dose intensity of 160 mg/m2 (0-200) of cisplatin in 5.5 weeks. With a median follow-up of 28 months for living patients, the 2-year overall survival rate was 67%. The median overall and relapse-free survival times were 36 and 31 months, respectively.
HFRCB in combination with weekly cisplatin achieves a high rate of locoregional control and survival. Four weekly cycles of 40 mg/m2 cisplatin seem to be the dose limit for most patients.
Head & Neck 02/2005; 27(1):36-43. · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Randomized controlled studies have shown that preservation of the larynx function in patients with advanced resectable laryngeal and hypopharyngeal cancer is possible without compromising survival compared to total laryngectomy (TL). Options for preserving the larynx include function-sparing surgery, radiotherapy alone, induction chemotherapy followed by radiotherapy of responders, and concomitant radiochemotherapy. The current data suggest that induction chemotherapy followed by radiotherapy of responders is an acceptable alternative to TL for patients desiring larynx preservation. Concomitant radiochemotherapy (platinum/5-FU) leads to superior local control and larynx preservation rates compared to induction chemotherapy followed by radiation. The optimal treatment sequence for newer cytotoxic agents is, however, unclear. Such cytotoxic agents and more effective fractionation regimens as well as more advanced surgical techniques are currently evaluated. Predictive tests to successfully stratify patients for the optimal treatment option and more effective systemic therapy are needed to improve therapeutic possibilities and survival.
[show abstract][hide abstract] ABSTRACT: The aim of gene therapy includes the tight spatial and temporal control of transgenic expression. There are several approaches concerning externally inducible gene promoters used for the control of suicide genes. Two of the promoters that might play a role in head and neck cancer gene therapy are the hyperthermia-inducible human heat shock protein-70 (hsp70) promotor, as well as the radiation-inducible promoter of the early growth response-1 gene (egr-1). We tested the hsp-70 promoter as well as a promoter construct, containing synthetic radio-responsive elements of the egr-1 enhancer for the effect on reporter gene expression in two stably transfected head and neck carcinoma cell lines in vitro and measured the success of gene activation by FACS analysis, western blot analysis and fluorescence microscopy. With the hsp70 promoter we reached a 5.83-fold increase of reporter gene expression after hyperthermic treatment in one of the two cell lines tested. The radiation-inducible construct revealed only weak gene induction and was marked by high background expression. Both systems worked in a highly cell-type dependent manner. The possible clinical use of externally inducible transgene expression in head and neck carcinoma gene therapy is critically discussed.
Archiv für Klinische und Experimentelle Ohren- Nasen- und Kehlkopfheilkunde 05/2004; 261(4):208-15. · 1.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Computed tomography reliably evaluates hypopharyngeal squamous cell carcinomas (SCC) regarding the infiltration of specific anatomic structures and tumor volumes, both of which have been shown to be predictors of local control in patients treated with radiation therapy alone. However, an association of specific infiltrated structures and/or tumor volume with local control has not been investigated for surgical treatment; thus, we determined relationships of various infiltrated anatomic structures and tumor volume with local control in patients with hypopharyngeal SCC treated with primary surgery. In 45 hypopharyngeal SCC, tumor volumes were measured by pretreatment CT, and extent of tumor infiltration was determined by postoperative pathologic examination. All patients had clinical follow-up for recurrent tumor at the primary site. Statistical analysis basically consisted of chi-square and U-tests. Local control rate was 84.4% (38 of 45). Tumor volume was significantly associated with local control (p=0.004). Six of 16 (38%) patients with tumor volumes > or =8.1 cm3 (mean) had a local recurrence, which is significantly (p=0.003) more compared with 1 of 29 (3%) in the group of patients with volumes <8.1 cm3. Among all evaluated anatomic structures, only a tendency for significant association with local control was found for tumor involvement of the tonsils and the extralaryngeal soft tissues. The determination of tumor volumes by CT helps predict local control in patients with hypopharyngeal SCC treated with primary surgery.
European Radiology 03/2004; 14(2):286-91. · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: The histological detection of a peritumoral lymphocytic infiltration (PLI) and a sharp tumor border in patients with squamous cell carcinoma (SCC) of the larynx, pharynx or oral cavity is inversely correlated with the development of cervical lymph node metastases and is therefore a favorable prognostic factor. However, preoperative biopsies are often too small for an evaluation of these tumor features. Here, we examined retrospectively whether elevation of peritumoral density values as determined by contrast-enhanced computed tomography (CT) correlates with PLI and the presence of cervical lymph node metastases. A total of 40 patients with primarily resected SCC were studied (pT1=8, pT2=13, pT3=9, pT4=10); 25 patients were pN-positive. All tumors were histologically analyzed regarding PLI (present or not) and the tumor border (sharp or infiltrating). Based on standardized CT examinations (90 ml contrast agent at 1.5 ml/s), repeated region-of-interest (ROI)-based peritumoral density measurements were obtained. Correlations between CT density, PLI, tumor border and metastatic involvement of regional lymph nodes were statistically evaluated. CT densities were significantly higher (P<0.001) in patients with PLI and sharp tumor borders than in patients without PLI and patients with infiltrating tumor borders. Moreover, the presence of PLI, sharp tumor borders and elevated peritumoral CT densities were each correlated with the absence of lymph node metastases (P<0.001). An elevation of peritumoral CT densities is linked to PLI and sharp tumor borders on histology and a lower risk to develop lymph node metastases. For a patient-adapted therapy, these relations have to be prospectively evaluated regarding their prognostic relevance.
Archiv für Klinische und Experimentelle Ohren- Nasen- und Kehlkopfheilkunde 11/2003; 260(10):558-64. · 1.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Assessment of the diagnostic value of multiplanar reformations (MPR) in multi-slice computed tomography (MSCT) by comparing relevant anatomic structures of the larynx and hypopharynx.
MSCT of the neck was performed in 69 consecutive patients (including 30 laryngeal and 12 hypopharyngeal carcinomas). From a 4 x 1.0 mm collimation data set, 3.0-mm and 1.25-mm axial slices as well as 3-mm coronal and sagittal slices were reconstructed. Using the histological examination as gold standard, sensitivity and specificity regarding tumor infiltration for all relevant anatomical structures of the larynx and the hypopharynx were determined for each reconstruction and compared with the McNemar test. Moreover, 42 patients with laryngeal and/or hypopharyngeal carcinoma were subjectively evaluated to determine whether the respective reconstructions enables a better topographical visualization of the tumor in relation to surrounding structures and, furthermore, whether this has an influence on the therapeutical strategy (operation versus radiation therapy, type of operation, surgical approach).
Sensitivities and specificities were not significantly different between the reconstructions. However, coronal and sagittal MPR provided a better topographical visualization of the tumor in 14 of 42 (33 %) of the patients, and influenced the therapeutical strategy in 8 of 42 (19 %) of the patients. A lowered signal-to-noise ratio impeded the evaluation of the relatively thin 1.25-mm axial slices in more than 23 % of the cases.
Besides the 3-mm axial slices, coronal and sagittal MPR can improve the topographical visualization of laryngopharyngeal tumors and are recommended for preoperative MSCT of laryngeal and/or hypopharyngeal carcinomas. Additionally reconstructed 1.25-mm axial slices can be discarded since they do not hold a higher value compared to 3-mm axial reconstructions.
RöFo - Fortschritte auf dem Gebiet der R 09/2003; 175(8):1079-85. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the effect of paclitaxel/cisplatin induction chemotherapy (ICHT) and CT-based radiotherapy (RT) on larynx preservation, tumor control, and survival in patients with larynx/hypopharynx carcinoma eligible for total laryngectomy (TL) or TL plus partial pharyngectomy (TLPP).
Fifty patients eligible for TL or TLPP were enrolled onto a prospective study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22). In patients with complete or partial tumor response RT (69.9 Gy in 5.5 weeks at the gross tumor, 50.4 Gy in the lymphatic drainage; single dose: 1.8 Gy, concomitant boost: 1.5 Gy) was applied. Non-responders had TL/TLPP and RT with total doses adapted to the radicality of tumor resection (56-70 Gy).
The response rate to ICHT was 88% (10% complete, 78% partial response). At a median follow-up period of 25 months the larynx preservation rate was 84%. The 2-year local-regional control rate was 91% and the 2-year overall survival rate was 72.3%. The 3-year estimate to survive with functional larynx is 60%.
In a large portion of patients eligible for TL or TLPP the larynx was preserved by paclitaxel/cisplatin ICHT and 3D RT.
Radiotherapy and Oncology 09/2003; 68(2):163-70. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the prognostic implication of tumor infiltration and volume in primarily operated oropharyngeal carcinomas.
In 80 patients with oropharyngeal squamous cell carcinomas (pT 1 = 22, pT 2 = 30, pT 3 = 19 and pT 4 = 9), the tumor volume was measured by pretreatment CT and the extent of tumor infiltration determined by postoperative histologic examination. All patients were followed clinically for local tumor recurrence for at least two years after therapy. The statistical analysis consisted of chi 2 and U tests.
The local control rate was 79 % (63/80). Of all evaluated anatomic structures, only midline crossing correlated significantly with local recurrence (p = 0.06). No correlation of tumor volume (p = 0.19) or T stage (p = 0.60) with the local recurrence rate was found.
After primary surgery, oropharyngeal carcinomas with midline crossing have an increased risk of local recurrence, whereas the tumor volume only has a minor impact on the recurrence rate. This is in contrast to laryngeal or hypopharyngeal carcinomas.
RöFo - Fortschritte auf dem Gebiet der R 02/2003; 175(1):61-6. · 2.76 Impact Factor