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.
Uncertainty in the properties of semi-finished parts can cause fluctuations in the product properties, especially if they have a strong effect on the process and cannot be compensated by process ...adjustments. Incremental forming processes have the potential to react to changing conditions by adapting the tool movement during the process. This paper analyzes the feasibility of controlling material flow in an orbital forming process in order to selectively fill those geometric elements which were specified with narrow tolerances by the designer. The effect of different process parameters on the mushroom effect and the degree of mold filling are analyzed by FEM simulations and experiments. In order to realize online monitoring and control, an estimation model is introduced, which maps signals from sensors and the process control to the geometric target values.
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
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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.
Paclitaxel (Taxol®)is an antimicrotubular agent which blocks the cells in the G2/M phase of the cell cycle. Because of this mechanism it is presumed that this drug could function as a radiation ...sensitizer. The cytotoxic and genotoxic effects of paclitaxel and a combination of paclitaxel and radiation were studied in the human laryngeal carcinoma cell line HLac 79. The growth of the cells was significantly reduced at concentrations of paclitaxel as low as 10 nM. Flow cytometry data showed a G2/M block after exposure to paclitaxel. Radiation at 12 and 24 h after drug treatment exerted an additive but no radiation sensitizing effect. As genotoxic effect paclitaxel induced multinucleated cells, possibly in a synergistic manner, at low concentrations (10 nM) and radiation doses up to 3 Gy.
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