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.

[The value of supracricoid partial laryngectomy in moderately advanced laryngeal cancer (T3-T4a)]. / Stellenwert der suprakrikoidalen Teilresektion beim moderat fortgeschrittenen Glottiskarzinom (T3-T4a).

BACKGROUND: Transoral laser microsurgery (TLM) is the method of choice for partial laryngectomy in Germany. In advanced stages, chemoradiotherapy is increasingly indicated for organ preservation. OBJECTIVE: This report considers the indications for and outcomes of supracricoid partial laryngectomy (SPL), also known as crico-hyoido-(epiglotto)-pexy, as an option for surgical organ preservation in moderately advanced laryngeal cancer (T3-T4a), in the well-defined gap between TLM and chemoradiotherapy protocols in Germany. METHODS: Retrospective evaluation of functional and oncological outcomes of all SPLs conducted between 2008 and 2014. During this period, 17 SPLs with resection of rpT2 (n = 2), (r)pT3 (n = 11), and (r)pT4a (n = 4) were performed with resection of one arytenoid. Mean age was 58 years (range 47-75 years). In 5 patients, SPL was for a first or second local recurrence after TLM or open partial laryngectomy. Adjuvant radiotherapy was received by 7 patients staged pT4a or pN+. RESULTS: Salvage laryngectomy with adjuvant radiotherapy was required by 2 patients. The remaining patients (n = 15) had a mean tumor-free follow-up of 4 years with a functional intact larynx: these patients can eat and drink, have a closed tracheotomy, and a good voice. After 3 years tumor-free follow-up with a functional intact larynx, 2 patients died due to cardiac comorbidity at the age of 76 years. DISCUSSION: SPL is a rare but valuable option for surgical larynx preservation in stage pT3-4a laryngeal cancer.

Laryngomalacia and complicated, life-threatening mTOR-positive Kaposiform hemangioendothelioma cured by Supraglottoplasty and sirolimus.

The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE.

Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer.

In head and neck squamous cell carcinoma (HNSCC) aerobic glycolysis is the key feature for energy supply of the tumor. Quantitative microdialysis (µD) offers an online method to measure parameters of the carbohydrate metabolism in vivo. The aim was to standardize a quantitative µD-study in patients with HNSCC and to prove if a ketogenic diet would differently influence the carbohydrate metabolism of the tumor tissue. Commercially available 100 kDa-CMA71-µD- catheters were implanted in tumor-free and in tumor tissue in patients with HNSCC for simultaneous measurements up to 5 days. The metabolic pattern and circadian rhythm of urea, glucose, lactate, and pyruvate was monitored during 24 h of western diet and subsequent up to 4 days of ketogenic diet. After 3 days of ketogenic diet the mean lactate concentration declines to a greater extent in the tumor tissue than in the tumor-free mucosa, whereas the mean glucose and pyruvate concentrations rise. The in vivo glucose metabolism of the tumor tissue is clearly influenced by nutrition. The decline of mean lactate concentration in the tumor tissue after ketogenic diet supports the hypothesis that HNSCC tumor cells might use lactate as fuel for oxidative glucose metabolism.

[Dysplasia and laryngeal carcinoma in situ]. / Dysplasien und Carcinomata in situ des Larynx.

Although the glottis is amenable to chemotherapy, currently most lesions from stage I laryngeal dysplasia up to carcinoma in situ are excised. This literature review presents selected molecular biological aspects especially in relation to dysplasia of the larynx and its therapy, as well as currently preferred biomarkers for chemotherapeutic prevention of laryngeal dysplasia.

Hoarseness after laryngeal blunt trauma: a differential diagnosis between an injury to the external branch of the superior laryngeal nerve and an arytenoid subluxation. A case report and literature review.

Arytenoid subluxation is a well-known cause of hoarseness due to incomplete glottic closure with intact inferior laryngeal nerves after severe laryngeal trauma. We report the case of a young man presenting after laryngeal blunt trauma with hoarseness, easy fatigue during phonation, marked difficulty with his high-pitch and singing voice and decreased phonation time, but intact function of both inferior laryngeal nerves, intact endolaryngeal mucosa sensibility and normal CT scans of the larynx and the neck. Due to the asymmetric anteromedial position of the right arytenoid with incomplete glottic closure, the primary diagnosis was arytenoid subluxation, and the patient was referred for instantaneous relocation therapy. The stroboscopic and electromyographic diagnosis of a unilateral paresis of the external branch of the right superior laryngeal nerve caused the therapy to be changed. Without repositioning, the patient had a total recovery of voice quality when the paresis receded 2 months later. In conclusion, the unilateral paresis of the external branch of the superior laryngeal nerve after laryngeal blunt trauma is reported here for the first time. Although the clinical findings are familiar sequelae of thyroid surgery, they may be misdiagnosed as arytenoid subluxation after laryngeal blunt trauma. Stroboscopy and electromyography permitted the correct diagnosis.

Neuroblastoma directed therapy by a rational prodrug design of etoposide as a substrate for tyrosine hydroxylase.

Tumor directed cytotoxic therapy is one of the major challenges for the success of chemotherapy. In order to accomplish this goal in neuroblastoma, we rationally designed a prodrug of etoposide as substrate for tyrosine hydroxylase, a well established neuroblastoma associated enzyme. Here, we report synthesis and characterization of a 3,4 dihydroxy-phenyl carbamate derivative of etoposide. In order to demonstrate activation by tyrosine hydroxylase, the coding sequence of murine tyrosine hydroxylase was generated by reverse transcriptase-polymerase chain reaction from NXS2 neuroblastoma cells and cloned into the pRSET-A bacterial expression vector. The enzyme was expressed in Escherichia coli, characterized by Western blot and enzymatic activity was demonstrated by conversion of tyrosine into DOPA in the presence of cofactors using reversed phase high-performance liquid chromatography. Under these enzymatic conditions, we demonstrate conversion of 3,4 dihydroxy-phenyl carbamate prodrug into free etoposide. This effect was clearly mediated by the enzyme since bacteria transformed with the empty vector were ineffective of prodrug activation. Furthermore, tyrosine hydroxylase positive cells exposed to the etoposide prodrug were effectively killed in contrast to tyrosine hydroxylase negative controls. These findings demonstrate that etoposide can be designed as a prodrug substrate for tyrosine hydroxylase and thereby establish proof of concept for neuroblastoma directed enzyme prodrug therapy.

Rationally designed hydrolytically activated etoposide prodrugs, a novel strategy for the treatment of neuroblastoma.

Effective chemotherapy in neuroblastoma is limited by poor anti-tumor efficacy, systemic toxicity and the induction of drug resistance. Here, we provide further evidence that a hydrolytic activated prodrug design may overcome these problems. For this purpose, VP-16 was functionally blocked by a carbonate linker to generate two novel chemically stable prodrugs of VP-16, ProVP-16 I and II. We demonstrate profoundly different biological effects in vitro and in vivo of the prodrugs compared to parental VP-16. First, we established an up to >2 log higher in vitro toxicity of the two prodrugs compared to VP-16 on a panel of neuroblastoma cell lines. The highest increase of prodrug mediated cytotoxicity was observed in multi drug resistant cell lines. Second, in vivo studies showed a maximum tolerated dose (MTD) of ProVP-16 II (60 mg/kg), which was at least threefold higher than that of VP-16 (20 mg/kg). Tests of ProVP-16 II in a syngeneic NXS2 neuroblastoma model indicated that mice treated with this prodrug at 1/3 of the MTD was as effective as VP-16 parental compound used at the MTD in suppression of tumor growth. In summary, the etoposide prodrugs proved effective and less toxic and are therefore highly promising new anti-neuroblastoma compounds.

Efficacy and benefit of mediastinal computed tomography as a selection method for mediastinoscopy.

In 95 consecutive patients with proven or suspected bronchial carcinoma, computed tomographic evaluation of the upper mediastinum for N2 disease was performed prospectively. Patients with positive results underwent mediastinoscopy. Patients with perinodal N2 or N3 disease at mediastinoscopy were not considered candidates for operation. The mediastinum was declared negative only when intraoperative mediastinal lymph node dissection showed tumor-free nodes. Of the 95 patients, 12 had benign lesions, 14 were excluded from further evaluation because the lymph node status of the mediastinum was not proven intraoperatively, and 6 others were excluded from the final evaluation because of violation of the protocol. Twenty-two of the 75 remaining patients had a positive computed tomographic scan and underwent mediastinoscopy. Fourteen patients with positive results were considered to have inoperable disease. Fifty-three patients (70.7%) did not undergo mediastinoscopy. We performed seven probably incomplete resections, two for palliative reasons, and two thoracotomies without resection in patients with N2 disease. A policy of routine mediastinoscopy would have prevented only 5% of the thoracotomies performed in patients with lung cancer.