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.

[Dermato-urology: Male genital lesions urologist should know]. / Dermato-urologie : les lésions des organes génitaux externes de l'homme à connaître par l'urologue.

This article aimed to gather male genital dermatoses that may lead to consult a urologist, except pre-neoplastic or neoplastic lesion. METHOD: This review is based on a research on Pubmed and EM-consult database, in English and in French, using the following key terms "male genital dermatoses", "male genital lesions", "balanitis", "balanoposthitis", "dermatoses des organes génitaux externes masculines", "lésions des organes génitaux externes de l'homme", "balanoposthites". RESULTS: It highlights normal morphological aspects, acute balanoposthitis (nonspecific, infectious, allergic, irritative and traumatic), common skin disease localized to male genital and male genital specific dermatoses. CONCLUSION: Any suspicious, fixed, must lead to a skin biopsy.

High-frequency ultrasound quantification of acute radiation dermatitis: pilot study of patients undergoing radiotherapy for breast cancer.

BACKGROUND: Acute radiation dermatitis (ARD) is a frequent complication after breast cancer radiotherapy and is usually assessed by semi-quantitative clinical scores, which may be subject to inter-observer variability. High-frequency ultrasound imaging of the skin can reliably quantify thickness and edema in diseased skin. We aimed to compare the relative increase in dermal thickness of the irradiated zone in breast-cancer patients undergoing radiotherapy, with clinical severity. METHODS: A consecutive series of patients undergoing treatment for breast cancer by lumpectomy and radiotherapy in a 6-month period also underwent clinical and ultrasound evaluation of ARD. RESULTS: We included 34 female patients 17 had grade 1 (group 1), 17 had grade 2 or grade 3 ARD (group 2). The mean relative increase in dermal thickness in irradiated skin (RIDTIS) was greater for group 2 than 1: 0.53 vs 0.29 mm (P=.023). On univariate analysis, ARD was associated with skin phototype, breast volume and RIDTIS, and on multivariable analysis, breast volume and age remained predictive of the disease. CONCLUSION: Patients with more severe dermatitis showed significantly increased dermal thickness. Dermal thickness is a quantitative variable that could help quantify the efficacy of drugs and improve the treatment of this disease in patients undergoing radiotherapy.

[Introduction of the Screening Tool OncoFunction for Functional Follow-up of Head and Neck Patients]. / Vorstellung des Screeningsystems (OncoFunction) für Funktionsstörungen im Kopf-Hals-Tumor-Follow-up.

INTRODUCTION: The follow-up for head and neck cancer (HNC) focussed on therapy control. Accessory long term functionality is important. Impairment of function is observed, but a comparable documentation is not established. Additional we frequently see psychooncological comorbidities, what complicates the assessment. This was the reason why Tschiesner et al. developed on the base of the "ICF Core set for head and neck cancer" a guideline for the Assessment of Function in HNC. In consequence of good results in other tumour entities we developed an electronic version (OncoFunction). METHODS: In a proof of concept study all patients of our follow up consultation from 07/13 to 03/14 were included. OncoFunction was given to patients in a digital form using tablet computers. The results were visible to the physician in a concentrated form before consultation and were supplemented by a physician questionnaire. Furthermore we evaluated the usability in 202 patients. RESULTS: We had 682 patient contacts. 530 patient contacts (77, 7%) used the questionnaire. The physician questionnaire was answered in 470 times. Finally there are from 69.8% of the patient contacts full datasets available. Between users and non-users of the questionnaire we see no difference. CONCLUSION: The use of a computer-based screening and feedback system (OncoFunction) in clinical use is feasible and excellent assessed by patients. The patient data are visible in a compact form for the physician and problems can clear addressed to the patient. One more benefit is the standardized follow up documentation and the use of comparable data in research.

TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO).

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN. PATIENTS AND METHODS: The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after ≥1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence. RESULTS: A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0-54.6). The median PFS and OS were 56 days (95% CI 36-113 days) and 152 days (76-256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF. CONCLUSION: Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies. CLINICAL TRIALS NUMBER: NCT01172769.

Impact of indication-shift of primary and adjuvant chemo radiation in advanced laryngeal and hypopharyngeal squamous cell carcinoma.

Based on level I evidence, postoperative platinum-based radiochemotherapy (PORCT) is the recommended standard of care in defined risk situations after resection of squamous cell carcinomas of the larynx and hypopharynx (LHSCC). The value of the addition of chemotherapy to adjuvant radiation in intermediate and high risk situations other than extracapsular spread or R1-/R2 resection is still debated. From 1993 to 2009, 555 patients (median follow-up: 24.4 months) with advanced LHSCC (UICC stages III-IVB) were treated in a curative intent. Patient data were continuously documented in the county of Leipzig cancer registry and were retrospectively analyzed as mono institutional survey. PORCT was introduced into the standard procedures in 2004, but also applied before in selected cases. Based on this paradigm shift, the patient population was divided into two comparative groups treated before and after 2004. 361 patients were treated before 2004. 43.8 % received primary surgery (OP) + postoperative radiotherapy (PORT) and 20.2 % OP + PORCT. 194 patients were treated after 2004: 21.1 % received OP + PORT and 35.6 % OP + PORCT. Regarding the PORCT groups, 20.6 % received cisplatin plus 5FU before 2004 which shifted to 59.4 % after 2004. The 3-year tumor-specific-survival rate of the whole cohort was improved from 47 to 60 % (p = 0.006). The subgroup treated with OP + PORT or PORCT improved from 56.1 to 68.5 % (p = 0.028). Localization proved to be a significant and independent factor. Only patients with advanced laryngeal cancer had significant improved survival (p < 0.01), while the improvement for hypopharyngeal cancer patients was not significant (p < 0.2). After 2004, there was a slight increase (+10.2 %) of primary radiochemotherapy (pRCT) due to stronger selection if R0 > 5 mm-resectability is unlikely. Standardised use of PORCT and pRCT considering clear indications showed to be significantly involved in improved survival in advanced LHSCC.

Initial clinical results of simultaneous 18F-FDG PET/MRI in comparison to 18F-FDG PET/CT in patients with head and neck cancer.

PURPOSE: The aim of this study was to evaluate the diagnostic capability of simultaneous (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI compared to (18)F-FDG PET/CT as well as their single components in head and neck cancer patients. METHODS: In a prospective study 17 patients underwent (18)F-FDG PET/CT for staging or follow-up and an additional (18)F-FDG PET/MRI scan with whole-body imaging and dedicated examination of the neck. MRI, CT and PET images as well as PET/MRI and PET/CT examinations were evaluated independently and in a blinded fashion by two reader groups. Results were compared with the reference standard (final diagnosis determined in consensus using all available data including histology and follow-up). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: A total of 23 malignant tumours were found with the reference standard. PET/CT showed a sensitivity of 82.7%, a specificity of 87.3%, a PPV of 73.2% and a NPV of 92.4%. Corresponding values for PET/MRI were 80.5, 88.2, 75.6 and 92.5%. No statistically significant difference in diagnostic capability could be found between PET/CT and PET/MRI. Evaluation of the PET part from PET/CT revealed highest sensitivity of 95.7%, and MRI showed best specificity of 96.4%. There was a high inter-rater agreement in all modalities (Cohen's kappa 0.61-0.82). CONCLUSION: PET/MRI of patients with head and neck cancer yielded good diagnostic capability, similar to PET/CT. Further studies on larger cohorts to prove these first results seem justified.

[Decision process in a multidisciplinary cancer team with limited evidence]. / Entscheidungsprozesse im Tumorboard bei eingeschränkter Evidenzlage.

BACKGROUND: The Head and Neck Cancer Tumor Board is a multispeciality comprehensive conference that brings together experts with different backgrounds to make group decisions about the appropriate treatment. Due to the complexity of the patient cases and the collaboration of different medical disciplines most of these decisions have to be made under uncertainty, i. e., with-out knowing all relevant factors and without being quite sure about the outcome. METHODS: To develop effective team decision making under uncertainty, it is necessary to understand how medical experts perceive and handle uncertainties. The aim of this field study was to develop a knowledge base by exploring additionally the factors that influence group decision making processes. A structured nonparticipant observational study was employed to address the research goal. Video data were analyzed by 2 independent observers using an observation checklist. A total of 20 videotaped case discussions were studied. Observations were complemented by a questionnaire gathering subjective evaluations of board members about the process and quality of their decisions (N=15). RESULTS: The results show that uncertainty is recognized by board members. Reasons for uncertainty may stem from the complexity of the cases (e. g. therapy options) or the assessment from different disciplines coming together at the board. CONCLUSION: With respect to handling uncertainty and guaranteeing an optimal decision making process potential for improvement could be defined. This pertains to the handling of different levels of competence, the promotion of a positive discussion culture as well as structuring of the decision making process.

[Use of cancer support groups by laryngectomees in central Germany]. / Inanspruchnahme von Selbsthilfegruppen für Laryngektomierte in Mitteldeutschland.

BACKGROUND: Cancer support groups provide information and coping resources as well as represent patients' interests. To date it is unknown how often cancer patients post-laryngectomy use support groups and in which parameters users of support groups differ from non-users. MATERIAL AND METHODS: In a multicentre study, 224 laryngectomees were asked about their support group membership. Further, possible predictors for membership one year post-surgery were assessed. Data were collected with a semi-structured interview and standardized instruments. RESULTS: Overall, 23% of the laryngectomized patients are actively involved in cancer support groups. The probability of a membership increases if patients are well-educated, are living in good economic conditions and in a partnership, if they perceive low family support and wish additional counselling with a physician. CONCLUSION: A cancer support group seems to "buffer" family support perceived to be insufficient. However, support group users are living more frequently in a partnership and in good economic conditions compared to non-users. Physicians and speech therapists are important mediators to cancer support groups. They particularly should inform laryngectomees who are living in bad economic conditions and who are not living in a partnership about the availability of cancer support groups.

[Multimodal laryngeal preservation: current data-based opinion]. / Multimodaler Larynxerhalt: Wege zur besseren Patientenselektion.

This article presents the current data and discussion on multimodal laryngeal preservation strategies in advanced laryngeal/hypopharyngeal carcinoma. Principally a distinction is made between simultaneous and induction chemoradiation protocols. In terms of late toxicity and related functional limitations, induction protocols are far superior to simultaneous platinum-based chemoradiation. Currently, the individual response to the first cycle of (short) induction chemotherapy appears to be the most reliable clinical marker for making treatment decisions, and this is under clinical investigation. No standard multimodal therapeutic alternative to laryngectomy exists; therefore, at this time multimodal strategies should only be carried out within the framework of clinical trials.

[Computer assistance to improve therapy planning for head neck oncology]. / Computergestützte Assistenz zur Verbesserung der Therapie-Planung in der Kopf-Hals-Onkologie.

The ongoing development in therapies of head and neck malignomas has led to a further differentiation of treatment options. Complex surgical procedures, a wide variety of multi modal therapy options, changing radiation technologies (IMRT - Intensity-modulated radiation therapy) and numerous "targeted therapies" emphasize the need for a precise treatment plan. Beside this, imaging has seen significant improvements beyond the technical ones, e. g. with the implementation of PET/CT scanners. This increase in pre-therapeutic data volume, together with a diversification of treatment options calls for a further discussion of the basics of therapeutic decisions. Planning relevant data processing by computer assisted systems can aid in these decisions. This work describes the current status of relevant computer assisted systems undergoing first testing for head and neck cancer therapy planning. Here, the integration of 3-dimensional patient data plays a central role. This planning tool forms the integrated base for a further development in the areas of radiation planning, documentation and study management.

[Treatment related swallowing dysfunction and the potentialities of IMRT]. / Schluckstörungen nach Kopf-Hals-Tumortherapie und die Möglichkeiten der IMRT.

Altered fractionated radiotherapy and concurrent chemoradiation could improve local control and survival for patients with locally advanced head and neck cancer. However, intensified treatment seems to increase late toxicity. Late swallowing dysfunction is common and has a large impact on quality of life and can get life-threatening character. Recent studies could show interrelations between the radiation dose to certain anatomical structures involved in the swallowing process and the risk of swallowing dysfunction. Important structures seem to be the pharyngeal constrictors and the supraglottic and glottic larynx. Further prospective clinical validations using standardized diagnostic protocols for dysphagia are necessary to establish dose constraints to anatomical structures involved in swallowing.

[Current developments in measuring quality of life with instruments of the European organisation for research and treatment of cancer (EORTC)]. / Aktuelle Entwicklungen bei der Erfassung der Lebensqualität mit Instrumenten der European Organisation for Research and Treatment of Cancer (EORTC).

Since many years, the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group develops and validates measures for the assessment of quality of life in cancer patients, using high standards of methodology. These questionnaires are meant to be used primarily in clinical trials.As treatment strategies are changing and because of some -methodological criticism, the head and neck module EORTC QLQ-H&N35 is currently being revised and updated.In this paper, we will present the current state of work and other recent developments regarding the EORTC Quality of Life questionnaire development.

[Current therapy options in recurrent head and neck cancer]. / Aktuelle Therapieoptionen bei rezidivierenden Kopf-Hals-Tumoren.

Recurrent disease is one of the main reasons for the persistently poor prognosis of squamous cell carcinoma of the head and neck (HNSCC; European 5-year survival, 42%). The main treatment option for primary and secondary malignancy as well as recurrent disease is surgical therapy. If R0 resection (resection margin >5 mm) for a primary tumor is not viable, survival probability is reduced by 50%. In recurrent or secondary tumors with R1- or -2 resection or in the presence of non-resectable metastases, a palliative situation results in more than 80% of cases. In the case of surgery following radiotherapy or radiochemotherapy, attention should be paid to the criteria for salvage surgery (tissue perfusion, fibrosis, wound healing) and the procedure adapted to focus on functionality. In the case of relapse, primary surgery can potentially be supplemented with adjuvant therapy protocols such as (re-) irradiation, as well as possibly with chemotherapeutic agents or targeted therapies. Interdisciplinary collaboration and case discussions should take place in the context of a tumor board.

[Three-dimensional visualization for preoperative planning and evaluation in head and neck surgery]. / Dreidimensionale Bildprozessierung in der HNO-Onkologie zur präoperativen Planung und Evaluierung.

There are a lot of diagnostic possibilities for the preoperative planning in head and neck surgery. So far, no study was performed to evaluate if there is an advantage of three-dimensional visualization compared to conventional computed tomography yet. Additionally, there are no specifications for such a visualization prior surgery in head and neck surgery. This work describes different possibilities for segmentation and three-dimensional visualization for preoperative planning in head and neck surgery and tumor volumetry compared to conventional computed tomography. We describe new techniques and specifications for three-dimensional visualization.

Comorbidity predicts survival in myelodysplastic syndromes or secondary acute myeloid leukaemia after allogeneic stem cell transplantation.

BACKGROUND: Recent data suggest that, among other factors, comorbidity may be an important prognostic variable in patients with myelodysplastic syndromes (MDS) who are eligible for haematopoietic stem cell transplantation (SCT). PATIENTS AND METHODS: We examined the overall survival (OS) and underlying risk factors in 45 adult patients with MDS (n = 38), chronic myelomonocytic leukaemia (n = 1), or secondary acute myeloid leukaemia (AML) arising from MDS (n = 6), who underwent allogeneic SCT at our Institution. RESULTS: With a median follow-up of 37 months, OS for all patients was 23%, post-transplant relapse occurred in 11 patients, and 10 patients died from treatment-related complications. The overall outcome and survival was independent of cytogenetic abnormalities and International Prognostic Scoring System (IPSS). However, we identified comorbidity as defined by the haematopoietic cell transplantation specific comorbidity index (HCT-CI), as a significant adverse prognostic variable in our MDS patients. CONCLUSIONS: Based on these data and similar published data we recommend selecting patients with MDS or secondary AML for SCT according to the presence of comorbidities.

The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25.

Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5' portion of cDNAs containing the 3' portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12: 9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocation-associated sarcomas. Oncogene (2001) 20, 48 - 57.

Unique solutions in pediatric critical care.

This pediatric intensive care unit (PICU) functions as a part of a multidisciplinary adult ICU and has evolved into a unique health care setting. The Special Care Unit (SCU), which is the name for our ICU, serves a population of adult and pediatric patients, including trauma, open-heart surgery, medicine, surgery, and neurosurgery. All staff are expected to provide care for adults and children without regard to admitting diagnosis. In addition to meeting the critical care needs of this diverse pediatric population in the SCU, we provide a pediatric critical care ground transport program for critically ill children from outlying hospitals. Competency-based orientation tools were developed and are used to guide the orientation process. The tools identify the required knowledge base necessary for a staff member to adequately care for the adult and pediatric populations and track each staff member's progress through orientation. The model used to deliver care to adults and children in this setting is innovative. This model represents one solution to providing critical care to both the adult and pediatric population in today's era of health care redesign.

Analysis of potential phosphorylation sites in human T cell leukemia virus type 1 Tax.

The human T cell leukemia virus type 1 (HTLV-1) Tax is a phosphoprotein, however, the contribution of phosphorylation to Tax activity is unknown. Previous studies have shown that phosphorylation of Tax occurs on serine residue(s), within one tryptic fragment, in response to 4beta-phorbol-12beta-myristate-13alpha-acetate, in both mouse and human cells. Studies were conducted in multiple cell lines to identify the specific phosphorylated serines as a prelude to functional analysis. The phosphorylation pattern of Tax was found to be different in 293T and COS-7 cells in comparison with MT-4 and Px-1 cells. However, one tryptic fragment remained consistent in comigration analyses among all cell lines. Using selected Tax serine mutants a tryptic fragment containing a serine at residue 113 believed to be the site of phosphorylation of Tax did not comigrate with the common phosphorylated tryptic fragment. Analysis of selected Tax mutants for ability to trans-activate the cytomegalovirus promoter demonstrated mutation of serine 77 to alanine reduced trans-activation by 90% compared to wild-type Tax. However, examination of the phosphorylation pattern of the serine 77 mutant demonstrated that it is not the site of phosphorylation. These studies demonstrate the importance of using relevant cell lines to characterize the role of phosphorylation in protein function.