An 80-Year-Old Man With Respiratory Insufficiency After Intravesical Mycobacterium bovis BCG Immunotherapy.

CASE PRESENTATION: An 80-year-old man came to the ED with fever, hematuria, and overall discomfort for 1 week. His medical history included a superficial urothelial carcinoma of the bladder for which he was adjunctively treated with intravesical Mycobacterium bovis BCG (bacillus Calmette-Guérin) immunotherapy for several months. The patient was admitted to the hospital and was initially treated with cephalosporins for a suspected complicated urinary tract infection, but his symptoms did not improve. Ten days after the initial admission, the patient developed hypoxemic respiratory failure during an episode of fever and cold chills and was admitted to the ICU.

Resection of the proximal femur during one-stage revision for infected hip arthroplasty : risk factors and effectiveness.

AIMS: One-stage revision hip arthroplasty for periprosthetic joint infection (PJI) has several advantages; however, resection of the proximal femur might be necessary to achieve higher success rates. We investigated the risk factors for resection and re-revisions, and assessed complications and subsequent re-revisions. METHODS: In this single-centre, case-control study, 57 patients who underwent one-stage revision arthroplasty for PJI of the hip and required resection of the proximal femur between 2009 and 2018 were identified. The control group consisted of 57 patients undergoing one-stage revision without bony resection. Logistic regression analysis was performed to identify any correlation with resection and the risk factors for re-revisions. Rates of all-causes re-revision, reinfection, and instability were compared between groups. RESULTS: Patients who required resection of the proximal femur were found to have a higher all-cause re-revision rate (29.8% vs 10.5%; p = 0.018), largely due to reinfection (15.8% vs 0%; p = 0.003), and dislocation (8.8% vs 10.5%; p = 0.762), and showed higher rate of in-hospital wound haematoma requiring aspiration or evacuation (p = 0.013), and wound revision (p = 0.008). The use of of dual mobility components/constrained liner in the resection group was higher than that of controls (94.7% vs 36.8%; p < 0.001). The presence and removal of additional metal hardware (odds ratio (OR) = 7.2), a sinus tract (OR 4), ten years' time interval between primary implantation and index infection (OR 3.3), and previous hip revision (OR 1.4) increased the risk of proximal femoral resection. A sinus tract (OR 9.2) and postoperative dislocation (OR 281.4) were associated with increased risk of subsequent re-revisions. CONCLUSION: Proximal femoral resection during one-stage revision hip arthroplasty for PJI may be required to reduce the risk of of recurrent or further infection. Patients with additional metalware needing removal or transcortical sinus tracts and chronic osteomyelitis are particularly at higher risk of needing proximal femoral excision. However, radical resection is associated with higher surgical complications and increased re-revision rates. The use of constrained acetabular liners and dual mobility components maintained an acceptable dislocation rate. These results, including identified risk factors, may aid in preoperative planning, patient consultation and consent, and intraoperative decision-making. Cite this article: Bone Joint J 2021;103-B(11):1678-1685.

Mini- or Less-open Sublay Operation (MILOS): A New Minimally Invasive Technique for the Extraperitoneal Mesh Repair of Incisional Hernias.

OBJECTIVE: Improvement of ventral hernia repair. BACKGROUND: Despite the use of mesh and other recent improvements, the currently popular techniques of ventral hernia repair have specific disadvantages and risks. METHODS: We developed the endoscopically assisted mini- or less-open sublay (MILOS) concept. The operation is performed transhernially via a small incision with light-holding laparoscopic instruments either under direct, or endoscopic visualization. An endoscopic light tube was developed to facilitate this approach (EndotorchTM Wolf Company). Each MILOS operation can be converted to standard total extraperitoneal gas endoscopy once an extraperitoneal space of at least 8 cm has been created. All MILOS operations were prospectively documented in the German Hernia registry with 1 year questionnaire follow-up. Propensity score matching of incisional hernia operations comparing the results of the MILOS operation with the laparoscopic intraperitoneal onlay mesh operation (IPOM) and open sublay repair from other German Hernia registry institutions was performed. RESULTS: Six hundred fifteen MILOS incisional hernia operations were included. Compared with laparoscopic IPOM incisional hernia operation, the MILOS repair is associated with significantly a fewer postoperative surgical complications (P < 0.001) general complications (P < 0.004), recurrences (P < 0.001), and less chronic pain (P < 0.001). Matched pair analysis with open sublay repair revealed significantly a fewer postoperative complications (P < 0.001), reoperations (P < 0.001), infections (P = 0.007), general complications (P < 0.001), recurrences (P = 0.017), and less chronic pain (P < 0.001). CONCLUSIONS: The MILOS technique allows minimally invasive transhernial repair of incisional hernias using large retromuscular/preperitoneal meshes with low morbidity. The technique combines the advantages of open sublay and the laparoscopic IPOM repair.ClinicalTrials.gov Identifier NCT03133000.

Epileptic Activity Increases Cerebral Amino Acid Transport Assessed by 18F-Fluoroethyl-l-Tyrosine Amino Acid PET: A Potential Brain Tumor Mimic.

O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET is a well-established method increasingly used for diagnosis, treatment planning, and monitoring in gliomas. Epileptic activity, frequently occurring in glioma patients, can influence MRI findings. Whether seizures also affect 18F-FET PET imaging is currently unknown. The aim of this retrospective analysis was to investigate the brain amino acid metabolism during epileptic seizures by 18F-FET PET and to elucidate the pathophysiologic background. METHODS: Ten patients with 11 episodes of serial seizures or status epilepticus, who underwent MRI and 18F-FET PET, were studied. The main diagnosis was glioma World Health Organization grade II-IV (n = 8); 2 patients suffered from nonneoplastic diseases. Immunohistochemical assessment of LAT1/LAT2/CD98 amino acid transporters was performed in seizure-affected cortex (n = 2) and compared with glioma tissues (n = 3). RESULTS: All patients exhibited increased seizure-associated strict gyral 18F-FET uptake, which was reversible in follow-up studies or negative shortly before and without any histologic or clinical signs of tumor recurrence. 18F-FET uptake corresponded to structural MRI changes, compatible with cortical vasogenic and cytotoxic edema, partial contrast enhancement, and hyperperfusion. Patients with prolonged postictal symptoms lasting up to 8 wk displayed intensive and widespread (≥ 1 lobe) cortical 18F-FET uptake. LAT1/LAT2/CD98 was strongly expressed in neurons and endothelium of seizure-affected brains and less in reactive astrocytosis. CONCLUSION: Seizure activity, in particular status epilepticus, increases cerebral amino acid transport with a strict gyral 18F-FET uptake pattern. Such periictal pseudoprogression represents a potential pitfall of 18F-FET PET and may mimic brain tumor. Our data also indicate a seizure-induced upregulation of neuronal, endothelial, and less astroglial LAT1/LAT2/CD98 amino acid transporter expression.

Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected nonsquamous nonsmall cell lung cancer.

Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab. Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg·m(-2) on day 1, every 3 weeks) and gemcitabine (1250 mg·m(-2) on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg·kg(-1) on day 1, every 3 weeks) (PGB) until progression. 224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39-2.45; p<0.0001) and overall survival (median 12.6 versus 17.8 months; HR 1.41, 95% CI 1.01-1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB. Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.

MR arthrography including abduction and external rotation images in the assessment of atraumatic multidirectional instability of the shoulder.

OBJECTIVE: To evaluate diagnostic signs and measurements in the assessment of capsular redundancy in atraumatic multidirectional instability (MDI) of the shoulder on MR arthrography (MR-A) including abduction/external rotation (ABER) images. METHODS: Twenty-one MR-A including ABER position of 20 patients with clinically diagnosed MDI and 17 patients without instability were assessed by three radiologists. On ABER images, presence of a layer of contrast between the humeral head (HH) and the anteroinferior glenohumeral ligament (AIGHL) (crescent sign) and a triangular-shaped space between the HH, AIGHL and glenoid (triangle sign) were evaluated; centring of the HH was measured. Anterosuperior herniation of the rotator interval (RI) capsule and glenoid version were determined on standard imaging planes. RESULTS: The crescent sign had a sensitivity of 57 %/62 %/48 % (observers 1/2/3) and specificity of 100 %/100 %/94 % in the diagnosis of MDI. The triangle sign had a sensitivity of 48 %/57 %/48 % and specificity of 94 %/94 %/100 %. The combination of both signs had a sensitivity of 86 %/90 %/81 % and specificity of 94 %/94 %/94 %. A positive triangle sign was significantly associated with decentring of the HH. Measurements of RI herniation, RI width and glenoid were not significantly different between both groups. CONCLUSIONS: Combined assessment of redundancy signs on ABER position MR-A allows for accurate differentiation between patients with atraumatic MDI and patients with clinically stable shoulders; measurements on standard imaging planes appear inappropriate. KEY POINTS: MR arthrography has the possibility to accurately identify patients with atraumatic MDI. Imaging of the shoulder in abduction and external rotation provides additive information. Capsular enlargement of the shoulder can be diagnosed on MR arthrography.

An all low-temperature fabrication of macroporous, electrochemically addressable anatase thin films.

Macroporous TiO2 (anatase) thin films are fabricated by an all low-temperature process in which substrates are dip-coated in suspensions of mixed anatase nanoparticles and polystyrene beads, and the templating agents are removed by ultraviolet (UV) irradiation at a temperature below 50 °C. Scanning electron microscopy (SEM) and Raman spectroscopy show that the templating polymer beads are removed by UV irradiation combined with the photocatalytic activity of TiO2. X-Ray diffraction reveals that nanoparticle growth is negligible in UV irradiated films, while nanoparticle size increases by almost 10 times in calcined films that are prepared for comparison. The macroporous films are prepared on FTO-(fluorine-doped tin oxide) coated glass and ITO (indium tin oxide) coated flexible plastics and thereby used as working electrodes. In both cases, the films are electrochemically addressable, and cyclic voltammetry is consistent with the response of bulk TiO2 for calcined films and of nanoscale-TiO2 for UV-irradiated films.

Strong sensitivity of Pine Island ice-shelf melting to climatic variability.

Pine Island Glacier has thinned and accelerated over recent decades, significantly contributing to global sea-level rise. Increased oceanic melting of its ice shelf is thought to have triggered those changes. Observations and numerical modeling reveal large fluctuations in the ocean heat available in the adjacent bay and enhanced sensitivity of ice-shelf melting to water temperatures at intermediate depth, as a seabed ridge blocks the deepest and warmest waters from reaching the thickest ice. Oceanic melting decreased by 50% between January 2010 and 2012, with ocean conditions in 2012 partly attributable to atmospheric forcing associated with a strong La Niña event. Both atmospheric variability and local ice shelf and seabed geometry play fundamental roles in determining the response of the Antarctic Ice Sheet to climate.

Bimodal mesoporous titanium dioxide anatase films templated by a block polymer and an ionic liquid: influence of the porosity on the permeability.

In the present paper, we report the synthesis of bimodal mesoporous anatase TiO2 films by the EISA (Evaporation-Induced Self-Assembly) method using sol-gel chemistry combining two porogen agents, a low molecular weight ionic template and a neutral block copolymer. The surfactant template (C16mimCl) generates non-oriented worm-like pores (8 to 10 nm) which connect the regularly packed ellipsoidal mesopores (15 to 20 nm diameter) formed by an amphiphilic block copolymer of the type poly(isobutylene)-b-poly(ethylene oxide) (PIB-PEO). The surfactant template can also significantly influence the size and packing of the ellipsoidal mesopores. The mesostructural organization and mesoporosity of the films are studied by Environmental Ellipsometry-Porosimetry (EEP), Grazing-Incidence Small-Angle X-ray Scattering (GISAXS) and electron microscopy techniques. Electrochemical characterization is performed to study the permeability of the films to liquid solutions, using two types of probe moieties (K3Fe(III)(CN)6 and Ru(bpy)3(2+)) by the wall-jet technique. An optimum ratio of C16mimCl/PIB-PEO provides anatase films with a continuous bimodal mesopore structure, possessing a permeability up to two times higher than that of the mesoporous films templated by PIB-PEO only (with partially isolated mesopores). When C16mimCl is used in large quantities, up to 20% weight vs. PIB-PEO, large overall porous volume and surface area are obtained, but the mesostructure is increasingly disrupted, leading to a severe loss of permeability of the bimodal films. A dye-sensitized solar cell set-up is used with anatase films as the photoelectrode. The photosensitizer loading and the total energy conversion efficiency of the solar cells using the mesoporous films templated by an optimal ratio of the two porogen agents C16mimCl and PIB-PEO can be substantially increased in comparison with the solar cells using mesoporous films templated by PIB-PEO only.

Lesions of the biceps pulley: diagnostic accuracy of MR arthrography of the shoulder and evaluation of previously described and new diagnostic signs.

PURPOSE: To retrospectively determine the diagnostic accuracy of magnetic resonance (MR) arthrography of the shoulder in the evaluation of lesions of the biceps pulley and to evaluate previously described and new diagnostic signs. MATERIALS AND METHODS: Institutional review board approval was obtained; the requirement for informed consent was waived. MR arthrograms of 80 consecutive patients (mean age, 34.2 years; 53 male, 27 female) with arthroscopically proved intact or torn pulley systems were assessed for the presence of a pulley lesion by three radiologists who were blinded to arthroscopic results. Criteria evaluated were displacement of the long head of the biceps tendon (LHBT) relative to the subscapularis tendon on oblique sagittal images (displacement sign), medial subluxation of the LHBT on transverse images, nonvisibility or discontinuity of the superior glenohumeral ligament (SGHL), presence of biceps tendinopathy, and rotator cuff tears adjacent to the rotator interval. RESULTS: There were 28 pulley lesions noted at arthroscopy. For observers 1, 2, and 3, respectively: MR arthrography showed a sensitivity of 89%, 86%, and 82% and a specificity of 96%, 98%, and 87% in the detection of pulley lesions. Nonvisibility or discontinuity of the SGHL was sensitive (79%, 89%, and 79%) and specific (83%, 79%, and 75%). With the displacement sign, sensitivity was 86%, 82%, and 75% and specificity was 96%, 98%, 90%. Tendinopathy of the LHBT on oblique sagittal images showed a sensitivity of 93%, 82%, 64%; specificity was 81%, 96%, and 85%. Subluxation of the LHBT was insensitive (36%, 50%, and 64%) but specific (100%, 98%, and 96%). CONCLUSION: MR arthrography is accurate in the detection of pulley lesions; the displacement sign, nonvisibility or discontinuity of the SGHL, and tendinopathy of the LHBT on oblique sagittal images are the most accurate criteria for the detection of pulley lesions.

The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy--an open-label, prospective, randomised controlled multicenter study.

BACKGROUND: Of the newer antiepileptic drugs, lamotrigine (LTG) and levetiracetam (LEV) are popular first choice drugs for epilepsy. The authors compared these drugs with regard to their efficacy and tolerability in the initial monotherapy for epilepsy. METHODS: A randomised, open-label, controlled, parallel group, multicenter trial was conducted to test the superiority of the LEV arm over the LTG arm. The primary endpoint was the rate of seizure-free patients in the first 6 weeks (two-sided Fisher's exact test, α=0.05, intent-to-treat set). Furthermore, efficacy, tolerability and quality of life were evaluated. The authors included 409 patients aged ≥12 years with newly diagnosed focal or generalised epilepsy defined by either two or more unprovoked seizures or one first seizure with high risk for recurrence. Patients were titrated to 2000 mg/day of LEV or 200 mg/day of LTG reached on day 22 or 71, respectively. Two dose adjustments by 500/50 mg were allowed. RESULTS: The proportions of seizure-free patients were 67.5% (LEV) versus 64.0% (LTG) 6 weeks after randomisation (p=0.47), and 45.2% (LEV) versus 47.8% (LTG) during the whole treatment period of 26 weeks. The HR (LEV vs. LTG) for seizure-free time was 0.86 (95% CI, 0.61 to 1.22). Adverse events occurred in 74.5% (LEV) versus 70.6% (LTG) of the patients (p=0.38). Adverse events associated with study discontinuation occurred in 17/204 (LEV) versus 8/201 (LTG) patients (p=0.07). CONCLUSIONS: There were no significant differences with regard to efficacy and tolerability of LEV and LTG in newly diagnosed focal and generalised epilepsy despite more rapid titration in the LEV arm. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT00242606.

Identification of selective class II histone deacetylase inhibitors using a novel dual-parameter binding assay based on fluorescence anisotropy and lifetime.

Histone deacetylases (HDACs) are important epigenetic factors regulating a variety of vital cellular functions such as cell cycle progression, differentiation, cell migration, and apoptosis. Consequently, HDACs have emerged as promising targets for cancer therapy. The drugability of HDACs has been shown by the discovery of several structural classes of inhibitors (HDACis), particularly by the recent approval of two HDACis, vorinostat (ZOLINZA) and romidepsin (Istodax), for the treatment of cutaneous T-cell lymphoma by the US Food and Drug Administration. The outstanding potential of HDACis, with a defined isoform selectivity profile as drugs against a plurality of diseases, vindicates increased effort in developing high-throughput capable assays for screening campaigns. In this study, a dual-competition assay exploiting changes in fluorescence anisotropy and lifetime was used to screen the LOPAC (Sigma-Aldrich, St Louis, MO) library against the bacterial histone deacetylase homologue HDAH from Bordetella, which shares 35% identity with the second deacetylase domain of HDAC6. The binding assay proved to be highly suitable for high-throughput screening campaigns. Several LOPAC compounds have been identified to inhibit HDAH in the lower micromolar range. Most interestingly, some of the hit compounds turned out to be weak but selective inhibitors of human class IIa and IIb HDACs.

A biomimetic principle for the chemical modification of metal surfaces: synthesis of tripodal catecholates as analogues of siderophores and mussel adhesion proteins.

By following a biomimetic design principle, tetravalent scaffolds based on an adamantyl and trisalkylmethyl core structure have been synthesized. These scaffolds have been coupled to three catecholamines, thus resembling the characteristic tripodal recognition motif of many natural metal binders, such as mussel adhesion proteins and siderophores, for example, enterobactin. Besides this tripodal recognition element, our scaffolds provide a fourth position for the conjugation of effector molecules. These effectors can be conjugated through biocompatible conjugation techniques to the scaffold and can be used to tailor the properties of different metal surfaces for a range of applications, for example, in implant engineering. Herein, we describe the synthesis of several tripodal metal binders and their immobilization on TiO(2) surfaces by using a simple dip-coating procedure. Furthermore, we demonstrate the conjugation of our surface binders to the dye eosin Y as an effector molecule by peptide coupling. The resulting surfaces have been analyzed by using ellipsometry, time-of-flight secondary ion mass spectrometry, IR spectroscopy, and contact-angle measurements to confirm the specific loading on TiO(2) films and nanoparticles with our trivalent surface binders. As a proof of concept, we have demonstrated the functionalization of TiO(2) nanoparticles with the eosin Y dye.

Early changes on electroencephalography in natalizumab-associated progressive multifocal leucoencephalopathy.

Progressive multifocal leucoencephalopathy has become a growing concern in natalizumab-treated multiple sclerosis patients. Here, we describe a 35-year-old patient who was treated with 34 infusions of natalizumab before complaining about visual deterioration. MRI was non-diagnostic and JC virus testing initially was negative. Electroencephalography showed severe slowing of the right hemisphere, and neuropsychological testing revealed right frontal and temporal deficits. The diagnosis of progressive multifocal leucoencephalopathy was established 2 months later by typical MRI presentation and detection of JC virus DNA in the cerebrospinal fluid. Functional neurological deficits may precede imaging features and should prompt early consideration of progressive multifocal leucoencephalopathy.

Femtosecond lenticule extraction for the correction of myopia: preliminary 6-month results.

PURPOSE: To report the 6-month results of a new method of refractive correction, femtosecond lenticule extraction (FLEx), and the preliminary outcomes in the first 108 eyes. METHODS: In this prospective study, a flap and a lenticule of intrastromal corneal tissue were cut simultaneously using a femtosecond laser. Thereafter, the lenticule was removed manually and the flap repositioned. One hundred and seven of 108 myopic eyes of 56 patients in the treatment group completed the final 6 months of follow-up. The patients' mean age was 35 years. The preoperative mean spherical equivalent (SE) was -4.59 +/- 1.3 diopters (D). The uncorrected visual acuity and the best spectacle-corrected visual acuity after 6 months, objective and manifest refractions, results of slit-lamp examination, the side effects, and the responses to a questionnaire are reported. RESULTS: Six months postoperatively, the mean SE was -0.19 +/- 0.47 D; 98.1% of treated eyes were within +/-1.0 D, and 74.8% of eyes within +/-0.5 D of the intended correction. Eight (7.4%) of 108 eyes lost one line of Snellen VA, one (0.9%) eye lost two Snellen lines, 46 eyes (43%) gained one line, ten eyes (9.3%) gained two Snellen lines, and the VA remained unchanged in 42 (39.3%) eyes. The patient responses to a standardized questionnaire indicated that 97.1% of patients were satisfied with the obtained results and would undergo the procedure again. CONCLUSION: FLEx appears to be a safe and promising corneal refractive procedure for correcting myopia.

Induction chemotherapy with paclitaxel and cisplatin followed by radiotherapy for larynx organ preservation in advanced laryngeal and hypopharyngeal cancer offers moderate late toxicity outcome (DeLOS-I-trial).

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.

Results after intensified therapy for advanced carcinoma of the hypopharynx.

We conducted a retrospective chart review of 85 patients (95% male) with advanced but resectable hypopharyngeal carcinoma to evaluate the effectiveness of an intensified multimodal treatment protocol. This protocol involved concomitant chemo- and radiotherapy before and after total laryngectomy, partial pharyngectomy, and radical neck dissection. Our study population was divided into two groups on the basis of extrasurgical therapy. Group A was made up of 19 patients who had received only postlaryngectomy radiotherapy; 6 of these patients had a stage III tumor and 13 had a stage IV tumor. Group B included 66 patients who had received the intensified treatment; 1 patient had stage II disease, 12 had stage III disease, and 53 had stage IV disease. We found no significant differences in 5-year survival (p = 0.86) or in disease-free interval (p = 0.57) between group A and group B; median survival was 45 and 50 months, respectively. Likewise, when we analyzed the patients in both groups according to tumor stage (stage III vs. stage IV), we found no significant differences in either 5-year survival (group A: p = 0.95; group B: p = 0.18) or disease-free interval (group A: p = 0.74; group B: p = 0.17). We conclude that the prognosis of advanced hypopharyngeal carcinoma remains poor despite treatment with an intensified multimodality protocol. Therefore, the therapeutic strategy should be to individualize treatment with the goal of preserving laryngeal function and optimizing postoperative quality of life.

Long-term results of a prospective multicenter phase II study to preserve the larynx function using concomitant boost radiochemotherapy with Carboplatin.

PURPOSE: This prospective phase II study was undertaken to assess the feasibility of a larynx preservation protocol with simultaneous radiochemotherapy. PATIENTS AND METHODS: Between 3/1998 and 10/2000, 42 patients with moderately advanced cancer of the larynx (n=25) and hypopharynx (n=17) eligible for total laryngectomy (LE) were treated in a prospective larynx preservation study. The study protocol scheduled 66Gy in 5 weeks using a concomitant boost technique and 70mg/m(2) Carboplatin on days 1-5 in weeks 1 and 5. RESULTS: The median follow-up time of the censored study patients was 41 months (9-95 months). The 5-year overall survival was 0.66 (95% CI 0.48-0.84), the 5-year laryngectomy-free survival 0.60 (95% CI 0.42-0.78), and the laryngeal preservation rate at 5 years 0.67 (95% CI 0.49-0.85). Cox multivariate regression analysis showed the total tumor volume to be the only statistically significant factor on locoregional failure-free survival. Six of 23 tumor-free long-term survivors received a tracheotomy because of late laryngeal toxicity associated with dysphagia 30-79 months after radiochemotherapy. CONCLUSIONS: Due to the late laryngeal toxicity observed the value of this regimen for larynx preservation is limited.

Enantiomerically pure isophorone diamine [3-(aminomethyl)-3,5,5-trimethylcyclohexylamine]: a chiral 1,4-diamine building block made available on large scale.

Isophorone diamine [IPDA, 3-(aminomethyl)-3,5,5-trimethylcyclohexylamine] is a chiral non-C2-symmetric 1,4-diamine which is produced industrially on large scale as the mixture of all four stereoisomers (cis/trans ca. 3:1). Starting from this industrial bulk product, the preparation of the bis-tosyl, bis-Fmoc, bis-Boc and bis-Z derivatives of cis-IPDA, the preparation of the pure cis enantiomers by HPLC on chiral stationary phase, and the assignment of absolute configurations to the isolated enantiomers are described. We furthermore report an efficient method for the optical resolution of IPDA by salt formation with dibenzoyl tartaric acid. The latter method conveniently affords enantiomerically pure cis-IPDA in 100 g quantities. A number of salen ligands have been prepared from this enantiomerically pure 1,4-diamine and fully characterized. The nickel complex of one of the salen ligands was prepared and analyzed by X-ray crystallography. The crystal structure of the Ni4L4 complex illustrates the pronounced preference of cis-IPDA for adopting the chair conformation in which both the amino- and the aminomethyl substituents occupy equatorial positions. As a consequence, the two salicylidene imine moieties of one ligand molecule do not converge on one metal ion, but act as bridging ligands between two nickel ions.