Head-to-head comparison of the hybrid tracer indocyanine green-99mTc-nanocolloid with 99mTc-Senti-Scint using sentinel node lymphoscintigraphy and single-photon emission computed tomography combined with computer tomography in melanoma.

OBJECTIVE: The hybrid tracer indocyanine green (ICG)-Tc-nanocolloid has been introduced for sentinel node imaging. However, until now, a comparison of this tracer with other radiocolloids with a larger particle size has not been effectuated. Based on a head-to-head evaluation in patients with melanoma, we have compared ICG-Tc-nanocolloid (particle size 5-80 nm) with Tc-Senti-Scint (particle size 100-600 nm) to establish differences in drainage pattern and sentinel node localization using lymphoscintigraphy and single-photon emission computed tomography combined with computer tomography (SPECT-CT) in melanoma patients scheduled for sentinel node biopsy. METHODS: Twenty-five patients (mean age: 56.9 years, range: 25-79 years) with a melanoma scheduled for SLN biopsy prior to (re)excision of the primary lesion (scar) were prospectively included following a two-day procedure. The first day, after Tc-Senti-Scint injection in four intradermal depots around the primary lesion or scar, early/delayed lymphoscintigraphy and SPECT-CT images were acquired. The injection sites were marked. The second day, after assessing lymph node radioactivity using planar scintigraphy, ICG-Tc-nanocolloid was injected at the previously marked skin points and imaging was performed. The paired planar and SPECT-CT images of both tracers were evaluated with respect to drainage patterns, SLN visualization and non-SLN appearing. RESULTS: Twenty-four out of 25 patients were evaluable. SLN visualization on a patient basis was 100% for ICG-Tc-nanocolloid and 96% for Tc-Senti-Scint, whereas uptake in non-SLNs was found in, respectively, 71% (17/24) and 61% (14/23). Concordance in drainage to 45 lymph node basins was 91%. Discordant drainage was found for two melanomas in the head-and-neck and one in the clavicular area. Unique lymph node basins were seen in 44/45 (98%) for ICG-Tc-nanocolloid and 42/45 (93%) for Tc-Senti-Scint. Concerning identified SLNs, the number was similar for both tracers (n = 58); however, more non-SLNs (65 vs 50) were visualized with ICG-Tc-nanocolloid than with Tc-Senti-Scint. CONCLUSION: A slightly higher SLN visualization accompanied by a tendency to depict more non-SLNs was found for ICG-Tc-nanocolloid. Excepting the head and neck area, an overall high concordance in drainage was found for both radiotracers. With an additional value for the hybrid tracer due to the combination of preoperative imaging and the additional visual signal in the operation room, added by the fluorescent component of the hybrid tracer, there was a preference for ICG-Tc-nanocolloid.

Lymphatic drainage of melanomas located on the manubrium sterni to cervical lymph nodes: a case series assessed by SPECT/CT.

The lymphatic drainage of cutaneous melanomas located on the upper trunk is often complex and sometimes follows an unexpected pattern. Occasionally, even direct drainage to cervical lymph nodes is seen. In this case series, 3 patients with lymphatic drainage to the neck derived from melanomas located over the manubrium sterni are described. There appears to be a restricted area that involves the manubrium sterni from which lymphatic drainage to different cervical node basins appears more frequent. SPECT/CT was helpful in visualizing these patterns and for the localization of the sentinel nodes.

Target volume definition for intensity-modulated radiotherapy after induction chemotherapy and patterns of treatment failure after sequential chemoradiotherapy in locoregionally advanced oropharyngeal squamous cell carcinoma.

AIMS: To validate our approach to target volume definition for intensity-modulated radiotherapy (IMRT) after induction chemotherapy and to analyse the pattern of treatment failure in patients with locoregionally advanced oropharyngeal squamous cell carcinoma (SCC) after sequential chemoradiotherapy (SCRT). MATERIALS AND METHODS: We studied all patients with locoregionally advanced oropharyngeal SCC treated with SCRT, definitive IMRT and no prior surgery between December 2004 and February 2010. SCRT consisted of three cycles of induction chemotherapy followed by IMRT with concurrent weekly chemotherapy. Our approach to IMRT tumour volume definition after induction chemotherapy was similar to recommendations from published clinical practice guidelines. Volumetric expansion was used to create the high-dose clinical target volume with a margin of 10 mm. The high-dose planning target volume (PTV) was treated to 65 Gy, whereas the prophylactic-dose PTV received 54 Gy over 30 fractions using the simultaneous integrated boost technique. The location and extent of each treatment failure was recorded, reconstructed on the planning computed tomography images and analysed using the dose distribution of the IMRT plan. RESULTS: Fifty-two patients were included. The median follow-up was 32.2 months (range 5.0-67.1 months). There were seven local failures, no regional recurrences and one with distant disease. None of the patients required post-treatment neck dissection. All local failures were in-field and occurred within the high-dose PTV. There were no marginal recurrences. Actuarial recurrence-free, disease-specific and overall survival rates at 3 years were 83.9, 85.9 and 79.7%, respectively. CONCLUSIONS: The absence of marginal recurrences validated the approach to IMRT target volume definition after induction chemotherapy proposed by clinical practice guidelines and practised at our institution. It suggested a lack of benefit with the use of larger geometric margins and additional anatomical expansion for the high-dose clinical target volume. SCRT resulted in excellent regional and distant disease control in patients with locoregionally advanced oropharyngeal SCC.

Interobserver variation in parotid gland delineation: a study of its impact on intensity-modulated radiotherapy solutions with a systematic review of the literature.

OBJECTIVES: This study evaluates the interobserver variation in parotid gland delineation and its impact on intensity-modulated radiotherapy (IMRT) solutions. METHODS: The CT volumetric data sets of 10 patients with oropharyngeal squamous cell carcinoma who had been treated with parotid-sparing IMRT were used. Four radiation oncologists and three radiologists delineated the parotid gland that had been spared using IMRT. The dose-volume histogram (DVH) for each study contour was calculated using the IMRT plan actually delivered for that patient. This was compared with the original DVH obtained when the plan was used clinically. RESULTS: 70 study contours were analysed. The mean parotid dose achieved during the actual treatment was within 10% of 24 Gy for all cases. Using the study contours, the mean parotid dose obtained was within 10% of 24 Gy for only 53% of volumes by radiation oncologists and 55% of volumes by radiologists. The parotid DVHs of 46% of the study contours were sufficiently different from those used clinically, such that a different IMRT plan would have been produced. CONCLUSION: Interobserver variation in parotid gland delineation is significant. Further studies are required to determine ways of improving the interobserver consistency in parotid gland definition.

Enhanced selectivity for the hydrolysis of block copoly(2-oxazoline)s in ethanol-water resulting in linear poly(ethylene imine) copolymers.

The ability of merging the properties of poly(2-oxazoline)s and poly(ethylene imine) is of high interest for various biomedical applications, including gene delivery, biosensors, and switchable surfaces and nanoparticles. In the present research, a methodology for the controlled and selective hydrolysis of (co)poly(2-oxazoline)s is developed in an ethanol-water solvent mixture, opening the path toward a wide range of block poly(2-oxazoline-co-ethylene imine) (POx-PEI) copolymers with tunable properties. The unexpected influence of the selected ethanol-water binary solvent mixture on the hydrolysis kinetics and selectivity is highlighted in the pursue of well-defined POx-PEI block copolymers.

Multidisciplinary collaborative gross tumour volume definition for lung cancer radiotherapy: a prospective study.

Variability in gross tumour volume (GTV) definition is a major source of systematic error in conformal radiotherapy. This prospective study assesses the role of multidisciplinary collaboration between oncologists and radiologists in defining lung cancer volumes. Twenty patients with non-small cell lung cancer due to receive three-dimensional conformal radiotherapy formed the study population. GTVs were defined by a radiologist (GTVrad) and an oncologist (GTVonc) using available clinical information and imaging. A collaborative meeting was then held to agree on a final, common GTV (GTVfin) to be used for treatment planning, and differences analysed. The collaboration changed the GTV in 19/20 patients with a total of 50 regions being edited. Changes made were categorized as (a) differentiation of tumour from atelectasis or ground glass shadowing, (b) separation of tumour from vasculature, and (c) defining mediastinal extent of tumour. Oncologists were more confident in the GTVfin than the GTVonc. The radiologist took longer to define the GTV than the oncologist. Real-time collaborative GTV definition by a radiologist and oncologist is practical and feasible. This approach allows specific areas of uncertainty to be categorized and focussed on, reducing systematic error in GTV definition. The physician's approach to risk and decision making for each patient may also play a role.

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis.

A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP.

Neck dissection can be avoided after sequential chemoradiotherapy and negative post-treatment positron emission tomography-computed tomography in N2 head and neck squamous cell carcinoma.

AIMS: This study assessed neck control in patients with N2 head and neck squamous cell carcinoma (HNSCC) treated with sequential chemoradiotherapy (SCRT) and the incidence of neck recurrence when neck dissection was withheld in those with negative post-treatment fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET). MATERIALS AND METHODS: Thirty-four consecutive patients with N2 HNSCC who were treated with radical intent using SCRT were included. Twenty-seven patients received concomitant platinum-based chemotherapy with their radiotherapy. Nineteen patients were treated with intensity-modulated radiotherapy. PET-computed tomography (PET-CT) was obtained 3 months after the completion of radical radiotherapy. Neck dissection was carried out only in those with increased FDG uptake in the neck. RESULTS: The median follow-up was 39.1 months. One patient had increased FDG uptake in the neck post-treatment, which was false positive for malignancy. The remaining 33 patients were observed without neck dissection. No regional recurrence occurred. The negative predictive value (NPV) of post-treatment PET-CT was 100%. CONCLUSIONS: Good disease control in the neck can be achieved in patients with N2 HNSCC with SCRT. Post-treatment PET-CT has a high NPV. Neck dissection can be avoided if post-treatment PET-CT is negative.

Synthesis and crystal structures of multifunctional tosylates as basis for star-shaped poly(2-ethyl-2-oxazoline)s.

The synthesis of well-defined polymer architectures is of major importance for the development of complex functional materials. In this contribution, we discuss the synthesis of a range of multifunctional star-shaped tosylates as potential initiators for the living cationic ring-opening polymerization (CROP) of 2-oxazolines resulting in star-shaped polymers. The synthesis of the tosylates was performed by esterification of the corresponding alcohols with tosyl chloride. Recrystallization of these tosylate compounds afforded single crystals, and the X-ray crystal structures of di-, tetra- and hexa-tosylates are reported. The use of tetra- and hexa-tosylates, based on (di)pentaerythritol as initiators for the CROP of 2-ethyl-2-oxazoline, resulted in very slow initiation and ill-defined polymers, which is most likely caused by steric hindrance in these initiators. As a consequence, a porphyrin-cored tetra-tosylate initiator was prepared, which yielded a well-defined star-shaped poly(2-ethyl-2-oxazoline) by CROP as demonstrated by SEC with RI, UV and diode-array detectors, as well as by ¹H NMR spectroscopy.

Fast surface modification by microwave assisted click reactions on silicon substrates.

Microwave irradiation has been used for the chemical modification of functional monolayers on silicon surfaces. The thermal and chemical stability of these layers was tested under microwave irradiation to investigate the possibility to use this alternative heating process for the surface functionalization of self-assembled monolayers. The quality and morphology of the monolayers before and after microwave irradiation was analyzed by surface-sensitive techniques, such as Fourier transform infrared (FTIR) spectroscopy, atomic force microscopy (AFM), and contact angle measurements. As a model reaction, the 1,3-dipolar cycloaddition of organic azides and terminal acetylenes was tested for the chemical modification of functional azide monolayers. Low and high molar mass compounds modified with an acetylene group were successfully clicked onto the surfaces as confirmed by FTIR spectroscopy and AFM investigations. It could be verified that the reaction can be performed in reaction times of 5 min, and a comparison to conventional heating mechanisms allowed us to conclude that the elevated reaction temperatures result in the fast reaction process.

Smoking after coronary artery bypass: high three-year mortality.

BACKGROUND: Coronary artery bypass grafting (CABG) is carried out for prognosis and symptomatic relief. Smoking is associated with increased postoperative complications, although its precise influence on long-term survival is unclear. We examined the influence of smoking and other risk factors on survival and myocardial ischaemia seven years after CABG. METHODS: 208 patients underwent elective CABG; 25 % were persistent smokers. 165 were alive at seven years. 128 (78 % of survivors) agreed to reexamination and 79 had thallium scans. RESULTS: Angina and dyspnoea were reported by 52 % and 69 %, respectively, of survivors; these were associated with smoking ( P = 0.029 and 0.0 009) but with no other risk factors. Smokers had higher stress thallium scores ( P = 0.057) and ischaemia scores (10.6 +/- 6.5 vs. 6.8 +/- 6.0; P = 0.036); ejection fractions were equivalent. Obesity was prevalent and worsened in men. 33 patients (17 %) died during follow-up. Initially there was no survival difference between smokers and nonsmokers but as early as three years postoperation smoking was associated with an increased mortality ( P = 0.011; log-rank test). CONCLUSIONS: Patients experienced almost universal improvement with the operation. However, persistent smoking completely removed the prognostic benefits of CABG by accelerating late mortality which was higher than previously reported. Higher indices of ischaemia in smokers were suggested by symptoms and confirmed by perfusion scans.

Star-Shaped Polyacrylates: Highly Functionalized Architectures via CuAAC Click Conjugation.

Well-defined functional star-shaped polymer structures with up to 29 arms have been successfully synthesized by the combination of atom transfer radical polymerization (ATRP) and click chemistry. First, azide end-functionalized poly(isobornyl acrylate) (PiBA) star-shaped polymers were prepared by successive ATRP and bromine substitution. Subsequently, alkyne end-functionalized molecules and polymers were introduced onto the star-shaped PiBA bearing pendant azide moieties by copper-catalyzed azide-alkyne cycloaddition (CuAAC). The possibilities and limits for the CuAAC on such highly branched polyacrylates are described.

Tuning the LCST of poly(2-oxazoline)s by varying composition and molecular weight: alternatives to poly(N-isopropylacrylamide)?

The cloud point of copolymers of 2-ethyl-2-oxazoline and 2-n-propyl-2-oxazoline could be tuned from 25 degrees C to 100 degrees C by varying molecular weight and composition; the reversibility and concentration dependence of the cloud points were evaluated to assess the potential of these copoly(2-oxazoline)s as alternatives to poly(N-isopropylacrylamide).

Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: suitable alternatives to PEG-conjugates?

Poly(2-ethyl-2-oxazoline) (POZ) was synthesized by living cationic ring-opening polymerization under microwave irradiation yielding polymers with low polydispersity indices (PDI, 1.15). The polymerization was quenched with sodium carbonate yielding a hydroxyl end-group with a high degree of functionality. The hydroxyl group was converted to carboxylate and the polymer was purified by ionic exchange chromatography. Following activation to succinimidyl ester, POZ-conjugates to high and low molecular weight biomolecules, trypsin and Ara-C, were obtained. The properties of the conjugates were compared to those of the corresponding conjugates with poly(ethylene glycol) (PEG) of similar size. The coupling of POZ to trypsin did not affect the enzymatic activity towards low mass substrates but, on the contrary, reduced the activity on the higher mass ones. Furthermore, the POZ-protein conjugates showed hydrodynamic volumes and protein rejecting properties similar to those of PEG-conjugates. Similarly, the POZ-Ara-C conjugate revealed a drug release profile, stability towards the degrading enzyme cytidine deaminase and in vitro cytotoxicity comparable to what has already been described for the PEG derivative. These data support the potential of POZ as a versatile alternative to the well-known and widely used PEG for protein and drug conjugation and delivery.

Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group.

PURPOSE: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study.

PURPOSE: To study the efficacy of concurrent chemoradiotherapy (CRT) and adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Patients with Ho's stage T3 or N2/N3 NPC or neck node > or = 4 cm were eligible. Patients were randomly assigned to have radiotherapy (RT) or CRT with uracil and tegafur and to have AC or no AC after RT/CRT. AC comprised alternating cisplatin, fluorouracil, vincristine, bleomycin, and methotrexate for six cycles. There were four treatment groups: A, RT; B, CRT; C, RT and AC; D, CRT and AC. For CRT versus RT, groups B and D were compared with groups A and C. For AC versus no AC, groups C and D were compared with groups A and B. RESULTS: Three-year failure-free survival (FFS) and overall survival (OS) for CRT versus RT were 69.3% versus 57.8% and 86.5% versus 76.8%, respectively (P =.14 and.06; n = 110 v 109). Distant metastases rate (DMR) was significantly reduced with CRT (14.8% v 29.4%; P =.026). Locoregional failure rates (LRFR) were similar (20% v 27.6%; P =.39). Three-year FFS and OS for AC versus no AC were 62.5% versus 65% and 80.4% versus 83.1%, respectively (P =.83 and.69; n = 111 v 108). DMR and LRFR were not reduced with AC (P =.34 and.15, respectively). Cox model showed CRT to be a favorable prognostic factor for OS (hazard ratio, 0.42; P =.009). CONCLUSION: An improvement in OS with CRT was observed but did not achieve statistical significance. The improvement seemed to be associated with a significant reduction in DMR. AC did not improve outcome.

Automated MALDI-TOF-MS sample preparation in combinatorial polymer research.

A new automated matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) sample spotting technique that allows the integration of MALDI sample preparation in the workflow of combinatorial polymer research is described. The technique is performed utilizing a commercially available synthetic robot and was first evaluated with polymer standards of known composition and later on used for the monitoring of the living cationic ring-opening polymerization of 2-ethyl-2-oxazoline. The spotting was carried out as a multiple layer approach, which offers the ability of complex sample preparation without the requirement of premixing the different components. The described technique reduces the time required for sample preparation and offers the possibility of automated sample spotting during polymerization reactions performed in a synthetic robot. This allows the integration of molecular weight screening and polymer end/group determination utilizing MALDI-TOF-MS as a high-throughput tool in combinatorial polymer research.

The comedo skin reaction to radiotherapy.

A 50-year-old man had a maxillectomy and post-operative radiotherapy for squamous carcinoma of the maxilla. The acute skin reaction merged at 2 months into a chronic comedo-type acneiform skin reaction in the irradiated area. Previous literature on this reaction to radiation is reviewed. The reaction is rare and occurs mostly in the head and neck area, more commonly in patients who have received acneigenic drugs, and with a latent period of between 2 weeks and 6 months from completion of radiotherapy. The pathogenesis of acne is discussed and a mechanism of post-irradiation acne is suggested.