First measurements of radon-220 diffusion in mice tumors, towards treatment planning in diffusing alpha-emitters radiation therapy.

BACKGROUND: Diffusing alpha-emitters radiation therapy ("Alpha-DaRT") is a new method for treating solid tumors with alpha particles, relying on the release of the short-lived alpha-emitting daughter atoms of radium-224 from interstitial sources inserted into the tumor. Alpha-DaRT tumor dosimetry is governed by the spread of radium's progeny around the source, as described by an approximate framework called the "diffusion-leakage model". The most important model parameters are the diffusion lengths of radon-220 and lead-212, and their estimation is therefore essential for treatment planning. PURPOSE: Previous works have provided initial estimates for the dominant diffusion length, by measuring the activity spread inside mice-borne tumors several days after the insertion of an Alpha-DaRT source. The measurements, taken when lead-212 was in secular equilibrium with radium-224, were interpreted as representing the lead-212 diffusion length. The aim of this work is to provide first experimental estimates for the diffusion length of radon-220, using a new methodology. METHODS: The diffusion length of radon-220 was estimated from autoradiography measurements of histological sections taken from 24 mice-borne subcutaneous tumors of five different types. Unlike previous studies, the source dwell time inside the tumor was limited to 30 min, to prevent the buildup of lead-212. To investigate the contribution of potential non-diffusive processes, experiments were done in two sets: fourteen in vivo tumors, where during the treatment the tumors were still carried by the mice with active blood supply, and 10 ex-vivo tumors, where the tumors were excised before source insertion and kept in a medium at 37 ∘ C $37^\circ {\text{C}}$ with the source inside. RESULTS: The measured diffusion lengths of radon-220, extracted by fitting the recorded activity pattern up to 1.5 mm from the source, lie in the range 0.25 - 0.6 mm ${0.25-0.6}\nobreakspace {\text{mm}}$ , with no significant difference between the average values measured in in-vivo and ex-vivo tumors: L R n i n - v i v o = 0.40 ± 0.08 mm $L_{Rn}^{in-vivo}=0.40{\pm }0.08\nobreakspace {\text{mm}}$ versus L R n e x - v i v o = 0.39 ± 0.07 mm $L_{Rn}^{ex-vivo}=0.39{\pm }0.07\nobreakspace {\text{mm}}$ . However, in-vivo tumors display an enhanced spread of activity 2-3 mm away from the source. This effect is not explained by the current model and is much less pronounced in ex-vivo tumors. CONCLUSIONS: The average measured radon-220 diffusion lengths in both in-vivo and ex-vivo tumors are consistent with published data on the diffusion length of radon in water and lie close to the upper limit of the previously estimated range of 0.2 - 0.4 mm $0.2-0.4\nobreakspace {\text{mm}}$ . The observation that close to the source there is no apparent difference between in-vivo and ex-vivo tumors, and the good agreement with the theoretical model in this region suggest that the spread of radon-220 is predominantly diffusive in this region. The departure from the model prediction in in-vivo tumors at large radial distances may hint at potential vascular contribution, which will be the subject of future works.

Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Deep inspiratory breath hold assisted by continuous positive airway pressure ventilation for lung stereotactic body radiotherapy.

PURPOSE: Continuous positive airway pressure (CPAP) ventilation hyperinflates the lungs and reduces diaphragmatic motion. We hypothesized that CPAP could be safely combined with deep inspiratory breath hold (CPAP-DIBH) during lung stereotactic radiotherapy (SBRT). MATERIAL AND METHODS: Patients with stage-1 lung cancer or lung metastasis treated with CPAP-DIBH SBRT between 3/2017-5/2021 were analyzed retrospectively. Patient characteristics, treatment parameters, duration of breath holds in all sessions and tolerance to CPAP-DIBH were recorded. Local control (LC) was assessed from CT or PET-CT imaging. The distances between the tumor and mediastinal organs at risk (OAR) in centrally located tumors using either free breathing (FB) or CPAP-DIBH were compared. Toxicity was graded retrospectively. RESULTS: Forty-five patients with 71 lesions were treated with CPAP-DIBH SBRT. Indications for CPAP-DIBH were prior radiation (35/71, 65%), lower lobe location (34/71, 48%), multiple lesions (26/71, 36.6%) and proximity to mediastinal OAR (7/71, 10%). Patient characteristics were: F:M 43%: 57%; mean gross tumor volume 4.5cm3 (SD 7.9), mean planning target volume 20cm3 (SD 27), primary: metastatic lesions (7%:93%). Mean radiation dose was 52.5 Gray (SD3.5). Mean lung volume was 5292cm3 (SD 1106). Mean duration of CPAP-DIBH was 41.3s (IQR 31-46.8). LC at 2 years was 89.5% (95% CI 76-95.5). In patients with central lesions, the distance between the tumor and mediastinal OAR increased from 0.84cm (SD 0.65) with FB to 1.23cm (SD 0.8) with CPAP-DIBH (p=0.002). Most patients tolerated CPAP well and completed all treatments after starting therapy. Three patients did not receive treatment: 2 were unable to tolerate CPAP and 1 had syncope (pre-existing). Toxicity was grade 2 in 4/65 (6%) and grade 3 in 1/65 (1.5%). There was no grade 2 or higher esophageal or tracheal toxicities. CONCLUSION: CPAP-DIBH assisted lung SBRT was tolerated well and was associated with minimal toxicity and favorable LC. This technique may be considered when treating multiple lung lesions, lesions located in the lower lobes or adjacent to mediastinal OAR.

Initial estimates of continuous positive airway pressure (CPAP) on heart volume, position and motion in patients receiving chest radiation.

To evaluate effects of Continuous Positive Airway Pressure (CPAP) on cardiac position, volume, and motion in a cohort of patients receiving thoracic radiation therapy (RT). Patients underwent 3-dimensional (3D) and 4D-computerized tomography (CT) imaging with free-breathing (FB) and CPAP for RT planning. All scans were co-registered on the treatment planning system for contouring, identification of the center of heart volume and comparative measurements of cardiac displacement, volume and motion. Heart volume (HV) was created from 3D-CT contours. Range of heart motion was estimated by creating an internal heart volume (IHV) from 4D-CT contours. Magnitude of cardiac motion (cardiac excursion) was recorded as the difference in volume between IHV and HV. Wilcoxon signed rank test and Spearmen's rank correlation coefficient were used to assess differences between variables and correlations between lung volume and heart parameters. Results from 9 patient data sets were available for this report. Compared to FB, CPAP use was associated with caudal displacement of the HV (1 cm, p < 0.008) and IHV (1.1 cm, p < 0.008). CPAP use decreased HV 6% (p < 0.008) and IHV 13% (p < 0.008). Cardiac excursion was 49% (p < 0.01) less with CPAP than with FB. CPAP use increased mean lung volume by 30% (p < 0.008) which correlated with caudal displacement of the HV (r = 0.83, p < 0.008) and IHV (r = 0.98, p < 0.001). The use of CPAP reduced cardiac motion and volume although the reduction in volume was minimal. The increase in lung volume correlated with caudal displacement of the heart. These results suggest the mechanism for achieving dosimetric benefit was obtained by cardiac displacement and decreased lung and heart motion rather than reduction of HV. Further evaluation of CPAP as a novel technique to reduce heart exposure when offering RT is warranted.

Benefits of Continuous Positive Airway Pressure (CPAP) During Radiation Therapy: A Prospective Trial.

PURPOSE: This study aimed to study the impact of continuous positive airway pressure (CPAP) on chest anatomy and tumor motion in patients receiving radiation therapy. METHODS AND MATERIALS: Patients with primary or secondary lung tumors, left-sided breast cancer, or liver metastases referred for radiation therapy were trained to breathe with a CPAP device using a face mask to a maximal pressure of 15 cm H2O. Three- and 4-dimensional computed tomography simulation was performed twice for each patient: once with free breathing (FB) and again using CPAP. Volumetric and dosimetric parameters of treatment plans were compared. RESULTS: Forty-nine patients were enrolled, of whom 6 withdrew consent before simulation and 3 withdrew because of discomfort. Thus, a total of 40 patients were analyzed. Twenty-seven patients (67.5%) were treated with CPAP based on confirmation of the volumetric or dosimetric benefit of CPAP. Mean lung volume increased by 37% (P < .001). The mean augmentation was 1283 ± 1128 cm3 (CPAP vs FB; P = .0006) in patients with normal lung function tests and 719 ± 341 cm3 (P = .003) in patients with a restrictive pattern. Increased lung volume was independent of age, body mass index, sex, chronic obstructive pulmonary disease, smoking status, and heart disease. Tumor motion in the lung was decreased as reflected in a mean reduction of planning target volume by 19% (P < .001). The greatest reduction of tumor trajectory and planning target volume occurred in tumors in the lower lung, particularly in the range of up to 6 cm above the dome of the diaphragm. The mean lung dose was reduced by 15%, lung V20 by 20%, lung V5 by 11%, and heart V5 by 16% (P < .01). CONCLUSIONS: In this prospective trial, the use of CPAP was associated with significant volumetric and dosimetric benefits compared with FB. CPAP was safe, simple to implement, and well tolerated by most patients, and it should be studied further as a method to reduce the risk of lung and heart toxicity.

Gallium-68 prostate-specific membrane antigen PET-CT and the clinical management of prostate cancer.

OBJECTIVES: The purpose of this study was to evaluate the use of Gallium-68 prostatic-specific membrane antigen (PSMA) PET-computerized tomography (CT) in patients with prostate cancer undergoing imaging for initial staging, biochemical failure or the evaluation of metastatic disease. METHODS: This is a single institution retrospective study of 95 patients with prostate cancer who were referred for PSMA PET-CT scans. The National Comprehensive Cancer Network guidelines were used to generate treatment recommendations. Univariate and multivariate statistical analyses were performed to identify parameters associated with positive findings on a PET-CT PSMA scan. RESULTS: Mean age, Gleason score, and median prostate serum antigen (PSA) were: 72 years, 7.6 and 4 ng/ml, respectively. PSMA PET-CT was positive in 75.5% of the patients. A maximum standardized uptake value was 10.7 ± 8.8. PSMA avidity increased with rising PSA level: PSA ≤ 1 ng/ml: 5/15 patients (33%); PSA 1-5 ng/ml: 18/27 patients (67%), and PSA ≥ 5 ng/ml: 33/34 patients (97%). Following imaging in nine high-risk patients referred for staging, changes in treatment occurred in 6 (67%). Treatment recommendations changed in 27/35 (65%) patients referred due to biochemical failure; these included recurrences suitable for salvage therapy (n = 14), metastatic disease not suitable for salvage therapy (n = 10), and no lesion (n = 17). No changes in treatment occurred in any of the 35 patients referred to evaluate metastatic disease. DISCUSSION: PSMA PET-CT imaging may have a substantial impact on clinical management in prostate cancer patients at the time of initial staging or with biochemical failure; yet this modality does not appear useful in the management of patients with known metastatic disease.

Use of 18F-FDG PET-CT imaging to determine internal mammary lymph node location for radiation therapy treatment planning in breast cancer patients.

PURPOSE: Adjuvant internal mammary lymph node (IMN) radiation is often delivered with 2-dimensional techniques that use anatomic landmarks and predetermined depths for field placement and dose specification. In contrast, 3-dimensional planning uses the internal mammary vessels (IMVs) to localize the IMNs for planning. Our purpose was to determine if localization of the involved IMN (i-IMN) by 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) offers opportunities to improve treatment. METHODS AND MATERIALS: Breast cancer patients (n = 80) who had i-IMNs (n = 112) on PET-CT for initial staging (n = 40) or recurrence (n = 40) were studied. Size, intercostal space (IC), and distance from skin, sternum, and IMVs were recorded. Effects on 2- and 3-dimensional planning were evaluated. RESULTS: Most i-IMNs (94.6%) were in the first to third ICs. Few were in the fourth (4.5%) or fifth (0.9%) IC. Mean i-IMN depth was 3.4 cm (range, 1.1-7.3 cm). Prescriptive depths of 4, 5, and 6 cm would result in undertreatment of 25%, 10.7%, and 5.3% of IMNs, respectively. Most IMNs (86.6%) were lateral or adjacent to the sternal edge. Only 13.4% of IMNs were posterior to the sternum. Use of the ipsilateral or contralateral sternal edge for field placement increases the risk of geographic miss or excess normal tissue exposure. Most i-IMNs were adjacent to (83%) or ≤0.5 cm (14%) from the IMV edge. Three (3%) were >0.5 cm beyond the IMV edge. The clinical target volume (CTV) defined by the first to third ICs encompassed 78% of i-IMNs. IMN-CTV coverage of i-IMNs increased with inclusion of the fourth IC (82%), 0.5 cm medial and lateral margin expansion (93%), or both (96.5%). CONCLUSION: Two-dimensional treatment techniques risk geographic miss of IMNs and exposure of excess normal tissue to radiation. An IMN-CTV defined by the IMVs from the first to third ICs with 0.5-cm medial and lateral margin expansion encompasses almost all i-IMNs identified on PET-CT imaging. Inclusion of the fourth IC offers modest coverage improvement, and its inclusion should be weighed against potential increase in cardiac exposure. SUMMARY: The use of 2-dimensional treatment techniques for adjuvant internal mammary lymph node (IMN) radiation may cause geographic miss of tumor and expose normal tissue to radiation injury. Conformal 3-dimensional planning improves coverage and reduces risk of normal tissue damage by using the internal mammary vessel to define an IMN clinical target volume (CTV). Contouring the IMN-CTV from the first to third intercostal spaces with a 0.5-cm expansion medially and laterally encompasses most IMN. Positron emission tomography-computed tomography may have a role in radiation planning by identifying involved-IMN for dose escalation.

Reexpansion of atelectasis caused by use of continuous positive airway pressure (CPAP) before radiation therapy (RT).

INTRODUCTION: Although radiation therapy (RT) is an effective treatment for malignant atelectasis, its accurate delivery is challenging because of difficulty differentiating between tumor and atelectatic lung. Furthermore, reexpansion of lung during treatment repositions tumor and normal structures necessitating replanning to ensure treatment accuracy. Facilitating lung reexpansion before initiation of RT may improve RT treatment accuracy, spare normal tissue, and reduce obstructive symptoms. We report a case of reexpansion of right upper lobe (RUL) atelectasis caused by use of continuous positive airway pressure (CPAP) before RT. CASE REPORT: A 52-year-old woman presented with dyspnea and cough. Imaging studies showed an RUL mass with atelectasis. Bronchoscopy showed extrinsic compression of the RUL and middle lobe bronchi. Biopsy showed small cell lung cancer. Staging with positron emission tomography-computed tomography (CT) and contrast enhanced CT of brain showed no other disease. Following 4 cycles of platinum-based chemotherapy, CT imaging showed a decrease in tumor volume, but persistent RUL atelectasis. She agreed to participate in an institutional study to evaluate the use of CPAP to reduce respiratory motion and immobilize tumors during RT. During CPAP training, she complained of vertigo, headache, and weakness and refused simulation. The next day she reported less dyspnea and completed training and CT simulation without difficulty. CT simulation with CPAP showed reexpansion of the RUL. Lung volume increased from 2170 to 3767 mL (74 %). Gross tumor volume, clinical volume, and planning volume decreased 46%, 45%, and 38%, respectively. Mean lung dose and mean heart dose decreased 20% and 51%, respectively. CPAP was used daily for 1 hour before and during treatment. Cone beam CT scans showed that the RUL remained inflated throughout treatment. CONCLUSION: This is the first reported use of CPAP for reexpansion of atelectasis before RT planning and treatment. Reexpansion of atelectasis improved RT planning, decreased dose to uninvolved lung, and removed the need for replanning. Further study of CPAP as an initial intervention to improve RT delivery in patients with malignant atelectasis is warranted.

Continuous Positive Airway Pressure for Motion Management in Stereotactic Body Radiation Therapy to the Lung: A Controlled Pilot Study.

OBJECTIVE: To determine the effect of continuous positive airway pressure (CPAP) on tumor motion, lung volume, and dose to critical organs in patients receiving stereotactic body radiation therapy (SBRT) for lung tumors. METHODS AND MATERIALS: After institutional review board approval in December 2013, patients with primary or secondary lung tumors referred for SBRT underwent 4-dimensional computed tomographic simulation twice: with free breathing and with CPAP. Tumor excursion was calculated by subtracting the vector of the greatest dimension of the gross tumor volume (GTV) from the internal target volume (ITV). Volumetric and dosimetric determinations were compared with the Wilcoxon signed-rank test. CPAP was used during treatment if judged beneficial. RESULTS: CPAP was tolerated well in 10 of the 11 patients enrolled. Ten patients with 18 lesions were evaluated. The use of CPAP decreased tumor excursion by 0.5 ± 0.8 cm, 0.4 ± 0.7 cm, and 0.6 ± 0.8 cm in the superior-inferior, right-left, and anterior-posterior planes, respectively (P ≤ .02). Relative to free breathing, the mean ITV reduction was 27% (95% confidence interval [CI] 16%-39%, P<.001). CPAP significantly augmented lung volume, with a mean absolute increase of 915 ± 432 cm(3) and a relative increase of 32% (95% CI 21%-42%, P=.003), contributing to a 22% relative reduction (95% CI 13%-32%, P=.001) in mean lung dose. The use of CPAP was also associated with a relative reduction in mean heart dose by 29% (95% CI 23%-36%, P=.001). CONCLUSION: In this pilot study, CPAP significantly reduced lung tumor motion compared with free breathing. The smaller ITV, the planning target volume (PTV), and the increase in total lung volume associated with CPAP contributed to a reduction in lung and heart dose. CPAP was well tolerated, reproducible, and simple to implement in the treatment room and should be evaluated further as a novel strategy for motion management in radiation therapy.

The transcervical approach for parapharyngeal space pleomorphic adenomas: indications and technique.

BACKGROUND: Head and Neck Parapharyngeal space tumors are rare. Pleomorphic Adenomas are the most common Parapharyngeal space tumors. The purpose of this study was to define preoperative criteria for enabling full extirpation of parapharyngeal space pleomorphic adenomas via the transcervical approach while minimizing functional and cosmetic morbidity. METHODS: The surgical records and medical charts of 19 females and 10 males with parapharyngeal space pleomorphic adenomas operated between 1993 and 2012 were reviewed. RESULTS: Fifteen patients were operated by a simple transcervical approach, 13 by a transparotid transcervical approach, and one by a transmandibular transcervical approach. Complications included facial nerve paralysis, infection, hemorrhage and first bite syndrome. There were three recurrences, but neither recurrence nor complications were associated with the type of surgical approach. CONCLUSION: A simple transcervical approach is preferred for parapharyngeal space pleomorphic adenomas with narrow attachments to the deep lobe of the parotid gland and for pleomorphic adenomas originating in a minor salivary gland within the parapharyngeal space.

Surgical management of tumors involving the orbit.

IMPORTANCE: Surgical treatment of orbital tumors is a complex task that requires thorough preparation and precise planning. Since a large variety of tumors of different origins, anatomical extents, and histologic subtypes affect the globe, no "1-size-fits-all" approach can be offered. OBJECTIVE: To describe an integrative approach for the optimal surgical management of patients with orbital tumors based on a review of the literature and on our own experience at a high-volume cancer center. EVIDENCE REVIEW: Peer-reviewed English-language literature and a single-center cohort of patients undergoing orbital exenteration with eye sparing, reconstruction, and preservation of orbital function. FINDINGS: Surgical treatment of orbital tumors is a complex task that requires thorough preparation and precise planning that would be aided by an algorithm. CONCLUSIONS AND RELEVANCE: We offer an algorithm that summarizes our approach toward the 2 main decision points of orbital surgery: extent of resection and method of reconstruction.

Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor.

Perineural invasion of cancer cells (CPNI) is found in most patients with pancreatic adenocarcinomas (PDA), prostate, or head and neck cancers. These patients undergo palliative rather than curative treatment due to dissemination of cancer along nerves, well beyond the extent of any local invasion. Although CPNI is a common source of distant tumor spread and a cause of significant morbidity, its exact mechanism is undefined. Immunohistochemical analysis of specimens excised from patients with PDAs showed a significant increase in the number of endoneurial macrophages (EMΦ) that lie around nerves invaded by cancer compared with normal nerves. Video microscopy and time-lapse analysis revealed that EMΦs are recruited by the tumor cells in response to colony-stimulated factor-1 secreted by invading cancer cells. Conditioned medium (CM) of tumor-activated EMΦs (tEMΦ) induced a 5-fold increase in migration of PDA cells compared with controls. Compared with resting EMΦs, tEMΦs secreted higher levels of glial-derived neurotrophic factor (GDNF), inducing phosphorylation of RET and downstream activation of extracellular signal-regulated kinases (ERK) in PDA cells. Genetic and pharmacologic inhibition of the GDNF receptors GFRA1 and RET abrogated the migratory effect of EMΦ-CM and reduced ERK phosphorylation. In an in vivo CPNI model, CCR2-deficient mice that have reduced macrophage recruitment and activation showed minimal nerve invasion, whereas wild-type mice developed complete sciatic nerve paralysis due to massive CPNI. Taken together, our results identify a paracrine response between EMΦs and PDA cells that orchestrates the formation of cancer nerve invasion.

Surgical ablation and free flap reconstruction in children with malignant head and neck tumors.

We assessed the feasibility and safety of free flap reconstruction in children undergoing extensive surgical excision of malignant head and neck tumors. We performed a retrospective review in a tertiary referral center of all patients aged 18 years or younger who underwent free flap reconstruction following resection of malignant head and neck tumors at our institution. Main outcome measures included complications at the primary and donor sites, functional and esthetic outcome, and tumor control. Eight of the 237 (3.4%) free flap reconstructions were performed on children. All tumors were malignant sarcomas. Ablative surgery was via a transfacial (n = 4) or a combined approach (n = 4). Transferred free flaps were the rectus abdominis (n = 3), gracilis (n = 3), fibula (n = 1), and anterolateral thigh (n = 1). The mean follow-up was 25.5 months. The overall early and late complication rates were 50% and 25%, respectively. There were no flap losses and no donor site complications. Functional outcome, including mastication, deglutition, and speech, was satisfactory. Local tumor control rate at last follow-up was 87.5%. Free flap reconstruction is an efficient and relatively safe technique for reconstructing surgical defects of the head and neck in children undergoing extensive surgery for malignant disease.

Utility of a three-dimensional endoscopic system in skull base surgery.

We evaluated the utility of a three-dimensional (3-D) endoscopic system for skull base surgery. We performed a retrospective case series in a tertiary care medical center. Thirty-six patients underwent skull base (nonpituitary) resections via 3-D endoscopic system. Fifteen patients (42%) were operated for excision of malignant tumors, 19 (53%) for excision of benign lesions, and 3 (8.3%) for skull base reconstruction. The tumors involved the cribriform plate (n = 13), sphenoid sinus and planum (n = 17), clivus (n = 7), and sella (n = 7). Complete tumor resection was achieved in 31 patients and subtotal resection in two. Five patients (14%) had postoperative complications. There was one case of meningitis, and there were no cases of cerebrospinal fluid leak. The surgeon's ability to recognize anatomic structures at the skull base was evaluated using the 3-D and two-dimensional systems. The 3-D technique was superior to the conventional technique for identification of the sella, carotid prominence, optic prominence, cribriform plate, sphenoid, and fovea ethmoidalis. The two systems were equal for detection of the turbinates, clivus, maxillary, ethmoids, and frontal sinuses. Endoscopic skull base surgery with stereoscopic viewing is feasible and safe. Further studies are required to evaluate the advantage of binocular vision in skull base surgery.

Functional aberrant expression of CCR2 receptor on chronically activated NK cells in patients with TAP-2 deficiency.

Chemokines play a pivotal role in homeostatic and inflammatory migration of naive and activated natural killer (NK) subsets. Recent studies have shown that aberrant chemokine receptor expression on certain immune cells underlies the pathogenesis of clinical conditions in which recruitment of such cells is altered. Progressive accumulation of activated NK cells, subsequently resulting in the formation of chronic granulomatous lesions in the respiratory tract and the skin, has been described in a number of patients with transporter associated with antigen processing 2 (TAP-2) deficiency in the later stages of disease. Therefore, the goal of the present study was to elucidate whether the dysregulation of chemoattracting receptor expression on NK cells could explain abnormal navigation of these cells in TAP-2 deficiency. High-throughput proteomic comparison, followed by verification with flow cytometry, revealed that chronically activated NK cells derived from 3 newly identified patients with TAP-2 deficiency consistently expressed aberrant levels of CC chemokine receptor 2 (CCR2) chemokine receptor in vitro and in vivo. This expression pattern translated into specific responsiveness of chronically activated NK cells derived from patients with TAP-2 deficiency to multiple ligands of CCR2. Moreover, the in vivo elevated levels of interleukin-2 (IL-2) and monocyte chemoattractant protein-1 (MCP-1) detected in serum and bronchoalveolar lavage samples derived from these patients highlight the potential involvement of the CCR2 pathway in aberrant NK-cell retention at chronic inflammatory sites.

[Hypnosis: clinical applications].

BACKGROUND: Hypnosis has a wide variety of applications in medicine. In recent years, recognition has grown for the need to subject the effectiveness of hypnosis to accepted research standards of clinical medicine. PURPOSE: This article aims to review salient studies of the effectiveness of hypnosis in several areas of medicine where hypnosis is commonly employed: analgesia, preparation for medical and surgical procedures, asthma, digestive disturbances, dermatological disorders, bleeding disorders, postsurgical and post-chemotherapeutic nausea and vomiting, and smoking cessation. METHODS: This survey emphasizes studies that fulfill accepted standards of clinical research, including randomization, control groups, and adequate sample size. RESULTS: Firm empirical evidence is to be found for the effectiveness of hypnosis in analgesia. In the other areas reviewed there is also some evidence for the possible clinical value for hypnosis. CONCLUSIONS: Additional research will be necessary to determine the proper place of hypnosis in clinical medical care.