Biological characterization of a novel in vitro cell irradiator.

To evaluate the overall robustness of a novel cellular irradiator we performed a series of well-characterized, dose-responsive assays to assess the consequences of DNA damage. We used a previously described novel irradiation system and a traditional 137Cs source to irradiate a cell line. The generation of reactive oxygen species was assessed using chloromethyl-H2DCFDA dye, the induction of DNA DSBs was observed using the comet assay, and the initiation of DNA break repair was assessed through γH2AX image cytometry. A high correlation between physical absorbed dose and biologic dose was seen for the production of intracellular reactive oxygen species, physical DNA double strand breaks, and modulation of the cellular double stand break pathway. The results compared favorably to irradiation with a traditional 137Cs source. The rapid, straightforward tests described form a reasonable approach for biologic characterization of novel irradiators. These additional testing metrics go beyond standard physics testing such as Monte Carlo simulation and thermo-luminescent dosimeter evaluation to confirm that a novel irradiator can produce the desired dose effects in vitro. Further, assessment of these biological metrics confirms that the physical handling of the cells during the irradiation process results in biologic effects that scale appropriately with dose.

Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil.

BACKGROUND: The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes. METHODS: A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3). RESULTS: The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT. CONCLUSIONS: Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. © 2017 American Cancer Society.

Late consequential surgical bed soft tissue necrosis in advanced oropharyngeal squamous cell carcinomas treated with transoral robotic surgery and postoperative radiation therapy.

PURPOSE: A subset of patients with oropharyngeal squamous cell carcinoma (OP-SCC) managed with transoral robotic surgery (TORS) and postoperative radiation therapy (PORT) developed soft tissue necrosis (STN) in the surgical bed months after completion of PORT. We investigated the frequency and risk factors. MATERIALS AND METHODS: This retrospective analysis included 170 consecutive OP-SCC patients treated with TORS and PORT between 2006 and 2012, with >6 months' of follow-up. STN was defined as ulceration of the surgical bed >6 weeks after completion of PORT, requiring opioids, biopsy, or hyperbaric oxygen therapy. RESULTS: A total of 47 of 170 patients (28%) had a diagnosis of STN. Tonsillar patients were more susceptible than base-of-tongue (BOT) patients, 39% (41 of 104) versus 9% (6 of 66), respectively. For patients with STN, median tumor size was 3.0 cm (range 1.0-5.6 cm), and depth of resection was 2.2 cm (range 1.0-5.1 cm). Median radiation dose and dose of fraction to the surgical bed were 6600 cGy and 220 cGy, respectively. Thirty-one patients (66%) received concurrent chemotherapy. Median time to STN was 2.5 months after PORT. All patients had resolution of STN after a median of 3.7 months. Multivariate analysis identified tonsillar primary (odds ratio [OR] 4.73, P=.01), depth of resection (OR 3.12, P=.001), total radiation dose to the resection bed (OR 1.51 per Gy, P<.01), and grade 3 acute mucositis (OR 3.47, P=.02) as risk factors for STN. Beginning May 2011, after implementing aggressive avoidance of delivering >2 Gy/day to the resection bed mucosa, only 8% (2 of 26 patients) experienced STN (all grade 2). CONCLUSIONS: A subset of OP-SCC patients treated with TORS and PORT are at risk for developing late consequential surgical bed STN. Risk factors include tonsillar location, depth of resection, radiation dose to the surgical bed, and severe mucositis. STN risk is significantly decreased with carefully avoiding a radiation dosage of >2 Gy/day to the surgical bed.

Influence of radiofrequency surgery on architecture of the palatine tonsils.

Radiofrequency surgery is a widely used modern technique for submucosal volume reduction of the tonsils. So far there is very limited information on morphologic changes in the human tonsils after radiofrequency surgery. We performed histopathological study of tonsillectomy specimens after previous bipolar radiofrequency induced thermotherapy (RFITT). A total of 83 patients underwent bipolar RFITT for hypertrophy of palatine tonsils. Tonsil volume reduction was measured by 3D ultrasonography. Five patients subsequently underwent tonsillectomy. Profound histopathological examination was performed to determine the effect of RFITT on tonsillar architecture. All tonsillectomy specimens showed the intact epithelium, intact germinal centers, normal vascularization, and no evidence of increased fibrosis. No microscopic morphological changes in tonsillectomy specimens after bipolar RFITT were observed. RFITT is an effective submucosal volume reduction procedure for treatment of hypertrophic palatine tonsils with no destructive effect on microscopic tonsillar architecture and hence most probably no functional adverse effect.

Low dose radiotherapy for adenotonsillar lymphoid hyperplasia in HIV-positive patients.

Lymphoid hyperplasia is common in HIV positive patients. The aim of this study was to determine the response to radiotherapy. Thirty-three adult patients with recurrent tonsillitis or upper airway obstruction due to tonsillar hyperplasia and conformed histology of follicular hyperplasia were included. Thirteen underwent a 24 Gy course of radiotherapy and were followed up for a minimum of 16 weeks post-radiotherapy. There was a statistically significant decrease in the median tonsillar size (95% confidence interval [-3;-2]) and in the median CD4 count (95% CI [3;152]) after 16 weeks. None of the patients had acute tonsillitis or airway obstruction after radiotherapy. Low dose radiotherapy is effective in the management of adenotonsillar hyperplasia in HIV positive patients.

Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT?

PURPOSE: To identify the anatomic structures whose damage or malfunction cause late dysphagia and aspiration after intensive chemotherapy and radiotherapy (RT) for head-and-neck cancer, and to explore whether they can be spared by intensity-modulated RT (IMRT) without compromising target RT. METHODS AND MATERIALS: A total of 26 patients receiving RT concurrent with gemcitabine, a regimen associated with a high rate of late dysphagia and aspiration, underwent prospective evaluation of swallowing with videofluoroscopy (VF), direct endoscopy, and CT. To assess whether the VF abnormalities were regimen specific, they were compared with the VF findings of 6 patients presenting with dysphagia after RT concurrent with high-dose intra-arterial cisplatin. The anatomic structures whose malfunction was likely to cause each of the VF abnormalities common to both regimens were determined by literature review. Pre- and posttherapy CT scans were reviewed for evidence of posttherapy damage to each of these structures, and those demonstrating posttherapy changes were deemed dysphagia/aspiration-related structures (DARS). Standard three-dimensional (3D) RT, standard IMRT (stIMRT), and dysphagia-optimized IMRT (doIMRT) plans in which sparing of the DARS was included in the optimization cost function, were produced for each of 20 consecutive patients with advanced head-and-neck cancer. RESULTS: The posttherapy VF abnormalities common to both regimens included weakness of the posterior motion of the base of tongue, prolonged pharyngeal transit time, lack of coordination between the swallowing phases, reduced elevation of the larynx, and reduced laryngeal closure and epiglottic inversion, contributing to a high rate of aspiration. The anatomic structures whose malfunction was the likely cause of each of these abnormalities, and that also demonstrated anatomic changes after RT concurrent with gemcitabine doses associated with dysphagia and aspiration, were the pharyngeal constrictor muscles (median thickness near midline 2.5 mm before therapy vs. 7 mm after therapy; p = 0.001), the supraglottic larynx (median thickness, 2 mm before therapy vs. 4 mm after therapy; p < 0.001), and, similarly, the glottic larynx. The constrictors and the glottic and supraglottic larynx were, therefore, deemed the DARS. The lowest maximal dose delivered to a stricture volume was 50 Gy. Reducing the volumes of the DARS receiving > or =50 Gy (V(50)) was, therefore, a planning and evaluation goal. Compared with the 3D plans, stIMRT reduced the V(50) of the pharyngeal constrictors by 10% on average (range, 0-36%, p < 0.001), and doIMRT reduced these volumes further, by an additional 10% on average (range, 0-38%; p <0.001). The V(50) of the larynx (glottic + supraglottic) was reduced marginally by stIMRT compared with 3D (by 7% on average, range, 0-56%; p = 0.054), and doIMRT reduced these volumes by an additional 11%, on average (range, 0-41%; p = 0.002). doIMRT reduced laryngeal V(50) compared with 3D, by 18% on average (range 0-61%; p = 0.001). Certain target delineation rules facilitated sparing of the DARS by IMRT. The maximal DARS doses were not reduced by IMRT because of their partial overlap with the targets. stIMRT and doIMRT did not differ in target doses, parotid gland mean dose, spinal cord, or nonspecified tissue maximal dose. CONCLUSIONS: The structures whose damage may cause dysphagia and aspiration after intensive chemotherapy and RT are the pharyngeal constrictors and the glottic and supraglottic larynx. Compared with 3D-RT, moderate sparing of these structures was achieved by stIMRT, and an additional benefit, whose extent varied among the patients, was gained by doIMRT, without compromising target doses. Clinical validation is required to determine whether the dosimetric gains are translated into clinical ones.

Induction of macrophage migration inhibitory factor precedes the onset of acute tonsillitis.

We investigated the serum macrophage migration inhibitory factor (MIF) levels of palmoplantar pustulosis patients, before and after the tonsillar provocation test. Higher serum MIF levels of palmoplantar pustulosis patients were decreased after the tonsillar provocation test (n=29). To confirm these phenomena, two patients with acute tonsillitis had their changes in body temperature, C-reactive protein (CRP) and serum MIF levels examined during the course of their illness. Surprisingly, increased MIF preceded fever and CRP elevation, and MIF subsequently decreased at the onset of fever and CRP elevation. Since MIF is an initiator of other proinflammatory cytokines, we suggest that the induction of MIF may precede other inflammatory conditions.

[Late effects of long-term exposure to low-dose ionizing radiation on lymphoid pharyngeal system in children]. / Otdalennye rezul'taty dlitel'nogo vozdeistviia malykh doz ioniziruiushchego izlucheniia na limfoidnyi apparat glotki u detei.

The examination of 468 children and adolescents estimated frequency and structure of chronic pathology of the pharyngeal ring in long-term exposure to low-dose radiation. Chronic disease of the tonsils and adenoids was detected in 194 children (45.4%). Chronic tonsillitis was diagnosed in 142 (33.3%) examinees. 31.7 and 59.9% cases had compensated and subcompensated disease. Decompensated process took place in 8.5% cases of chronic tonsillitis. Hypertrophy of the palatine tonsils and adenoids was detected in 96 (22.5%) children. High incidence of lymphadenopathy of the neck in combination with chronic tonsillitis and tonsil and adenoid hypertrophy was found. Structure of chronic pathology of the lymphoid pharyngeal ring correlated with internal radiation dose. Comparison of postnatally and antenatally radiated children demonstrated less frequent incidence of affected lymphoid pharyngeal ring in children born before the Chernobyl accident.

Involvement of tonsils in IgA nephropathy.

This study was intended to clarify the involvement of tonsils in the pathogenesis of IgA nephropathy. In 62 patients with IgA nephropathy and 20 patients with other renal diseases, their tonsils were stimulated by an ultra short wave. Forty of 62 patients with IgA nephropathy (65%) showed a deterioration of urinary findings after the stimulation compared with six of 20 patients with other renal diseases (30%). Previous episodes of gross hematuria following upper respiratory tract infections existed in 17 of 40 patients (Group A) who showed a deterioration of urinary findings after tonsil stimulation (43%) as against in four of 22 (Group B) without the deterioration (18%). The level of serum secretory IgA was higher in Group A than in Group B. It is suggested that chronic tonsillitis may play an important role in the development of IgA nephropathy. Thirty-six patients received tonsillectomy from 1980-2002. The frequency of gross hematuria at upper respiratory infection decreased in 56% of the patients The amount of urinary protein decreased in 33% of the patients and RBC counts decreased in 56% of the patients Eight patients with tonsillectomy were followed up longer than 16 years Two of them went to hemodialysis and five of them showed no urinary abnormalities at present. The effect of tonsillectomy in the long term was not clarified in this study.

A clinical feature associated with polymorphisms of the TNF region in Japanese patients with palmoplantar pustulosis.

We investigated the association of polymorphisms in the tumor necrosis factor (TNF) microsatellite as well as the promoter region of the TNFA gene and the TNFB gene with palmoplantar pustulosis (PPP). In order to clarify the heterogeneity of this disease, we performed a tonsillar provocation test on 78 patients and divided them into two groups according to the results; provocation positive (PP; n = 38) and provocation negative (PN; n = 40). We found that the phenotype frequency of the TNFB2 allele of the TNFB gene in the PN group was significantly higher than in controls (p = 0.0022, corrected p = 0.0044). There was also a significant increase in the frequency of allele B of the TNFA gene (TNFApB) in the PN group when compared with controls (p = 0.0049, corrected p = 0.025). Although there are no significant differences in the frequency of TNFa microsatellites, the frequency of the TNFd7 allele increased and that of the TNFd4 allele decreased in the PN group. An extended haplotype analysis revealed that the TNFd7-TNFApA-TNFB2 haplotype was more frequent in the PN group, implying that the PN group is associated with a low level of TNF-alpha production. These results indicate that detection of polymorphisms at the TNF locus may be a marker for determination of the heterogeneity of the disease, and that the allelic variation may influence the susceptibility.

Optical-thermal simulation of tonsillar tissue irradiation.

BACKGROUND AND OBJECTIVE: Despite laser applications targetted toward tonsillar tissue, there has been no characterization of underlying optical and thermal events during laser irradiation of tonsillar tissue. STUDY DESIGN/MATERIALS AND METHODS: The optical properties of canine and human tonsils were determined at 805 nm (diode laser) and 1,064 nm (Nd:YAG laser). An optical-thermal simulation was developed to predict the temperature rise in irradiated human tonsils. RESULTS: The optical properties of human and canine tonsillar tissue are similar at both wavelengths. The optical-thermal simulation was validated and predicts that at 10 W and 1 minute of irradiation, the heat will be contained within the human tonsil. The diode laser causes more superficial heating than the Nd:YAG laser. CONCLUSIONS: The safety of irradiating human tonsils was shown. The diode laser is superior to the Nd:YAG laser because less heat affects collateral structures. The optical-thermal simulation detailed in this study can be used to predict the temperature rise in tissues undergoing irradiation.

Optical-thermal simulation of human tonsillar tissue irradiation: clinical implications.

BACKGROUND AND OBJECTIVE: Mucosa intact laser tonsillar ablation is an alternative to conventional tonsillectomy. The efficacy of this procedure was demonstrated in canines, but establishing the safety of irradiating human tonsils is paramount. STUDY DESIGN/MATERIALS AND METHODS: An optical-thermal simulation of tonsillar tissue irradiation was previously developed, but the effect of varying parameters was not investigated. The tissue response to irradiation at 5-25 watts for 1 minute and 10 watts for 10 seconds to 162 seconds is simulated. RESULTS: At 15 watts and greater, the peak temperature is over 100 degrees C and the mucosal temperature is over 70 degrees C. At the depth of the tonsil, the temperature does not vary significantly. The peak temperature is at 1 mm. The radial temperature profile is not significantly altered by longer irradiation times. CONCLUSIONS: The optimal dosimetry parameters for irradiation of human tonsillar tissue at 805 nm with the MILTA technique is under 15 watts for approximately 1 minute.

Salivary gland tumors after childhood radiation treatment for benign conditions of the head and neck: dose-response relationships.

We have investigated the dose-response relationships for the incidence of salivary gland tumors in a cohort of 2945 individuals who were irradiated as children between 1939-1962. Most of the patients were treated to reduce the size of their tonsils and adenoids. The mean dose to the salivary glands (+/-SD) was 4.2 +/- 1.7 Gy. Eighty-nine patients developed 91 salivary gland neoplasms; 22 had single malignancies, 64 had single benign neoplasms, 2 developed two separate benign neoplasms, and 1 developed a single neoplasm but did not have surgery. The majority (81 of 89) of the patients developed neoplasms in the parotid glands. Mucoepidermoid carcinomas were the most common malignancy and mixed (pleomorphic) adenomas were the most common benign neoplasm. For all salivary gland tumors, the excess relative risk per gray (ERR/Gy) was 0.82; however, the 95% confidence interval was wide (0.04, upper bound indeterminate). The trend was determined principally by benign tumors, as there was no dose-response relationship for salivary gland cancer, although there were too few cases to draw definitive conclusions. Overall, our study provides support for an association between salivary gland tumors and radiation exposure. Although most salivary gland tumors are benign and are usually readily detected, they may cause morbidity, and people who have been irradiated in the area should be monitored for their occurrence.

Change induced by radiation therapy in FDG uptake in normal and malignant structures of the head and neck: quantitation with PET.

PURPOSE: To quantitate the changes induced in uptake of the glucose analog 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in normal structures in the head and neck and compare these to the change in uptake in malignant structures in patients with head and neck tumors undergoing radiation therapy. MATERIALS AND METHODS: Eleven patients with biopsy-confirmed squamous cell carcinoma of the head and neck were studied before, during, and after a 6-week course of radiation therapy with positron emission tomography (PET)-FDG imaging. A ratio of FDG uptake in the structure compared with that in the cerebellum (termed metabolic ratio) within and outside of the field of radiation was determined in the adenoids; lingual and palatine tonsils; parotid, submandibular, and sublingual glands; and nasal turbinates, soft palate, and gingiva. RESULTS: The average metabolic ratio in the tonsils, nasal turbinates, soft palate, and gingiva did not change significantly with treatment. CONCLUSION: FDG uptake in normal structures does not change with radiation therapy. This fact is in marked contrast to the FDG uptake in squamous cell carcinomas in the head and neck, which decrease dramatically with treatment (P < .005).

The effect of thin K-edge filters on radiation dose in dental radiography.

The use of thin K-edge filters has been found to reduce considerably the radiation dose in intra-oral radiography. The aim of this study was to investigate the effect of filtration on the skin entrance dose and several sites (representing organs or areas of interest within the head) along the central beam axis, at other points within the primary beam and at two points just outside the primary beam. The subject was a sliced head phantom (a human skull embedded in tissue-equivalent material) which was exposed to X rays from a conventional dental X-ray unit in the range of tube voltage 55-85 kVp for each of four filter systems. These were 2.7 mm of aluminium alone (the existing total filtration) or with an added 0.1 mm erbium, 0.1 mm yttrium or 0.05 mm niobium metal foils. Measurements of radiation dose were made using thermoluminescent dosemeters (TLD rods) and were adjusted to simulate the exposure resulting from a typical dental radiograph of a maxillary molar. The results suggest that the use of thin K-edge filters significantly reduces the entrance skin dose and to a certain extent reduces the total dose imparted to the head. However, the dose to the ipsilateral orbit at higher tube voltages may be increased.