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Meniere Disease (MD) is a chronic inner ear disorder characterized by vertigo attacks, sensorineural hearing loss, tinnitus, and aural fullness. Extensive evidence supporting the inflammatory etiology of MD has been found, therefore, by using transcriptome analysis, we aim to describe the inflammatory variants of MD. We performed Bulk RNAseq on 45 patients with definite MD and 15 healthy controls. MD patients were classified according to their basal levels of IL-1β into 2 groups: high and low. Differentially expression analysis was performed using the ExpHunter Suite, and cell type proportion was evaluated using the estimation algorithms xCell, ABIS, and CIBERSORTx. MD patients showed 15 differentially expressed genes (DEG) compared to controls. The top DEGs include IGHG1(p= 1.64 ×10−6) and IGLV3-21(p= 6.28 ×10−3), supporting a role in the adaptative immune response. Cytokine profiling defines a subgroup of patients with high levels of IL-1β with up-regulation of IL6(p= 7.65 ×10−8) and INHBA(p= 3.39 ×10−7) genes. Transcriptomic data from peripheral blood mononuclear cells support a proinflammatory subgroup of MD patients with high levels of IL6and an increase in naïve B-cells, and memory CD8+T cells.

IMPORTANCE: Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT. OBJECTIVE: To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to μg/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality. MAIN OUTCOMES AND MEASURES: For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%. RESULTS: Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P < .001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, −10.9%; 95% 1-sided upper confidence limit, −3.5; P = .01). CONCLUSIONS AND RELEVANCE: The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04189913

Hereditary transthyretin‐mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long‐standing treatment. However, disease progression continues post‐LT. This Phase 3b, open‐label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post‐LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty‐three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, −3.7 [2.7]; Norfolk Quality of Life‐Diabetic Neuropathy questionnaire, −6.5 [4.9]; least‐squares mean [SEM], Composite Autonomic Symptom Score‐31, −5.0 [2.6]); and stabilized disability (Rasch‐built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post‐LT (www.clinicaltrials.govNCT03862807). Patisiran, a small‐interfering RNA therapeutic, is well‐tolerated and stabilizes or improves multiple disease symptoms for patients with hereditary transthyretin‐mediated amyloidosis with polyneuropathy who experience disease progression after liver transplantation.

Background: Several phase III trials have demonstrated equivalent long-term survival between breast conserving surgery plus radiation therapy and mastectomy in patients with early-stage breast cancer but have not provided information on the optimal volume of breast tissue requiring post-lumpectomy radiation therapy. Therefore, we examined the 5-year results of a single institution's experience with radiation therapy limited to the region of the tumor bed (i.e., limited-field radiation therapy) in selected patients treated with breast-conserving therapy and compared them with results of matched breast-conserving therapy patients who underwent whole-breast radiation therapy. Methods: A total of 199 patients with early-stage breast cancer were treated prospectively with breast-conserving therapy and limited-field radiation therapy using interstitial brachytherapy. To compare potential differences in local recurrence rates based on the volume of breast tissue irradiated, patients in the limited-field radiation therapy group were matched with 199 patients treated with whole-breast radiation therapy. Match criteria included tumor size, lymph-node status, patient age, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Local-regional control and disease-free and overall survival were analyzed using the Kaplan-Meier method, and the statistical significance of differences between treatment groups was calculated using the log-rank test. All statistical tests were two-sided. Results: Median follow-up for surviving patients was 65 months (range = 12-115 months). Five ipsilateral breast failures (i.e., recurrences) were observed in patients treated with limited-field radiation therapy. The cumulative incidence of local recurrence was 1% (95% confidence interval [CI] = 0% to 2.8%). On matched-pair analysis, the rate of local recurrence was not statistically significantly different between the patient groups (1% [95% CI = 0% to 2.4%] for the whole-breast radiation therapy patients versus 1% [95% CI = 0% to 2.8%] for the limited-field radiation therapy patients: P = .65). Conclusions: Limited-field radiation therapy administered to the region of the tumor bed has comparable 5-year local control rates to whole-breast radiation therapy in selected patients.

Low-frequency sensorineural hearing loss (SNHL) is a rare hearing impairment affecting frequencies below 1000 Hz, previously associated with DIAPH1, WSF1, MYO7A, TNC, SLC26A4or CCDC50genes. By exome sequencing, we report a novel nonsense variant in CENPPgene, segregating low-frequency SNHL in five affected members in a Swiss family with autosomal dominant inheritance pattern. Audiological evaluation showed up-sloping audiometric configuration with mild-to-moderate losses below 1000 Hz, that progresses to high-frequencies over time. Protein modeling shows that the variant truncates five amino acids at the end, losing electrostatic interactions that alter protein stability. CENPPgene is expressed in the supporting cells of the organ of Corti and takes part as a subunit of the Constitutive Centromere Associated Network in the kinetochore, that fixes the centromere to the spindle microtubules. We report CENPPas a new candidate gene for low-frequency SNHL. Further functional characterization might enable us to elucidate its molecular role in SNHL.

Background. The clinical, radiographic, and bronchoscopic records of patients treated with out-patient high dose rate (HDR) endobronchial brachytherapy were reviewed to determine its effectiveness in patients with malignant airway obstruction (with or without prior external beam radiation). In addition, quality of life and acute and chronic morbidity were evaluated. Methods. From January 1, 1989 to June 30, 1993, 46 patients received 128 HDR endobronchial treatments employing a high activity Ir-192 source with a remote afterloader. Patients treated had a total of 22 primary and 17 recurrent bronchogenic carcinomas, 7 of which were metastatic nonpulmonary tumors. Three separate fractions of 7.0 Gy were prescribed to a depth of 1.0 cm. and given 1 week apart. Twelve patients (30%) received prior external beam irradiation (median dose, 58 Gy). Results. Median follow-up for the entire group was 5 months (17.5 for surviving patients). Of the eight asymptomatic patients, five (62%) remained asymptomatic for the remainder of their lives. Of the 38 symptomatic patients, 28 (74%) had significant clinical improvement, and 12 of them remained improved for the duration of their lives. Of thirty-six (78%) patients examined for radiographic response, 25 (69%) had a partial or complete response to this treatment. In patients without prior irradiation, there was a tendency for a higher percentage of clinical and radiographic response. Two patients (4%) experienced mild, transient dysphagia, four patients developed self-limited radiation pneumonitis (9%), and three patients (7%) suffered fatal hemoptysis (all of these patients received prior or concurrent external beam radiotherapy). No factor (i.e., prior radiation therapy, number of catheters placed, surgery, or chemotherapy) predicted an increased risk of complications (P = NS). Conclusions. Outpatient HDR endobronchial brachytherapy is effective in both preventing and relieving endobronchial obstruction in patients with or without prior irradiation, recurrent lesions, or metastatic nonpulmonary disease. A significant proportion of patients can be rendered asymptomatic for the duration of their lives, hence were provided with improved quality of life. These treatments are well tolerated and safe, and result in minimal long term morbidity. Cancer 1995; 75:2345-50.

Background. Several recent studies have suggested radiosensitizing effects of paclitaxel, a microtubular inhibitor. To test the universality of this finding, the interaction between paclitaxel and radiation treatment of cell lines derived from three common human carcinomas MCF-7 (breast cancer); DUT-145 (prostate cancer); and HT-29 (colon cancer) was evaluated. The study focused on the ability of paclitaxel to block cells at the G2-M phase of the cell cycle and potentially enhance the radiation, sensitivity of the cells. Methods. All cell lines were exposed to three different clinically achievable paclitaxel concentrations ranging from 2 nM to 25 nM. Paclitaxel pretreatment for 12 and 24 hours before radiation was tested in all three cell lines. The radiation dose ranged from 0 to 8 Gy delivered in a single fraction. Cellular survival after treatment with paclitaxel and/or radiation was determined by clonogenic assay. Cell cycle distribution as determined by flow cytometry was performed after various dose-time combinations of paclitaxel. Results. Cytotoxicity studies with paclitaxel alone demonstrated a time-dependent and dose-dependent survival relationship for all three cell lines. Resultant surviving fractions were in the range of 5 to 90% after 24-hour exposure to paclitaxel alone. The interaction between paclitaxel and radiation was primarily additive in each of the three cell lines for all paclitaxel dose-time combinations studied. Flow cytometric analysis failed to reveal a prominent G2-M block in all three cell lines after paclitaxel treatment for 24 hours. Conclusions. Paclitaxel lacked a radiosensitizing effect on MCF-7, DUT-145, and HT-29 cells in this study. These results should be considered when designing clinical trials that use paclitaxel as a potential radiosensitizer of certain human carcinomas. Cancer 1995; 75:2262-8. Key words; taxol, paclitaxel, radiation sensitizer, human carcinoma cell lines.

Background. The authors have reviewed their institution's experience with conservative surgery and radiation therapy for early stage breast cancer with the goal of defining the impact of infiltrating lobular histology (ILC) on the local recurrence rate. Also, they have examined the preoperative mammograms of the ILC patients to determine if mammographic features could be used to predict treatment outcome. Methods. Between January 1, 1980, and December 31, 1987, 402 cases of Stages I and II breast cancer were treated with conservative surgery and radiation therapy (BCT) at William Beaumont Hospital. Each patient had at least an excisional biopsy. Radiation consisted of 45-50 Gy to the entire breast followed by a supplemental boost dose, so that a minimum of 60 Gy was delivered to the tumor bed. Thirty cancers were classified histologically as infiltrating lobular carcinoma (ILC), 346 as infiltrating ductal carcinoma (IDC), and 26 as other. Median follow-up is 60 months. Results. There was no significant difference in 5 year actuarial local recurrence rates between ILC and IDC, 3.3 versus 4.2%, respectively, (P = not significant). Preoperative mammograms were retrospectively reviewed for 29 of the 30 ILC patients. A spiculated opacity was the most common primary mammographic finding (63%), followed by architectural distortion (17%), poorly defined opacity (7%), and negative (7%). Of the patients who had a preoperative primary mammographic finding of a spiculated opacity, 55% underwent reexcision after the initial excisional biopsy, and residual invasive carcinoma was found in 18% of the reexcision specimens. In contrast, of the patients with a primary mammographic finding of an architectural distortion, poorly defined opacity, or negative, 89% underwent reexcision after an initial excisional biopsy, and residual invasive carcinoma was found in 100% of the reexcision specimens. Conclusions. Infiltrating lobular carcinoma does not have a worse local recurrence rate compared with IDC when each is treated with breast-conserving therapy. The primary finding on preoperative mammograms in patients with ILC may prove to be a useful tool for predicting the likelihood of residual carcinoma in the breast after initial excisional biopsy. Cancer 1994; 74:640-7.

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Rather than portray formal and informal sector entrepreneurs as discrete groups, an emergent scholarship has conceptualized a continuum from wholly formal to wholly informal entrepreneurs. The aim of the article is to advance a degree of (in)formality approach by evaluating whether the institutional determinants found to explain whether an enterprise is formal or informal are also valid when explaining the level of (in)formality of enterprises. To do so, a 2017 survey of 500 retail microenterprises in the city of Lahore in Pakistan is reported. The finding is that higher levels of formality are more significantly associated with individual-level characteristics of the entrepreneur and enterprise, such as educational level and sales, than with formal and informal institutional conditions, as proposed by institutional theory. The article thus concludes by offering new theoretical implications and exploring some innovative policy measures to tackle informal entrepreneurship.

IntroductionMeniere’s disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has been mostly described in sporadic cases, familial cases being around 10% of the observed individuals. It is associated with an accumulation of endolymph in the inner ear, but the molecular underpinnings remain largely unknown. The main molecular pathways showing higher differentially expressed genes in the supporting cells of the inner ear are related to cochlea-vestibular innervation, cell adhesion and leucocyte extravasation. In this study, our objective is to find a burden of rare variants in genes that interact with the main signalling pathways in supporting cells of the inner ear in patients with sporadic MD.MethodsWe designed a targeted-sequencing panel including genes related with the main molecular pathways in supporting cells and sequenced 860 Spanish patients with sporadic MD. Variants with minor allele frequencies <0.1 in the gene panel were compared with three independent reference datasets. Variants were classified as loss of function, missense and synonymous. Missense variants with a combined annotation-dependent depletion score of >20 were classified as damaging missense variants.ResultsWe have observed a significant burden of damaging missense variants in few key genes, including the NTN4gene, associated with axon guidance signalling pathways in patients with sporadic MD. We have also identified active subnetworks having an enrichment of rare variants in sporadic MD.ConclusionThe burden of missense variants in the NTN4gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD.

While mitochondrial dysfunction is emerging as key in Parkinson’s disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophilamodels of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD. Our findings suggest NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases.

The identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets. PAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM. Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and 71% in the top 10 ranked variants. Our pipeline prioritizes a short list of heterozygous variants in exome datasets based on the top 10 concordant variants combining multiple systems.

Bathed in ethereal light from the 11-day-old Moon, this view of a star-filled sky over Yosemite National Park in central California was obtained on April 29, 2004. It shows the [...]

Autosomal dominant (AD) familial Meniere’s disease (FMD) is a rare disorder involving the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo. Here, we have identified two novel and rare heterozygous variants in the SEMA3D and DPT genes segregating with the complete phenotype that have variable expressivity in two pedigrees with AD-FMD. A detailed characterization of the phenotype within each family illustrates the clinical heterogeneity in the onset and progression of the disease. We also showed the expression of both genes in the human cochlea and performed in silico analyses of these variants. Three-dimensional protein modelling showed changes in the structure of the protein indicating potential physical interactions. These results confirm a genetic heterogeneity in FMD with incomplete penetrance and variable expressivity.

Hexanucleotide repeat expansions in C9ORF72are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that the hexanucleotide expansions cause the noncanonical translation of C9ORF72transcripts into neurotoxic dipeptide repeat proteins (DPRs) that contribute to neurodegeneration. We show that a cell-penetrant peptide blocked the nuclear export of C9ORF72-repeat transcripts in HEK293T cells by competing with the interaction between SR-rich splicing factor 1 (SRSF1) and nuclear export factor 1 (NXF1). The cell-penetrant peptide also blocked the translation of toxic DPRs in neurons differentiated from induced neural progenitor cells (iNPCs), which were derived from individuals carrying C9ORF72-linked ALS mutations. This peptide also increased survival of iNPC-differentiated C9ORF72-ALS motor neurons cocultured with astrocytes. Oral administration of the cell-penetrant peptide reduced DPR translation and rescued locomotor deficits in a Drosophilamodel of mutant C9ORF72-mediated ALS/FTD. Intrathecal injection of this peptide into the brains of ALS/FTD mice carrying a C9ORF72mutation resulted in reduced expression of DPRs in mouse brains. These findings demonstrate that disrupting the production of DPRs in cellular and animal models of ALS/FTD might be a strategy to ameliorate neurodegeneration in these diseases.

Protein polymerization and bundling play a central role in cell physiology. Predictive modeling of these processes remains an open challenge, especially when the proteins involved become large and their concentrations high. We present an effective kinetics model of filament formation, bundling, and depolymerization after GTP hydrolysis, which involves a relatively small number of species and reactions, and remains robust over a wide range of concentrations and timescales. We apply this general model to study assembly of FtsZ protein, a basic element in the division process of prokaryotic cells such as Escherichia coli, Bacillus subtilis, or Caulobacter crescentus. This analysis demonstrates that our model outperforms its counterparts in terms of both accuracy and computational efficiency. Because our model comprises only 17 ordinary differential equations, its computational cost is orders-of-magnitude smaller than the current alternatives consisting of up to 1000 ordinary differential equations. It also provides, to our knowledge, a new insight into the characteristics and functioning of FtsZ proteins at high concentrations. The simplicity and versatility of our model render it a powerful computational tool, which can be used either as a standalone descriptor of other biopolymers’ assembly or as a component in more complete kinetic models.

High-dose-rate (HDR) brachytherapy boost represents a method to dose escalate in high-risk prostate cancer; the purpose of this analysis is to report long-term outcomes for a group of high-risk patients with Gleason 8 through 10 prostate cancer treated with HDR brachytherapy boost from a multi-national cohort study. Between 1987 and 2002, 483 patients with Gleason 8–10 prostate cancer were treated on four prospective trials of HDR boost. Conformal external beam radiotherapy (EBRT) was delivered to the pelvis (dose range 36–50.4 Gy) along with HDR boost for a combined biologic equivalent dose (BED) of 215–366 Gy (α/β = 1.2) and cumulative dose of 64–72 Gy. Mean/median follow-up was 6.1/5.1 years. The 10-year rates of biochemical control (BC), distant metastases (DM), clinical failure (CF), cause-specific survival (CSS), and overall survival (OS) were 53.5, 22.1, 25.6, 82.6, and 62.7 %, respectively. Androgen deprivation was given in 69.9 % of patients (predominantly short course) but did not significantly improve BC, DM, CSS, or OS. When stratified by initial PSA (iPSA), 10-year outcomes were improved with lower iPSA (<40) including BC (57.4 vs. 10.3 %, p< 0.001); freedom from distant metastases (81.5 vs. 43.4 %, p< 0.001); CSS (85.0 vs. 59.1 %, p< 0.001); and OS (63.8 vs. 47.9 %, p= 0.02). A combination of HDR brachytherapy boost and EBRT provides a high BED with high rates of disease control and excellent disease specific survival for patients with Gleason 8 through 10 prostate cancer even with iPSA up to 40 ng/ml. Hormonal therapy did not improve outcomes in this cohort of patients when the radiation dose was escalated with an HDR prostate boost.

Over the past decade or so, two competing theoretical perspectives have arisen that explain participation in informal entrepreneurship as resulting from either too little or too much state intervention. To evaluate these competing explanations critically, the authors report on a 2012 UK survey of 595 small business owners. Twenty per cent of these owners said that they had traded informally when starting up their ventures, and the authors examine and evaluate their reasons for doing so. It was found that 41% of the entrepreneurs attributed their off-the-books trading to too little state intervention (for example, a lack of government advice and support), 35% to too much intervention (burdensome red tape, high taxes, etc) and 24% to a mix of both factors. However, a multivariate analysis displays significant socio-demographic, firm-level and regional variations in the reasons. The outcome is a call to move towards more nuanced context-bound explanations of entrepreneurship in the informal economy.

The aim is to evaluate critically whether small businesses start-up in the informal economy and whether they do so to test-trade the viability of their businesses. Reporting a 2012 survey of 595 small business owners in the UK, 20% report trading informally when starting their business, 64% of whom asserted a main reason was to test its viability. Some 13% of all small businesses therefore start-up test-trading in the informal economy, although multivariate analysis shows that businesses started by men, with low current annual turnovers in particular sectors are significantly more likely to do so. Regional variations are not significant. The outcome is a call for not only similar studies in other countries to determine the proportion of enterprises that start up test-trading in the informal economy but also a discussion of the policy implications of this finding.

The purpose of this study is to examine intrafraction variation and residual error (IFV + RE) during conebeam CT (CBCT)-guided hypofractionated prostate radiotherapy and evaluate factors associated along with target margins.Forty-six patients underwent hypofractionated prostate radiotherapy receiving 64 Gy in 20 fractions with on-line CBCT correction. Analysis of factors associated with IFV + RE including patient characteristics, treatment characteristics, and organ volumes was performed using univariate and multivariate analyses.The mean IFV + RE were 0.10 ± 1.1, −1.1 ± 2.5, and −1.5 ± 2.7 mm in the mediolateral (ML), anteroposterior (AP), and craniocaudad (CC) dimensions, respectively. The IFV + RE vector was 3.5 ± 2.5 mm. It was found that 1, 22, and 31 % of fractions had an IFV + RE greater than 3 mm in the ML, AP, and CC dimensions, respectively. Multivariate analysis found that age and rectal volumes are associated with increased IFV + RE. When evaluating IFV + RE greater than 3 mm, age, treatment time, and rectal volumes were associated. A treatment time of greater than 16.5 min was found to be a cut point for increased IFV + RE.IFV may represent a significant component of target margins utilized in hypofractionated prostate radiotherapy with target margins exceeding 3 mm in the CC and AP dimensions. Rectal volumes, treatment time, and age are associated with IFV + RE.

We analyzed differences in disease presentation, outcomes, and toxicities between African American (AA) and White (W) men treated with definitive radiation therapy for their prostate cancer.

To prospectively assess the quality of life (QOL) and hearing acuity in vestibular schwannoma (VS) patients after gamma knife surgery (GKS).

Cosmetic and functional reconstruction of large and complex calvarial defects remains a challenge for craniofacial surgeons. Computer-designed alloplastic implants have revolutionized the conceptualization and approach to these reconstructions and have become a reliable and irreplaceable part of the surgical armamentarium. We are reporting a case of complex orbito-fronto-temporal reconstruction using a computer-designed PEEK (polyetheretherketones)-Patient Specific Implant (PSI). To the best of our knowledge, no other similar cases regarding the use of these implants in cranial reconstruction have been reported previously.

The posttreatment prostate‐specific antigen (PSA) bounce phenomenon has been recognized in at least 20% of all patients treated with radiation. The purpose of the current report was to determine if there was a difference in biochemical and clinical control between the bounce and nonbounce (NB) patients using pooled data on 4839 patients with T1‐2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions between 1986 and 1995.The median follow‐up was 6.3 years. A posttreatment PSA bounce was defined by a minimal rise of 0.4 ng/mL over a 6‐month follow‐up period, followed by a drop in PSA level of any magnitude. Endpoints included no biochemical evidence of disease (bNED) failure (BF) (ASTRO definition), distant failure (DF), cause‐specific failure (CSF), and overall survival (OS). Patients were stratified by pretreatment PSA, Gleason score, T stage, age, dose, and risk group.In all, 978 (20%) patients experienced at least 1 posttreatment PSA bounce. Within 3 subgroups (risk group, pretreatment PSA, and age), statistically significant differences of remaining bounce‐free were observed on univariate analysis. Patients < 70 years had a 72% chance of remaining bounce‐free at 5 years compared with 75% for older patients (P = .04). The NB patients had 72% bNED control at 10 years compared with 58% for the bounce patients. The effect of a bounce remained statistically significant on multivariate analysis (P < .0001). No statistically significant difference in DF, CSF, or OS was observed.Patients treated with external beam radiation therapy alone who experience a posttreatment PSA bounce have increased risk of BF. However, this did not translate into a difference in clinical failure with the available follow‐up in the current study. Cancer 2006. © 2006 American Cancer Society.

Purpose:: To analyze the long-term effect of local dose escalation using conformal hypofractionated high-dose-rate brachytherapy (HDR-BT) boost and pelvic external-beam radiation therapy (EBRT) in hormone-naïve men with localized prostate cancer. Patients and Methods:: A total of 579 men were consecutively treated with pelvic EBRT and dose escalating HDR-BT since 1986 in two prospective trials: 378 patients at William Beaumont Hospital (1991–2002), and 201 patients at Kiel University (1986–1999). BT optimization was done modulating both, the dwell times and spatial source positions. A short course of neoadjuvant/concurrent androgen deprivation therapy was given to 222 patients. Hormone-naïve patients only (n = 324) with a follow-up ≥ 18 months were analyzed. All patients had at least one poor prognostic factor (stage ≥ T2b, Gleason Score ≥ 7, pretreatment prostate-specific antigen [PSA] ≥ 10 ng/ml): any one factor 122 patients, any two factors 122 patients, and three factors 80 patients. This cohort was stratified by equivalent dose (ED): dose level 1, ≤ 94 Gy, n = 58, and dose level 2, > 94 Gy, n = 266, assuming an α/β ratio of 1.2. The ASTRO definition for biochemical failure was used. Results:: Mean follow-up was 5.3 years (1.5–13.9 years). For all 324 patients, the 5-year biochemical control (BC) rate was 79%. Cancer-specific survival was 98%, and overall survival 90%. Similar analysis by institution demonstrated no difference in outcomes. For the entire cohort of hormone-naïve men, dose escalation to > 94 Gy resulted in a better 5-year BC of 59% versus 85% (p &lt; 0.001). Discriminating by risk group a striking dose escalation effect was seen in the groups with two or three poor prognostic factors (p = 0.022 and &lt; 0.001, respectively). In the group with only one poor prognostic factor, no statistical difference could be detected questioning the need for ED > 94 Gy. Conclusion:: The results demonstrate that conformal HDR-BT is a successful method for delivering very high radiation dose to the prostate. The ability to escalate dose to ED > 94 Gy was reflected in improved long-term outcomes in terms of BC, significantly for those patients with two or three poor prognostic factors reaching BC rates of 85%.

AbstractTwo types of media, a natural medium (wood chips) and a commercially engineered medium, were evaluated for sulfur inhibition and capacity for removal of hydrogen sulfide (H2S). Sulfate was added artificially (40, 65, and 100 mg of S/g of medium) to test its effect on removal efficiency and the media. A humidified gas stream of 50 ppm by volume H2S was passed through the media-packed columns, and effluent readings for H2S at the outlet were measured continuously. The overall H2S baseline removal efficiencies of the column packed with natural medium remained >95% over a 2-day period even with the accumulated sulfur species. Added sulfate at a concentration high enough to saturate the biofilter moisture phase did not appear to affect the H2S removal process efficiency. The results of additional experiments with a commercial granular medium also demonstrated that the accumulation of amounts of sulfate sufficient enough to saturate the moisture phase of the medium did not have a significant effect on H2S removal.When the pH of the biofilter medium was lowered to 4, H2S removal efficiency did drop to 36%. This work suggests that sulfate mass transfer through the moisture phase to the biofilm phase does not appear to inhibit H2S removal rates in biofilters. Thus, performance degradation for odor-removing biofilters or H2S breakthrough in field applications is probably caused by other consequences of high H2S loading, such as sulfur precipitation.

We evaluated the potential for differing acute and chronic toxicities between 2 monotherapy methods of image guided conformal brachytherapy, high dose rate (HDR) brachytherapy alone and low dose rate (LDR) permanent palladium seeds.

To improve outcome for patients with prostate cancer with poor prognostic factors higher than conventional radiation doses are required. To achieve this outcome a brachytherapy boost was given. We report the results of the first high dose rate dose-escalation brachytherapy trial.

We examined the survival impact of a course of 6 months or less of adjuvant/concurrent androgen deprivation in patients with unfavorable prostate cancer treated to high radiation doses with external beam (EBRT) and a high dose rate (HDR) brachytherapy boost.

Over the past 2 decades, numerous advances and innovations have occurred in all technical aspects of radiation therapy (RT), including three-dimensional (3D) treatment planning, conformal radiation delivery, intensity-modulated radiation therapy (IMRT), patient immobilization, and precise treatment verification. Despite incredible progress on all fronts, standard RT for breast cancer has changed very little and has not fully exploited many of the advances commonly used to treat most other malignancies. Increasing data have also accumulated, indicating that dose non-uniformities within the breast with traditional RT techniques can be greater than in many other anatomic sites. These significant dose inhomogeneities can produce unnecessary acute and chronic toxicities as well as unacceptable long-term cosmetic results. In addition, the lack of accurate verification of target volume coverage (e.g. lumpectomy cavity or chest wall) may result in diminished tumor control.

We studied relationships among clinicopathologic factors in 78 patients with unfavorable prostate adenocarcinoma treated in a dose-escalation radiation therapy (RT) study using pre- and 18-month protocol post-RT biopsy specimens. Pre-RT factors analyzed were serum prostate-specific antigen (PSA) level, Gleason score, and percentage of needle cores with adenocarcinoma; post-RT factors were percentage of needle cores with adenocarcinoma and amount of radiation effect on the adenocarcinoma. Of 78 patients, 42 (54%) had residual adenocarcinoma in the post-RT biopsy specimen. Lower total RT dose and dose per implant and greater serum PSA level were associated with an increasing percentage of needle cores with residual post-RT adenocarcinoma. Lower RT dose, an increasing percentage of pre-RT needle cores with adenocarcinoma, and a greater serum PSA level were associated with an increasing percentage of post-RT needle cores with no to moderate RT effect scores in adenocarcinoma. The mean percentage of pre-RT and post-RT needle cores with adenocarcinoma was greater in patients with post-RT biopsy specimens with no to moderate RT effect. The percentage of pre-RT needle cores with adenocarcinoma (a surrogate marker of adenocarcinoma volume), serum PSA level, and RT dose are the key components in the dose-response relationship. Gleason score and gland volume did not contribute significantly to this relationship.