Osteosarcomas of the mandible: multidisciplinary management of a rare tumor of the young adult a cooperative study of the GSF-GETO, Rare Cancer Network, GETTEC/REFCOR and SFCE.

BACKGROUND: Mandibular osteosarcomas (MOS) mostly affect young adults. Their treatment is extrapolated from that of extragnathic osteosarcomas. MATERIAL AND METHODS: A retrospective multicooperative group study was conducted to determine the impact of chemotherapy, adjuvant radiation therapy and surgery on outcomes and to identify prognostic factors. This ethical committee-approved study included a centralized review of histology slides and operative reports. RESULTS: Of 111 patients, 58.6% were male, median age 35 years (13%, ≤18 years). Histology was osteoblastic, chondroblastic, fibroblastic, conventional not otherwise specified and others in 39.6%, 30.6%, 8.1%, 12.6% and 8.0%, respectively. Pathological World Health Organisation grades were low, intermediate and high grade in 6.4%, 11.8% and 81.8%, respectively. Surgery was carried out for 94.5% of patients. Neoadjuvant chemotherapy (mixed protocols) was carried out in 93.1% of patients. Postoperative chemotherapy and radiotherapy were carried out in 54.7% and 23.8%, respectively. Median follow-up was 59.6 months (range). Five-year local control, metastasis-free, disease-free and overall survival rates were 64.6%, 68.9%, 53.2% and 69.2%, respectively. Survival was significantly associated with age, tumor size and surgery. Wide surgery with clear margins and free flap reconstruction was the strongest prognostic factor. Neoadjuvant chemotherapy improved disease-free and metastatic-free survival and increased clear margins rates from 50% to 68%. Intermediate grades behaved like high grades in terms of metastatic-free and disease-free survival. CONCLUSION: This homogeneous series is the largest to date and emphasizes the major impact of clear margins and multidisciplinary management. Neoadjuvant chemotherapy improves disease-free survival and should be recommended for both high and intermediate grade MOS.

Esophageal self-expandable stent material and mesh grid density are the major determining factors of external beam radiation dose perturbation: results from a phantom model.

BACKGROUND: Self-expandable esophageal stents are increasingly used for palliation or as an adjunct to chemoradiation for esophageal neoplasia. The optimal esophageal stent design and material to minimize dose perturbation with external beam radiation are unknown. We sought to quantify the deviation from intended radiation dose as a function of stent material and mesh density design. METHODS: A laboratory dosimetric film model was used to quantify perturbation of intended radiation dose among 16 different esophageal stents with varying material and stent mesh density design. RESULTS: Radiation dose enhancement due to stent backscatter ranged from 0 % to 7.3 %, collectively representing a standard difference from the intended mean radiation dose of 1.9 (95 % confidence interval [CI] 1.5 - 2.2). This enhancement was negligible for polymer-based stents and approached 0 % for the biodegradable stents. In contrast, all metal alloy stents had significant radiation backscatter; this was largely determined by the density of mesh design and not by the type of alloy used. CONCLUSIONS: Stent characteristics should be considered when selecting the optimal stent for treatment and palliation of malignant esophageal strictures, especially when adjuvant or neo-adjuvant radiotherapy is planned.

Overall survival and self-reported fatigue in patients with esophageal cancer.

PURPOSE: A prospective cohort study was conducted to analyze whether self-reported fatigue predicts overall survival in patients with esophageal cancer. METHODS: Patients enrolled in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry between September 2001 and January 2009 who completed a baseline quality of life instrument were eligible for evaluation. The fatigue component was scored on a 0-10 scale, with 0 as extreme fatigue. Patients were categorized as having a decreased energy level if they reported a score of ≤ 5. Fatigue scores ≥ 6 reflect normal levels of energy. RESULTS: Data from a total of 659 enrolled patients were analyzed. A total of 392 (59 %) and 267 (41 %) patients reported decreased and normal energy, respectively. Univariate analysis indicates patients with normal energy had improved 5-year survival compared to patients with decreased energy (37 vs 28 %, hazard ratio (HR) 0.74, p = 0.006). Among the patients with locally advanced disease, the same relationship was seen (28 vs 17 %, HR = 0.67, p = 0.003); this remained significant on multivariate analysis (HR = 0.71, p = 0.015). CONCLUSIONS: A decreased energy level is associated with poor survival in patients with esophageal cancer. Thus, patients with high levels of fatigue should be referred for psychological support and be considered for therapy aimed at amelioration of fatigue symptoms.

The Effect of Body Mass Index and Residence in Food Priority Areas on Patterns-of-Care and Cancer Outcomes in Patients With Stage III Non-Small Cell Lung Cancer.

PURPOSE: Patients living in food priority areas (FPAs), where access to healthy meals is challenging, may be at greater risk of nutritional deficits, leading to poorer cancer outcomes. Currently, there are no published data analyzing how FPAs affect patterns-of-care or outcomes for patients with locally advanced non-small cell lung cancer (NSCLC). We aimed to analyze the effect of residing in an FPA on treatments rendered and cancer outcomes in patients with stage III NSCLC treated at a single institution. METHODS AND MATERIALS: This is a retrospective study of 573 patients with locally advanced NSCLC consecutively treated from January 2000 to January 2020. χ2 and Mann-Whitney U tests were performed to determine differences between select variables. Kaplan-Meier analysis and Cox proportional hazard models were used to analyze overall survival (OS) and freedom from recurrence. Cox regression with forward model selection was used for multivariate analysis. RESULTS: Thirty-two percent of patients resided in an FPA (n = 183) and were more likely to self-identify as Black (P < .0001), single (P < .001), <60 years of age (P = .001), and uninsured (P < .0001), with a lower median income (P < .001). Patients in FPAs also had lower mean pre-chemoradiation (CRT) albumin (P = .002), lower pre-CRT body mass index (BMI) (P = .026), and were less likely to receive trimodality therapy (P ≤ .001) compared with patients not living in FPAs. There was no difference in OS or freedom from recurrence between the 2 cohorts. However, in patients with a normal BMI, either pre-CRT (median OS, 18.4 vs 25.0 months; P = .005) or after CRT (15.1 vs 28.1 months, P = .002), residing in an FPA resulted in an OS detriment. CONCLUSIONS: We demonstrated a clear socioeconomic divide in our patient population with stage III NSCLC, where residing in FPAs was associated with less-aggressive therapy and an OS detriment for patients with a normal-weight BMI. We are currently conducting a prospective study characterizing the nutritional needs of patients, particularly those who live in FPAs.

Treatment results and prognostic factors in primary thyroid lymphoma patients: a rare cancer network study.

BACKGROUND: this study analyzed prognostic factors and treatment outcomes of primary thyroid lymphoma. PATIENTS AND METHODS: data were retrospectively collected for 87 patients (53 stage I and 34 stage II) with median age 65 years. Fifty-two patients were treated with single modality (31 with chemotherapy alone and 21 with radiotherapy alone) and 35 with combined modality treatment. Median follow-up was 51 months. RESULTS: sixty patients had aggressive lymphoma and 27 had indolent lymphoma. The 5- and 10-year overall survival (OS) rates were 74% and 71%, respectively, and the disease-free survival (DFS) rates were 68% and 64%. Univariate analysis revealed that age, tumor size, stage, lymph node involvement, B symptoms, and treatment modality were prognostic factors for OS, DFS, and local control (LC). Patients with thyroiditis had significantly better LC rates. In multivariate analysis, OS was influenced by age, B symptoms, lymph node involvement, and tumor size, whereas DFS and LC were influenced by B symptoms and tumor size. Compared with single modality treatment, patients treated with combined modality had better 5-year OS, DFS, and LC. CONCLUSIONS: combined modality leads to an excellent prognosis for patients with aggressive lymphoma but does not improve OS and LC in patients with indolent lymphoma.

Small cell carcinoma of the esophagus: a multicentre Rare Cancer Network study.

Small cell carcinoma of the esophagus (SCCE) is a rare and aggressive malignant tumor with a poor prognosis. The aims of this retrospective study were to analyze the epidemiology, clinical characteristics, and treatment outcomes of these patients. Between 1994 and 2004, 24 patients with SCCE from several centers were reviewed for data on demographics, presenting symptoms, diagnosis, disease stage, type of treatment, and outcome. SCCE occurs in the sixth decade: median age (interquartile range [IQR]): 65 (59-69) years with a male predominance (63%). The most common complaining symptoms were rapidly progressive dysphagia (79%), weight loss (54%), and retrosternal/epigastric pain (46%). The tumor arises primarily in the middle (52%) or in the lower (35%) third of the esophagus. History of tobacco and alcohol exposure was present in 90% and 70% of case, respectively. Extensive disease was present in 13 cases (54%) at initial diagnosis. The overall median survival (IQR) was 11 (8-20) months for all 24 patients, and the 2-year overall survival was 25.1%. Four patients were alive more than 2 years after treatment. Chemotherapy increased the survival compared with symptomatic management in extensive disease (median survival [IQR]: 9.5 [6-14] vs. 6 [4-7] months, P= 0.05). In limited disease, concurrent chemo-radiotherapy was more effective than non-concurrent treatment (median survival [IQR]: 36 [14-93] vs. 11 [9-15] months, P= 0.04). Two patients were treated by surgery and chemoradiation therapy with a survival of 35 and 66 months. Chemotherapy is the cornerstone of treatment of SCCE in all stage. For limited disease SCCE, concurrent chemo-radiotherapy is the primary choice compared with sequential approach. The role of surgery was not assessable in our study.

Secretion of a bacterial cellulase by yeast.

Gene fusions were constructed between a yeast expression plasmid and a Cellulomonas fimi DNA fragment encoding an endo-1,4-beta-D-glucanase or carboxymethylcellulase. Yeast transformed with the recombinant plasmids secreted carboxymethylcellulase activity. Secretion of active enzyme was greatly increased when the leader of a secreted yeast protein, the Kl toxin, was inserted immediately upstream of and in frame with the bacterial cellulase sequence. This is the first step in constructing a functional cellulase complex in Saccharomyces cerevisiae. It also provides an excellent system for the detailed examination of the determinants of protein secretion because of the ease with which secreted cellulase can be detected.

Impact of endoscopic ultrasonography and physician specialty on the management of patients with esophagus cancer.

While endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) are the most accurate techniques for locoregional staging of esophageal cancer, little evidence exists that these innovations impact on clinical care. The objective on this study was to determine the frequency with which EUS and EUS-FNA alter the management of patients with localized esophageal cancer, and assess practice variation among specialists at a tertiary care center. Three gastroenterologists, three medical oncologists, three radiation oncologists and four thoracic surgeons were asked to independently report their management recommendations as the anonymized staging information of 50 prospectively enrolled patients from another study were sequentially disclosed on-line. Compared to initial management recommendations, that were based upon history, physical examination, upper endoscopy and CT scan results, EUS prompted a change in management 24% (95% CI: 12-36%) of the time; usually to a more resource-intensive approach (71%), for example from recommending palliation to recommending neoadjuvant chemoradiation therapy. EUS-FNA plus cytology results altered management an additional 8% (95% CI: 6-15%) of the time. Agreement between specialists ranged from fair (intraclass correlation [ICC=0.32) to substantial (ICC=0.65); improving with additional information. Among specialists, agreement was greatest for patients with stage I disease. EUS and EUS-FNA changed patient management the most for patients with stages IIA, IIB or III disease. EUS, with or without FNA, significantly impacts the management of patients with localized esophageal cancer. With respect to the optimal treatment for each patient, agreement among physicians incrementally increases with endoscopic ultrasound results. Specialty training appears to influence therapeutic decision-making behavior.

Treatment data and technical process challenges for practical big data efforts in radiation oncology.

The term Big Data has come to encompass a number of concepts and uses within medicine. This paper lays out the relevance and application of large collections of data in the radiation oncology community. We describe the potential importance and uses in clinical practice. The important concepts are then described and how they have been or could be implemented are discussed. Impediments to progress in the collection and use of sufficient quantities of data are also described. Finally, recommendations for how the community can move forward to achieve the potential of big data in radiation oncology are provided.

Small differences in Drosophila tropomyosin expression have significant effects on muscle function.

The effects of promoter deletions on Drosophila tropomyosin I (TmI) gene expression have been determined by measuring TmI RNA levels in transformed flies. Decreases in RNA levels have been correlated with rescue of flightless and jumpless mutant phenotypes in Ifm(3)3 mutant transformed flies and changes in muscle ultrastructure. The results of this analysis have allowed us to identify a region responsible for 20% of maximal TmI expression, estimate threshold levels of TmI RNA required for indirect flight and jump muscle function, and obtain evidence suggesting that sarcomere length may be an important determinant of flight muscle function.

Acute and long-term cytogenetic effects of childhood cancer chemotherapy and radiotherapy.

Approximately 30 banded karyotypes per subject from the lymphocytes of 66 childhood cancer patients and 14 noncancer control subjects have been analyzed in an attempt to gauge the late effects of anticancer chemotherapy and chemotherapy plus radiotherapy on the genetic material, i.e., the chromosomes. The frequencies (f) of aberrant cells were: f = 1/306 among cells from noncancer controls; f = 1/377 from cancer patients prior to therapy, f = 1/15 from patients currently on chemotherapy; and f = 1/32 from posttherapy patients (range, 3 months to 22 years poattherapy). The frequency of chromosomally aberrant cells did not appear to change with time among posttherapy patients, and the majority of aberrations detected in subjects from this group were balanced rearrangements. This was not the case for the on-therapy group where unbalanced rearrangements and unstable aberrations predominated.

Modification of sister chromatid exchanges and radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids.

Modification of sister chromatid exchanges and radiation-induced transformation in mouse C3H/10T 1/2 and Syrian hamster embryo cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, the trimethylmethoxyphenyl analog of N-ethyl retinamide and beta-all-trans-retinoic acid, has been studied. 12-O-tetradecanoylphorbol-13-acetate alone enhances, and retinoids alone reduce radiation-induced transformation. When both compounds were present, the retinoids not only reduced the oncogenic effects of radiation but completely eliminated the promoting effects of 12-O-tetradecanoylphorbol-13-acetate. These results were not paralleled by changes in sister chromatid exchange frequencies, indicating that, while sister chromatid exchanges may be useful as indicators of primary carcinogen mutagens, they may have little utility when secondary agents after the response of cells to a primary initiator.

Radiosensitivity of skin fibroblasts from atomic bomb survivors with and without breast cancer.

Fibroblasts were established in vitro from skin biopsies obtained from 55 women and 1 man with or without breast cancer and with or without exposure to radiation from the atomic bomb explosion in Hiroshima. The radiosensitivity of these cells was evaluated by clonogenic assays after exposure to X-rays or to fission neutrons from a 252Cf source. Data were fitted to a multitarget model, S/S0 = A [1 - (1 - ekD)N], for both X-ray and neutron dose-survival curves. A single hit model, S/S0 = AekD, fits the neutron dose-survival responses as well. There were no differences in the means or variances of radiosensitivity between exposed and nonexposed groups or between patients with or without breast cancer. Hence, although the sample is not large, it provides no support for the hypothesis that atomic bomb radiation preferentially induces breast cancer in women whose cells in vitro are sensitive to cell killing by radiation.

Long-term efficacy of intracoronary irradiation in inhibiting in-stent restenosis.

BACKGROUND: Intracoronary irradiation is a promising modality for inhibition of in-stent restenosis. Results of randomized clinical trials at 6 months after gamma ray irradiation are highly encouraging. The first results at 3 years after irradiation, while still showing benefit, have shown significant late loss. The probable mechanism of the radiation is to inactivate (prevent from dividing) most cells that otherwise could proliferate to produce neointimal formation. We measured the proportion of cells that survive with their clonogenic potential intact after the doses and dose rates used in the randomized trials, and we then modeled the subsequent repopulation of the surviving cells that might cause late restenosis. METHODS AND RESULTS: Human aortic smooth muscle cells were irradiated with gamma rays, including the doses and dose rates used in current trials, and clonogenic surviving fractions were measured. The subsequent repopulation of the surviving cells was modeled with the assumption that the repopulation kinetics were similar to those in unirradiated cells. The radiation is expected to delay the time to restenosis by factors of approximately 6 to 8, depending on the dose, shifting the delay from a median of 6 months (for no irradiation) to median values from 36 months (for a nominal 13 Gy) to 43 months (for a nominal 15 Gy). CONCLUSIONS: These results and predictions are quantitatively consistent with clinical results and suggest that clonogenic inactivation (prevention of cellular division) is the dominant mechanism of radiation action in the delay of restenosis. Intracoronary radiotherapy is a very promising modality for significantly delaying, although probably not preventing, in-stent restenosis.

Endothelins--from receptors to medicine.

Since the discovery of endothelins, peptides with exceptional vasoconstrictor potency that were originally suggested to act by causing the opening of Ca2+ channels, it has emerged that these agents are important in intercellular communication in many tissues. They exert their effects through G protein-coupled receptors, of which two classes have been cloned. Robert Miller, John Pelton and John Huggins review the progress made towards a molecular understanding of ligand recognition by endothelin receptors. Receptor-selective agonists and antagonists have emerged from attempts to understand the three-dimensional structure of the endothelin pharmacophore, from structure-activity studies and from rapid-screening programmes. From the nature of the secretion and action of endothelins, it would seem that these peptides are involved in long-term changes rather than in acute responses to stimuli, and that they are likely to be important in a number of pathological states. Evidence suggests that receptor antagonists with appropriate affinity and selectivity may be useful in the treatment of conditions as diverse as hypertension, ulcerogenesis and ciclosporin toxicity.

The structure and specificity of endothelin receptors: their importance in physiology and medicine.

In addition to involvement in vascular endothelium-smooth muscle communication, the secretion of and receptors for, endothelins are widely distributed. Two cloned receptor subtypes are G-protein-coupled to several intracellular messengers, predominantly inositol phosphates. From a knowledge of structure-activity relationships and peptide conformations, details of receptor architecture and selective agents, including nonpeptides and antagonists, have been discovered. From the nature of the actions of endothelins, receptor distributions (including CNS) and plasma levels, it is concluded that they are paracrine factors normally involved in long-term cellular regulation, but which may be important in several pathologies, many of which are stress-related.

Extensive microheterogeneity of serine tRNA genes from Drosophila melanogaster.

The nucleotide sequences of nine genes corresponding to tRNA(Ser)4 or tRNA(Ser)7 of Drosophila melanogaster were determined. Eight of the genes compose the major tRNA(Ser)4,7 cluster at 12DE on the X chromosome, while the other is from 23E on the left arm of chromosome 2. Among the eight X-linked genes, five different, interrelated, classes of sequence were found. Four of the eight genes correspond to tRNA(Ser)4 and tRNA(Ser)7 (which are 96% homologous), two appear to result from single crossovers between tRNA(Ser)4 and tRNA(Ser)7 genes, one is an apparent double crossover product, and the last differs from a tRNA(Ser)4 gene by a single C to T transition at position 50. The single autosomal gene corresponds to tRNA(Ser)7. Comparison of a pair of genes corresponding to tRNA(Ser)4 from D. melanogaster and Drosophila simulans showed that, while gene flanking sequences may diverge considerably by accumulation of point changes, gene sequences are maintained intact. Our data indicate that recombination occurs between non-allelic tRNA(Ser) genes, and suggest that at least some recombinational events may be intergenic conversions.

Crystallization and preliminary X-ray diffraction analysis of the catalytic domain of Cex, an exo-beta-1,4-glucanase and beta-1,4-xylanase from the bacterium Cellulomonas fimi.

Single crystals of the catalytic domain of Cex, an exo-beta-1,4-glucanase and beta-1,4-xylanase from the cellulolytic bacterium Cellulomonas fimi, have been grown in the presence of polyethylene glycol 4000 using the vapour diffusion technique. The crystals, which diffract to better than 2.0 A resolution, belong to space group P4(1)2(1)2 or P4(3)2(1)2 and have cell constants: a = b = 88.21 A, c = 81.10 A; alpha = beta = gamma = 90 degrees.

A Canadian high-energy neutron spectrometry system for measurements in space.

Bubble Technology Industries Inc. (BTI), with the support of the Canadian Space Agency, has finished the construction of the Canadian High-Energy Neutron Spectrometry System (CHENSS). This spectrometer is intended to measure the high energy neutron spectrum (approximately 1-100 MeV) encountered in spacecraft in low earth orbit. CHENSS is designed to fly aboard a US space shuttle and its scientific results should facilitate the prediction of neutron dose to astronauts in space from readings of different types of radiation dosimeters that are being used in various missions.

Morphological characterization of cultured bovine aortic endothelial cells and the effects of atriopeptin II and sodium nitroprusside on cellular and extracellular accumulation of cyclic GMP.

Primary, first and second passaged endothelial cells from bovine aorta were grown in plastic culture dishes or on glass coverslips. The cells were characterized by their monolayer cobblestone appearance at confluence, their immunofluorescent staining for factor VIII-related antigen, their specific uptake of low density lipoprotein and by their ultrastructure. Following stimulation of the cells by atriopeptin II or sodium nitroprusside, both cellular and extracellular cyclic GMP levels were measured. Cellular cyclic GMP content was increased greatly by atriopeptin II in a time-dependent manner while sodium nitroprusside was essentially without effect. Increases in tissue cyclic GMP levels were associated with a time-dependent accumulation of the nucleotide in the extracellular compartment. Zaprinast, a specific inhibitor of cyclic GMP phosphodiesterases, did not significantly affect either basal or atriopeptin II-stimulated increases in cyclic GMP content, nor extracellular accumulation of the nucleotide. It is concluded that the cyclic GMP content of endothelial cells is not solely dependent on degradation by phosphodiesterases but also involves release of cyclic GMP into the extracellular compartment.