Phenomenological modeling of tumor diameter growth based on a mixed effects model

Over the last few years, taking advantage of the linear kinetics of the tumor growth during the steady-state phase, tumor diameter-based rather than tumor volume-based models have been developed for the phenomenological modeling of tumor growth. In this study, we propose a new tumor diameter growth model characterizing early, late and steady-state treatment effects. Model parameters consist of growth rhythms, growth delays and time constants and are meaningful for biologists. Biological experiments provide in vivo longitudinal data. The latter are analyzed using a mixed effects model based on the new diameter growth function, to take into account inter-mouse variability and treatment factors. The relevance of the tumor growth mixed model is firstly assessed by analyzing the effects of three therapeutic strategies for cancer treatment (radiotherapy, concomitant radiochemotherapy and photodynamic therapy) administered on mice. Then, effects of the radiochemotherapy treatment duration are estimated within the mixed model. The results highlight the model suitability for analyzing therapeutic efficiency, comparing treatment responses and optimizing, when used in combination with optimal experiment design, anti-cancer treatment modalities.     

Treatment of low malignancy brain neoplasms by means of stereotactic interstitial radiotherapy

The authors report their results of 37 patients with low malignancy brain tumors seated in deep or highly functional areas not amenable to traditional surgery, nor to conventional radiochemotherapy. In the past 5 years these patients were treated by means of stereotactic interstitial radiotherapy. The isotope employed in all cases was 125I. Stereotactic radioisotope implants were always preceded by multiple stereotactic biopsies affording precise histological diagnoses. A 6-month to 5-year follow-up shows a survival rate of 72.6% (29 patients), and of these patients, 80.9% (26 out of 29) had complete social reentry.     

Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial

Purpose

Dendritic cell (DC)-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard postoperative radiochemotherapy are studied in 77 patients with newly diagnosed glioblastoma.

Patients and methods

Autologous DC are generated after leukapheresis, which is performed before the start of radiochemotherapy. Four weekly induction vaccines are administered after the 6-week course of concomitant radiochemotherapy. During maintenance chemotherapy, 4 boost vaccines are given. Feasibility and progression-free survival (PFS) at 6?months (6mo-PFS) are the primary end points. Overall survival (OS) and immune profiling, rather than monitoring, as assessed in patients’ blood samples, are the secondary end points. Analysis has been done on intent-to-treat basis.

Results

The treatment was feasible without major toxicity. The 6mo-PFS was 70.1?% from inclusion. Median OS was 18.3?months. Outcome improved significantly with lower EORTC RPA classification. Median OS was 39.7, 18.3, and 10.7?months for RPA classes III, IV, and V, respectively. Patients with a methylated MGMT promoter had significantly better PFS (p?=?0.0027) and OS (p?=?0.0082) as compared to patients with an unmethylated status. Exploratory “immunological profiles” were built to compare to clinical outcome, but no statistical significant evidence was found for these profiles to predict clinical outcome.

Conclusion

Full integration of autologous DC-based tumor vaccination into standard postoperative radiochemotherapy for newly diagnosed glioblastoma seems safe and possibly beneficial. These results were used to power the currently running phase IIb randomized clinical trial.     

Biological basis of radiochemotherapy

The tumor biological and radiobiological aspects, the mechanism of actions and general considerations of clinical application of radiochemotherapy are discussed. The aims of radiochemotherapy are to prolong the patient's survival by improving local tumor control and decreasing distant metastases. The goal of radiochemotherapy is to enhance the therapeutic effect of radiation with tolerable and controllable local and systemic side effects. The mechanism of action of the most frequently used drugs are also discussed.     

Valeur pronostique de la TEP au F-FDG dans le bilan d’extension initial du cancer de l’œsophage traité par radiochimiothérapie exclusive

The aim of this retrospective study was to investigate the prognostic significance of initial FDG-PET in patients with newly diagnosed oesophageal carcinoma before exclusive radiochemotherapy. FDG-PET was performed in 29 patients with newly diagnosed oesophageal carcinoma before radiochemotherapy. Maximum standardized uptake value (SUV_max) was determined in each primary lesion and the presence of one or more PET-positive lymph nodes was recorded. Primary tumour volume and tumour length were assessed using two different thresholds for tumour delimitation: SUV = 2.5 and SUV = 40% of SUV_max. Patients were followed clinically during at least 1 year after initial FDG-PET. The median follow-up was 35 months (IC 95% = 26-41 months). Thirteen patients (45%) died during the follow-up. By univariate logistic regression analysis, the SUV_max of primary tumour and the presence of one or more positive lymph nodes were significantly associated with the overall survival. In contrast, no significant difference of prognosis was observed concerning age, sex, tumour cell type, primary site, clinical stage, primary tumour volume and length. Multivariate analysis was not performed due to the too small number of events. FDG-PET provides early prognostic informations in oesophageal carcinoma treated by radiochemotherapy.     

Additive Damage Models for Cellular Pharmacodynamics of Radiation–Chemotherapy Combinations

Many cancer patients receive combination treatments with radiation and chemotherapy. Available mathematical models for cellular pharmacodynamics have limited ability to represent observed in vitro responses to radiochemotherapy. Here, a family of additive damage models is proposed to describe cell kill resulting from radiochemotherapy with fixed schedule and variable doses. The pathways by which the agents produce cellular damage are assumed to converge in a single cell death process, so that survival depends on total damage, which can be represented as a sum of contributions from the various damage pathways. Heterogeneity in response across the cell population is ascribed to variations in the damage threshold for cell kill. The family of proposed models includes effects of one or two pathways of damage for each agent, saturation in drug responses, and cooperative or antagonistic interactions between agents. Models from this family with 4–7 unknown parameters are tested for their ability to fit 218 in vitro literature data sets for a range of drugs and cell lines. Overall, the additive damage models are found to outperform models based on the existing concept of independent cell kill, according to the corrected Akaike Information Criterion. The results are used to assess the importance of the various effects included in the models. These additive damage models have potential applications to the optimization of treatment and to the analysis and interpretation of in vitro screening data for new drug–radiation combinations.     

Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant treatment

One of the major prognostic factors in rectal cancer is lymph node metastasis. The formation of lymph node metastases is dependent on the existence of a premetastatic niche. An important factor preceding metastasis are lymph vessels which are located in the lymph node. Accordingly, the occurrence of intranodal lymphangiogenesis is thought to indicate distant metastasis and worse prognosis. To evaluate the significance of lymph node lymphangiogenesis, we studied formalin fixed, paraffin embedded adenocarcinomas and regional lymph nodes of 203 rectal cancer patients who were treated with neoadjuvant radiochemotherapy and consecutive curative surgery with cancer free surgical margins (R0). Regional lymph node lymph vessels were detected by immunohistochemistry for podoplanin (D2-40). Our results show that the presence of lymphatic vessels in regional lymph nodes significantly affects the disease-free survival in univariate and multivariate analyses. In contrast, there was no correlation between peritumoral or intratumoral lymph vessel density and prognosis. Indeed, our study demonstrates the importance of lymphangiogenesis in regional lymph nodes after neoadjuvant radiochemotherapy and consecutive surgery as an independent prognostic marker. Staining for intranodal lymphangiogenesis and methods of intravital imaging of lymphangiogenesis and lymphatic flow may be a useful strategy to predict long-term outcome in rectal cancer patients. Furthermore, addition of VEGF-blocking agents to standardized neoadjuvant treatment schemes might be indicated in advanced rectal cancer.     

Parents' age at birth of their offspring and child survival

This study presents some new results on parental age as a risk factor for child survival. The study is based on individual registration forms for live births and infant deaths collected in Hungary from 1984 to 1988. Logistic regression models have been fitted for early neonatal and neonatal mortality on the one hand, and post-neonatal mortality on the other hand. Children of older males and females have significantly higher early neonatal and neonatal mortality rates compared to those of younger males and females. The impact of age of both parents remains, however, slighter than that of other biological characteristics such as previous number of fetal deaths, induced abortions, or live births. The authors discuss possible biological explanations.     

Influence of energy metabolism on the repair of X-ray damage in living cells

Summary Effects of the glucose antimetabolite, 2-deoxy-D-glucose (2DG) on liquid-holding reactivation (LHR) in X-irradiated yeast cells were studied. It has been observed that LHR in respiratory-deficient mutants is completely inhibited at a molar concentration ratio 2DG/glucose equal to 1, whereas for the wild-type this ratio is 10. Significance of these results for a radiochemotherapy of tumors is discussed.Dedicated to Prof. Dr. Dr. h. c. mult. B. Rajewsky on the occasion of his 80th birthday.     

Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation

To analyze the effects of radiochemotherapy on the pro-oxidative/antioxidative balance in plasma, we measured the total radical antioxidant parameter of plasma (TRAP) and single plasma antioxidants (uric acid, sulfhydryl groups, alpha-tocopherol, ubiquinone-10/total coenzyme-Q10 ratio, ascorbate, and bilirubin) every 12 h during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation (BMT). Nontransferrin-bound iron (NTBI) was monitored as a potential pro-oxidant. Plasma levels of polyunsaturated fatty acids (PUFA) were measured as substrates, and thiobarbituric acid-reactive substances (TBARS) were measured as products of lipid peroxidation. Allantoin was analyzed as the product of uric acid oxidation. Patients receiving busulfan, VP-16, and cyclophosphamide (BU/VP/CY) (n = 8) were compared with those receiving total body irradiation in addition to VP-16 and cyclophosphamide (TBI/VP/CY) (n = 8). TRAP values were within the normal range before therapy and decreased after BU/VP/CY by 37% (p <. 02) and after TBI/VP/CY by 39% (p <.02). During TBI and after VP-16, a temporary increase in TRAP values occurred, which was not related to changes in individual antioxidants. In vitro experiments confirmed that VP-16 had an antioxidative effect. The concentration of uric acid declined in both groups and correlated with TRAP (BU/VP/CY: r =.80, p <.001; TBI/VP/CY: r =.84, p <.001). Levels of NTBI, which is normally not found in plasma, increased rapidly during conditioning therapy (p <.02 in both groups) and correlated inversely with TRAP (weighted intraindividual Spearman rank correlation coefficient for both groups: NTBI and TRAP: r = -.59, p <.001) and PUFA (in the radiochemotherapy group: r = -.67, p <.001). Whereas PUFA declined (p <.02 in both groups), TBARS increased (p <. 05 in both groups). Furthermore, an increase of allantoin and ubiquinone-10/total coenzyme-Q10 ratio in the BU/VP/CY group was found (allantoin: p <.02; ubiquinone-10/total coenzyme-Q10 ratio: p <.05). Antioxidants only partially recovered to baseline values until day 14 after BMT. Our findings indicate oxidative stress after high-dose radiochemotherapy and suggest a contribution of NTBI therein.     

Current treatment of rectal cancer adapted to the individual patient

Preoperative radiochemotherapy and total mesorectal excision surgery is a recommended standard therapy for patients with locally advanced rectal cancer. However, some subgroups of patients benefit more than others from this approach. In order to avoid long-term complications of radiation and chemotherapy, efforts are being made to subdivide T3N0 stage using advanced imaging techniques, and to analyze prognostic factors that help to define subgroup risk patients. Long-course radiochemotherapy has the potential of downsizing the tumor before surgery and may increase the chance of sphincter preservation in some patients. Short-course radiotherapy (SCRT), on the other hand, is a practical schedule that better suits patients with intermediated risk tumors, located far from the anal margin. SCRT is also increasingly being used among patients with disseminated disease, before resection of the rectal tumor. Improvements in radiation technique, such as keeping the irradiation target below S2/S3 junction, and the use of IMRT, can reduce the toxicity associated with radiation, specially long-term small bowel toxicity.     

Invasion as target for therapy of glioblastoma multiforme

The survival of cancer patients suffering from glioblastoma multiforme is limited to just a few months even after treatment with the most advanced techniques. The indefinable borders of glioblastoma cell infiltration into the surrounding healthy tissue prevent complete surgical removal. In addition, genetic mutations, epigenetic modifications and microenvironmental heterogeneity cause resistance to radio- and chemotherapy altogether resulting in a hardly to overcome therapeutic scenario. Therefore, the development of efficient therapeutic strategies to combat these tumors requires a better knowledge of genetic and proteomic alterations as well as the infiltrative behavior of glioblastoma cells and how this can be targeted. Among many cell surface receptors, members of the integrin family are known to regulate glioblastoma cell invasion in concert with extracellular matrix degrading proteases. While preclinical and early clinical trials suggested specific integrin targeting as a promising therapeutic approach, clinical trials failed to deliver improved cure rates up to now. Little is known about glioblastoma cell motility, but switches in invasion modes and adaption to specific microenvironmental cues as a consequence of treatment may maintain tumor cell resistance to therapy. Thus, understanding the molecular basis of integrin and protease function for glioblastoma cell invasion in the context of radiochemotherapy is a pressing issue and may be beneficial for the design of efficient therapeutic approaches. This review article summarizes the latest findings on integrins and extracellular matrix in glioblastoma and adds some perspective thoughts on how this knowledge might be exploited for optimized multimodal therapy approaches.     

Art Comes to Life in a Steel Mill Town

In this article, the authors investigate how Korea's current educational policy's emphasis on artistic expression, and therefore music education, has been realized in the praxis of early childhood education. The authors view policy as discourses and texts that early childhood educators interpret and reinterpret within specific contexts. Policy rhetoric and practice fail to recognize the integration of musical conceptual development, expressive ability, creativity, and communication. The musical development of a child should be viewed as his or her right to nurture a musical self in a meaningful musical context.     

Early- and late-emerging Drosophila melanogaster fruit flies differ in their sensitivity to light during morning and evening

The authors derived early and late populations of fruit flies showing increased incidence of emergence during morning or evening hours by imposing selection for timing of emergence under 12:12 h light/dark (LD) cycles. From previous studies, it was clear that the increased incidence of adult emergence during morning and evening hours in early and late populations was a result of evolution of divergent and characteristic emergence waveforms in these populations. Such characteristic waveforms are henceforth referred to as "evolved emergence waveforms" (EEWs). The early and late populations also evolved different circadian clocks, which is evident from the divergence in their clock period (τ) and photic phase response curve (PRC). Although correlation between emergence waveforms and clock properties suggests functional significance of circadian clocks, τ and PRCs do not satisfactorily explain the early and late emergence phenotypes. In order to understand the functional significance of the PRC for early and late emergence phenotypes, the authors investigated whether circadian clocks of these flies exhibit any difference in photosensitivity under entrained conditions. Such differences would suggest that the light requirement for circadian entrainment of the emergence rhythm in early and late populations is different. To test this, they examined if early and late flies differ in their light utilization behavior, first by assaying their emergence rhythm under complete photoperiod and then in three different skeleton photoperiods. The results showed that early and late populations require different durations of light during the morning and evening to achieve their EEWs, suggesting that for the circadian entrainment of the emergence rhythm, early and late flies utilize light from different parts of the day.     

Evaluation of the findings of computed tomography of the lungs in patients with nonspecific pneumothorax in late periods after surgical treatment

By using the results of examination of 54 patients operated on for nonspecific spontaneous pneumothorax (NSP), the authors conclude that X-ray computed tomography (CT) is of high value. In addition to external respiratory function that identifies pulmonary functional changes, it is recommended that a comprehensive examination should include X-ray CT with parenchymal densitometry of the upper, middle and lower lung to reveal lung tissue structural changes. The examination of patients should be performed as soon as possible when the disease is detected and in the late postoperative period for early surgical correction of an emphysematous process in the lung.     

Quantitative Susceptibility Mapping Differentiates between Blood Depositions and Calcifications in Patients with Glioblastoma

Objectives

The application of susceptibility weighted imaging (SWI) in brain tumor imaging is mainly used to assess tumor-related “susceptibility based signals” (SBS). The origin of SBS in glioblastoma is still unknown, potentially representing calcifications or blood depositions. Reliable differentiation between both entities may be important to evaluate treatment response and to identify glioblastoma with oligodendroglial components that are supposed to present calcifications. Since calcifications and blood deposits are difficult to differentiate using conventional MRI, we investigated whether a new post-processing approach, quantitative susceptibility mapping (QSM), is able to distinguish between both entities reliably.

Materials and Methods

SWI, FLAIR, and T1-w images were acquired from 46 patients with glioblastoma (14 newly diagnosed, 24 treated with radiochemotherapy, 8 treated with radiochemotherapy and additional anti-angiogenic medication). Susceptibility maps were calculated from SWI data. All glioblastoma were evaluated for the appearance of hypointense or hyperintense correlates of SBS on the susceptibility maps.

Results

43 of 46 glioblastoma presented only hyperintense intratumoral SBS on susceptibility maps, indicating blood deposits. Additional hypointense correlates of tumor-related SBS on susceptibility maps, indicating calcification, were identified in 2 patients being treated with radiochemotherapy and in one patient being treated with additional anti-angiogenic medication. Histopathologic reports revealed an oligodendroglial component in one patient that presented calcifications on susceptibility maps.

Conclusions

QSM provides a quantitative, local MRI contrast, which reliably differentiates between blood deposits and calcifications. Thus, quantitative susceptibility mapping appears promising to identify rare variants of glioblastoma with oligodendroglial components non-invasively and may allow monitoring the role of calcification in the context of different therapy regimes.     

Medical abortion: what does the research tell us?

Dr. Ellen R. Wiebe''s study of the use of methotrexate and misoprostol in combination for early termination of intrauterine pregnancy (see pages 165 to 170 of this issue) is the first Canadian study of the use of this drug combination for medical abortion. The authors compare Wiebe''s findings with those of earlier studies on methotrexate and misoprostol, as well as with European findings on the use of mifepristone with prostaglandins. The authors argue that although the methotrexate-misoprostol combination appears to be reasonably safe for the woman, the failure rate and the teratogenicity of methotrexate and misoprosol give cause for concern. The authors conclude that medical abortions ought to be offered only where there is adequate access to laboratory and surgical facilities and where losses to follow-up are systematically minimized to reduce the potential for continued pregnancy resulting in congenital abnormality.     

The x-ray morphological characteristics of the early manifestations of sarcoidosis

The paper is devoted to an analysis of combined x-ray findings supplemented by CT findings in patients with sarcoidosis detected for the first time with early signs of this disease. A conclusion has been made that apart from lymph node enlargement, sarcoidosis is characterized by lung parenchymal changes which manifest themselves as symptoms of broncho-alveolitis. Characteristic x-ray symptom complexes are described. Roentgeno-semiotics of these changes were compared with the results of morphological investigation of transbronchial puncture specimens. Roentgenologically detectable changes showed good correlation with morphology findings. The authors have also emphasized the importance of morphological verification of this disease at early stages.     

原发不育症子宫内膜花生凝集素受体的研究

本文以PNA(花生凝集素)为探针,应用ABC亲和组化技术,对69例原发不育症患者的子宫内膜PNA受体进行了检测.结果表明,原发不育症子宫内膜的增生期、分泌期PNA受体的阳性率均显著低于年龄相似、有生育史的对照组子宫内膜的阳性率.不育症子宫内膜分泌欠佳的PNA受体阳性率显著低于不育症分泌期不同时期子宫内膜的阳性率.提示,这种差异可能与雌孕激素对两组子宫内膜作用水平的不同引起.     

Serve and return: Communication foundations for early childhood music policy stakeholders

ABSTRACT

Serve-and-return interactions between a young child and caregiver are cited as integral to healthy child development and language development. In this article, the authors assert that serve-and-return interactions offer a relevant model for policy development in early childhood music education. They share contemporary evidence that music learning and development begins in the womb, continues during infancy, and needs to be prioritized in preschool and early elementary years. Next, they trace the policy landscape for early childhood education and music education in the United States since 2008. Although the landscape has remained stark, the authors offer recent glimmers of possibilities and conclude with actionable steps for improving early childhood music education policies.