Identifying patients suitable for targeted adjuvant therapy: advances in the field of developing biomarkers for tumor recurrence following irradiation.

Introduction: Radiation therapy (RT) is commonly used to treat cancer in conjunction with chemotherapy, immunotherapy, and targeted therapies. Despite the effectiveness of RT, tumor recurrence due to treatment resistance still lead to treatment failure. RT-specific biomarkers are currently lacking and remain challenging to investigate with existing data since, for many common malignancies, standard of care (SOC) paradigms involve the administration of RT in conjunction with other agents. Areas Covered: Established clinically relevant biomarkers are used in surveillance, as prognostic indicators, and sometimes for treatment planning; however, the inability to intercept early recurrence or predict upfront resistance to treatment remains a significant challenge that limits the selection of patients for adjuvant therapy. We discuss attempts at intercepting early failure. We examine biomarkers that have made it into the clinic where they are used for treatment monitoring and management alteration, and novel biomarkers that lead the field with targeted adjuvant therapy seeking to harness these. Expert Opinion: Given the growth of data correlating interventions with omic analysis toward identifying biomarkers of radiation resistance, more robust markers of recurrence that link to biology will increasingly be leveraged toward targeted adjuvant therapy to make a successful transition to the clinic in the coming years.

Prediction of Total-Body and Partial-Body Exposures to Radiation Using Plasma Proteomic Expression Profiles.

There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL/6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P < 0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use.

AI-Driven Image Analysis in Central Nervous System Tumors-Traditional Machine Learning, Deep Learning and Hybrid Models.

The interpretation of imaging in medicine in general and in oncology specifically remains problematic due to several limitations which include the need to incorporate detailed clinical history, patient and disease-specific history, clinical exam features, previous and ongoing treatment, and account for the dependency on reproducible human interpretation of multiple factors with incomplete data linkage. To standardize reporting, minimize bias, expedite management, and improve outcomes, the use of Artificial Intelligence (AI) has gained significant prominence in imaging analysis. In oncology, AI methods have as a result been explored in most cancer types with ongoing progress in employing AI towards imaging for oncology treatment, assessing treatment response, and understanding and communicating prognosis. Challenges remain with limited available data sets, variability in imaging changes over time augmented by a growing heterogeneity in analysis approaches. We review the imaging analysis workflow and examine how hand-crafted features also referred to as traditional Machine Learning (ML), Deep Learning (DL) approaches, and hybrid analyses, are being employed in AI-driven imaging analysis in central nervous system tumors. ML, DL, and hybrid approaches coexist, and their combination may produce superior results although data in this space is as yet novel, and conclusions and pitfalls have yet to be fully explored. We note the growing technical complexities that may become increasingly separated from the clinic and enforce the acute need for clinician engagement to guide progress and ensure that conclusions derived from AI-driven imaging analysis reflect that same level of scrutiny lent to other avenues of clinical research.

Towards effective machine learning in medical imaging analysis: A novel approach and expert evaluation of high-grade glioma 'ground truth' simulation on MRI.

PURPOSE/OBJECTIVE(S): Gliomas are uniformly fatal brain tumours with significant neurological and quality of life detriment to patients. Improvement in outcomes has remained largely unchanged in nearly 20 years. MRI (magnetic resonance imaging) is often used in diagnosis and management. Machine learning analyses of large-scale MRI data are pivotal in advancing the diagnosis, management and improve outcomes in neuro-oncology. A common challenge to robust machine learning approaches is the lack of large 'ground truth' datasets in supervised learning for building classification and prediction models. The creation of these datasets relies on human-expert input and is time-consuming and subjective error-prone, limiting effective machine learning applications. Simulation of mechanistic aspects such as geometry, location and physical properties of brain tumours can generate large-scale ground-truth datasets allowing for comparison of analysis techniques in clinical applications. We aimed to develop a transparent and convenient method for building 'ground truth' presentations of simulated glioma lesions on anatomical MRI. MATERIALS/METHODS: The simulation workflow was created using the Feature Manipulation Engine (FME®), a data integration platform specializing in the spatial data processing. By compiling and integrating FME's functions to read, integrate, transform, validate, save, and display MRI data, and experimenting with ways to manipulate the parameters concerning location, size, shape, and signal intensity with the presentations of glioma, we were able to generate simulated appearances of high-grade gliomas on gadolinium-based high-resolution 3D T1-weighted MRI (1 mm3). Data of patients with canonical high-grade tumours were used as real-world tumours for validating the accuracy of the simulation. Twenty raters who are experienced with brain tumour interpretation on MRI independently completed a survey, designed to distinguish simulated and real-world brain tumours. Sensitivity and specificity were calculated for assessing the performance of the approach with the binary classification of simulated vs real-world tumours. Correlation and regression were used in run time analysis, assessing the software toolset's efficiency in producing different numbers of simulated lesions. Differences in the group means were examined using the non-parametric Kruskal-Wallis test. RESULTS: The simulation method was developed as an interpretable and useful workflow for the easy creation of tumour simulations and incorporation into 3D MRI. A linear increase in the running time and memory usage was observed with an increasing number of generated lesions. The respondents' accuracy rate ranged between 33.3 and 83.3 %. The sensitivity and specificity were low for a human expert to differentiate simulated lesions from real gliomas (0.43 and 0.58) or vice versa (0.65 and 0.62). The mean scores ranking the real-world gliomas did not differ between the simulated and real tumours. CONCLUSION: The reliable and user-friendly software method can allow for robust simulation of high-grade glioma on MRI. Ongoing research efforts include optimizing the workflow for generating glioma datasets as well as adapting it to simulating additional MRI brain changes.

The addition of Valproic acid to concurrent radiation therapy and temozolomide improves patient outcome: a Correlative analysis of RTOG 0525, SEER and a Phase II NCI trial.

PURPOSE/OBJECTIVES: Valproic Acid (VPA) is an antiepileptic agent with HDACi (histone deacetylase inhibitor) activity shown to radiosensitize glioblastoma (GBM) cells. We evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in an open-label, phase II study (NCI-06-C-0112). The intent of the current study was to compare our patient outcomes with modern era standard of care data (RTOG 0525) and general population data (SEER 2006-2013). MATERIALS/METHODS: 37 patients with newly diagnosed GBM were treated in a phase II NCI trial with daily VPA (25 mg/kg) in addition to concurrent RT and TMZ (2006 - 2013) and 411 patients with newly diagnosed GBM were treated in the standard TMZ dose arm of RTOG 0525 (2006 - 2008). Using the SEER database, adult patients (age > 15) with diagnostic codes 9440-9443 (third edition (IDC-O-3) diagnosed between 2006 - 2013 were identified and 6083 were included in the analysis. Kaplan-Meier method was used to estimate OS and PFS. The effect of patient characteristics and clinical factors on OS and PFS was analyzed using univariate analysis and a Cox regression model. A landmark analysis was performed to correlate recurrence to OS and conditional probabilities of surviving an additional 12 months at diagnosis, 6, 12, 18, 24 and 30 months were calculated for both the trial data and the SEER data. RESULTS: Updated median OS in the NCI cohort was 30.9m (22.2- 65.6m), compared to RTOG 0525 18.9m (16.8-20.3m) (p= 0.007) and the SEER cohort of 11m. Median PFS in the NCI cohort was 11.1m (6.6 - 49.6m) compared to RTOG 0525 with a median PFS of 7.5m (6.9-8.2m) (p = 0.004). Younger age, class V RPA and MGMT status were significant for PFS in both the NCI cohort and the RTOG 0525 cohort, in addition KPS was also significant for OS. In comparison to RTOG 0525, the population in the NCI cohort had a more favorable KPS and RPA, and a higher proportion of patients receiving bevacizumab after protocol therapy however with the exception of RPA (V) (8% vs 18%) (0.026), the effects of these factors on PFS and OS were not significantly different between the two cohorts. CONCLUSION: Previously reported improvements in PFS and OS with the addition of VPA to concurrent RT and TMZ in the NCI phase II study were confirmed by comparison to both a trial population receiving standard of care (RTOG 0525) and a contemporary SEER cohort. These results provide further justification of a phase III trial of VPA/RT/TMZ.

The role of external Ca²âº in the action of Ca²âº-channel agonists and antagonists on isolated human thoracic arteries.

In systemic atherosclerosis develops the abnormal vascular tone which is associated with elevated calcium influx into smooth muscle cells and their calcification that may be proportional to the extent and severity of atherosclerotic disease. The goal of the present study was to investigate the responses of isolated human arterial samples to Ca²âº-channel agonists and antagonists by varying the external Ca²âº concentration. Two dihydropyridine type calcium-channel blockers, amlodipine and cerebrocrast, were used in this study. The benzodiazepine-type calcium-channel blocker diltiazem, the benzimidazole derivative 1-acetyl-5,6-dimethoxy-2-methylthiobenzimidazole and 3,4'-bipyridine derivative milrinone were also used. Experiments were carried out on isolated human thoracic artery samples obtained from 74 patients, aged 38-88 years, during conventional myocardial revascularisation operations. The contraction of artery samples was recorded using an iFOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10⁻7 to 10⁻4 M) were established by varying the external Ca²âº concentration from 0.9 mM to 2.7 mM. Cerebrocrast, regardless of the Ca²âº concentration significantly increased arterial contraction, particularly at the lower Ca²âº (≈77%). Diltiazem, the benzimidazole derivative and milrinone caused the artery samples to relax at 10⁻4 M concentrations by 55%, 55% and 44%, respectively, when the external Ca²âº corresponded to the physiological standard. Shifting to lower or higher Ca²âº concentrations significantly altered the response of vessel samples by increasing their contraction. In conclusion, the present study shows that the response of isolated human thoracic artery samples to both the slow calcium channel suppressant diltiazem and to agonists of that channel (milrinone and the benzimidazole derivative) is regulated by the amount of calcium present in the physiological solution. Treatment with a slow calcium channel inhibitor, the 1,4-dihydropyridine derivative cerebrocrast, resulted in a response that was independent of the external Ca²âº concentration.

Quality-of-life outcomes in high-risk prostate cancer patients treated with helical tomotherapy in a hypofractionated radiation schedule with long-term androgen suppression.

PURPOSE: We examined the impact of hypofractionated radiation therapy and androgen suppression therapy (AST) on quality of life (QOL) in high-risk prostate cancer patients. METHODS: Between March 2005 and March 2007, 60 patients with high-risk prostate cancer were enrolled in a prospective phase ii study. All patients received 68 Gy (2.72 Gy per fraction) to the prostate gland and 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes in 25 fractions over 5 weeks. Of the 60 patients, 58 received ast. The University of California-Los Angeles Prostate Cancer Index questionnaire was used to prospectively measure QOL at baseline (month 0) and at 1, 6, 12, 18, 24, 30, and 36 months after radiation treatment. The generalized estimating equation approach was used to compare the QOL scores at 1, 6, 12, 18, 24, 30, and 36 months with those at baseline. RESULTS: We observed a significant decrease in QOL items related to bowel and sexual function. Several QOL items related to bowel function were significantly adversely affected at both 1 and 6 months, with improvement toward 6 months. Although decreased QOL scores persisted beyond the 6-month mark, they began to re-approach baseline at the 18- to 24-month mark. Most sexual function items were significantly adversely affected at both 1 and 6 months, but the effects were not considered to be a problem by most patients. A complete return to baseline was not observed for either bowel or sexual function. Urinary function items remained largely unaffected, with overall urinary function being the only item adversely affected at 6 months, but not at 1 month. Urinary function returned to baseline and remained unimpaired from 18 months onwards. CONCLUSIONS: In our study population, who received hypofractionated radiation delivered using dynamic intensity-modulated radiotherapy with inclusion of the pelvic lymph nodes, and 2-3 years of ast prescription, QOL with respect to bowel and sexual function was significantly affected; QOL with respect to urinary function was largely unaffected. Our results are comparable to those in other published studies.

Distribution of hemoglobin phenotypes in four different districts of Porto Velho, Rondônia, Brazil.

Hemoglobin profile studies have been carried out in four samples from different districts of Porto Velho (Rondônia State) in the western Amazonian region of Brazil: Candelária, Bate Estaca, Hemeron (at the State Blood Bank), and São Carlos. Samples from 337 unrelated individuals were collected during medical and paramedical team visits by professionals from the Instituto de Pesquisa em Patologia Tropical and the Centro de Pesquisa em Patologias Tropicais (both research institutes in tropical diseases). The aim of this study is to assess the frequency of alleles in the hemoglobin system, mainly alleles HB*A, *S, and *E. The overall phenotype frequencies were HB A,S = 0.025, HB A,E = 0.006, and HB A,A = 0.969. Samples from the blood bank subjects and samples from the homogeneous areas of São Carlos and Candelária plus Bate Estaca have a chi-square of heterogeneity of 6.383 (p = 0.041) and 8.406 (p = 0.015), respectively. The allele frequencies (HB*A = 0.984, HB*S = 0.012, and HB*E = 0.003) do not significantly differ from frequencies found in other Brazilian regions.

3,4-trans-4-Aryl-3-(1-pyridinio)-1,2,3,4-tetrahydropyridine-6-thiolates--new group of potential cardiotonic drugs.

3,4-trans-4-Aryl-3-(1-pyridinio)-1,2,3,4-tetrahydropyridine-6-thiolates 6-11 were prepared by a Michael reaction of N-acetonylpyridinium chloride with 3-aryl-2-cyanothioacrylamides or by a one-pot three-carbon condensation of N-acetonylpyridinium chloride, aromatic aldehyde and 2-cyanothioacetamide, and their cardiotonic properties were studied. 3,4-trans-5-cyano-2-hydroxy-2-methyl-4-(3-nitrophenyl)-3-(1-pyridinio)-1,2,3,4-tetrahydropyridine-6-thiolate 8 was considered as a lead compound in this series since it in vitro experiments (spontaneously beating rat atria) showed a cardiotonic activity similar to that of milrinone 2, however compound 8 induced activity at lover concentrations and without influence on chronotropic action of the heart. Unlike milrinone 2, thiolate 8 in vivo experiments (anaesthetized rats) did not influence blood pressure and heart rate. The acute toxicity of compound 8 was more than 10 times lower than that of milrinone 2.

[High risk acute lymphoblastic leukaemia in children. Preliminary report after introducing a new version of New York (1997) protocol adjusted to the age of the patients. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Ostra bialaczka limfoblastyczna u dzieci w grupie duzego ryzyka. Wstepne obserwacje po wprowadzeniu kolejnej modyfikacji (1997) protokolu Nowy York dostosowanej do wieku. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczki i Chloniaków.

The paper presents the experience of the Polish Paediatric Leukaemia/Lymphoma Study Group in the treatment of high-risk acute lymphoblastic leukaemia in children using a new version of the New York (1997-1999). Protocol with treatment intensity adjusted according to the age of the patients. From April 1997 to December 1999 a group of 49 children with leukocytosis ranging from 50 900/mm3 to 580 000/mm3 (median 122 000/mm3) and 6 children with leukocytosis below 50 000/mm3 and poor response to steroids were treated with this protocol. Children below 10 years (43 patients) were treated according to the previous protocol, children above 10 years (12 patients) were treated with intensified protocol (high doses of ARA-C in consolidation and intermediate doses of Mtx in maintenance). Induction was identical for all patients. Complete remission was achieved in 92.6% patients. There were 2 relapses. Six children died - 3 without remission, 2 due to a relapse, 1 due to treatment complications. The current opinions concerning classification of HRG-ALL and treatment possibilities in this group of children are discussed.

[Results of treatment of children with chronic myelogenous leukaemia (CML) obtained by the Polish Paediatric Leukaemia/Lymphoma Study Group]. / Wyniki leczenia dzieci chorych na przewlekla bialaczke, szpikowa (CML) w materiale Polskiej Pediatrycznej Grupy ds Leczenia Bialaczek i Chloniaków u Dzieci.

Retrospective analysis of 102 children with CML from 9 paediatric centres in Poland has been performed. A total number of 102 children: 58 boys and 44 girls aged 1-17 years (median 9.4 years old) with CML, treated in the period 1975-1999 were included in the study. Forty eight of 102 (47.1 %) children were treated with cytostatic drugs without IFN alpha: busulfan, hydroxyurea, 6-mercaptopurine or etoposide (VP-16). Fifty four of 102 (52.9%) patients were treated with interferon alpha (IFN alpha) after cytoreductive pretreatment. Thirty out of 102 (29.4%) patients underwent stem cell transplantation (SCT): 24 - matched related donor allo-BMT, 2 - matched unrelated donor allo-BMT, 1 - partially matched related donor T-cell depleted allo-PBPCT, 1 - syngeneic allo-BMT and 2 - autologous PBPCT. Overall survival analysis revealed that 46 of the 102 (45.1%) children remained alive: 5/35 (14.3%) children treated with cytostatics alone, 22/37 (59.5%) children treated with IFN alpha and 19/30 (63.3%) children treated with SCT. Among SCT survivors there are 10/17 (58.8%) children treated with IFN alpha prior to SCT and 9/13 (69.2%) children treated with cytostatics alone prior to SCT. The probability of 5-year survival is 0.51 in the group treated with SCT (median follow-up 58 months); 0.43 in the group treated with IFN alpha (median follow-up 53 months) and 0.23 in the group treated with cytostatics (median follow-up 31 months). Our data show, that BMT is the treatment of choice in CML in children. IFN alpha could be successfully applied as an alternative treatment for those, who do not have a suitable donor for allogeneic SCT. Better outcome in post BMT children, who were not treated with IFN alpha prior to SCT requires confirmation by studies on larger groups of patients. However, it seems to be justified to stop IFN alpha therapy at least 3 months before SCT. The main reason for unsuccessful treatment outcome in patients with CML in Poland remains the still insufficient access to MUD-BMT.

[Treatment outcome for myelodysplastic syndromes (MDS) obtained by the Polish Children's Leukemia/Lymphoma Study Group]. / Wyniki leczenia zespolów mielodysplastycznych (MDS) uzyskane przez Polska Grupe ds Leczenia Bialaczek i Chloniaków u Dzieci.

Fourty children with MDS treated in seven centres of The Polish Children's Leukemia Lymphoma Study Group in period 1975-1998y were included to the study. In 16 children RAEB-T, in 2 CMML in 10 RA and in 12 RAEB were diagnosed. Our and literature data showed that BMT is the best therapy for children with MDS. For children, who don't have a donor for BMT. Roacutan therapy seems to be the most effective.

[How to improve the results of treatment of myelodysplastic syndromes in the studies of Polish pediatric leukemia/lymphoma group]. / Co zrobic dla poprawy wyników leczenia zespolów mielodysplastycznych w Polskiej Pediatrycznej Grupie ds. Leczenia Bialaczek i Chloniaków.

Fourty two children with myelodysplastic syndrome (MDS) treated in seven centres of The Polish Paediatric Leukaemia/Lymphoma Study Group in period 1975-1998 were included in the study. In 16 children RAEB-T, in 3 CMML, in 10 RA and in 13 RAEB were diagnosed. BMT is the best therapy for children with MDS. For children, who have not a donor for BMT, Roacutan therapy seems to be the most effective.

[The analysis of failures in the treatment of children with chronic myelocytic leukemia in the studies of Polish pediatric leukemia/ lymphoma group]. / Analiza niepowodzen w leczeniu dzieci chorych na przewlekla bialaczke szpikowa w materiale Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

94 children with chronic myelocytic leukaemia--CML treated in period 1975-1998 were included in the study. Twenty seven of 60 children were treated with hydroxyurea or busulfan with 6 MP. In 33 children aged 1, 5-17 years IFN (Interferon alfa) was applied at the dose of 3 millions units every second day subcutaneously. Our data showed that IFN alfa could be applied as an alternative treatment in children with CML, who have not a donor for allogenic BMT (bone marrow transplantation).

[Ototoxicity of drugs]. / Ototoksycznosc leków.

The paper included the most current information about the mechanisms of ototoxicity of five groups of the most popular drugs: a) antibiotics, b) chemotherapeutics (cytostatic) agents, c) loop diuretics, d) salicylate and nonsteroidal anti-inflammatory drugs, as well as e) progestagen contraceptives minimized or even prevented by thoughtful selection of drug, attention to risk factors and careful patient monitoring.

[Results of treating chronic myelogenous leukemia in children]. / Wyniki leczenia przewleklej bialaczki szpikowej u dzieci.

Retrospective analysis of the results of treatment chronic myeloid (CML) leukemia in 80 children was done. From among 72 children treated by conventional methods the probability of 10 years survival had 17%. Statistically significant better results was obtained in the group of children with adult than juvenile type of CML (23 and 8%). Allogenic bone marrow transplantation was performed in six children, two children were treated with interferon. New approaches of treatment may offer the better chance for constitution of normal bone marrow function.

Growth, bone age and nutritional status in neglected coeliac disease.

In 43 children with neglected coeliac disease (NCD) the growth and nutritional status (NS) were followed-up and analysed in the period between the age of 3 and 9 years in which prolonged exposure to gluten resulted in the persistent enteropathy. The significant "weight for age" and "height for age" deficits without concomitant "weight for height" deficits were observed at each yearly interval in the monitored period. The significant positive correlation between the percentage of children with the deficient NS and the duration of the exposure to gluten was found for the total examined period. There was also evidenced the significant bone age v. height age deficit. The linear growth retardation observed in NCD may be considered as the result of the progressive deficiency of NS.