Lysophosphatidic acid receptor 1 (LPA1) antagonists as potential migrastatics for triple negative breast cancer.

Metastasis is responsible for about 90% of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA1) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compound 12f, the most potent and highly selective in this series with an IC50 value of 16.0 nM in the cAMP assay and 18.4 nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBC cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA1 as a migrastatic target. Consequently, the LPA1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC.

Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2.

AIM: Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. METHODS: Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. KEY FINDINGS: Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin-C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SIGNIFICANCE: DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.

The efficacy and safety of vibrating capsules for functional constipation: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Chronic constipation is a challenging functional gastrointestinal disorder that remains a global burden. Pharmacologic therapy, including laxatives and dietary fibers, are suggested as lines of treatment. Recent trials introduced an orally ingested vibrating capsule (VC) as an eligible option for chronic constipation management. METHODS: We conducted a literature search in English on electronic databases CENTRAL, PubMed, EMBASE, Scopus, and WOS until February 27th, 2023. RevMan was used to perform the meta-analysis. The results were reported as risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs). The study protocol was registered in PROSPERO with ID: (CRD42023409422). RESULTS: Three RCTs with a total of 601 patients were included in our analysis. There was no difference between the VC and placebo in responder rate (RR: 1.37 with 95% CI [0.82, 2.28], p = .22), CSBM change from baseline (MD: 0.21 with 95% CI [-0.26, 0.69], p = .38), SBM change from baseline (MD: 0.14 with 95% CI [-0.22, 0.49], p = .46), and the incidence of any adverse event (RR: 1.45 with a 95% CI of [0.79, 2.63], p = .23). However, VC was associated with increased vibration sensation (RR: 17.23, 95% CI [3.29, 90.20], p = .0008). CONCLUSIONS: VC was not effective to improve bowel movement in patients with functional constipation with no difference in response rate. However, evidence is still uncertain, with only three small RCTs that yielded heterogenous findings, mainly due to the different vibration protocols. Also, our findings suggest that VC is safe and well-tolerated, with no significant harmful effects observed. Therefore, more large-scale RCTs are needed to confirm the efficacy and safety of VC in patients with functional constipation, determining the most effective dose, frequency, and duration of treatment.

Simultaneous Bilateral Patellar Tendon Rupture: A Systematic Review.

The extensor mechanism of the knee can be damaged due to various modes of injury, which, in most cases, will require urgent surgical intervention for repair. Single patellar tendon ruptures are uncommon, but simultaneous bilateral events are even rarer and have been scarcely reviewed in English literature. Research in this area is mainly confined to case series, with some literature reviews but no evidence of more substantial analysis. Therefore, this systematic review was done to analyse the existing literature on bilateral simultaneous patellar tendon ruptures and propose a systematic and standardised approach to diagnosing and managing these injuries. A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The search terms included 'bilateral patellar tendon rupture', 'bilateral', 'patellar', 'tendon' and 'rupture'. Three independent reviewers conducted searches in PubMed, OvidSP for Medline, Embase and the Cochrane Library using the same search strategy. The eligibility criteria included studies on bilateral concomitant patellar tendon rupture published in English. Bilateral simultaneous patellar tendon ruptures of traumatic and atraumatic origin in human patients were included. The study types comprised case reports and literature reviews. The key limitation of this study was the low number of patients covered by the eligible literature. Patellar tendon ruptures are a rare and scarcely documented injury, and there is a need for studies with a high level of evidence, especially regarding surgical treatment choice and methods, as well as post-operative management, which could potentially lead to improved outcomes in the management of this injury.

The potential curative and hepatoprotective effects of platelet rich plasma on liver fibrosis in Schistosoma mansoni experimentally infected mice.

Trapped Schistosoma mansoni eggs trigger fibrotic liver disease that can continue to liver cirrhosis and failure. This work evaluates the outcome of platelet rich plasma (PRP) on S. mansoni-induced liver fibrosis by intraperitoneal (IP) and intrahepatic (IH) routes with/without Praziquantel (PZQ) treatment. Swiss albino mice (n = 162) were divided into non-infected (n = 66) and infected (n = 96) groups, then subdivided into non-treated and treated subgroups with PRP(IP), PRP(IH) 6th and 10th weeks post-infection, PZQ, PZQ + PRP(IP) and PZQ + PRP(IH) 6th and 10th weeks post-infection. Effects of treatments were evaluated by parasitological, histopathological and Immunohistochemical assessments. In the early assessment (12th week post-infection) of infected-treated groups, the mean granuloma number showed significant reduction in groups treated with PZQ + PRP (IH) 10th week, PRP (IP), PZQ + PRP (IP) and PZQ + PRP (IH) 6th week (33.33%, 33%, 27.77% and 27.22%, respectively). Furthermore, the mean granuloma diameter showed significant reduction in groups treated with PRP (IH) 10th week and PZQ + PRP (IP) (24.17% and 15.5%, respectively). Also, the fibrotic index showed significant reduction in groups treated with PZQ + PRP (IP), PRP (IP) and PZQ + PRP (IH) 6th week (48.18%, 46.81% and 41.36%, respectively). Transforming growth factor ß1(TGF-ß1) expression was in correlation with parasitological and histopathological results. Diminished TGF-ß1 expression was mostly in infected groups treated with PZQ + PRP (IP), PZQ + PRP (IH) 6th week and PRP (IP) (88.63%, 88.63% and 77.27%, respectively). In the late assessment (14th week post-infection) of infected treated groups, TGF-ß1expression was reduced in groups treated with PZQ, PRP (IH) 10th weeks, PRP (IP) (83.33%, 66.66%, 33.33% respectively). PRP showed promising anti-fibrotic effects on S. mansoni-induced liver fibrosis.

The outcomes of a low-cost, non-valved glaucoma drainage device using mitomycin-C: 1-year results.

PURPOSE: To evaluate the indications, outcomes, and complications of the usage of Aurolab Aqueous Drainage Implant (AADI) using mitomycin-C. METHODS: A retrospective case series of patients who underwent AADI placement using mitomycin-C between April 2018 and June 2020 at Ain Shams University Hospitals, Cairo, Egypt. The data was extracted from the records of the patients with a minimum of 1 year of follow-up. Complete success was defined as IOP ≥ 5 mmHg and ≤ 21 mmHg or reduction of IOP by ≥ 20% from baseline without antiglaucoma medications (AGMs). Qualified success was defined as reaching the same IOP range with the aid of AGM. RESULTS: A total of 50 eyes of 48 patients were included. Neovascular glaucoma represented the commonest indication (13 patients, 26%). The mean preoperative IOP was 34.0 ± 7.1 mmHg, with a median number of AGM of 3 (mean ± SD = 2.84 ± 1), while the mean IOP after 12 months was 14.3 ± 4 with a median number of AGM of 0. (mean ± SD = 0.52 ± 0.89) (p < 0.001). Complete success was achieved in 33 patients (66%). Qualified success was achieved in 14 patients (28%). Thirteen eyes (26%) had variable postoperative complications; none of them required explantation of the device or affected the visual acuity (except one patient). CONCLUSION: AADI with using mitomycin-C and ripcord during the surgery is an effective and relatively safe method of control of IOP in refractory and advanced cases of glaucoma, with an overall success rate of 94%.

Ameliorative potential role of Rosmarinus officinalis extract on toxicity induced by etoposide in male albino rats.

The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.

Atypical Teratoid Rhabdoid Tumors (ATRT): King Faisal Specialist Hospital and Research Centre experience.

BACKGROUND: Atypical teratoid rhabdoid tumor is an uncommon aggressive central nervous system tumor. All retrospective series have shown a short mean overall survival rate. Considering the rarity of the disease, few prospective clinical trials addressed treatment recommendations for such aggressive tumors, and consequently no definitive treatment guidelines have been established. In this study, we are reviewing our experience in treating atypical teratoid rhabdoid tumor patients. METHODS: We reviewed the medical charts of 43 patients with atypical teratoid rhabdoid tumor who were treated in King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, between 1996 and 2013. We evaluated the overall survival rate and the influence of different clinical features and treatment protocols on survival. RESULTS: The median overall survival time was 16.9 months (95% Confidence Interval, 5.2-32.9 months) with an estimated 2- and 5-year overall survival of 41.9% ± 9.6 and 27.9% ± 9.2, respectively. Patients receiving trimodal treatment (surgery, chemotherapy, and radiotherapy) exhibited significantly better median overall survival time compared to their counterparts (P value < .001). CONCLUSIONS: Atypical teratoid rhabdoid tumor is rare and aggressive central nervous system tumor. Despite the limitations of the study, our results support several of clinical practice development. Utilization of postoperative radiotherapy and the adoption of trimodal therapy are associated with significant improvement of median survival. Prompt management with aggressive trimodal therapy should be the standard for future treatment protocols.

The radiotherapy utilization rate in pediatric tumors: An analysis of 13,305 patients.

PURPOSE: Although the radiotherapy utilization rate (RUR) is determined for most adult cancers, it is seldom reported in childhood tumors, particularly in low- and middle-income countries (LMIC) where the majority of pediatric cancer patients reside. This study aims to investigate the real-life RUR for pediatric tumors in a large LMIC center. MATERIALS AND METHODS: The electronic files of patients treated at a single institution during 2010-2017 were reviewed and the RUR was defined as the percentage of patients who received at least one radiotherapy (RT) course from the total number of patients. RESULTS: A total of 4390 out of 13,305 pediatric cancer patients received at least one RT course with a RUR of 33%. The curative, salvage, and palliative RURs were 27.8%, 2%, and 5.7%, respectively. There was a considerable variation in the RUR between various tumors, ranging from 0% in choroid plexus papilloma and other rare tumors to 100% in intracranial germinoma. Moreover, the RUR varied among different stages within each tumor type. Overall, 753 patients received 920 palliative RT courses (range 1-9) at a median dose of 30 Gy. The most commonly irradiated metastatic sites were the bone (34%) and the brain (9.8%). CONCLUSION: This is the first analysis to provide valuable insights into the RUR for childhood tumors. Together with population-based pediatric cancer registries, this will help decipher pediatric RT needs and deficits. Additionally, the underutilization of palliative RT calls for multidisciplinary palliative care provision for pediatric cancer patients.

Pediatric low grade focal brainstem glioma: outcomes of different treatment strategies and prognostic factors.

Background: This study explores the prognostic factors and outcomes of different treatment modalities in focal brain stem glioma (FBSG). Materials & methods: Pediatric FBSG patients diagnosed during 2010-2017 were retrospectively reviewed for clinical and therapeutic data. Results: A total of 71 cases were identified and the median age was 6.4 years. The 5-year overall- and progression-free survival were 74.5 and 70.6%, respectively. Radiotherapy was the main line of treatment (66.2%) and there were no survival differences between radiotherapy, chemotherapy and surveillance groups. Two independent poor prognostic factors were identified on multivariate analysis: age <8 years and cervicomedullary tumor site (p = 0.02 for both). Conclusion: Surveillance, radiotherapy and chemotherapy have comparable clinical outcomes in pediatric FBSG.

Is economic status the main determinant of radiation therapy availability? The Arab world as an example of developing countries.

BACKGROUND AND PURPOSE: Arab countries share a common location, history, language and culture with different economic characteristics. In this study, we analyze the availability and factors influencing radiotherapy services and cancer mortality incidence ratio (MIR) in Arabic countries. MATERIALS AND METHODS: Data were collected from GLOBOCAN report, World Health Organization, World Bank, United Nation and Directory of Radiotherapy Centre databases. RESULTS: The average number of megavoltage machines (MVM) in Arab countries is 0.84 machine per 1000 cancer patients. The number of MVM per 1000 cancer patients was found to be significantly correlated with gross domestic product (GDP) per capita (r = 0.583, P = 0.006). In addition, it was found to be significantly more in politically stable countries compared to unstable ones (P = 0.004) and more in high and upper-middle income countries (median 0.94 ±â€¯1.0) compared to lower-middle and low income countries (median 0.3 ±â€¯0.51) (P = 0.013). MIR was found to be significantly correlated with GDP per capita, physicians per 1000 population, MVM per 1000 cancer patients and absolute MVM deficit (r = -0.555, -0.625, -0.42, -0.436 and P = 0.009, 0.006, 0.047, 0.043, respectively). On multivariate regression analysis, the number of physicians per 1000 population had the strongest prediction of MIR in Arabic countries (P = 0.01). CONCLUSION: Although the economic status is of paramount importance, it is not the only factor determining the quantity and quality of radiotherapy services in the Arab world. More efforts are urgently needed to improve the status of radiation oncology and fill its gap in the Arab countries.

Volumetric-modulated arc therapy (VMAT) versus 3D-conformal radiation therapy in supra-diaphragmatic Hodgkin's Lymphoma with mediastinal involvement: A dosimetric comparison.

PURPOSE: To compare volumetric-modulated arc therapy (VMAT) with 3D-conformal radiation therapy (3D-CRT) mediastinal irradiation for stage I-II supra-diaphragmatic Hodgkin's Lymphoma (HL). PATIENTS AND METHODS: Eleven patients were planned for RT after 4-6 cycles of ABVD chemotherapy: conventional 3D-CRT (AP/PA) and VMAT plans were conformed to the same PTV. Objective was to choose the best PTV coverage plan with the least OAR dose. The 2 plans were compared for: PTV coverage, mean dose and V5,V20lung, mean dose and V30heart, V5, V10, V15breast (female patients), and the integral body dose. RESULTS: Both techniques achieved adequate PTV coverage. Mean lung and heart dose was consistently lower in VMAT plans. The lung V20 dose was acceptable for VMAT, but exceeded the tolerance threshold in 6 cases with 3DCRT plans. A mean difference of 15.9% for both lungs V20 favored VMAT plans; average MLD difference was 2.3Gy less for VMAT plans. Similarly, lower maximum and mean heart doses with a 3.3Gy dose reduction and a 9.4% difference in V30 favored VMAT plans. Mean V5lung/female breast and integral dose were invariably higher in VMAT plans because of the low-dose spread. CONCLUSIONS: VMAT is a valuable technique for treatment of large mediastinal HL. VMAT spares the lung and heart compared to 3DCRT using ISRT in select HL cases. VMAT allows dose escalation for post-chemotherapy residual disease with minimal dose to OARs. VMAT low radiation dose (V5) to the normal tissues, and the increased integral dose should be considered.

I Hear You Eat and Speak: Automatic Recognition of Eating Condition and Food Type, Use-Cases, and Impact on ASR Performance.

We propose a new recognition task in the area of computational paralinguistics: automatic recognition of eating conditions in speech, i. e., whether people are eating while speaking, and what they are eating. To this end, we introduce the audio-visual iHEARu-EAT database featuring 1.6 k utterances of 30 subjects (mean age: 26.1 years, standard deviation: 2.66 years, gender balanced, German speakers), six types of food (Apple, Nectarine, Banana, Haribo Smurfs, Biscuit, and Crisps), and read as well as spontaneous speech, which is made publicly available for research purposes. We start with demonstrating that for automatic speech recognition (ASR), it pays off to know whether speakers are eating or not. We also propose automatic classification both by brute-forcing of low-level acoustic features as well as higher-level features related to intelligibility, obtained from an Automatic Speech Recogniser. Prediction of the eating condition was performed with a Support Vector Machine (SVM) classifier employed in a leave-one-speaker-out evaluation framework. Results show that the binary prediction of eating condition (i. e., eating or not eating) can be easily solved independently of the speaking condition; the obtained average recalls are all above 90%. Low-level acoustic features provide the best performance on spontaneous speech, which reaches up to 62.3% average recall for multi-way classification of the eating condition, i. e., discriminating the six types of food, as well as not eating. The early fusion of features related to intelligibility with the brute-forced acoustic feature set improves the performance on read speech, reaching a 66.4% average recall for the multi-way classification task. Analysing features and classifier errors leads to a suitable ordinal scale for eating conditions, on which automatic regression can be performed with up to 56.2% determination coefficient.

Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial.

BACKGROUND: The pediatric diffuse intrinsic pontine glioma (DIPG) outcome remains dismal despite multiple therapeutic attempts. PURPOSE: To compare the results of treatment of pediatric diffuse intrinsic pontine glioma (DIPG) using hypofractionated versus conventional radiotherapy. PATIENTS AND METHODS: Seventy-one newly diagnosed DIPG children were randomized into hypofractionated (HF) (39Gy/13 fractions in 2.6weeks) and conventional (CF) arm (54Gy/30 fractions in 6weeks). RESULTS: The median and one-year overall survival (OS) was 7.8months and 36.4±8.2% for the hypofractionated arm, and 9.5 and 26.2±7.4% for the conventional arm respectively. The 18-month OS difference was 2.2%. The OS hazard ratio (HR) was 1.14 (95% CI: 0.70-1.89) (p=0.59). The hypofractionated arm had a median and one-year progression-free survival (PFS) of 6.6months and 22.5±7.1%, compared to 7.3 and 17.9±7.1% for the conventional arm. The PFS HR was 1.10 (95% CI: 0.67-1.90) (p=0.71). The 18-month PFS difference was 1.1%. These differences exceed the non-inferiority margin. The immediate and delayed side effects were not different in the 2 arms. CONCLUSIONS: Hypofractionated radiotherapy offers lesser burden on the patients, their families and the treating departments, with nearly comparable results to conventional fractionation, though not fulfilling the non-inferiority assumption.

Cone beam CT for organs motion evaluation in pediatric abdominal neuroblastoma.

BACKGROUND AND PURPOSE: To quantify the organ motion relative to bone in different breathing states in pediatric neuroblastoma using cone beam CT (CBCT) for better definition of the planning margins during abdominal IMRT. METHODS AND MATERIALS: Forty-two datasets of kV CBCT for 9 pediatric patients with abdominal neuroblastoma treated with IMRT were evaluated. Organs positions on planning CT scan were considered the reference position against which organs and target motions were evaluated. The position of the kidneys and the liver was assessed in all scans. The target movement was evaluated in four patients who were treated for gross residual disease. RESULTS: The mean age of the patients was 4.1 ± 1.6 years. The range of target movement in the craniocaudal direction (CC) was 5mm. In the CC direction, the range of movement was 10mm for the right kidney, and 8mm for the left kidney. Similarly, the liver upper edge range of motion was 11 mm while the lower edge range of motion was 13 mm. CONCLUSIONS: With the use of daily CBCT we may be able to reduce the PTV margin. If CBCT is not used daily, a wider margin is needed.

Intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer: a dose-escalation planning study.

PURPOSE: To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). METHODS AND MATERIALS: For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). RESULTS: IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. CONCLUSION: In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT.

Stereotactic radiosurgery and radiotherapy in benign intracranial meningioma.

PURPOSE: To investigate the role of stereotactic radio surgery (SRS) and hypo-fractionated stereotactic radiotherapy (SRT) in treatment of benign intracranial meningioma. PATIENTS AND METHODS: Between 2003 and 2010, 32 patients with a median age of 44 years (range 21-67 years) were treated with SRS (n=19), and hypo-fractionated SRT (n=13) for intracranial meningioma. Fourteen patients underwent SRS or SRT as their primary treatment, while 18 patients underwent post operative SRS or SRT (PORT). Cumulative progression free survival, overall cumulative survival, toxicity and symptomatology were evaluated. RESULTS: The median follow up period was 39 months (range 6-72 months). The 5 year overall survival and progression free survival were 90 ± 5% and 94 ± 4% after SRT or SRS respectively. Symptoms were improved or stable in 94% of patients. Acute toxicity was mild, and was seen in 41% of patients. Clinically significant late morbidity or new cranial nerve palsies did not occur. CONCLUSION: Stereotactic radio surgery (SRS) and hypo-fractionated stereotactic radiotherapy (SRT) are effective and safe treatment modality for local control of meningioma with low risk of significant late toxicity. In case of large tumor size and adjacent critical structures, hypo-fractionated SRT is highly recommended.

Trimodality treatment for bladder cancer: does modern radiotherapy improve the end results?

With the advancement in endoscopic surgery, radiation treatment planning and execution, as well as the use of new chemotherapeutic regimens, bladder conservation has evolved into a competing alternative to radical cystectomy. Trimodality treatment has the great advantage of preserving a normally functioning urinary bladder. Despite the absence of direct randomized trials comparing both modalities, trimodality treatment comprising maximal transuretheral resection of bladder tumors followed by different regimens of combined radiochemotherapy achieved comparable results to radical cystectomy in many trials. Those who did not achieve complete remission after induction radiochemotherapy were salvaged by radical cystectomy. Improving the radiotherapeutic window is a challenging issue. In radiotherapy for bladder cancer, uncertainties include set-up errors, patient movement, internal organ movement and volume changes due to bladder filling (both inter- and intrafraction). The advancement in treatment verification procedures in modern radiotherapy and the use of fiducial markers reduces set-up errors, while adaptive radiotherapy could decrease the unnecessary irradiation of normal tissues by tracking bladder volume changes. In addition, new radiotherapeutic techniques, such as intensity-modulated radiotherapy and volume-modulated radiotherapy, permit dose escalation to the target without increasing the dose to the surrounding normal tissues.

A randomized controlled trial to assess the safety and efficacy of silymarin on symptoms, signs and biomarkers of acute hepatitis.

PURPOSE: Milk thistle or its purified extract, silymarin (Silybum marianum), is widely used in treating acute or chronic hepatitis. Although silymarin is hepatoprotective in animal experiments and some human hepatotoxic exposures, its efficacy in ameliorating the symptoms of acute clinical hepatitis remains inconclusive. In this study, our purpose was to determine whether silymarin improves symptoms, signs and laboratory test results in patients with acute clinical hepatitis, regardless of etiology. METHODS: This is a randomized, placebo-controlled trial in which participants, treating physicians and data management staff were blinded to treatment group. The study was conducted at two fever hospitals in Tanta and Banha, Egypt where patients with symptoms compatible with acute clinical hepatitis and serum alanine aminotransferase (ALT) levels >2.5 times the upper limit of normal were enrolled. The intervention consisted of three times daily ingestion of either a standard recommended dose of 140 mg of silymarin (Legalon, MADAUS GmbH, Cologne, Germany), or a vitamin placebo for four weeks with an additional four-week follow-up. The primary outcomes were symptoms and signs of acute hepatitis and results of liver function tests on days 2, 4 and 7 and weeks 2, 4, and 8. Side-effects and adverse events were ascertained by self-report. RESULTS: From July 2003 through October 2005, 105 eligible patients were enrolled after providing informed consent. No adverse events were noted and both silymarin and placebo were well tolerated. Patients randomized to the silymarin group had quicker resolution of symptoms related to biliary retention: dark urine (p=0.013), jaundice (p=0.02) and scleral icterus (p=0.043). There was a reduction in indirect bilirubin among those assigned to silymarin (p=0.012), but other variables including direct bilirubin, ALT and aspartate aminotransferase (AST) were not significantly reduced. CONCLUSIONS: Patients receiving silymarin had earlier improvement in subjective and clinical markers of biliary excretion. Despite a modest sample size and multiple etiologies for acute clinical hepatitis, our results suggest that standard recommended doses of silymarin are safe and may be potentially effective in improving symptoms of acute clinical hepatitis despite lack of a detectable effect on biomarkers of the underlying hepatocellular inflammatory process.

Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma.

BACKGROUND AND PURPOSE: In this study on PDR treatment planning of utero-vaginal carcinoma, we analysed the dosimetry of traditional X-ray based plans as it presents on MR images. The potential gain of MRI-based dose optimisation was assessed. PATIENTS AND METHODS: Sixteen patients boosted with PDR brachytherapy after external beam therapy were included. The clinical X-ray based plans were projected on MR images. The GTV, HR-CTV and IR-CTV were retrospectively contoured, as well as the bladder, rectum and sigmoid colon. The dose in the critical organs and target coverage was investigated. In a second phase, the plans were manually optimised using the MR information. The objectives were to lower the dose in the critical organs (or= 85 Gy(alphabeta10). RESULTS: In the X-ray based plans, D(2cc) in bladder and sigmoid colon exceeded the tolerance doses in 10/16 and 7/16 patients, respectively. Coverage of the IR-CTV with the 60 Gy(alphabeta10) was acceptable. D90 of the HR-CTV was below 85 Gy(alphabeta10) in 13 out of 16 patients. After optimisation, the dose constraints in the OAR were not exceeded anymore in any patient. The average D(2cc) dose reduction was 7+/-6 Gy(alphabeta3) in the bladder and 7+/-4 Gy(alphabeta3) in the sigmoid colon for those patients in which the dose constraint was initially exceeded. In addition, an average dose increase of 3 Gy(alphabeta10) was accomplished in the HR-CTV. CONCLUSIONS: MRI-based dose optimisation can play an important role to reduce the dose delivered to the critical organs and to improve target coverage.