Pediatric Nasopharyngeal Carcinoma: A Rare Tumor in a Developing Country-What Do We Learn?

BACKGROUND/AIM: Nasopharyngeal carcinoma (NPC) is rare in children, accounting for 1% of pediatric malignancies. The 5-fluorouracil Cisplatin regimen could be considered as a standard of care induction chemotherapy followed by concomitant chemoradiotherapy. This study aimed at detecting the survival outcome in correlation with different prognostic factors together with the toxicity of different treatment modalities. PATIENTS AND METHODS: This was a retrospective study carried out from 2007 to 2016 that included all NPC patients below 18 years treated at the National Cancer Institute, Egypt. RESULTS: A total of 21 patients were included with a median follow-up period of 33.9 months. The median age was 14.8 years (range: 9 to 18). All patients were treated by neoadjuvant chemotherapy with cisplatin and 5- fluorouracil, followed by concurrent radiotherapy (median dose: 61.2 Gy) and cisplatin as a radiosensitizer. After induction chemotherapy, the response rate was 53%. After completion of treatment, 67% had a complete response; partial response was seen in 14%; and progressive disease was seen in 19%. By the end of the study, 7 (33.3%) patients had progression/relapse; 4 of them died from disease. The 3-year overall survival and event-free survival were 85.7% and 66.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy was an effective strategy in the treatment of pediatric NPC with good overall survival and event-free survival. High systemic failure (33.3%) remains another challenge to solve. More efforts should be made to improve survival by developing more efficient systemic treatment modalities, especially for progressive/relapsed disease. Multicenter studies on a larger number of patients are needed to identify different prognostic factors and standardize treatment strategies.

Outcome and prognostic factors of pediatric patients with Hodgkin lymphoma: a single-center experience.

BACKGROUND: Hodgkin lymphoma (HL) is a highly curable malignant tumor. Risk-adapted treatment for children with HL aims to maximize survival while minimizing toxicity. The purpose of this study is to evaluate the outcome and prognostic characteristics of Egyptian pediatric HL patients treated at the National Cancer Institute (NCI), Cairo University. METHODS: All newly diagnosed cases of classic HL treated between January 2016 and December 2018 were included in this study. RESULTS: The median age at initial presentation was 8 years in 69 eligible individuals, with a male-to-female ratio of 4.7:1. Eighteen percent of patients had an elevated erythrocyte sedimentation rate (ESR) of more than 50, 42% had more than three lymph node (LN) group involvements, 18.8% had bulky disease, 52.2% were at an advanced stage, and 34% had B symptoms. Age > 15 years, B symptoms, > 3 LN group involvement, extra-nodal disease, and advanced stages significantly affected the overall survival rate (OS) (P-values = 0.03, 0.033, 0.008, 0.017, and 0.032). There was no statistically significant difference between patients who got combined modality therapy (CMT) and those who received chemotherapy alone (3-year OS and event-free survival (EFS) were 95.5% and 87.6% vs. 89.9% and 83.3%, P-values of 0.70 and 0.90). Patients with an interim-negative positron emission tomography-computed tomography (PET-CT) had a 3-year OS of 94.7%, compared to 74.1% in patients with an interim-positive PET-CT (P = 0.06), suggesting that rapid early response (RER) is a significant prognostic factor. There was no statistically significant survival difference between patients with a negative interim PET-CT who got CMT and those who received chemotherapy alone (3-year OS and EFS: 100% and 88.2% vs. 95% and 90%; P = 0.35 and 0.70, respectively). Three-year OS was 93.3% and 100%, and EFS was 74.3% and 100% (P = 0.495 and 0.196%) for those who got 15 Gy versus those who received 20 Gy or more, respectively. At the end of the study, the OS and EFS at 3 years for the whole group were 91.9% and 83.6%. CONCLUSION: Treatment with risk- and response-adaptive treatment should be the standard of care for treating pediatric patients with HL.

Design and synthesis of polyethylene glycol-modified biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.

Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.

Pediatric ependymoma: A single-center experience from a developing country.

BACKGROUND: Ependymomas are the third most common pediatric central nervous system (CNS) tumors, accounting for 6-12% of brain tumors in children. Management of these tumors remains challenging and recurrence occurs in over 50% of cases, mainly when complete resection is not achieved before radiotherapy. The 5-year overall survival (OS) ranges from 39 to 64%, with a 5-year progression-free survival (PFS) rate of 23-45%. The study aimed to describe the OS and PFS rates of cases of pediatric ependymoma. It also aimed to evaluate the effects of different variables on disease outcomes. Variables examined included patient age, the extent of surgical resection, radiotherapy and chemotherapy delivered, the histopathological subtype of the tumor, primary tumor location, and extent of the disease at presentation. Last, the challenges that potentially compromise treatment outcomes in resource-limited countries were to be highlighted. METHODS: This is a retrospective cohort study, representing a single-center experience that included 47 pediatric patients treated at the National Cancer Institute, Cairo University, between January 2009 and December 2014. RESULTS: Median follow-up stood at 23.5 months (range: 2-77 months). The average 3-year OS and PFS rates were 43.7 and 43.3%, respectively. CONCLUSION: The extent of surgical excision (maximal resection) and the adequacy of postoperative radiotherapy were the only two factors that had significantly affected the outcome. Understandably, treatment outcomes for ependymomas in developing countries still lag behind best reported outcomes, mainly due to inadequate surgical excision and postoperative radiotherapy.

Low-dose fractionated radiation with induction docetaxel and cisplatin followed by concurrent cisplatin and radiation therapy in locally advanced nasopharyngeal cancer: A randomized phase II-III trial.

OBJECTIVE/BACKGROUND: To evaluate the efficacy and outcome of adding low-dose fractionated radiotherapy (LDFRT) to induction chemotherapy plus concurrent chemoradiation in locally advanced nasopharyngeal carcinoma (LANPC). METHODS: A single-institute, phase II-III, prospectively controlled randomized clinical trial was performed at King Faisal Specialist Hospital and Research Centre. Patients aged 18-70 years with WHO type II and III, stage III-IVB nasopharyngeal carcinoma, Eastern Cooperative Oncology Group performance score of 0-2, with adequate hematological, renal, and hepatic function were eligible. In total, 108 patients were enrolled in this trial. All patients received two cycles of induction docetaxel and cisplatin (75 mg/m2 each) chemotherapy on Days 1 and 22, followed by concurrent chemoradiation therapy. Radiation therapy consisted of 70 Gy in 33 fractions, with concurrent cisplatin 25 mg/m2 for 4 days on Days 43 and 64. Patients were randomly assigned to either adding LDFRT (0.5 Gy twice daily 6 hours apart for 2 days) to induction chemotherapy in the experimental arm (54 patients) or induction chemotherapy alone in the control arm (54 patients). RESULTS: There was no significant difference in the post-induction response rates (RRs) or in toxicity between the two treatment arms. The 3-year overall survival (OS), locoregional control (LRC), and distant metastases-free survival (DMFS) rates for experimental arm and control arm were 94% versus 93% (p = .8), 84.8% versus 87.5% (p = .58), and 84.1% versus 91.6% (p = .25), respectively. CONCLUSION: The results showed no benefit from adding LDFRT to induction chemotherapy in terms of RR, OS, LRC, and DMFS.

Management and outcome of pediatric metastatic Wilms' tumor at the National Cancer Institute, Egypt.

BACKGROUND: Wilms' tumor (WT) is the most common renal malignant tumor of childhood. Metastatic WT has a worse prognosis than localized disease. This study aims to assess the clinical outcome and different prognostic factors that influence treatment outcome of pediatric metastatic WT cases treated at National Cancer Institute (NCI), Egypt, between January 2008 and December 2015. Medical records were retrospectively reviewed for clinical, radiological and histopathological data, treatment received, and survival outcome. RESULTS: In the specified study period, 24/103 (23.3%) patients with WT were metastatic at presentation. The mean age was 5.25 ± 2.87 years (range 2.0-12.7). Abdominal swelling/mass was the commonest presentation (70.8%). Only 3 patients (12.5%) had combined lung and liver metastases while 21 patients (87.5%) had pulmonary-only metastases. All patients had favorable histology tumors with no anaplasia. Nine patients (37.5%) underwent upfront nephrectomy. Majority of patients (91.7%) had local stage III disease. Surgical complications were reported in 4 patients; 3 of them had up-front nephrectomy. Only 7/21 patients achieved rapid complete response of pulmonary nodules after 6 weeks of chemotherapy (CTH), and they had a better survival outcome. Patients were followed up till December 2017. Thirteen patients (54.1%) experienced events during the study period including 5 relapses, 6 cases with disease progression, and 2 patients died out of sepsis. The 3-year event-free and overall survival rates were 48.2% and 54.2%, respectively. CONCLUSION: Neo-adjuvant CTH followed by delayed nephrectomy seems more suitable approach in our institute. Pulmonary response to neo-adjuvant CTH appears to be a strong predictor for outcome.

Endovascular treatment for spontaneous supraceliac isolated abdominal aortic dissection is a fabulous option. (Case report).

Aortic dissection originates from isolated tear in the abdominal aorta is rare but potentially life or limb-threatening condition particularly if misdiagnosed. It may have a number of clinical presentations with potentially serious adverse effects and should be considered in the differential diagnosis of any patient with an acute onset of abdominal pain radiating to the back and the buttocks together with presence or absence of a pulsatile abdominal mass, signs of limb ischemia, or discernible risk factors. Surgical and endovascular treatments are two valid options for these cases according to their clinical and anatomical considerations with acceptable results. We present a quite unusual case of a spontaneous supraceliac isolated abdominal aortic dissection with contained peri-aortic hematoma and manifesting as acute persistent abdominal pain. Better illustration of the natural history of this ill-defined pathology is needed to understand and improve patient care.

Biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.

Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.

Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients.

OBJECTIVES: To evaluate the clinical presentation and treatment end results of primary adenocarcinoma of the urinary bladder, and to determine the significant independent prognostic factors that determine this outcome. PATIENTS AND METHODS: Of 3659 patients who underwent cystectomy, 192 had adenocarcinoma of the urinary bladder, with a relative frequency of 5.2%. Most of these patients (68.2%) presented in late stages (P3 + P4). The incidence of pelvic lymph nodes involvement was 25.5%. Mucinous adenocarcinoma was reported in 28 patients (14.6%), papillary in 20 (10.4%), signet ring in 14 (7.3%), while not otherwise specified was reported in 130 (67.7%) in the cystectomy specimens. RESULTS: Mucinous and signet-ring histologic subtypes showed increased frequency of high stages and high grades, and more nodal involvement than the papillary and not otherwise specified. All patients were treated with radical cystectomy and pelvic lymphadenectomy with (69 patients) or without (123) postoperative radiotherapy. The 5-year disease-free survival rate was 46 +/- 4% for all patients with adenocarcinoma. Postoperative radiotherapy improved the disease-free survival significantly. The 5-year disease-free survival rate for the postoperative radiotherapy group was 61 +/- 6% compared to 37 +/- 5% for the cystectomy alone group (P = 0.002). Local control rate was significantly improved from 53 +/- 7% for cystectomy alone to 96 +/- 3% for postoperative radiotherapy patients (P = 0.00001). Distant metastases were the leading cause of death in the postoperative radiotherapy group. CONCLUSIONS: Within the limitations provided by retrospective studies, it could be concluded that postoperative radiotherapy improved the disease-free survival through its effect on local control. The disease-free survival independent prognostic variables were tumor stage, postoperative radiotherapy, nodal involvement, and adenocarcinoma subclassification. These factors, except the adeno-subclassification, were also found to determine the local control rate. On the other hand, the independent prognostic factors for distant metastasis were lymph nodal involvement, stage, and adeno-subclassification.

Hypofractionated Volumetric Modulated Arc Radiotherapy with simultaneous Elective Nodal Irradiation is feasible in prostate cancer patients: A single institution experience.

PURPOSE: To assess feasibility, toxicity and biochemical relapse-free survival (b-RFS) for a group of organ confined (OC) Saudi prostate cancer patients treated by hypo-fractionated Volumetric Modulated Arc Radiation Therapy (VMAT) Simultaneous Integrated Boost (SIB) Elective Nodal Irradiation (ENI) whole pelvic radiotherapy (WPRT). PATIENTS AND METHODS: Between March 2009 and January 2014, 29 OC prostate cancer patients; median age 64years, PS 0-1 were treated in King Faisal Specialist Hospital - Riyadh, Kingdom of Saudi Arabia using VMAT-SIB-ENI-WPRT, to a total dose of 70Gy in 28 fractions. Twenty Four patients (83%) were treated with neo-adjuvant; concurrent androgen deprivation therapy (ADT). Median follow-up (FU) was 42months (range: 18-72months). RESULTS: The 3-year actuarial b-RFS for low/intermediate and high risk groups were 100%, and 48%, respectively (p=0.09) with a median FU period of 34months (range: 14-53months). Gleason Score (p=0.02), and pretreatment PSA (p=0.01) were predictive for biochemical failure on univariate analysis; with no observed prostate cancer-related deaths. Grade 2 acute/late GI and GU toxicities were 28%/0% and 17%/10% respectively with no reported grade 3/4 toxicities. Four (50%) out of the 8 patients with baseline partial potency, retained sexual function on long term follow-up. CONCLUSIONS: Hypo-fractionation dose escalation VMAT-SIB-ENI-WPRT using 2 arcs is a feasible technique for intermediate/high risk OC prostate cancer patients, with acceptable rates of acute/late toxicities, much favorable planning target volume (PTV) coverage, and shorter overall treatment time. Prospective randomized controlled trials are encouraged to confirm its equivalence to other fractionation schemes.

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.

X-ray crystallographic studies of serotonin N-acetyltransferase catalysis and inhibition.

The structure of serotonin N-acetyltransferase (also known as arylalkylamine N-acetyltransferase; AANAT) bound to a potent bisubstrate analog inhibitor has been determined at 2.0 A resolution using a two-edge (Se, Br) multiwavelength anomalous diffraction (MAD) experiment. This acetyl-CoA dependent enzyme is a member of the GCN5-related family of N-acetyltransferases (GNATs), which share four conserved sequence motifs (A-D). In serotonin N-acetyltransferase, motif A adopts an alpha/beta conformation characteristic of the phylogenetically invariant cofactor binding site seen in all previously characterized GNATs. Motif B displays a significantly lower level of conservation among family members, giving rise to a novel alpha/beta structure for the serotonin binding slot. Utilization of a brominated CoA-S-acetyl-tryptamine-bisubstrate analog inhibitor and the MAD method permitted conclusive identification of two radically different conformations for the tryptamine moiety in the catalytic site (cis and trans). A second high-resolution X-ray structure of the enzyme bound to a bisubstrate analog inhibitor, with a longer tether between the acetyl-CoA and tryptamine moieties, demonstrates only the trans conformation. Given a previous proposal that AANAT can catalyze an alkyltransferase reaction in a conformationally altered active site relative to its acetyltransferase activity, it is possible that the two conformations of the bisubstrate analog observed crystallographically correspond to these alternative reaction pathways. Our findings may ultimately lead to the design of analogs with improved AANAT inhibitory properties for in vivo applications.

Treatment results of pediatric nasopharyngeal carcinoma, NCI, Cairo University experience.

BACKGROUND: Investigate treatment outcome, prognostic factors and survival among selected group of Egyptian pediatric nasopharyngeal carcinoma patients. PATIENTS AND METHODS: Thirty patients treated from non-metastatic nasopharyngeal carcinoma between 1997 and 2012 were retrospectively evaluated including: TNM staging, chemo-radiotherapy regimens. Survival analysis was done using Kaplan-Meier survival curves. RESULTS: Twenty-three males and 7 females (M:F 3.2:1) with median age of 14 years; 84% with stages III/IV. Neck node enlargement was reported in 90% (27/30). Induction chemotherapy followed by radiotherapy was implemented in 80% of patients. Mucositis (87%) was the commonest treatment related toxicity. Nineteen patients (63%) were in CR with a median FU of 69 months (range 24-160). Eleven patients had treatment local and distant failures (2 local, 7 distant and 2 local/distant) at a median FU of 24 and 34 months respectively. 5-year overall and event-free survival rates were 77% and 63% respectively. Prolonged OAP of RT⩾50 days, Hb<11g% and T4 stage affected EFS and OAS on UVA; while on MVA; prolonged OAP of RT⩾50 days (p=0.002) and T4 stage (p=0.004) affected EFS and only Hb<11g% (p=0.019) affected OAS. Late toxicity was reported in 70% of irradiated patients. CONCLUSION: Radio-chemotherapy management for pediatric NPC resulted in comparable treatment outcomes with tolerable late effects. Response adapted radio-chemotherapy regimens in addition to the potential use of IMRT should be recommended to decrease treatment related side effects. Prolonged OAP of RT⩾50 days and low Hb level were encountered as adverse prognostic factors; findings that need further investigation.

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.

Treatment results of adults and children with medulloblastoma NCI, Cairo University experience.

PURPOSE: To evaluate treatment outcome and prognostic factors of adults and pediatric medulloblastoma patients treated by adjuvant postoperative craniospinal irradiation (CSI) and chemotherapy. PATIENTS AND METHODS: Between 1997 and 2004, 67 patients were treated in the National cancer Institute- Cairo University; 51 pediatric patients with a median age of 7 years and 16 adult patients with a median age of 25 years. According to the Chang staging system; 50%-35% , 37.5%-47% and 12.5%-18% had T2, T3 and T4 tumors of adults and pediatric patient's population respectively. M1, M2 and M4 were reported in 16% , 3% and in 1.5% respectively. All patients underwent primary surgical resection; near total resection in 25% , Subtotal resection in 61% ; with tumor residual < 1.5cm(2) in 49% compared to 51% with > 1.5cm(2) residual tumor and 14% , had biopsy only. All patients were treated by craniospinal radiotherapy (RT); with a median dose of 34Gy to the whole brain, 54Gy to the posterior fossa and 32Gy to the spinal axis. The median interval between surgery and RT was 45 days and 38 days for the pediatric and adult groups respectively. The median duration of RT was 54 days and 52 days for pediatric and adult patients respectively. Thirty four pediatric patients (67% ) received concomitant chemotherapy, while 61% received adjuvant (postoperative) chemotherapy and 57% received sequential chemotherapy. Only 33% of patients did not receive chemotherapy. The median follow-up was 49 months for the whole group of patients (range 11-121). RESULTS: For the pediatric and adult patients, the 5- and 7-year overall and disease-free survival rates were 89% & 78% Vs. 84% & 56% and 80% & 68% Vs. 79% & 52% respectively. Fourteen patients (21% ) relapsed (10 pediatric and 4 adults) at a median time of 11 months vs. 23 months and a median follow-up period of 8 and 12 months respectively; Neuro-axis was the most common site of relapse (11 patients). Ninety percent (9/10) of the pediatric relapses were of the high risk group (8 received no chemotherapy) and took place within 2 years; similarly all adult relapses were of the high risk group; three relapses took place after 2 years. In univariate analysis, T stages, M stages, extent of surgery, CSF seedling and risk category were significant prognostic factors for disease free survival for the pediatric age group. At 5 years, 87% , 87% , 78% , 85% and 85% of T2, M0, near total resection, negative CSF seedling and low risk patients were estimated to be disease-free respectively, compared to none of the T4, M +, biopsy only, positive CSF seedling patients and only 41% of the high risk patients achieved 5 years without recurrence (p=0.001, <0.001, <0.001, <0.001, <0.001). Patients who did not receive chemotherapy had a 69% 5-year DFS Vs. 76% (p=0.286). For adult patients; only the risk category was a significant prognostic factor with 5-year disease-free survival rate of 100% Vs. 40% for low and high risk respectively (p=0.03). On multivaiate analysis only the risk category and the T-stage were significant prognostic factors for disease free survival for the pediatric age group (p=0.042 and 0.031). CONCLUSION: Survival rates of medulloblastoma pediatric patients were better than the adult ones. Neuro-axis relapse was the most common site of relapse for pediatric patients. Late relapses, lateral tumor location and shorter median follow up were noted in adult patients. Advanced tumor stage, metastases at presentation, limited tumor resection were powerful prognostic factors among the pediatric patients. In addition, high risk category was shown to be a prognostic factor for both pediatric and adult patients.

Overdose problem associated with treatment planning software for high energy photons in response of Panama's accident.

BACKGROUND AND PURPOSE: The purpose of this study was to quantify dose distribution errors by comparing actual dose measurements with the calculated values done by the software. To evaluate the outcome of radiation overexposure related to Panama's accident and in response to ensure that the treatment planning systems (T.P.S.) are being operated in accordance with the appropriate quality assurance programme, we studied the central axis and pripheral depth dose data using complex field shaped with blocks to quantify dose distribution errors. MATERIAL AND METHODS: Multidata T.P.S. software versions 2.35 and 2.40 and Helax T.P.S. software version 5.1 B were assesed. The calculated data of the software treatment planning systems were verified by comparing these data with the actual dose measurements for open and blocked high energy photon fields (Co-60, 6MV & 18MV photons). RESULTS: Close calculated and measured results were obtained for the 2-D (Multidata) and 3-D treatment planning (TMS Helax). These results were correct within 1 to 2% for open fields and 0.5 to 2.5% for peripheral blocked fields. Discrepancies between calculated and measured data ranged between 13. to 36% along the central axis of complex blocked fields when normalisation point was selected at the Dmax, when the normalisation point was selected near or under the blocks, the variation between the calculated and the measured data was up to 500% difference. CONCLUSIONS: The present results emphasize the importance of the proper selection of the normalization point in the radiation field, as this facilitates detection of aberrant dose distribution (over exposure or under exposure).

The synthesis and SAR of 2-amino-pyrrolo[2,3-d]pyrimidines: a new class of Aurora-A kinase inhibitors.

A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical assay and are able to inhibit tumor cell proliferation. This study culminates in compound 30, an inhibitor with potent activity against Aurora A (IC50=0.008 microM), anti-proliferative activity against several tumor cell lines and induces polyploidy in H460 cells.

A novel series of arylsulfonylthiophene-2-carboxamidine inhibitors of the complement component C1s.

Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.

A novel series of potent and selective small molecule inhibitors of the complement component C1s.

Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.