CD40 ligand and tdTomato-armed vaccinia virus for induction of antitumor immune response and tumor imaging.

Oncolytic vaccinia virus is an attractive platform for immunotherapy. Oncolysis releases tumor antigens and provides co-stimulatory danger signals. However, arming the virus can improve efficacy further. CD40 ligand (CD40L, CD154) can induce apoptosis of tumor cells and it also triggers several immune mechanisms. One of these is a T-helper type 1 (Th1) response that leads to activation of cytotoxic T-cells and reduction of immune suppression. Therefore, we constructed an oncolytic vaccinia virus expressing hCD40L (vvdd-hCD40L-tdTomato), which in addition features a cDNA expressing the tdTomato fluorochrome for detection of virus, potentially important for biosafety evaluation. We show effective expression of functional CD40L both in vitro and in vivo. In a xenograft model of bladder carcinoma sensitive to CD40L treatment, we show that growth of tumors was significantly inhibited by the oncolysis and apoptosis following both intravenous and intratumoral administration. In a CD40-negative model, CD40L expression did not add potency to vaccinia oncolysis. Tumors treated with vvdd-mCD40L-tdtomato showed enhanced efficacy in a syngenic mouse model and induced recruitment of antigen-presenting cells and lymphocytes at the tumor site. In summary, oncolytic vaccinia virus coding for CD40L mediates multiple antitumor effects including oncolysis, apoptosis and induction of Th1 type T-cell responses.

Is it advantageous to use quality by design (QbD) to develop nanoparticle-based dosage forms for parenteral drug administration?

Parenteral administration is one of the most commonly used drug delivery routes for nanoparticle-based dosage forms, such as lipid-based and polymeric nanoparticles. For the treatment of various diseases, parenteral administration include intravenous, subcutaneous, and intramuscular route. In drug development phase, multiparameter strategy with a focus on drug physicochemical properties and the specificity of the administration route is required. Nanoparticle properties in terms of size and targeted delivery, among others, are able to surpass many drawbacks of conventional dosage forms, but these unique properties can be a bottleneck for approval by regulatory authorities. Quality by Design (QbD) approach has been widely utilized in development of parenteral nanoparticle-based dosage forms. It fosters knowledge of product and process quality by involving sound scientific data and risk assessment strategies. A full and comprehensive investigation into the state of implementation and applications of the QbD approach in these complex drug products can highlight the gaps and challenges. In this review, the analysis of critical attributes and Design of Experiment (DoE) approach in different nanoparticulate systems, together with the proper utilization of Process Analytical Technology (PAT) applications are described. The essential of QbD approach for the design and development of nanoparticle-based dosage forms for delivery via parenteral routes is discussed thoroughly.

Risk factors for 1-year mortality in patients with nontraumatic intracranial hemorrhage requiring intensive care.

BACKGROUND: Mortality in patients with intracranial hemorrhage remains high. The aim of this study was to determine the 1-year survival and potential risk factors for 1-year mortality in patients with nontraumatic intracranial hemorrhage requiring intensive care. METHODS: This was a 3-year (2005-2007) retrospective study in a university-level intensive care unit (ICU). Patient characteristics, level of consciousness, and radiological findings of the primary head computed tomography were recorded on admission. Sequential Organ Failure Assessment scores were recorded during the ICU stay. Patients were divided into two groups: subarachnoid hemorrhage (SAH) group and intracerebral hemorrhage (ICH) group. Kaplan-Meier survival curves were constructed, and independent risk factors were determined using Cox proportional hazards regression analyses. RESULTS: Two hundred twenty-nine patients were analyzed. The 1-year mortality rate was 32% in patients with SAH and 44% in patients with ICH. The risk factors for 1-year mortality in both groups were unconsciousness on admission [SAH: hazard ratio (HR) 6.2, P = 0.017 and ICH: HR 3.0, P = 0.004] and renal failure during the ICU stay (SAH: HR 2.5, P = 0.021 and ICH: HR 3.6, P = 0.021). Risk factors specific to the type of hemorrhage were the presence of ICH (HR 2.0, P = 0.033) and diffuse cerebral edema (HR 2.3, P = 0.017) in the SAH group and a prior use of warfarin (HR 5.1, P = 0.016) in the ICH group. CONCLUSIONS: In addition to decreased level of consciousness on admission, renal failure during the ICU stay is an independent risk factor for 1-year mortality in nontraumatic SAH as well as ICH.

Robustness of a continuous direct compression line against disturbances in feeding.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term manufacture. The study included a primary formulation, with API of standard particle size, which was manufactured at 5 and 10 kg/h production rates, and a modified formulation, with API of large particle size, which was manufactured at 5 kg/h production rate. Overall, the CDC line smoothened all the disturbances, fulfilling the USP uniformity of dosage units (UDU) limit for single tablets. However, runs with the modified formulation failed the pharmacopoeia UDU requirements for the entire run due to high variation between tablets. The primary formulation passed the requirements in all cases. The residence time distribution (RTD) results indicated that the primary formulation allowed better smoothening ability, and an increase in production rate led to poorer smoothening due to shorter RTD. The RTDs revealed that a substantial part of back-mixing took place after the blender. Thus, the tablet press has an important role in smoothening disturbances longer than the mean residence time of the blender, which was very short.

Chronic hydrocephalus after neurosurgical and endovascular treatment of ruptured intracranial aneurysms.

BACKGROUND: Chronic hydrocephalus is a common sequela of subarachnoid hemorrhage (SAH). The technical procedure used to treat intracranial aneurysms, whether neurosurgical clipping or endovascular coiling, may lead to differences in the incidence of chronic posthemorrhagic hydrocephalus. PURPOSE: To compare the effects of early neurosurgical and early endovascular treatment on the development of chronic hydrocephalus in patients with SAH. MATERIAL AND METHODS: A retrospective study included 102 clipped and 107 coiled patients with aneurysmal SAH. Clinical condition at admission and shunt dependence were verified from patient data records. The initial and follow-up computed tomography (CT) images were reviewed, and the amount and distribution of blood and the occurrence of hydrocephalus were registered. The values of the cella media index and the width of the third ventricle were calculated. Statistical analysis of the data was performed. RESULTS: No statistically significant differences in the incidence of chronic hydrocephalus or the need for shunting emerged between the treatment groups. After clipping 35% and after coiling 39% of the patients developed chronic hydrocephalus. Twenty-nine percent of the clipped and 31% of the coiled patients underwent a shunt operation. CONCLUSION: The treatment method used for acutely ruptured intracranial aneurysms, i.e., neurosurgical clipping or endovascular coiling, has no statistically significant effect on the development of chronic hydrocephalus.

RTD-based material tracking in a fully-continuous dry granulation tableting line.

Continuous manufacturing (CM) offers quality and cost-effectiveness benefits over currently dominating batch processing. One challenge that needs to be addressed when implementing CM is traceability of materials through the process, which is needed for the batch/lot definition and control strategy. In this work the residence time distributions (RTD) of single unit operations (blender, roller compactor and tablet press) of a continuous dry granulation tableting line were captured with NIR based methods at selected mass flow rates to create training data. RTD models for continuous operated unit operations and the entire line were developed based on transfer functions. For semi-continuously operated bucket conveyor and pneumatic transport an assumption based the operation frequency was used. For validation of the parametrized process model, a pre-defined API step change and its propagation through the manufacturing line was computed and compared to multi-scale experimental runs conducted with the fully assembled continuous operated manufacturing line. This novel approach showed a very good prediction power at the selected mass flow rates for a complete continuous dry granulation line. Furthermore, it shows and proves the capabilities of process simulation as a tool to support development and control of pharmaceutical manufacturing processes.

Low-field MR imaging of meningiomas including dynamic contrast enhancement study: evaluation of surgical and histopathologic characteristics.

BACKGROUND AND PURPOSE: Risks associated with surgery of meningiomas, especially those located in the skull base, are influenced by tumor consistency and vascularity. The purpose of this study was to find out if vascularity, consistency, and histologic characteristics of meningioma can be predicted preoperatively by using low-field MR imaging, including dynamic imaging of contrast enhancement. MATERIALS AND METHODS: Twenty-one patients (mean age, 56; range, 34-73 years; 16 women, 5 men) with meningioma requiring first surgery were imaged by a 0.23T scanner. Time to maximum enhancement, maximum enhancement, and maximum intensity increase were noted from the enhancement curve of dynamic imaging. Relative intensity of tumor in fluid-attenuated inversion recovery (FLAIR) and T2-weighted images was calculated. The neurosurgeon evaluated surgical bleeding and hardness of tumor on a visual analog scale. Histopathologic analysis included subtype, World Health Organization grade, mitotic activity, grades of progesterone receptor expression and collagen content, proliferation activity by Ki-67 (MIB-1), and microvessel density by CD34. Correlations were studied with Kendall tau statistics. RESULTS: The most powerful association was found between time to maximum enhancement and microvessel density (tau = -0.60, P < .001). Surgical bleeding (tau = 0.49, P = .002), blood loss during surgery (tau = 0.49, P = .002), progesterone receptor expression (tau = 0.59, P < .001), and collagen content (tau = -0.54, P < .001) were statistically best correlated with the relative intensity of meningioma on FLAIR images. Tissue hardness correlated best with relative intensity on T2-weighted images (tau = 0.40, P = .012). CONCLUSION: Assessment of microvessel density, collagen content, and progesterone receptor expression of meningioma may be clinically feasible by using low-field MR imaging.

Br2F7- and Br3F10-: peculiar anions showing µ2- and µ3-bridging F-atoms.

RbCl and CsCl react with BrF3 yielding the corresponding decafluoridotribromates(iii), MBr3F10 (M = Rb, Cs), which were structurally characterized for the first time. The Br3F10- anion is surprisingly not linear but contains a µ3-bridging fluorine atom and seems to be the first example of µ3-F bridging of Br atoms. The compounds are highly reactive and cannot be handled in glassware. As for the tetrafluoridobromates themselves, they are powerful oxidizers and thus suitable for the dry-chemical recycling of precious metals and additionally feature a significantly higher BrF3 content.

Superselective intra-arterial chemotherapy with mitomycin C in hepatic neoplasms.

The results of superselective intra-arterial chemotherapy with Mitomycin C (SIAC) in cases of hepatic neoplasms continue to be poor. Survival time was related to the percentage of hepatic replacement (PHR) but only 19% of the patients with Stage I tumours (PHR < 25%) survived for over 5 years and all the others died within 4 years. The patients with hepatic metastases from colorectal cancer achieved a significantly better cumulative 5-year survival figure than those with hepatocellular cancer (P < 0.05). The median survival times for patients with hepatic metastases from colorectal cancer, hepatocellular cancer and gallbladder cancer were 15 months, 6 months and 13 months, respectively. The overall response rate was only 27% (26/97), that for primary liver cancer 20% (7/35), that for hepatic metastases from colorectal cancer 22% (8/37) and that for gallbladder cancer 44% (11/25) and the patients who responded to SIAC (n = 27) had a significantly better cumulative 5-year survival rate (P < 0.005). Cessation of SIAC was necessary in 74% (72/97) of the cases, because of tumour progression in 53% (51/97), major complications in 19% (18/97) and patient refusal in 3% (3/97). The results of this trial may be regarded as disappointing, and we are going to use SIAC for Stage I tumours only. Resection of the tumour continues to provide the only chance of a permanent cure with these patients.

Embolization for the treatment of posterior epistaxis. An analysis of 31 cases.

Thirty-one patients with posterior epistaxis refractory to nasal packing alone or in combination with surgical ligation (n = 8) underwent diagnostic angiography and therapeutic embolization of the internal maxillary artery. Embolization resulted in the cure of epistaxis in 22 cases (71.0%). Of the nine failures (29.0%), seven underwent successful surgical clipping of the ethmoid arteries, and two were treated conservatively and died of their primary hematologic disease within 33 days. Late rebleeding occurred in two patients: one underwent re-embolization and the other was treated surgically. No severe or permanent complications occurred. The results indicate that embolization is a feasible alternative to surgical intervention for patients with posterior epistaxis, and we recommend it as the treatment of choice in cases with high surgical risk or failure of prior arterial ligation.

Justification of CT examinations in young adults and children can be improved by education, guideline implementation and increased MRI capacity.

OBJECTIVE: To determine whether the justification of CT examinations performed on young patients can be improved by various interventions and whether these have an effect on the total number of CTs performed. METHODS: Specific interventions-education, guideline implementation and increased MRI capacity-were introduced at the Oulu University Hospital, Oulu, Finland, following a previous study demonstrating unjustified use of CT examination in young patients. In the present study, the justification of 177 CT examinations of the lumbar and cervical spine, head, abdomen, nasal sinuses and trauma performed on patients aged under 35 years in 2009 was analysed retrospectively by looking at requests and corresponding patient files. The indications of the examinations were compared with the referral guidelines recommended by the European Commission. Results from our previously published similar study carried out before the interventions were used as a reference. RESULTS: The proportion of justified CT examinations increased from 71% (141/200) in 2005 to 87% (154/177) in 2009 (p<0.001), and in the lumbar spine group from 23% (7/30) to 81% (22/27) (p<0.001). In the case of most of the unjustified examinations, MRI could have been performed instead. The total number of CT examinations carried out on young patients decreased by 7% (p=0.012) and in the lumbar spine group by 79% (p<0.001). CONCLUSION: The implemented interventions decreased the number of CT examinations performed on young patients, and the justification of the examinations improved significantly. ADVANCES IN KNOWLEDGE: This study demonstrates that it is possible to reduce the number of various CT examinations and to improve their justification in young patients by regular education, guideline implementation and increased MRI capacity.

A comparison of radiation exposure between diagnostic CTA and DSA examinations of cerebral and cervicocerebral vessels.

BACKGROUND AND PURPOSE: While the number of CTA examinations is continually increasing compared with DSA examinations, there is little comparative dose information about the different imaging techniques. We compared patient radiation exposure resulting from diagnostic CTA and DSA examinations for both cerebral and cervicocerebral vessels. MATERIALS AND METHODS: An anthropomorphic phantom was irradiated by using typical diagnostic CTA and DSA setups and imaging parameters. For both imaging techniques, the imaging area of cerebral vessels included intracranial vessels only, while the imaging area of cervicocerebral vessels included both cervical and intracranial vessels from the aortic arch to the vertex. The effective dose was determined by using RPLDs. The DSA examination was simulated by using a biplane angiography system, and the CTA examination, by using a 64-row multidetector CT scanner. RESULTS: For the imaging of cerebral vessels, the effective dose according to ICRP 103 was 0.67 mSv for CTA and 2.71 mSv for DSA. For the imaging of cervicocerebral vessels, the effective dose was 4.85 mSv for CTA and 3.60 mSv for DSA. The maximum absorbed dose (milligray) for skin, brain, salivary glands, and eyes was 166.2, 73.5, 35.6, and 21.8 mGy for DSA and 19.0, 16.9, 20.4, and 14.8 mGy for CTA, respectively. The conversion factors from DAP and DLP to effective dose were calculated. CONCLUSIONS: The effective dose for CTA assessment of cerebral vessels was approximately one-fifth the dose compared with DSA. In the imaging of cervicocerebral vessels, the effective dose for CTA was approximately one-third higher compared with DSA.

Increasing benefit of magnetic resonance imaging in multiple sclerosis.

Magnetic resonance imaging (MRI) has emerged as an essential tool of multiple sclerosis (MS) diagnosis and has opened up completely new prospects in MS research and treatment trials. It is a sensitive method that gives direct evidence of tissue pathology and has greatly increased our knowledge of MS. In clinical work, MRI is used to confirm and exclude the diagnosis of MS. The international recommendation is that every suspected MS patient should undergo at least one brain MRI. T2-weighted images are the standard tool in clinical work, and functional imaging methods are mainly used in MS research. The subtypes and the course of the disease cause variation in MRI findings. Here, we present a general overview of MR findings in MS.

The multiple diverticulosis of the small bowel--a rare radiological finding using double contrast enema--a case report.

Multiple diverticulosis of the small bowel is a rare sickness and a rare radiological finding. Positive diagnosis can be made with radiological examination or laparatomy of patients.

Rupture of cerebral aneurysm during angiography.

The rupture of a cerebral aneurysm during angiography is an unusual event. There are approximately 35 reported cases in the literature. Our case was documented by both angiography and computed tomography.

Value of the quantity and distribution of subarachnoid haemorrhage on CT in the localization of a ruptured cerebral aneurysm.

BACKGROUND: Computed tomography (CT) is the "gold standard" for detecting subarachnoid haemorrhage (SAH) and digital subtraction angiography (DSA) for visualising the vascular pathology. We studied retrospectively 180 patients with subarachnoid haemorrhage (SAH) who underwent first non-enhanced computed tomography (CT), then digital subtraction angiography (DSA) and finally operative aneurysm clipping. Our aim was to assess if the location of the ruptured aneurysm could be predicted on the basis of the quantity and distribution of haemorrhage on the initial CT scan. METHODS: 180 patients with SAH were retrospectively studied. All the CT and DSA examinations were performed at the same hospital. CT was performed within 24 hours after the initial haemorrhage. DSA was performed after the CT, within 48 hours after the initial haemorrhage. Two neuroradiologists, blind to the DSA results, analysed and scored independently the quantity and distribution of the haemorrhage and predicted the site of the ruptured aneurysm on the basis of the non-enhanced CT. DSA provided the location of the ruptured aneurysm. All the patients were operated upon, and the location of the ruptured aneurysm was determined. FINDINGS: The overall reliability value (kappa-value) between the two neuroradiologists for locating all ruptured aneurysms was 0.780. The corresponding value for the right MCA was 0.911, that for the left MCA 0.877 and that for the AcoA 0.736. Not all of the kappa-values were calculated, either because the location of the rupture was constant or because the number of ruptures in the vessel was too small. Subarachnoid haemorrhage with a parenchymal hematoma is an excellent predictor of the site of the ruptured aneurysm with a statistical significance of p=0.003. INTERPRETATION: The quantity and pattern of the blood clot on CT within the day of onset of SAH is a reliable and quick tool for locating a ruptured MCA or AcoA aneurysm. It is not, however, reliable for locating other ruptured aneurysms. Subarachnoid haemorrhage with a parenchymal hematoma is an excellent predictor of the site of a ruptured aneurysm.

Patency and complications of percutaneously inserted metallic stents in malignant biliary obstruction.

PURPOSE: The aim of this study was to analyze the patency of percutaneously inserted metallic stents in malignant biliary obstruction and to evaluate all the complications associated with the stents and the reinterventions needed. MATERIALS AND METHODS: Thirty-nine patients with 42 malignant strictures were treated percutaneously with 55 metallic self-expandable stents. Forty-eight were Wallstents and seven were Memotherm stents. Twenty-five strictures were hilar, 16 were in the common bile duct, and one was in the hepaticojejunal anastomosis. The patients were followed until death and the mean follow-up was 6.4 months. RESULTS: Stent insertion was successful in 97% of the patients. Thirty percent had early complications (<30 days), and as many as 66% had late complications, including stent occlusions, which were seen in 10 patients. The patency rates of patients with cholangio-carcinoma were significantly lower than those of the patients with other diagnoses. There was also a tendency toward obstruction with less dilation of the stents, Y, T or tandem-style stent placement, an increasing number of stents, longer strictures, and hilar strictures. Thirty-one percent of the patients alive after the first 30 days had late reinterventions. CONCLUSIONS: Although metallic stents offer an alternative in the palliation of malignant bile duct obstruction, there seem to be numerous early and late complications.

Primary malignant sacrococcygeal tumours: reasons for diagnostic delay.

Primary malignant sacrococcygeal tumours are relatively rare and difficult to detect. In our series of nine cases there were five sarcomas, two chordomas, one lymphoma and one myeloma. The tumours were from 5 to 16 cm in diameter when detected. The patient delay varied from 2 to 12 months, the doctors' delay from 2 to 6 months. The radiological method leading to the diagnosis was plain film in four, CT in three, tomography in one, and myelography in one. CT showed especially the soft tissue involvement. In four cases, the tumour was not visible on the plain film. The tumour was palpable per rectum in three cases. Our experiences show that many sacrococcygeal tumours are missed in a plain X-ray. Tomography and CT produce the most useful diagnostic information. CT and MRI are replacing conventional tomography. We believe that CT examinations of the sacrococcygeal region should be performed when symptoms suggest a tumour to be present.

Factors related to acute hydrocephalus after subarachnoid hemorrhage.

PURPOSE: To evaluate the influence of the amount and distribution of blood on acute ventricular enlargement in subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: In a retrospective study, non-contrast computed tomography (CT) images of 180 patients with aneurysmal SAH were analysed by two neuroradiologists. The amount and distribution of the hemorrhage were scored, and prospective hydrocephalus was identified on the basis of acute CT images by calculating the cella media index, by measuring the width of the third ventricle, and by visual impression. Statistical analysis was done using the logistic regression model, analysis of variance, and chi-square test. RESULTS: The incidence of acute hydrocephalus was higher among the patients with blood distributed in the anterior, lateral, and basal regions (70.8%) than among the patients who did not have blood distributed in all three areas (P=0.010). The proportion of acute hydrocephalus differed depending on the type of hemorrhage (P<0.001). Intraventricular hemorrhage was the most consistent predictive factor in the logistic regression model, while the other predictive factors included the total blood amount score and the volume of intracerebral hemorrhage. CONCLUSIONS: A positive correlation was found between acute hydrocephalus and the amount of subarachnoid and, more importantly, intraventricular blood. This is consistent with the literature and confirms the current pathophysiologic concepts that the acute hydrocephalus following SAH is an obstructive form of hydrocephalus.

Treatment of symptomatic congenital hepatic cysts with single-session percutaneous drainage and ethanol sclerosis: technique and outcome.

PURPOSE: To evaluate the safety and efficacy of percutaneous aspiration and ethanol sclerotherapy as the sole treatment for symptomatic, nonneoplastic, congenital hepatic cysts. PATIENTS AND METHODS: In a prospective study, 59 symptomatic, congenital hepatic cysts in 25 patients were treated with ultrasound-guided percutaneous aspiration and ethanol sclerotherapy. Eleven patients had a solitary cyst, and 14 patients had polycystic liver disease. Mean follow-up was 4 years. RESULTS: Fifty-seven (97%) of 59 sclerotherapy procedures were technically successful, and there were no recurrences. Eight cysts in six patients disappeared totally. The mean diameter of the remaining 49 cysts decreased from 9 cm to 3 cm. At the last follow-up visit, 14 patients were asymptomatic, four had milder epigastric pain than before the treatment, and seven with polycystic liver disease had recurrent symptoms due to growth of nontreated cysts. No major complications occurred. CONCLUSION: Percutaneous aspiration with ethanol sclerotherapy is a safe, effective, and minimally invasive treatment method for symptomatic congenital cysts. It is the initial treatment of choice for all patients with symptomatic congenital hepatic cysts.