Model Selection for the Preclinical Development of New Drug-Radiotherapy Combinations.

Radiotherapy plays an essential role in the treatment of more than half of all patients with cancer. In recent decades, advances in devices that deliver radiation and the development of treatment planning software have helped radiotherapy attain precise tumour targeting with minimal toxicity to surrounding tissues. Simultaneously, as more targeted drug therapies are being brought into the market, there has been significant interest in improving cure rates for cancer by adding drugs to radiotherapy to widen the therapeutic window, the difference between normal tissue toxicity and treatment efficacy. The development of new combination therapies will require judicious adaptation of preclinical models that are routinely used for traditional drug discovery. Here we highlight the strengths and weaknesses of each of these preclinical models and discuss how they can be used optimally to identify new and clinically beneficial drug-radiotherapy combinations.

Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints.

T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. Chemokines are credited with guiding the multistep recruitment of CD8(+) T cells across tumour vessels. However, the multiplicity of chemokines within tumours has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signalling at effector sites. Here we investigate the hierarchy of chemokine receptor requirements during T-cell trafficking to murine and human melanoma. These studies reveal a non-redundant role for Gαi-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8(+) effectors that is indispensable for therapeutic efficacy. In contrast, functional CCR2 and CCR5 on CD8(+) effectors fail to support trafficking despite the presence of intratumoral cognate chemokines. Taken together, these studies identify CXCR3-mediated trafficking at the tumour vascular interface as a critical checkpoint to effective T-cell-based cancer immunotherapy.

Effect of sevoflurane/nitrous oxide versus propofol anaesthesia on somatosensory evoked potential monitoring of the spinal cord during surgery to correct scoliosis.

BACKGROUND: Use of intraoperative somatosensory evoked potential (SSEP) monitoring is helpful in spinal corrective surgery but may be affected by anaesthetic drugs. An anaesthetic technique that has less effect on SSEP or allows faster recovery is an advantage. We compared the effects on SSEP and the clinical recovery profiles of sevoflurane/nitrous oxide and propofol anaesthesia during surgery to correct scoliosis. METHODS: Twenty adolescent patients were randomized into two groups of 10. One group received sevoflurane-nitrous oxide anaesthesia and the other received propofol i.v. anaesthesia. An alfentanil infusion was used for analgesia in both groups. RESULTS: Changes in anaesthetic concentration produced little effect on the latency of SSEP, but the effect on the variability of SSEP amplitude was significant (P<0.05). Sevoflurane produced a faster decrease in SSEP and a faster recovery than propofol (P<0.05). On emergence, patients who received sevoflurane tended to have shorter recovery times to eye opening (mean 5.1 vs 20.6 min, P=0.09) and toe movement (mean 7.9 vs 15.7 min, P=0.22). Those who had received sevoflurane were significantly more lucid and cooperative in recovery. CONCLUSIONS: Sevoflurane produces a faster decrease and recovery of SSEP amplitude as well as a better conscious state on emergence than propofol.

Low cost reclamation using the Advanced Integrated Wastewater Pond Systems Technology and reverse osmosis.

The sustainability of wastewater reclamation and reuse schemes is often limited by the increase in salt concentration that occurs with each water use. In this pilot study, we show that the cost of reclaiming wastewater and removing salt can be dramatically decreased by integrating recent advances in wastewater pond design, solids separation equipment, and membrane technology. Effluent from an AIWPS Facility was clarified in a Krofta Supracell Dissolved Air Flotation (DAF) unit and a Slow Sand Filter (SSF) prior to final treatment in an Expertise S.r.l. reverse osmosis (RO) unit. The ponds of the AIWPS Facility removed an average of 82% of soluble BOD and 80% of soluble nitrogen. Following clarification, filtration, and RO treatment, the pollutant removals were > 99% for soluble BOD, > 99% for soluble nitrogen, and 98% for TDS. Based on membrane fouling rate data, the cleaning interval for the RO membranes in a full-scale AIWPS-RO Facility would be over 100 days. This interval is on par with that typically seen in full-scale reclamation facilities treating secondary activated sludge effluent with microfiltration prior to reverse osmosis. A 4-MLD AIWPS-RO Facility is expected to produce permeate water at substantially lower cost and lower energy consumption (US $698 and 443 kWh per million liters treated) than a system of equal capacity using conventional activated sludge secondary treatment followed by microfiltration and reverse osmosis (US $1274 and 911 kWh per million litres treated). This cost and energy differential is attributable to the lower capital and operating expenses of the AIWPS Technology in comparison with activated sludge.

Vallecular cyst: report of four cases--one with co-existing laryngomalacia.

Congenital vallecular cysts are rare. In this report, four infants having vallecular cysts encountered over a six-year period from 1992 to 1997 were reviewed. All of them presented with upper aerodigestive tract symptoms. Marsupialization was performed in three of them and CO2 laser excision was performed in the fourth patient. There was no recurrence of the cyst in any patient. One of them also had co-existing laryngomalacia. The degree of airway collapse caused by laryngomalacia improved after cyst removal. The laryngomalacia resolved spontaneously. Cyst fluid culture was performed in one of the patients and yielded Staphylococcus aureus but there was no other definite indicator of infection. Staphylococcus aureus could also be isolated in the respiratory tract from two of the other patients.

Gaulin homogenization: a mechanistic study.

Free radical-based oxidation has been detected in the normal operating regime of the Gaulin homogenizer, demonstrating that cavitation occurs in this important industrial bioprocessing equipment. Free radical generation is suppressed by imposition of back pressure, proving that such cavitation occurs in the impingement section. The calculated value of the cavitation number is consistent with submerged jet cavitation, wherein a high-speed jet exiting from the valve gap accelerates fluid in the impingement region, creating the vacuum conditions for cavitation. Using polysaccharides as a model shear-sensitive compound, their breakage pattern in the homogenizer was characterized by molecular size and polydispersity and compared to those of fluid shear flows in capillary tubes and cavitating flow from a sonic horn. The results indicate that breakage occurs primarily by fluid shear, although a contribution by cavitation is also apparent when back pressure is applied. Because biological molecules can readily react with free radicals and the alterations caused thereby are subtle in nature, a thorough evaluation of the impact of free radicals in upstream homogenization is warranted.

The first case of H5N1 avian influenza infection in a human with complications of adult respiratory distress syndrome and Reye's syndrome.

Avian influenza virus was not known to cause systemic infection in humans before. We report a 3-year-old boy with good past health who developed pneumonia caused by H5N1 avian influenza A virus (A/Hong Kong/156/97). The virus was isolated from a tracheal aspirate. There were complications of Reye's syndrome, adult respiratory distress syndrome, and multiple organ system failure. He had a history of receiving aspirin. His adult respiratory distress syndrome did not respond to endotracheal surfactant replacement therapy. He died 6 days after admission. Clinicians should be alert to the importance of a new human influenza strain.

Isolated straight sinus thrombosis: clinical and neuroradiologic correlates.

A rare case of straight sinus thrombosis in a 36-year-old female with sudden onset of status migrainosus is presented. This condition was demonstrated by a linear density in the midline on a noncontrast computed tomography scan, as a filling defect at the location of straight sinus on magnetic resonance imaging, and by the inability to visualize blood flow in the straight sinus on magnetic resonance venography, with a similar demonstration on a 4-vessel digital subtraction angiography.

Herpes zoster polyradiculopathy.

Herpes zoster infection, resulting from reactivation of the dormant varicella zoster virus in the dorsal root ganglia, usually causes a painful dermatomal vesicular rash. Rarely, associated peripheral motor weakness is present, the mechanism of which is unclear. Three patients are reported who had focal limb muscle weakness associated with zoster infection. Physical and occupational therapy played a key role in motor function recovery of the patients, yet emphasis on the rehabilitation of postherpetic motor weakness is lacking in the literature. Physiatrists evaluating patients with limb muscle weakness following herpes zoster infection should be alert to this condition. The clinical syndrome of herpes zoster radiculopathy and the rehabilitation of these patients are discussed.

Tethered thoracic cord resulting from spinal cord herniation.

Tethered cord syndrome (TCS) usually involves tethering of the lower cord at the conus medullaris from dural abnormalities, but may occur after spinal cord herniation. A tethered thoracic spinal cord is rare. We present an unusual case of a 30-year-old woman with a history of myelopathy presumed to be secondary to T6 cord compression resulting from T6-T8 arachnoid cyst. She continued to deteriorate after partial excision of the cyst. Repeat magnetic resonance imaging suggested recurrence of the presumed arachnoid cyst with cord compression and showed tethering at T6-T8. Surgical exploration revealed myelocele with cord herniation through the anterior thoracic dura. Pathologic diagnosis showed neural tissue with gliosis. After physical therapy treatments, the patient had increased lower extremity strength, ambulated with a cane, and regained some bladder control. Progressive myelopathy may represent tethering of the cord resulting from cord herniation. Early recognition of TCS, even in patients with minimal neurologic deficits, could prevent progressive disability.

Balloon-assisted coil placement in wide-necked aneurysms. Technical note.

Saccular intracranial aneurysms are a common and often fatal lesion. Whereas surgical treatment of these aneurysms continues to be the gold standard of care, certain situations arise for which surgery may not be the best option. In some of these cases, electrolytically detachable coils have been proven to provide outcomes superior to those seen for medical management alone. The authors present two cases of ophthalmic artery aneurysms that would not hold the Guglielmi detachable coils on the initial attempt. One aneurysm was 7 mm and one 4 mm, both with wide necks relative to the aneurysm sac. By using a balloon-assisted technique and blocking the parent artery with a nondetachable balloon, the coils could be safely placed in these aneurysms without herniation when the balloon was deflated. Both patients exhibited embolic symptoms after the procedure, one with a mild but permanent deficit. Although this technique requires manipulation of a second microcatheter and balloon, which increases its technical difficulties and is a higher risk procedure than standard coil placement, it has utility in patients who are not candidates for surgery.

Selective language aphasia from herpes simplex encephalitis.

We report the case of a 16-year-old right-handed Chinese/English bilingual patient who developed herpes simplex encephalitis involving the left temporal lobe, with resultant aphasia. His native language was Mandarin, but he had received extensive training in English for 6 years after moving to the United States and was fluent in English. One week after admission, he could not speak, comprehend, repeat, name, read, or write in English, but he had relative preservation of most of these facilities in Mandarin. He could not write in Mandarin, and his syntax was simplified. Two months later, along with intensive bilingual speech therapy, his reading, writing, and naming in English had almost recovered.

Upper limb reflex sympathetic dystrophy associated with occult malignancy.

Reflex sympathetic dystrophy, characterized by pain, swelling, vasomotor instability, and trophic changes in an extremity, has been infrequently described in patients with occult malignancy. Two cases of reflex sympathetic dystrophy associated with local tumor involvement are reported. Both patients had a history of cancer in clinical remission. Despite aggressive physical therapy measures, the patients' symptoms persisted. Workup of the first patient found an apical paravertebral mass in the lung; biopsy revealed recurrent breast carcinoma. In the second case, workup found an axillary mass contiguous with the lower brachial plexus. Biopsy revealed lymphoma, a second primary malignancy. In both cases, medical treatment of the tumor was instituted, with consequent improvement of hand and shoulder function. Both patients required prolonged hospitalization and multiple procedures that might have been avoided if malignancy had been suspected. Spontaneous development of reflex sympathetic dystrophy in patients with a history of cancer should alert the physician to the possibility of occult malignancy.

Omental transposition in chronic spinal cord injury.

The results of omental transposition in chronic spinal cord injury have been reported in 160 patients operated upon in the United States, Great Britain, China, Japan, India and Mexico, with detailed outcomes reported in few studies. Recovery of function to a greater degree than expected by natural history has been reported. In this series, 15 patients with chronic traumatic spinal cord injury (> 1.5 years from injury) underwent transposition of pedicled omentum to the area of the spinal cord injury. Of the first series of four patients who were operated upon in 1988, one died, one was lost to follow-up and two were followed with sequential neurological examinations and Magnetic Resonance Imaging (MRI) scans preoperatively, at 1 year post injury and 4 1/2 years post injury. Another 11 patients were operated in 1992 and underwent detailed neurological and neurophysiological examinations and had MRI scans preoperatively and every 4 months for at least 1 year after surgery. All patients completed a detailed self-report form. Of the total of 13 operated patients in both series followed for 1-4 1/2 years, six reported some enhanced function at 1 year and five of these felt the changes justified surgery primarily because of improved truncal control and decreased spasticity. MRI scans showed enlargement of the spinal cord as compared to preoperative scans in seven patients. Increased T2 signal intensity of the spinal cord was found by 1 year after surgery in eight of 13 operated patients. Neurophysiological examinations of 11 patients in the second series agreed with self-reports of increases or decreases in spasticity (r = 0.65, P < 0.03). Somatosensory evoked potentials and motor evoked potentials at 4 month intervals up to 1 year in these patients showed no change after surgery. Neurological testing, using the American Spinal Injury Association (ASIA) and International Medical Society of Paraplegia (IMSOP) international scoring standards, failed to show any significant changes when the 1-year post operative examination was compared to the first preoperative examination except for decreased sensory function after surgery which approached statistical significance. When the 11 patients in the second series were compared to eight non-operated matched patients, followed for a similar length of time, no significant differences were found. Complications encountered in the operated patients from both series included one postoperative death from a pulmonary embolus, one postoperative pneumonia, three chronic subcutaneous cerebrospinal fluid (CSF) fistulae requiring wound revision, and one patient who developed biceps and wrist extensor weakness bilaterally requiring graft removal. We conclude that the omental graft remains viable over time and this operation can induce anatomical changes in the spinal cord as judged by MRI. Some patients reported subjective improvement but this was not supported by objective testing. We, therefore, find no justification for further clinical trials of this procedure in patients who have complete or sensory incomplete lesions. Further testing in motor incomplete patients would seem appropriate only with compelling supportive data.

Lumbosacral radiculopathy secondary to L5 metastatic melanoma of unknown primary.

Lumbosacral radiculopathy secondary to spinal malignancy is rare. Spinal melanoma without cutaneous manifestations is even more unusual. We present the case of a 45-year-old physician with a history of degenerative disease of lumbar spine and chronic back pain who presented with increasing back pain with right radiculopathy despite conservative management for 6 months. Computed tomography showed a destructive lesion of the L5 vertebral body. Results from a biopsy guided by computed tomography suggested neoplasm of unknown origin. The patient underwent anterior vertebrectomy with instrumentation and fusion. Surgical pathology study results showed metastatic melanoma of unknown primary. The patient had no cutaneous manifestation of the disease. This is the first reported case of radiculopathy due to melanoma metastatic to the lumbar spine. In view of the atypical presentation of our patient's malignancy, we emphasize the importance of including malignancy of lumbar spine in the differential diagnosis of progressive lower back pain with radiculopathy.

Neurosarcoidosis of the conus medullaris and cauda equina presenting as paraparesis: case report and literature review.

Sarcoidosis is a multi-system, non-caseating granulomatous disease of unknown etiology. Although spinal cord involvement is rare, it may cause severe neurological complications. We report the case of a 52-year-old woman who developed low back pain and a progressive flaccid paraparesis whose investigations revealed pulmonary and spinal sarcoidosis. To our knowledge, this is the first reported case of sarcoidosis of the conus medullaris and cauda equina diagnosed by an unusual enhancement pattern observed on magnetic resonance imaging with gadolinium. Biopsy of the lumbar nerve roots and of the lung revealed a non-caseating granuloma. Treatment with steroids and intensive rehabilitation resulted in remarkable functional improvement. Although rare, sarcoidosis of the conus medullaris and cauda equina should be considered in the differential diagnosis of flaccid paraparesis, particularly in patients with non-diagnostic evaluations.