A hybrid approach for fusing 4D-MRI temporal information with 3D-CT for the study of lung and lung tumor motion.

PURPOSE: Accurate visualization of lung motion is important in many clinical applications, such as radiotherapy of lung cancer. Advancement in imaging modalities [e.g., computed tomography (CT) and MRI] has allowed dynamic imaging of lung and lung tumor motion. However, each imaging modality has its advantages and disadvantages. The study presented in this paper aims at generating synthetic 4D-CT dataset for lung cancer patients by combining both continuous three-dimensional (3D) motion captured by 4D-MRI and the high spatial resolution captured by CT using the authors' proposed approach. METHODS: A novel hybrid approach based on deformable image registration (DIR) and finite element method simulation was developed to fuse a static 3D-CT volume (acquired under breath-hold) and the 3D motion information extracted from 4D-MRI dataset, creating a synthetic 4D-CT dataset. RESULTS: The study focuses on imaging of lung and lung tumor. Comparing the synthetic 4D-CT dataset with the acquired 4D-CT dataset of six lung cancer patients based on 420 landmarks, accurate results (average error <2 mm) were achieved using the authors' proposed approach. Their hybrid approach achieved a 40% error reduction (based on landmarks assessment) over using only DIR techniques. CONCLUSIONS: The synthetic 4D-CT dataset generated has high spatial resolution, has excellent lung details, and is able to show movement of lung and lung tumor over multiple breathing cycles.

Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly different from the Tortuga formulation and that all three formulations exhibited absorption rate-limited elimination.

Thalidomide dose proportionality assessment following single doses to healthy subjects.

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single-dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid thalidomide formulation in an open-label, single-dose, three-way crossover study. Fifteen healthy subjects were given 50, 200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dose-normalized Cmax and AUC0-infinity. No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for Cmax with increases being less than proportional than changes in dose. AUC0-infinity increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip-flop phenomenon). The terminal rate constant (absorption rate constant) for the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.

Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs.

Fifty-six adult beagle dogs (28 male, 28 female) were orally administered thalidomide at 43, 200, or 1000 mg/kg/day for 53 weeks. Sixteen (2/sex/dose group) and 32 (4/sex/dose group) dogs were euthanized and necropsied after 26 and 53 weeks of dosing, respectively. The remaining 8 animals (2/sex/group; high-dose and control groups) were dosed for 53 weeks, euthanized, and necropsied at 58 weeks after a 5-week recovery period. There were no deaths during the study. The only observed clinical signs attributable to thalidomide administration were green-colored urine, white-colored fecal residue presumed to be unchanged thalidomide, enlarged and/or blue coloration of female mammary tissue, and prolonged estrus. There were no thalidomide-related changes in body weights, food consumption, electrocardiography, ophthalmoscopy, neurological function, and endocrine function. The mostly slight and/or transient variations observed in some hematology and blood chemistry values of dosed dogs were considered to be toxicologically insignificant and were supported by the lack of histopathologic correlates. The only gross finding attributable to thalidomide was a yellow-green discoloration of the femur, rib, and/or calvarium that was observed at each euthanization interval including recovery. There was no microscopic correlate for this finding. No thalidomide-related microscopic changes were seen in any of the organs and tissues at 26 weeks. Mammary duct dilatation and/or glandular hyperplasia observed in females at 53 and 58 weeks and hepatic bile pigment exhibited by high-dose males at 53 weeks were microscopic changes considered to be thalidomide-related. There was no gross and histopathologic evidence of any tumors. In summary, thalidomide at up to 1000 mg/kg/day for 53 weeks did not induce any major systemic toxicity or tumors in dogs. The NOAEL was 200 mg/kg/day.

Assessment of a combined preparation of isoniazid, rifampicin and pyrazinamide (Rifater) in the initial phase of chemotherapy in three 6-month regimens for smear-positive pulmonary tuberculosis: a five-year follow-up report.

SETTING: Singapore Tuberculosis Service. OBJECTIVE: To assess the acceptability, efficacy and relapse rate of a combined formulation of three drugs--isoniazid, rifampicin and pyrazinamide (Rifater)--given in the initial phase of chemotherapy in three 6-month regimens (2SHRZ/4H3R3, 1SHRZ/5H3R3 and 2HRZ/4H3R3) under direct observation for all patients. DESIGN: A randomised, controlled, unblinded study comparing a group of patients treated with Rifater and another given the three component drugs as separate formulations. RESULTS: The 310 patients admitted to the study were divided into two groups of 155 patients. The frequency of side effects was similar in both groups. Of 271 patients with drug-sensitive strains who had completed treatment without interruption, sputum cultures converted in all patients. At the end of 5 years, there were 15 relapses: three (2.2%) in the separate drugs group and 12 (9.3%) in the Rifater group. Exclusion of two cases in the Rifater group, one with silicotuberculosis and another with no bacteriological confirmation of diagnosis, gave a relapse rate of 7.9% (P = 0.03 for the comparison of relapse rates in the two groups). CONCLUSION: A combined formulation of three drugs given daily in the initial phase of 6-month short-course therapy, followed by intermittent treatment with isoniazid and rifampicin given three times a week under direct observation for all patients, appears to be less effective than treatment with the component drugs given as separate formulations.

Rodent tissue distribution of 2-cyanoethylene oxide, the epoxide metabolite of acrylonitrile.

The direct acting mutagen 2-cyanoethylene oxide (CEO), formed in the liver by oxidation of acrylonitrile (ACN), is thought to mediate the extrahepatic carcinogenic effects of ACN in rats. This study determined the tissue distribution of CEO (3 mg/kg p.o.) in F-344 rats and B6C3F1 mice. Radioactivity from [2,3-14C]CEO was widely distributed in the major organs of rodents by 2 h and decreased by 71% to 90% within 24 h, demonstrating that there was no preferential tissue uptake or retention of CEO. CEO was detected in rodent blood and brain 5-10 min after an oral dose of ACN (10 mg/kg), demonstrating that this mutagenic epoxide metabolite circulates to extrahepatic target organs following ACN administration.

Endobronchial tuberculosis--a report of 5 cases.

Endobronchial tuberculosis is not as well-known to internists as tuberculosis involving the lung parenchyma. Five cases with this condition are reported to illustrate the varied clinical manifestations. The presenting features of the 5 cases were lobar or lung collapse, unresolved pneumonia, dyspnoea and stridor. Bronchostenosis developed in 2 patients many years following chemotherapy, while stenosis of the trachea developed in one patient during chemotherapy. In another patient, the tuberculous granulation tissue simulated a lung cancer at bronchoscopy. Diagnosis can be difficult as endobronchial tuberculosis can occur in the absence of chest X-ray abnormality and sputum smear may also be negative for acid fast bacilli (AFB). Therefore, bronchoscopy should be done when the condition is suspected in a patient who has unexplained cough, wheezing, dyspnoea or haemoptysis. The modalities of treatment for fibrostenosis of a large airway include surgical resection followed by anastomosis, balloon dilatation, laser photoresection or a combination of both procedures.

Nontuberculous mycobacterial disease of the lungs in Singapore.

Information on lung disease due to nontuberculous mycobacteria (NTM) is lacking in Singapore. A review of the records at the Central Tuberculosis Laboratory up to the end of 1988 showed that 23 patients seen between 1976 to 1988 inclusive had cultures which were repeatedly positive for NTM. Of the 23 cases analyzed, 15 were found to have lung disease which could be attributed to NTM. There were 9 males and 6 females with a male to female ratio of 1.5:1. The patients were either middle aged or elderly. The 2 main infective agents were M avium-intracellulare and M kansasii. Ten (67%) patients had moderately advanced and 5 (33%) had far advanced disease. Concurrent disease of the lung was present in 10 patients (67%). Seven (47%) patients had bronchiectasis, 1 (7%) had both bronchiectasis and chronic obstructive pulmonary disease (COPD) and 2 (13%) had COPD. A past history of pulmonary tuberculosis was present in 10 patients (67%). Lung disease due to NTM is uncommon in Singapore. Treatment failure was attributed to poor compliance, a possibility which could not be excluded in those patients who had adverse reactions.

Hypoglycaemia in the elderly.

AIM: To determine the prevalence, presentation, causes and consequences of hypoglycaemia in the elderly, and to make preventive recommendations. METHOD: Retrospective review of case records. RESULTS: The definition of hypoglycaemia is defined as symptoms with a capillary blood sugar of less than 3 mmol/L measured on the Reflolux II or Accutrend glucometer. Out of 1,919 admissions to our department from November 1993 to January 1996, there were 45 cases of hypoglycaemia. The average age was 76.2 years (range 66 to 89 years); 32 were females, 13 males, 35 had diabetes mellitus and 10 were non-diabetics. Forty patients presented with neuroglycopaenic symptoms and 5 patients presented with adrenergic symptoms. Thirteen patients presented were solely due to drugs (mainly glibenclamide); 9 cases were due only to disease (mainly psychiatric illnesses with poor intake); 23 cases were due to both drugs and diseases (mainly a combination of glibenclamide, tolbutamide and psychiatric illness with poor intake, renal failure, gastroenteritis and sepsis). All were easily reversed with an intravenous bolus of 50% glucose or continuous 10% glucose infusions. Forty-three patients did not suffer any morbidity, one suffered a stroke and another fell because of giddiness. CONCLUSION: We recommend that: (1) the importance of having regular meals be emphasised to elderly patients and their carers, especially if they are taking hypoglycaemic agents; (2) regular home glucose monitoring for diabetic patients; (3) assessment and monitoring of renal function before prescribing hypoglycaemic agents; (4) avoidance of the use of long or medium acting sulphonylureas eg. chlorpropamide, glibenclamide in the elderly; (5) adjustment of hypoglycaemic agents (in consultation with a trained nurse/doctor) if the patient suffers from gastroenteritis and (6) less stringent blood glucose control in those with psychiatric illnesses who may have variable food intake.

Tuberculosis in the elderly.

A study of 120 cases of tuberculosis in patients aged 65 years and above revealed that there were more males than females with the disease compared with the younger age group of 15 to 45 years old. The elderly group also had significantly more severe and more had bacteriologically positive disease. The majority of them were born outside Singapore and immigrated more than 30 years ago. Risk factors such as diabetes mellitus, past history of tuberculosis, malignancy and gastrectomy were more common in the elderly group. Standard 6-month regimens were well tolerated and adverse side effects to the drugs were negligible.

A fulminant case of neuroleptic malignant syndrome.

We report a fulminant case of Neuroleptic Malignant Syndrome in a 31-year-old male schizophrenic on haloperidol, thioridazine, benzhexol and flurazepam who presented with rigidity, fever, stupor and autonomic instability. He succumbed rapidly over 6 days to rhabdomyolysis, acute renal failure, status epilepticus and disseminated intravascular coagulopathy despite treatment with dantrolene and bromocriptine at the outset.

Mass methanol poisoning: a clinico-biochemical analysis of 10 cases.

Methanol is a common ingredient in many household products and intoxication can arise easily from inadvertent exposure through ingestion, inhalation or percutaneous absorption. We analysed ten cases of methanol poisoning who presented with visual, neurological and gastrointestinal symptoms, of whom one died and nine were successfully detoxified with ethanol and bicarbonate infusions. Clinical symptoms were not found to correlate with the severity of poisoning. Serum methanol level was found to correlate significantly with arterial pH (correlation coefficient -0.74, p = 0.014) and serum standard bicarbonate levels (correlation coefficient -0.87, p = 0.001). We found that an arterial pH of < 7.33 or a serum standard bicarbonate of < 20 mmol/L correlated well with a serum methanol level of > 45 mg/dL ie severe poisoning (X2 test with Yate's correction factor, p < 0.02). We conclude that arterial pH or serum standard bicarbonate levels can be used as surrogate indicators of the severity of methanol poisoning. They can be used to guide physicians in the method of detoxification (ie whether intravenous or oral ethanol or dialysis should be used) whilst awaiting serum methanol levels in cases where the index of suspicion for methanol poisoning is high. Some cases of severe poisoning can be successfully treated with oral ethanol if the intravenous form is not available.

The spectrum of cutaneous and internal malignancies in chronic arsenic toxicity.

We report 3 patients of chronic arsenic poisoning with characteristic skin changes. All 3 patients had a past history of asthma and were treated with Traditional Chinese Medication. We believe that the Chinese medications were the source of arsenic poisoning. Two of the 3 patients also had internal malignancy. The association of arsenic with internal malignancy is reviewed.

Auto-antibodies in the hospitalised Oriental elderly.

Aches and pains are a common problem in the elderly and often a positive auto-antibody result is difficult to interpret in the given clinical setting. We studied 96 unselected hospitalised Oriental elderly aged 65 years and above to determine the prevalence of auto-antibodies and their clinical significance. Anti-nuclear antibody (ANA) was positive in 33%; commonest titres were low (i.e. 1:40); commonest patterns were speckled and homogeneous; 44% had no known cause for a positive result apart from their age; 37% were taking drugs known to be associated with a positive ANA and 19% had both a disease and a drug known to be associated with a positive ANA. Rheumatoid factor (RF) was positive in 16%; 47% had titres < or = 40 IU/ml and 87% had no known cause of positive RF. Other auto-antibodies tested were negative. We conclude that the prevalence of auto-antibodies in the hospitalised Oriental elderly are common and of no clinical significance if accompanying features of an auto-immune disease are absent.

Tuberculosis chemotherapy--developments in Singapore from 1957-1982.

The last 25 years have seen many important developments in tuberculosis chemotherapy in Singapore. Beginning in the 1950s, chemotherapy consisting of streptomycin (S), isoniazid (H) and p-aminosalicylic acid (PAS) was introduced at first with 2-drug and later 3-drug combinations (i.e., SPH/PH for a total of 18 to 24 months). In the 1960s, 2 early studies showed that thiacetazone (T) could not be substituted for PAS in standard chemotherapy as it was a more toxic and less potent drug. Routine tuberculosis treatment achieved good results for patients followed up for 5 years after completing treatment. A fully supervised regimen of streptomycin and isoniazid (S2H2) given twice weekly proved to be as effective as a largely self administered regimen of PAS/INH. Ethambutol (EMB) was shown to be effective in the initial treatment of pulmonary tuberculosis when combined with isoniazid. In the 1970s, rifampicin (R) was first investigated starting with an intermittent regimen of isoniazid and rifampicin given once or twice weekly. The success of this regimen led to 2 short course studies of 6-month regimens. Rifampicin was given daily for the full duration of 6 months (2SHRZ/HR; 2SHRZ/HRZ; Z = pyrazinamide) or intermittently 3 times a week in the continuation phase (2SHRZ/H3R3; 2HRZ/H3R3; 1SHRZ/H3R3). All the 6 months regimens were highly effective.

Four-month chemotherapy in the treatment of smear-negative pulmonary tuberculosis: results at 30 to 60 months.

INTRODUCTION: Most patients with active pulmonary tuberculosis (PTB) are treated with a 6-month short course regimen. The purpose of the present study was to assess the efficacy of using 4 months of chemotherapy to treat patients with smear-negative PTB. METHODS: A total of 314 patients were randomised to a daily or combined (daily and intermittent) regimen as follows: (1) 2HRZ/2HR--2 months of isoniazid (H), rifampicin (R) and pyrazinamide (Z), followed by 2 months of H and R or (2) 2HRZ/2H3R3--2 months of HRZ as in regimen 1, followed by H and R given 3 times weekly for 2 months or 4 months if initial sputum specimens were culture positive. RESULTS: One hundred and fifty-eight patients were assigned to the daily regimen and 156 to the combined regimen. Of the 158 patients, 99 had negative cultures and 59 had positive cultures. There was no relapse among 96 culture-negative patients assessed at 30 months and 68 patients at 60 months. However, 6 patients had no radiological response while 1 was considered on review to have non-tuberculous disease. There was no relapse among 57 culture-positive patients assessed at 30 months and 41 at 60 months. In the combined regimen group, 102 had negative cultures and 54 had positive cultures. There was 1 relapse in the culture-negative group of 100 patients assessed at 30 months and 74 at 60 months. There was no radiological response in 5 patients. One patient in the culture-positive group failed therapy but there were no relapses during follow-up to 60 months. CONCLUSION: A 4-month daily or combined regimen appears to be highly effective in the treatment of non-immunocompromised patients with smear- and culture-negative PTB.

Are antacids necessary as routine prescriptives with non-steroidal anti-inflammatory drugs?

In Singapore, there exists a local habit to routinely prescribe antacids with non-steroidal anti-inflammatory drugs (NSAIDs) perhaps in the belief that gastrointestinal (GI) symptoms and complications are common, and that antacids protect from them. We prospectively studied 140 adults in an orthopaedic clinic who were prescribed a short course of NSAIDs (1 to 4 weeks) without antacids to determine the frequency and severity of GI symptoms. Symptomatic patients were then given antacids to determine their effect on the GI symptoms and followed up by telephone interview. These patients had mild inflammation, soft tissue rheumatism, injury or degenerative disease. All were otherwise well with no known peptic ulcer disease or major illness and were not on ulcerogenic drugs. Only 13 (9.3%) had significant GI symptoms, of which 6 (4.2%) of the total took antacid and 5 (3.5%) had partial or total relief. In this study, GI symptoms were not common with short course NSAIDs in otherwise well patients. Antacids may afford symptomatic relief for GI symptoms. However, because antacids may offer no significant protection against NSAID-induced peptic ulcer, may dangerously mask symptoms of GI irritation, may be troublesome to take and costly on a large scale, we should stop routine prescription of antacids in patients requiring only short-term NSAIDs and not at risk for peptic ulcer disease.