Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

A prospective investigation of pulmonary embolism in women and men.

OBJECTIVE. The aim of this study was to compare, in women and men suspected of pulmonary embolism, the frequency, risk factors, diagnosis, and presentation of pulmonary embolism as well as the accuracy of the ventilation/perfusion scan (V/Q scan) as a diagnostic tool. DESIGN. Data were collected during a prospective study (the Prospective Investigation of Pulmonary Embolism Diagnosis) to establish the accuracy of the V/Q scan compared with pulmonary angiograms. SETTING. Six tertiary medical centers in Massachusetts, Michigan, Connecticut, Pennsylvania, and North Carolina. PARTICIPANTS. Patients suspected of pulmonary embolism for whom a request was made for a V/Q scan or pulmonary angiogram (496 women and 406 men). RESULTS. Women 50 years old and under had a decreased frequency of pulmonary embolism compared with men of that age (16% vs 32%), but there was no difference in patients over 50 years old (Breslow-Day test, P less than .01). Risk factors for pulmonary embolism, the usefulness of the V/Q scan, and 1-year mortality were not different for women and men. Estrogen use in women was not associated with an increased frequency of pulmonary embolism, except in women using oral contraceptives who had undergone surgery within 3 months; four of five (80%) had emboli compared with four of 28 (14%) age-matched surgical patients not using estrogens (P less than .01). CONCLUSION. Women 50 years old and under (even young women using oral contraceptives) who were suspected of having pulmonary emboli and were enrolled in the Prospective Investigation of Pulmonary Embolism Diagnosis study had a smaller frequency of pulmonary embolism than men of that age, The risk factors for pulmonary embolism were the same for women and men, except that women using oral contraceptives had an increased risk of pulmonary embolism following surgery. Although the V/Q scan was a useful tool in the preliminary evaluation for pulmonary embolism in these women, a pulmonary angiogram was often needed for accurate diagnosis.     

Mutation analysis of feline Niemann-Pick C1 disease

Niemann-Pick C (NPC) disease is an autosomal recessive neurovisceral lysosomal storage disorder that results in defective intracellular transport of cholesterol. The major form of human NPC (NPC1) has been mapped to chromosome 18, the NPC1 gene (NPC1) has been sequenced and several mutations have been identified in NPC1 patients. A feline model of NPC has been characterized and is phenotypically, morphologically, and biochemically similar to human NPC1. Complementation studies using cultured fibroblasts from NPC affected cats and NPC1 affected humans support that the gene responsible for the NPC phenotype in this colony of cats is orthologous to human NPC1. Using human-based PCR primers, initial fragments of the feline NPC cDNA were amplified and sequenced. From these sequences, feline-specific PCR primers were generated and designed to amplify six overlapping bands that span the entire feline NPC1 open reading frame. A single base substitution (2864G-C) was identified in NPC1 affected cats. Obligate carriers are heterozygous at the same allele and a PCR-based assay was developed to identify the geneotype of all cats in the colony. The mutation results in an amino acid change from cysteine to serine (C955S). Several of the mutations identified in people occur in the same region. Marked similarity exists between the human and feline NPC1 cDNA sequences, and is greater than that between the human and murine NPC1 sequences. The human cDNA sequence predicts a 1278aa protein with a lysosomal targeting sequence, several trans-membrane domains and extensive homology with other known mediators of cholesterol homeostasis.     

Fine-needle aspiration cytology of pancreatic somatostatinoma: the importance of immunohistochemistry for the cytologic diagnosis of pancreatic endocrine neoplasms

Pancreatic somatostatinoma is a rare pancreatic endocrine neoplasm representing as little as 1% of pancreatic endocrine neoplasms (PENs). The histologic features of this tumor are like those of other PENs, except that it commonly forms acinar structures and often has cells with abundant, granular cytoplasm. We have recently encountered two of these neoplasms sampled by endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). We discuss the cytologic and immunohistochemical findings of these two cases and the cytologic similarities these neoplasms share with pancreatic acinar-cell carcinoma (PACC). We review the cytologic features of PEN and PACC and discuss the importance of cell block immunohistochemistry in the diagnosis of pancreatic neoplasia sampled by EUS-guided FNA.     

Abnormalities of pathways of fibrin turnover in lung lavage of rats with oleic acid and bleomycin-induced lung injury support alveolar fibrin deposition.

Alveolar fibrin deposition commonly accompanies acute lung injury, but the nature of the local abnormalities of coagulation and fibrinolysis that support pathologic fibrin deposition are not well understood. The trended abnormalities of procoagulant and fibrinolytic activities occurring in lung lavage fluids of Fischer 344 rats after lung injury induced by intravenous oleic acid (OA) or intratracheal bleomycin were studied. After injury by either agent, bronchoalveolar lavage (BAL) contained increased procoagulant activity and decreased fibrinolytic activity. Lavage procoagulant activity was mainly due to an activator of Factor X attributable to the extrinsic coagulation pathway, and fibrinolytic activity was almost completely plasminogen dependent. Major mechanisms of inhibition of fibrinolytic activity involved both the inhibition of the plasminogen activator (PA) and plasmin. These abnormalities were temporally associated with prominent alveolar fibrin deposition in both models. In OA-treated animals, lavage fibrinolytic activity was absent or profoundly decreased, and antiplasmin and procoagulant activities were increased within 4 hours after the induction of acute lung injury. By 24 hours after OA, lavage PA inhibitor (PAI) activity was elevated with sustained antiplasmin activity. By 3 days after OA, these abnormalities had resolved in association with almost complete resolution of alveolar fibrin deposits. Within 3 days after bleomycin-induced lung injury, lavage procoagulant activity was increased and fibrinolytic activity was depressed due to increased antiplasmin and PAI activities. These conditions persisted for 2 weeks, during which time alveolar fibrin deposition was associated with the development of pulmonary fibrosis. These data indicate that a disruption of the normal balance between procoagulant and fibrinolytic activities occurs in alveolar lining fluids of rats with alveolitis induced by either OA or bleomycin, and that concurrent abnormalities of pathways of fibrin turnover that occur in alveolar lining fluids promote the alveolar fibrin deposition associated with these lung injuries.     

Hepatic arterial perfusion scintigraphy with Tc-99m-MAA. Use of a totally implanted drug delivery system

Tc-99m-MAA hepatic arterial perfusion scintigraphy ( HAPS ) using a totally implanted drug delivery system was employed for hepatic arterial chemotherapy in 147 patients (335 studies). Complete perfusion of the involved liver was seen in 88% of patients initially [more so in those with normal hepatic vascular anatomy (93%) than those with vascular variants (79%)] and remained good on follow-up. In 67 consecutive patients (95 studies), arteriovenous shunting to the lung ranged from 0.4 to 32% (mean, 6.2% +/- 4.1 S.D.). Uptake at the tip of the catheter was increased in 20% of patients, but good perfusion was usually maintained. A significant decrease in hepatic and/or extrahepatic perfusion associated with a "hot spot" at the tip of the catheter indicated hepatic arterial thrombosis. Extrahepatic perfusion was seen in 14% of cases, usually in the distribution of the stomach, small bowel, and spleen. Significant symptoms of drug toxicity were seen in 70% of patients with extrahepatic perfusion, compared to 19% of those without it.     

Measuring Tumor Hypoxia

A variety of techniques for measuring oxygen in normal and tumor tissue has been developed over the years in response to the realization that hypoxia is important in a number of pathophysiological conditions in normal tissues and in the response of tumors to radiation treatment. A review of the techniques for measuring tissue oxygenation is presented with an emphasis on clinical results. Histomorphometry, DNA strand break analysis (comet assay), oxygen microelectrodes and hypoxia markers are highlighted. Comparison among techniques is touched on and a short discussion of the possibility that hypoxia is not an independent variable in determining the outcome of radiation therapy is presented.     

A Real-Time Method to Evaluate the Nasal Deposition and Clearance of Acetone in the Human Volunteer

Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled [13 C]acetone at approximately 1 ppm concentration for 30 min under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhale mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 s. A second ion-trap mass spectrometer simultaneously sampled from the volunteer's exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the [13 C]acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart-rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in [13 C]acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analyses of [13 C]acetone concentrations indicate that between 40 and 75% of the compound is absorbed upon inhalation and nearly all of that absorbed is released back into the breath stream during exhalation.