Cleft Laterality Dental Arch Relationship Outcomes for Children with Unilateral Cleft Lip and Palate in New Zealand.

OBJECTIVES: To investigate cleft laterality dental arch relationship outcomes of children with non-syndromic complete unilateral cleft lip and palate (UCLP) in New Zealand. DESIGN: A retrospective nationwide study. SETTINGS: Virtual 3D orthodontic study models collected prior to undertaking secondary alveolar bone grafting. PARTICIPANTS: A total of 104 patients with UCLP (L = 80: R = 24). OUTCOME MEASURES: Four calibrated assessors used the GOSLON Yardstick and 100 mm Visual Analogue Scale (VAS) to score the randomised models on 2 separate assessment sessions. Weighted Kappa were used to determine the intra/inter-rater reliability for the GOSLON and correlations for the VAS. RESULTS: Intra-rater reliability ranged from 0.57-0.88 (GOSLON) and 0.45-0.93 (VAS). Inter-rater reliability ranged from 0.62-0.86 (GOSLON) and 0.64-0.93 (VAS).GOSLON scores for the left UCLP were 31.2% for good/very good; 26.3% for fair; 42.5% for poor/very poor while the right UCLP scored 8.3% for good/very good; 37.5% for fair; 54.2% for poor/very poor. The mean VAS for left and right UCLP were 53.4 (sd 22.5) and 44.6 (sd 17.1) respectively. Neither the GOSLON nor VAS differences reached statistical significance (both P = .08). CONCLUSIONS: From a clinical perspective right UCLP had worse dental arch relationship outcomes, however, these differences failed to reach statistical significance. Further studies using larger sample sizes are required to determine if cleft laterality is an important consideration when investigating UCLP dental arch outcomes.

Randomized Controlled Study to Evaluate Microbial Ecological Effects of CPP-ACP and Cranberry on Dental Plaque.

INTRODUCTION: Ecological approaches to dental caries prevention play a key role in attaining long-term control over the disease and maintaining a symbiotic oral microbiome. OBJECTIVES: This study aimed to investigate the microbial ecological effects of 2 interventional dentifrices: a casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) dentifrice and the same dentifrice supplemented with a polyphenol-rich cranberry extract. METHODS: The interventional toothpastes were compared with each other and with an active control fluoride dentifrice in a double-blinded randomized controlled trial. Real-time quantitative polymerase chain reaction (qPCR) analysis was used to determine changes in the bacterial loads of 14 key bacterial species (8 caries associated and 6 health associated) in the dental plaque of trial participants after they used the dentifrices for 5 to 6 wk. RESULTS: From the baseline to the recall visit, significant differences were observed between the treatment groups in the bacterial loads of 2 caries-associated bacterial species (Streptococcus mutans [P < 0.001] and Veillonella parvula [P < 0.001]) and 3 health-associated bacterial species (Corynebacterium durum [P = 0.008], Neisseria flavescens [P = 0.005], and Streptococcus sanguinis [P < 0.001]). Compared to the fluoride control dentifrice, the CPP-ACP dentifrice demonstrated significant differences for S. mutans (P = 0.032), C. durum (P = 0.007), and S. sanguinis (P < 0.001), while combination CPP-ACP-cranberry dentifrice showed significant differences for S. mutans (P < 0.001), V. parvula (P < 0.001), N. flavescens (P = 0.003), and S. sanguinis (P < 0.001). However, no significant differences were observed in the bacterial load comparisons between the CPP-ACP and combination dentifrices for any of the targeted bacterial species (P > 0.05). CONCLUSIONS: Overall, the results indicate that dentifrices containing CPP-ACP and polyphenol-rich cranberry extracts can influence a species-level shift in the ecology of the oral microbiome, resulting in a microbial community less associated with dental caries (Australian New Zealand Clinical Trial Registry ANZCTR 12618000095268). KNOWLEDGE TRANSFER STATEMENT: The results of this randomized controlled trial indicate that dentifrices containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and polyphenol-rich cranberry extracts were able to beneficially modulate the microbial ecology of dental plaque in a group of high caries-risk patients. This could contribute toward lowering the risk of developing new caries lesions, an important goal sought by patients, clinicians, and policy makers.

Prevention and caries risk management in teenage and orthodontic patients.

As patients progress from childhood through to teenage years, they progress through periods of high caries risk as they undergo changes in lifestyle and oral microflora. Removable or fixed orthodontic treatment also alters the oral microflora and can dramatically increase caries risk. This paper outlines ways to identify the transition to higher caries risk, and practical ways to lower the risk of hard tissue loss from dental caries during orthodontic treatment across the teenage years, including tooth surface protection, optimised use of mechanical and chemical plaque control, and appropriate delivery of remineralising agents over time.

Does behavioural inhibition system dysfunction contribute to Attention Deficit Hyperactivity Disorder?

The Reinforcement Sensitivity Theory of Personality has as its main foundation a Behavioural Inhibition System (BIS), defined by anxiolytic drugs, in which high trait sensitivity should lead to internalising, anxiety, disorders. Conversely, it has been suggested that low BIS sensitivity would be a characteristic of externalising disorders. BIS output should lead to increased arousal and attention as well as behavioural inhibition. Here, therefore, we tested whether an externalising disorder, Attention Deficit Hyperactivity Disorder (ADHD), involves low BIS sensitivity. Goal-Conflict-Specific Rhythmicity (GCSR) in an auditory Stop Signal Task is a right frontal EEG biomarker of BIS function. We assessed children diagnosed with ADHD-I (inattentive) or ADHD-C (combined) and healthy control groups for GCSR in: a) an initial smaller study in Dunedin, New Zealand (population ~120,000: 15 control, 10 ADHD-I, 10 ADHD-C); and b) a main larger one in Tehran, Iran (population ~9 [city]-16 [metropolis] million: 27 control, 18 ADHD-I, 21 ADHD-C). GCSR was clear in controls (particularly at 6-7 Hz) and in ADHD-C (particularly at 8-9 Hz) but was reduced in ADHD-I. Reduced attention and arousal in ADHD-I could be due, in part, to BIS dysfunction. However, hyperactivity and impulsivity in ADHD-C are unlikely to reflect reduced BIS activity. Increased GCSR frequency in ADHD-C may be due to increased input to the BIS. BIS dysfunction may contribute to some aspects of ADHD (and potentially other externalising disorders) and to some differences between the ADHD subtypes but other prefrontal systems (and, e.g. dopamine) are also important.

Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases.

Background: Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods: Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results: After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50-0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61-0.81). Rates of treatment-related hepatic adverse events (primarily grade 1-2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions: After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration: CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Intuitive eating is associated with glycaemic control in adolescents with type I diabetes mellitus.

BACKGROUND: While there have been considerable advances in the medical management of type 1 diabetes mellitus (T1DM), for many, glycaemic control remains substandard. Nutrition and eating behaviour are important additional factors to consider with regards to T1DM management and outcomes. Intuitive eating is one such factor, and has not previously been investigated in T1DM. With this in mind, we undertook a study examining the relationship between intuitive eating and glycaemic control in adolescents with T1DM. METHODS: A case-control study of adolescents with established T1DM, and age/sex matched controls was conducted. Demographic information, the Intuitive Eating Scale (IES), and HbA1c were collected. Statistical analysis was undertaken to explore associations between the IES and HbA1c as a marker of glycaemic control. RESULTS: Data on 38 adolescents with T1DM, and 39 age/sex matched controls were obtained. Those with T1DM had significantly lower (by 0.5 SD) IES scores compared to controls (p = 0.009). Higher values of both total IES and the Eating for physical rather than emotional reasons subscale were associated with lower HbA1c: HbA1c 22% lower/whole unit increase in total IES mean score, HbA1c 11% lower/whole unit increase in Eating for physical rather than emotional reasons mean score, p = 0.017 and p = 0.009 respectively. CONCLUSION: In adolescents with T1DM, there appears to be a strong association between intuitive eating, in particular the effect of emotion on eating, and glycaemic control. In addition, those with T1DM have lower scores for their intuitive eating behaviour compared to controls. Emotional eating could be a future target for screening and potentially intervening in those with T1DM, as part of a wider treatment package to improve glycaemic control. Continuing efforts are needed to fully understand the important dynamics of diabetes, adolescence, diet, emotion, and how these factors affect long term outcomes in those with T1DM.

Family CHAOS is associated with glycaemic control in children and adolescents with type 1 diabetes mellitus.

BACKGROUND: Despite advances in the medical management of type 1 diabetes mellitus (T1DM), for many, glycaemic control remains substandard. Other factors are clearly important in determining success, or lack thereof, with diabetes management. With this in mind, we have investigated whether family CHAOS may provide a novel tool to identify when environmental confusion could impact on diabetes management and subsequent glycaemic control. METHODS: A case-control study of children and adolescents with established T1DM and age-/sex-matched controls was conducted. Demographic information, both maternal and paternal CHAOS scores, and HbA1c were collected. Statistical analysis was undertaken to explore associations between T1DM and CHAOS and between CHAOS and HbA1c. RESULTS: Data on 65 children with T1DM and 60 age-/sex-matched controls were obtained. There was no evidence of group differences for maternal CHAOS (p = 0.227), but paternal CHAOS scores were higher for the T1DM group (p = 0.041). Greater maternal and paternal CHAOS scores were both associated with higher HbA1c (p ≤ 0.027). The maternal association remained after controlling for diabetes duration, SMBG frequency, and insulin therapy. CONCLUSION: In children with T1DM, there appears to be a negative association between increased environmental confusion, as rated by CHAOS, and glycaemic control. In addition, when compared to controls, fathers of children and adolescents with T1DM appear to experience CHAOS differently to mothers. These findings contribute to the growing body of literature exploring psychosocial factors in T1DM. Continuing efforts are required to fully understand how the family and psychosocial environment interact with diabetes to impact on long-term health outcomes.

Genetic variation in the structural pattern of osteoclast activity during post-natal growth of mouse femora.

While the spatial activity of osteoblasts has been associated with modeling of bones during development, few studies have examined if variation in the spatial activity of osteoclasts also contributes to the morphogenesis of skeletal tissues. We examined this question by histomorphometric analysis and reconstructing the three-dimensional spatial distribution of osteoclasts in the femora of three inbred strains of male mice (A/J, C57BL/6J [B6], and C3H/HeJ [C3H]) that have differing skeletal, structural, and material properties. Our data show that total osteoclast surface area and osteoclast numbers are related to the overall bone density, but not related to the development of bone diameter or overall cortical area. The analysis of the spatial distribution of the osteoclasts showed that the asymmetrical mid-diaphyseal distribution of osteoclasts in A/J and B6 compared to the more uniform distribution of these cells around the circumference in the C3H mice was consistent with the more ellipsoid shape of A/J and B6 femora compared to the more circular mid-diaphyseal shape of the femora in the C3H mice. The statistically 2- to 3-fold fewer cells on the periosteal surface in the C3H compared to either the B6 or A/J mice is also consistent with the greater cortical thickness that is seen for the C3H mice compared to either B6 or A/J strains. In vitro studies of osteoclastogenesis and the expression of numerous phenotypic properties of osteoclasts prepared from the three strains of mice showed that A/J and B6 mice developed statistically greater numbers of tartrate resistant acid phosphatase (TRAP) positive cells and expressed statistically higher levels of multiple mRNAs that are unique to differentiated osteoclasts than those isolated from the C3H strain. In summary, the 3D reconstructions and histomorphometric analysis suggest that genetic differences lead to spatial variation in the distribution of osteoclasts. These variations in spatial distribution of osteoclasts in turn contribute in part to the development of the structural variations of the femora that are seen in the three strains of mice. In vitro studies suggest that intrinsic genetic variation in osteoclastogenesis and their phenotypic expression may contribute to the differences in their functional activities that give rise to the unique spatial distributions of these cells in bones.

The Dimensions of Expansion: report of the 2007 NZAO Symposium.

The biennial symposium of the Education, Research and Development Group (ERDG) of the New ZealandAssociation of Orthodontists (NZAO) was held in Queenstown on August 17 and 18, 2007. Following a well-tested format, the symposium considered the effects of expansion of the dental arches in the three planes of space and over time, a timely but difficult topic given the current fashion to avoid the extraction of teeth to correct dental crowding. The findings reported here represent the consensus reached by delegates attending the symposium.

Dendritic cells for active immunotherapy: optimizing design and manufacture in order to develop commercially and clinically viable products.

Dendritic cell (DC) active immunotherapy is potentially efficacious in a broad array of malignant disease settings. However, challenges remain in optimizing DC-based therapy for maximum clinical efficacy within manufacturing processes that permit quality control and scale-up of consistent products. In this review we discuss the critical issues that must be addressed in order to optimize DC-based product design and manufacture, and highlight the DC based platforms currently addressing these issues. Variables in DC-based product design include the type of antigenic payload used, DC maturation steps and activation processes, and functional assays. Issues to consider in development include: (a) minimizing the invasiveness of patient biological material collection; (b) minimizing handling and manipulations of tissue at the clinical site; (c) centralized product manufacturing and standardized processing and capacity for commercial-scale production; (d) rapid product release turnaround time; (e) the ability to manufacture sufficient product from limited starting material; and (f) standardized release criteria for DC phenotype and function. Improvements in the design and manufacture of DC products have resulted in a handful of promising leads currently in clinical development.

Acute renal failure due to mantle cell lymphoma--a case report and discussion of the literature.

Acute renal failure secondary to lymphomatous infiltration of the kidneys is a rare manifestation raer mantle cell lymphoma (MCL). We present the case of a 76-year-old gentleman with acute renal failure an a background of previously treated low grade non-hodgkin lymphoma. At the time of presentation he complained only of mild lethargy und had no lymphadenopathy or organomegaly. Renal ultrasound revealed bilaterally enlarged kidneys and renal biopsy confirmed MCL. Mantle cell lymphoma runs an aggressive course and accurate diagnosis is very important in guiding appropriate treatment. This case demonstrates the importance of renal biopsy in the diagnosis of renal lymphomatous infiltration but also highlights the potential utility of histological examination in guiding targeted therapy.

Orthodontic movement of two root fractured teeth: a case report.

AIM: To illustrate significant tipping orthodontic movement of root fractured teeth. SUMMARY: As the frequency of root fractured maxillary teeth is related to increased overjet and reduced lip coverage, orthodontic treatment may increase lip coverage and reduce the risk of trauma or its severity. It may also be necessary to move previously traumatized teeth. Two root fractured teeth were tipped through a considerable angle (19 degrees ) to reduce a large overjet and followed up for 5 years. KEY LEARNING POINTS: -- Reduction of large overjets involving root fractured teeth may not affect pulp vitality. -- Root fragment separation prior to orthodontics did not appear to increase in this patient, but angulation of the fragments did not completely follow the major change to the coronal part of the tooth.

Unusual fatal dog attack in Dunedin, New Zealand.

A case of a fatal dog attack on a middle aged woman is presented. The offending dog was her own Bull-mastiff, which had previously shown signs of aggression towards her. Most of the injuries were found on the victim's face, neck and skull. A noteworthy feature of this attack was that the victim was known to suffer from Huntington disease. It is postulated that the involuntary movements, progressive dementia and increased moodiness characteristic of the disease may have had a significant role in triggering the attack.

Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). DESIGN: Cross-sectional genetic study. PARTICIPANTS: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. METHODS: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. CONCLUSIONS: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

A multi-institutional phase II study of BMS-182248-01 (BR96-doxorubicin conjugate) administered every 21 days in patients with advanced gastric adenocarcinoma.

PURPOSE: High levels (> 200,000 molecules per carcinoma cell) of the LewisY antigen are expressed on the surface of most (> 75%) gastric carcinomas. The BMS-182248-01 is a chimeric variant of anti-LewisY monoclonal antibody that is conjugated with doxorubicin. In a phase I study, BMS-182248-01 resulted in a partial response in a patient with gastric carcinoma. We, therefore, conducted a multi-institutional phase II study of BMS-182248-01 in patients with advanced gastric carcinoma. METHODS AND PATIENTS: Only patients with evidence of LewisY antigen by immunohistochemical method on their gastric carcinoma were treated. Patients with unresectable gastric adenocarcinoma were eligible. Patients had to have adequate liver, renal, and marrow functions. Written consent was obtained from all patients. All patients were hospitalized. BMS-182248-01 was administered at the starting dose of 700 mg/m2 i.v. over 24 hours on day 1 every 3 weeks. RESULTS: Fifteen patients were enrolled. There were 10 men and 5 women. The median age at enrollment was 56 years, with ages ranging from 34 to 80 years. No objective responses were observed. Five patients had disease stabilization. The remaining 10 patients progressed on study. Rapidly reversible gastrointestinal toxicity, primarily nausea and emesis, was predominant. There was no neutropenia, thrombocytopenia, or cardiomyopathy. CONCLUSIONS: Although BMS-182248-01 represents a novel approach of monoclonal antibody conjugated with an active chemotherapy agent, delivered intracellularly, it was ineffective in patients with gastric carcinoma whose tumors carried LewisY antigen.

Accuracy and implications of a reported family history of glaucoma: experience from the Glaucoma Inheritance Study in Tasmania.

OBJECTIVES: To ascertain the prevalence of previously undiagnosed primary open-angle glaucoma (POAG) within 5 large POAG pedigrees and to evaluate the reliability of a reported family history of glaucoma within these pedigrees. METHODS: The Glaucoma Inheritance Study in Tasmania (GIST) identified several large adult POAG pedigrees. Intraocular pressure (IOP), optic disc stereophotography, and automated perimetry were performed on all adult pedigree members. Participants were classified as normal (IOP <22 mm Hg and normal optic disc and field); glaucoma suspect (normal field, but an IOP >/=22 mm Hg and/or suspicious optic disc); or POAG (field defect and glaucomatous optic disc). Some individuals with POAG had been previously diagnosed by their local ophthalmologist; others were diagnosed as a result of the GIST project. Family members with a prior diagnosis of POAG were asked to report if they were aware of any relatives with POAG. This reported family history was then directly compared with the actual pedigree (before the diagnosis of new cases) to calculate agreement. MAIN OUTCOME MEASURE: The rate of glaucoma in pedigrees and percentage of previously diagnosed glaucoma cases who were aware of the positive family history of POAG. RESULTS: Four hundred forty-two subjects (mean age, 54 years [range, 13-97 years]) from 5 pedigrees were examined: 316 subjects (71%) were normal, 47 (11%) were previously diagnosed with POAG, and 8 (2%) were previously diagnosed glaucoma suspects; 30 cases (7%) of POAG and 41 suspects (9%) were newly diagnosed as a direct result of the GIST examination. Of the 47 previously diagnosed POAG cases, 41 were questioned about their prior knowledge of any family history and 11 (27%) were unaware of their family history of POAG. CONCLUSIONS: Examination of all adult subjects from POAG families yields new cases. Even in large POAG pedigrees, 27% of previously diagnosed POAG patients were unaware of their positive family history. These findings suggest that a higher percentage of adult POAG may be inherited than hitherto reported. Arch Ophthalmol. 2000;118:900-904

Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors.

PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti-Lewis Y (Le(Y)) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the Le(Y) antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox. PATIENTS AND METHODS: This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles. RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m(2) (doxorubicin equivalent, 25 mg/m(2)) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m(2) BR96-Dox (doxorubicin equivalent, 19 mg/m(2)) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m(2) dose, the half-life (mean +/- SD) of BR96 and doxorubicin was 300 +/- 95 hours and 43 +/- 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients. CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to Le(Y)-expressing tumor and was well tolerated at doses of 700 mg/m(2) every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.

Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer.

PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease. RESULTS: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent. CONCLUSION: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.

Factors involved in the pathogenesis of neutrophilic vasculitis in MRL/Mp-lpr/lpr mice: a model for human microscopic angiitis.

Anti-neutrophil cytoplasm antibodies (ANCA) directed against myeloperoxidase (MPO) are detected in patients with microscopic angiitis. Human MPO autoantibodies stimulate neutrophil degranulation in vitro and are thought to be pathogenic. We have previously shown that MRL-lpr mice with MPO autoantibodies have a higher incidence of vasculitis than their seronegative littermates. The aim of the present study is to determine the relationship between MPO autoantibodies and microscopic angiitis. The neutrophil binding properties of anti-MPO monoclonal antibodies (mAbs) from MRL-lpr mice were tested using murine heterophils (neutrophils) present in blood and induced peritoneal exudates. MRL anti-MPO mAbs selectively bind activated neutrophils which express MPO in vitro. The pathogenicity of an IgG2b anti-MPO mAb, C6, was investigated in vivo. Anti-MPO mAb, C6 was administered to young MRL mice which had been primed with exogenous TNF alpha to induce neutrophil activation and expression of MPO. Neutrophilic vasculitis similar to microscopic angiitis occurred in 33% of MRL mice which had been treated with anti-MPO mAb. The lesions were mainly restricted to sites of previous endothelial insult which suggests an active role for injured endothelium in this pathology.