Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3

The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse.     

PS1-17: Assessing Communication During Cancer Care: Multiple Perspectives, Multiple Considerations

Background/Aims Patient-centered communication (PCC) between clinicians and patients is necessary for quality care. Measurement of communication over the cancer care continuum is an important step in describing current practices and remediating breakdowns. As a first step in developing a system to assess PCC longitudinally across the cancer care continuum, we interviewed patients, family members, physicians, health information technology (HIT) leaders, and health plan leaders. The purpose of the present study was to expand our understanding of possible approaches to create and implement such a system by conducting a symposium with experts and stakeholders. Methods We conducted a symposium with experts in the field of HIT, academic researchers, investigators from the 14 Cancer Research Network sites, information technology (IT) advisors from each CRN site, National Cancer Institute staff, and investigators and consultants involved with the project. The purpose of the symposium was to have experts in the field of HIT present possible approaches to computerizing data collection and feedback of patients' experiences with PCC and to engage in an active dialogue around the strengths and weaknesses of the different approaches proposed. Prior to the meeting, we distributed a list of questions for the IT experts to address in their presentations, based on issues, which have been identified during the interviews. The symposium was digitally recorded, professionally transcribed, and coded using grounded theory approaches. Results Themes identified during the symposium focused on contextual factors to be considered when creating a communication feedback system; data liquidity, using one system in multiple healthcare environments that are very diverse, and hat modality to use when there are a variety of preferences for communication and the technology is constantly evolving. The symposium also confirmed themes that emerged from the interviews; the system would need to be flexible and provide choices, the data obtained would need to be aggregated at a meaningful level, and feedback must be timely. Discussion Our multiple pronged approaches have provided us with unique insights that will be used in the development of a prototype data collection system, pilot testing of the system, and ultimately implementation of the system in multiple health plans.     

Complementary and alternative medicine use among newly diagnosed prostate cancer patients

Purpose  

We surveyed prostate cancer patients about complementary and alternative medicine (CAM) use and evaluated patient factors that correlated with CAM use 6 months following diagnosis.     

Parkinsonism and dropped head: Dystonia,myopathy or both?

BackgroundDropped head syndrome (DHS) occurring with parkinsonism is often suggested to be a clue to multiple system atrophy (MSA), but it may occur in other parkinsonian conditions. The substrate for DHS is controversial, with some concluding that the cause is myopathic and others, exclusively dystonic. We report our clinical series of DHS arising in the setting of parkinsonism.MethodsPatients with DHS were initially identified by a retrospective computer search of the Mayo Clinic (Rochester, MN) medical record database from January 1997 to July 2010. Subsequent record review confirmed DHS and documented those with parkinsonism.ResultsWe identified 21 patients with DHS and parkinsonism, 12 male, 9, female. The median age of DHS onset was 69 years (interquartile range: 63.6–77.5 years). This included 10 patients with Parkinson‘s disease (PD), 10 with MSA, and 1 with drug-induced parkinsonism. The DHS component of their disorder segregated into three different subgroups: dystonia-alone (12 patients); myopathy-alone (4 patients; focal cervical myopathy in 3 and generalized myopathy in one); coexisting dystonia and myopathy (5 patients; 3 generalized, 2 focal cervical myopathy).ConclusionsDHS may be seen in either MSA or PD. It may be due to myopathy, dystonia or both. In some cases, the myopathy was focal, confined to the neck musculature. Whether dystonic antecollis predisposes to local muscle pathology is open to speculation.     

Drug-induced hypersensitivity syndrome with human herpesvirus-6 reactivation

A 45-year-old man, on carbamazepine for the past 3 months, was referred as a case of atypical measles. On examination, he had high-grade fever, generalized itchy rash, cough, vomiting and jaundice. A provisional diagnosis of drug hypersensitivity syndrome to carbamazepine was made with a differential diagnosis of viral exanthema with systemic complications. Laboratory investigations revealed leukocytosis with eosnophilia and elevated liver enzymes. Real-time multiplex polymerase chain reaction (PCR) on throat swab and blood was suggestive of human herpesvirus-6 (HHV-6). Measles was ruled out by PCR and serology. The diagnosis of drug-induced hypersensitivity syndrome (DIHS) was confirmed, which could explain all the features manifested by the patient. HHV-6 infects almost all humans by age 2 years. It infects and replicates in CD4 T lymphocytes and establishes latency in human peripheral blood monocytes or macrophages and early bone marrow progenitors. In DIHS, allergic reaction to the causative drug stimulates T cells, which leads to reactivation of the herpesvirus genome. DIHS is treated by withdrawal of the culprit drug and administration of systemic steroids. Our patient responded well to steroids and HHV-6 was negative on repeat real-time multiplex PCR at the end of treatment.     

Atonic variant of benign childhood epilepsy with centrotemporal spikes (atonic-BECTS): a distinct electro-clinical syndrome

Purpose

To describe the clinical and electroencephalographic features, treatment strategies and outcome in a series of children with the atonic variant of benign childhood epilepsy with centrotemporal spikes (atonic-BECTS).

Material and methods

Out of the 148 patients with BECTS reviewed from January 2005 to June 2010 in our Institute, there were seven (5%) with atonic-BECTS. All underwent video EEG, high-resolution magnetic resonance imaging (MRI), neuropsychological evaluation and language assessment. Their progress was followed. In addition to sodium valproate, three were treated with steroids, followed by intravenous immunoglobulin (IVIG) when the seizures relapsed while tapering or after stopping the steroids.

Results

All of the children had earlier onset (mean = 2.4 years), increased frequency and increased duration of focal seizures compared to typical BECTS. Head drop and truncal sway due to axial or axiorhizomelic atonia occurring several times per day or week was the key manifestation. The atonic seizures worsened with carbamazepine in three, clonazepam in two and clobazam in one. When the atypical seizures commenced, some children developed one or more of the following problems: hyperactivity, attention deficit, clumsy gait, and mild cognitive or language dysfunction. Three children became seizure free, one on steroids and the other two on IVIG.

Conclusions

BECTS in children with an early age of onset and frequent and prolonged seizures is more likely to evolve into atonic-BECTS. Carbamazepine and some benzodiazepines may worsen these seizures. Three children became seizure free with immunomodulatory therapy, one on steroids and the other two on IVIG, and had complete resolution of the transient motor and cognitive impairment. Atonic-BECTS needs to be differentiated from Lennox–Gastaut syndrome since it is potentially treatable and children recover with no sequel. Although all the children in this series continued to be on treatment with sodium valproate it is currently undetermined whether they would have required to do so if followed up for an extended period of time.     

Hypothermia for acute brain injury--mechanisms and practical aspects

Hypothermia is widely accepted as the gold-standard method by which the body can protect the brain. Therapeutic cooling--or targeted temperature management (TTM)--is increasingly being used to prevent secondary brain injury in patients admitted to the emergency department and intensive care unit. Rapid cooling to 33 °C for 24 h is considered the standard of care for minimizing neurological injury after cardiac arrest, mild-to-moderate hypothermia (33-35 °C) can be used as an effective component of multimodal therapy for patients with elevated intracranial pressure, and advanced cooling technology can control fever in patients who have experienced trauma, haemorrhagic stroke, or other forms of severe brain injury. However, the practical application of therapeutic hypothermia is not trivial, and the treatment carries risks. Development of clinical management protocols that focus on detection and control of shivering and minimize the risk of other potential complications of TTM will be essential to maximize the benefits of this emerging therapeutic modality. This Review provides an overview of the potential neuroprotective mechanisms of hypothermia, practical considerations for the application of TTM, and disease-specific evidence for the use of this therapy in patients with acute brain injuries.     

Roles of syndecan-1, bcl6 and p53 in diagnosis and prognostication of immunoproliferative small intestinal disease

AIM: To evaluate roles of syndecan-1, bcl6 and p53 in diagnosis and prognostication of immunoproliferative small intestinal disease (IPSID) and to study profiles of kappa (κ) and lambda (λ) light chains and IgA heavy chain. METHODS: The study consisted of 11 cases of IPSID and similar number of controls which included 11 of normal intestinal mucosa and 11 of high grade B cell lymphoma of ileum. The parameters analyzed included clinical profiles, biochemical and other laboratory investigations, radiologic and histological findings including immunohistochemistry. RESULTS: All IPSID cases had demonstrable serum IgA heavy chain and heavy mucosal plasma cell infiltration. According to Galian's histological staging, there were 4 patients with stage A and 7 with stage B.κandλlight chains were over-expressed in 7 patients; 1 stage A patient had H pylori-positive active gastritis and eradication of H pylori led to disease remission. Stage A biopsies had higher expression for syndecan-1, while stage B had higher expression for bcl6 and p53. Syndecan-1,κandλ, light chains and IgA heavy chain showed inverse relationship with bcl6 and p53. All patients were treated with doxycycline. CHOP regime was added in 5 patients who developed frank lymphoma. Three died of the disease due to extensive organ infiltration. CONCLUSION: Certain immunomarkers like syndecan-1,κandλ, light chains and IgA heavy chain could be of much help in identifying early stage IPSID. Stage B IPSID showed higher expression for bcl6 and p53 than stage A IPSID. bcl6 and p53 expressions correlated with a more advanced disease stage and aggressive tumour behavior.