Considerations for Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease.

Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies. To help address these challenges, the US Food and Drug Administration recently published a draft guidance entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease." Here we provide additional information on specific aspects of targeted therapy development in diseases with low-frequency molecular subsets.

A case of cerebellopontine angle meningioma presenting with neck and upper extremity pain.

OBJECTIVE: The purpose of this case report is to describe and discuss the clinical presentation, diagnosis, and management of a patient with a cerebellopontine angle meningioma. CLINICAL FEATURES: A 29-year-old man presented to a chiropractor with diffuse musculoskeletal pain in the neck and right upper extremity. The findings of the clinical examination included a unilateral lower cranial nerve motor deficit. INTERVENTION AND OUTCOME: Magnetic resonance imaging studies of the neck and brain revealed a posterior fossa tumor, which was eventually diagnosed as a benign meningioma. Partial surgical removal of the tumor mass was followed by radiation therapy. Postoperative morbidity was fairly low. Lower cranial nerve function normalized after surgery. CONCLUSION: Patients with brain lesions may present to chiropractic practices with predominantly musculoskeletal symptoms. Chiropractors can aid in the multidisciplinary and integrated management of such conditions through careful interviewing and appropriate neurological examination.

The effects of high-intensity, low-frequency active sonar on rainbow trout.

This study investigated the effects on rainbow trout (Oncorhynchus mykiss) of exposure to high-intensity, low-frequency sonar using an element of the standard Surveillance Towed Array Sensor System Low Frequency Active (LFA) sonar source array. Effects of the LFA sonar on hearing were tested using auditory brainstem responses. Effects were also examined on inner ear morphology using scanning electron microscopy and on nonauditory tissues using general pathology and histopathology. Animals were exposed to a maximum received rms sound pressure level of 193 dB re 1 microPa(2) for 324 or 648 s, an exposure that is far in excess of any exposure a fish would normally encounter in the wild. The most significant effect was a 20-dB auditory threshold shift at 400 Hz. However, the results varied with different groups of trout, suggesting developmental and/or genetic impacts on how sound exposure affects hearing. There was no fish mortality during or after exposure. Sensory tissue of the inner ears did not show morphological damage even several days post-sound exposure. Similarly, gross- and histopathology observations demonstrated no effects on nonauditory tissues.