Purpose It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. Experimnetal Design A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. Results 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Conclusion Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

Because inner ear symptoms are common in patients with migraine, we questioned whether benign positional vertigo (BPV) is more common in patients with migraine than in the general population. We reviewed the records of 247 patients seen in our neurotology clinic over the past 5 years with a confirmed diagnosis of BPV. Each patient had the typical history of BPV, and in each case the characteristic torsional vertical positioning nystagmus was identified. All were interviewed regarding migraine symptoms by means of standard International Headache Society criteria. Migraine was 3 times more common in patients with BPV of unknown cause than in those with BPV secondary to trauma or surgical procedures. Most patients were cured with the particle repositioning maneuver, regardless of the cause. Presumably, patients with migraine suffer recurrent damage to the inner ear (due to vasospasm or some other mechanism) that predisposes them to recurrent bouts of BPV.

The partial sparing of the inferior vestibular labyrinth may indicate a decreased vulnerability to ischemia because of its better collateral blood supply.

Normal sensory transduction requires the efficient disposal of acid (H+) generated by neuronal and sensory receptor activity. Multiple highly sensitive transport mechanisms have evolved in prokaryotic and eukaryotic organisms to maintain acidity within strict limits. It is currently assumed that the multiplicity of these processes provides a biological robustness. Here we report that the visual and auditory systems have a specific requirement for H+ disposal mediated by the sodium bicarbonate cotransporter NBC3 (refs. 7,8). Mice lacking NBC3 develop blindness and auditory impairment because of degeneration of sensory receptors in the eye and inner ear as in Usher syndrome. Our results indicate that in certain sensory organs, in which the requirement to transduce specific environmental signals with speed, sensitivity and reliability is paramount, the choice of the H+ disposal mechanism used is limited.

The sudden left-sided deafness likely resulted from ischemia, possibly due to migraine-associated vasospasm. Presumably, the right ear suffered only minimal damage when the patient was 50 years old, but this damage later led to the development of delayed endolymphatic hydrops on the right. Otolithic crises are thought to result from pressure changes across the utricular macule. We speculate that loss of hair cells in the utricular macule resulted from a collapse of the utricular membrane onto the macule.

We report the immunolocalization of aquaporins (AQPs) 1, 4, and 6 in the human auditory and vestibular endorgans. A rapid protocol was applied to audiovestibular endorgans microdissected from postmortem human temporal bones from six subjects (ages ranging from 75 to 97 years) with no history of audiovestibular disease. Temporal bones were fixed in formalin, and the endorgans were immediately microdissected. Cryostat sections were obtained from audiovestibular endorgans and were subjected to double-immunohistochemical staining with antibodies against AQPs and several cellular markers. In the human cochlea, AQP1 immunoreactivity was localized to the fibrocytes of the spiral ligament and the sub-basilar tympanic cells; AQP4 immunoreactivity was localized to the outer sulcus cells, Hensen's cells, and Claudius' cells; AQP6 immunoreactivity was localized to the apical portion of interdental cells in the spiral limbus. In the vestibular endorgans (macula utriculi and cristae), AQP1 was localized to fibrocytes and blood vessels of the underlying stroma and trabecular perilymphatic tissue; AQP4 immunoreactivity was localized to the basal pole of vestibular supporting cells; AQP6 was localized to the apical portion of vestibular supporting cells. Cochlear and vestibular hair cells and nerve fibers were not immunoreactive for any AQP. Supporting cells were identified with antibodies against glial fibrilar acidic protein. Nerve fibers and terminals were identified with antibodies against neurofilaments and Na(+)K(+)ATPase. The high degree of conservation of AQP expression in the human inner ear suggests that AQPs play a critical role in inner ear water homeostasis.

Papillary squamous neoplasms of the upper respiratory tract are rare variants of squamous cell carcinoma and are related temporally to proliferative verrucous leukoplakia. Fifty-two cases of papillary squamous neoplasms were selected from 2366 cases of squamous cell carcinoma. This is the first study to characterize the biological behavior of papillary squamous neoplasms. Papillary squamous neoplasms exhibit two distinct, yet sometimes overlapping, histologic patterns including an exophytic papillary and an inverting verrucous morphologic appearance. A high rate of synchronous or metachronous lesions were found, especially with the inverting-type of papillary squamous neoplasm. Stage T3 and T4 lesions had a high rate of neck metastasis. Early surgical intervention and close long-term follow-up is mandatory.

Increased cochlea/medulla ratio indicates increased blood-labyrinth barrier permeability in Menière disease compared with idiopathic sudden sensorineural hearing loss. Increased cochlea/medulla ratio in asymptomatic ears of patients with Menière disease also suggests an underlying systemic cause of Menière disease and may provide a pathophysiologic biomarker.