Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients.

PURPOSE: Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8(+) CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. EXPERIMENTAL DESIGN: FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)-specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-γ release assays and flow cytometry. RESULTS: FcγRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR(853-861)-specific CD8(+) T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR(+) tumor cells and FcγRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ-dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (T(H)1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell-induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3. CONCLUSION: Cetuximab-activated NK cells promote DC maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through "NK-DC cross-talk." FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response.

Perioperative incidence and management of hyponatremia in vWD patients undergoing adenotonsillectomy.

OBJECTIVES/HYPOTHESIS: To analyze the incidence and severity of hyponatremia in patients receiving synthetic desmopressin (DDAVP) in the perioperative setting of oropharyngeal surgery in the treatment of von Willebrand disease and to propose a standardized protocol for perioperative fluid resuscitation and postoperative sodium monitoring after DDAVP administration. STUDY DESIGN: Retrospective medical record review. METHODS: A retrospective medical record review in an academic pediatric medical center was conducted. From October 1, 2002, to February 1, 2009, all patients undergoing adenotonsillectomy and receiving DDAVP preoperatively for the treatment of von Willebrand disease were identified. A total of 76 patients were identified by initial database review; 63 patients were included in the study, and 13 patients were excluded secondary to incomplete data. DDAVP dose and timing, perioperative fluid volume and composition, and postoperative sodium levels were collected. Extreme adverse events related to hyponatremia were recorded. RESULTS: Forty-seven of 63 (74.6%) patients developed some degree of hyponatremia after DDAVP administration, and six of 63 (9.5%) patients developed extreme hyponatremia, with the degree of hyponatremia related to the volume of perioperative fluid resuscitation. The sodium nadir occurred within 9 to 20 hours after DDAVP administration. No serious adverse events related to hyponatremia were recorded during the study period. CONCLUSIONS: The incidence of hyponatremia in children receiving DDAVP for prophylaxis of intraoperative bleeding following oropharyngeal surgery is high. The degree of hyponatremia is related to the perioperative fluid volume administered. A protocol for DDAVP administration, perioperative fluid resuscitation, and postoperative sodium monitoring that aims to reduce the incidence of hyponatremia in this population is proposed.

Immunotherapy for head and neck cancer.

Overall survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has not improved appreciably over the past few decades. Novel therapeutic approaches, such as immunotherapy, are under clinical investigation since the standard treatments are toxic and have not successfully controlled this disease with sufficiently high success rates. Cancer immunotherapy describes various techniques to expand and activate the immune system to control tumor growth in vivo, and clinical evaluation has so far demonstrated low toxicity. Immunotherapy appears to have the most applicability in settings of minimal residual disease and to reduce distant metastases after other therapeutic interventions, and its potential clinical value is now receiving intensive evaluation. Emerging forms of SCCHN immunotherapy involve both the use of monoclonal antibodies (mAb) that target growth factor receptors where immune activation appears to contribute to tumor cell lysis, as well as various forms of active vaccination strategies which activate and direct the patient's cellular immunity against the tumor. This article reviews immunotherapeutic strategies currently in clinical trials or under development for patients with SCCHN.

Papillary thyroid cancer: controversies in the management of neck metastasis.

OBJECTIVE/HYPOTHESIS: To describe our institution's experience with the management of cervical metastasis in papillary thyroid carcinoma (PTC) and suggest a treatment strategy based on the incidence of pathologic nodes and cervical recurrence in patients undergoing varied surgical approaches to address lymphadenopathy over the study dates. MATERIALS AND METHODS: Between December 1, 1972 and September 1, 2007, 183 total patients diagnosed with PTC at the University of Pittsburgh Medical Center were treated with lymphadenectomy. Pathologic parameters, including number of pathologic nodes and extent of lymphadenectomy were correlated to disease recurrence. STUDY DESIGN: Retrospective chart review. RESULTS: The incidence of pathologic nodes in lymphadenectomy specimens (57.9%) and the recurrence rate (33.7%) were high, in our study population. In comparing techniques with address lymphadenopathy, the highest recurrence rate was observed in patients with pathologic nodes treated with "lymph node plucking" procedures at the time of thyroidectomy and those patients with multiple nodes involved. Few patients with no pathologic nodes, regardless of lymphadenectomy extent recurred. CONCLUSIONS: Our data show that limited neck dissection and disease burden are associated with the highest rates of cervical recurrence in regional metastatic PTC. Comprehensive functional neck dissection would seem to offer the patient the best opportunity for control of cervical metastasis. The American Thyroid Association recommends thyroglobulin monitoring and ultrasound evaluation of the neck in all postoperative patients. Therefore patients with the diagnosis of papillary thyroid cancer need preoperative ultrasound of the lateral neck and fine needle aspiration of suspicious nodes to avoid under-treating patients scheduled for total thyroidectomy. Neck dissection of the compartments in which pathologic nodes were detected (central, lateral, or both) should then be undertaken at the time of initial thyroidectomy. Eliminating all disease remains elusive and the prognostic significance of cervical disease persistence and recurrence is still unknown. Patients with cervical metastasis are at substantial risk of regional recurrence, necessitating repeat surgery. Parathyroid implantation should be considered at the time of the initial surgery to reduce the risk of hypoparathyroidism should subsequent procedures be required. More information will be necessary to better understand the prognostic significance of these regional metastases. In the interim, many patients may be over-treated, whereas some remain at risk of death because of disease.