Publications

A recurrent clinical dilemma in the management of patients with painful metastatic lesions is achieving a balance between effective analgesic therapies versus intolerable side effects, in particular altered mental status. We present the case of an immunosuppressed patient post-lung transplant who was suffering from intractable pain caused by widely metastatic squamous cell carcinoma. The patient's progressive, excruciating neuropathic pain was localized to the area of the left wrist and forearm. Additionally, the patient complained of moderate pain at sites of tumor involvement on her right arm and scalp. Attempts to adequately manage her left upper extremity pain included a combination of pharmacologic treatments intended to treat neuropathic pain (gabapentin, SNRI, ketamine, opioids) and focused regional analgesia (infraclavicular infusion of local anesthetic). However, the patient developed intolerable side effects including altered mental status and delirium associated with the systemic agents and suboptimal control with the infraclavicular infusion. Given that the most severe pain was well localized, we undertook a diagnostic block of the cutaneous nerves of the left forearm. As this intervention significantly reduced her pain, we subsequently performed neurectomies to the left superficial radial nerve, lateral cutaneous nerve of the forearm and the posterior cutaneous nerve of the forearm. This resulted in immediate and continued relief of her left upper extremity pain without an altered mental status. Residual focal pain from lesions over her right arm and scalp was successfully managed with daily topical applications of lidocaine and capsaicin cream. Successful pain control continued until the patient's death five months later.

Mucous hypersecretion is an important feature of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Multiple stimuli induce mucin production via activation of an epidermal growth factor receptor (EGFR) cascade, but the mechanisms that exaggerate mucin production in obstructive airway diseases remain unknown. In this study, we show that binding of CCL20, a G protein-coupled receptor (GPCR) ligand that is upregulated in the airways of subjects with obstructive airway diseases, to its unique GPCR CCR6 induces MUC5AC mucin production in human airway epithelial (NCI-H292) cells via metalloprotease TNF-α-converting enzyme (TACE)-dependent EGFR activation. We also show that EGFR activation by its potent ligand TGF-α induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating mucin production in the NCI-H292 cells. In NCI-H292 cells, TGF-α stimulation induced two phases of EGFR phosphorylation (EGFR-P). The second EGFR-P was TACE-dependent and was responsible for most of the total mucin induced by TGF-α. Binding of endogenously produced CCL20 to CCR6 increased the second EGFR-P and subsequent mucin production induced by TGF-α. In NHBE cells, TGF-α-induced EGFR activation did not lead to significant CCL20 production or to EGFR rephosphorylation, and less mucin was produced. We conclude that NCI-H292 cells but not NHBE cells produce CCL20 in response to EGFR activation, which leads to a second phase of EGFR-P and subsequent exaggerated mucin production. These findings have potentially important therapeutic implications in obstructive airway diseases.