Spinal actions of ω-conotoxins, CVID, MVIIA and related peptides in a rat neuropathic pain model.

BACKGROUND AND PURPOSE: Antagonists of the N-type voltage gated calcium channel (VGCC), Cav 2.2, have a potentially important role in the treatment of chronic neuropathic pain. ω-conotoxins, such MVIIA and CVID are effective in neuropathic pain models. CVID is reported to have a greater therapeutic index than MVIIA in neuropathic pain models, and it has been suggested that this is due to faster reversibility of binding, but it is not known whether this can be improved further. EXPERIMENTAL APPROACH: We examined the potency of CVID, MVIIA and two intermediate hybrids ([K10R]CVID and [R10K]MVIIA) to reverse signs of neuropathic pain in a rat nerve ligation model in parallel with production of side effects. We also examined the potency and reversibility to inhibit primary afferent synaptic neurotransmission in rat spinal cord slices. KEY RESULTS: All ω-conotoxins produced dose-dependent reduction in mechanical allodynia. They also produced side effects on the rotarod test and in a visual side-effect score. CVID displayed a marginally better therapeutic index than MVIIA. The hybrids had a lesser effect in the rotarod test than either of their parent peptides. Finally, the conotoxins all presynaptically inhibited excitatory synaptic neurotransmission into the dorsal horn and displayed recovery that was largely dependent upon the magnitude of inhibition and not the conotoxin type. CONCLUSIONS AND IMPLICATIONS: These findings indicate that CVID provides only a marginal improvement over MVIIA in a preclinical model of neuropathic pain, which appears to be unrelated to reversibility from binding. Hybrids of these conotoxins might provide viable alternative treatments.

An analgesic role for cannabinoids.

Cannabinoids have significant analgesic properties in animal models, particularly for chronic pain states, but there are few human studies. An endogenous cannabinoid system, with specific receptors and transmitters, has recently been discovered. This discovery has led pharmacologists to explore the potential of synthetic cannabinoids to selectively target chronic pain disorders without producing the side effects associated with cannabis. Well-controlled clinical trials on cannabinoids, and cannabinoid delivery systems, are now required.

Inhibition by adenosine receptor agonists of synaptic transmission in rat periaqueductal grey neurons.

1. The actions of selective adenosine A1 and A2 receptor agonists were examined on synaptic currents in periaqueductal grey (PAG) neurons using patch-clamp recordings in brain slices. 2. The A1 receptor agonist 2-chloro-N-cyclopentyladenosine (CCPA), but not the A2 agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS21680), inhibited both electrically evoked inhibitory (eIPSCs) and excitatory (eEPSCs) postsynaptic currents. The actions of CCPA were reversed by the A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). 3. In the absence or presence of forskolin, DPCPX had no effect on eIPSCs, suggesting that concentrations of tonically released adenosine are not sufficient to inhibit synaptic transmission in the PAG. 4. CCPA decreased the frequency of spontaneous miniature action potential-independent IPSCs (mIPSCs) but had no effect on their amplitude distributions. Inhibition persisted in nominally Ca2+-free, high Mg2+ solutions and in 4-aminopyridine. 5. The CCPA-induced decrease in mIPSC frequency was partially blocked by the non-selective protein kinase inhibitor staurosporine, the specific protein kinase A inhibitor 8-para-chlorophenylthioadenosine-3',5'-cyclic monophosphorothioate (Rp-8-CPT-cAMPS), and by 8-bromoadenosine cyclic 3',5' monophosphate (8-Br-cAMP). 6. These results suggest that A1 adenosine receptor agonists inhibit both GABAergic and glutamatergic synaptic transmission in the PAG. Inhibition of GABAergic transmission is mediated by presynaptic mechanisms that partly involve protein kinase A.

Enhanced opioid efficacy in opioid dependence is caused by an altered signal transduction pathway.

Chronic morphine administration induces adaptations in neurons resulting in opioid tolerance and dependence. Functional studies have implicated a role for the periaqueductal gray area (PAG) in the expression of many signs of opioid withdrawal, but the cellular mechanisms are not fully understood. This study describes an increased efficacy, rather than tolerance, of opioid agonists at mu-receptors on GABAergic (but not glutamatergic) nerve terminals in PAG after chronic morphine treatment. Opioid withdrawal enhanced the amplitudes of electrically evoked inhibitory synaptic currents mediated by GABAA receptors and increased the frequency of spontaneous miniature GABAergic synaptic currents. These effects were not blocked by 4-aminopyridine or dendrotoxin, although both Kv channel blockers abolish acute opioid presynaptic inhibition of GABA release in PAG. Instead, the withdrawal-induced increases were blocked by protein kinase A inhibitors and occluded by metabolically stable cAMP analogs, which do not prevent acute opioid actions. These findings indicate that opioid dependence induces efficacious coupling of mu-receptors to presynaptic inhibition in GABAergic nerve terminals via adenylyl cyclase- and protein kinase A-dependent processes in PAG. The potential role of these adaptations in expression of withdrawal behavior was supported by inhibition of enhanced GABAergic synaptic transmission by the alpha2 adrenoceptor agonist clonidine. These findings provide a cellular mechanism that is consistent with other studies demonstrating attenuated opioid withdrawal behavior after injections of protein kinase A inhibitors into PAG and suggest a general mechanism whereby opioid withdrawal may enhance synaptic neurotransmission.

Symptoms in early head and neck cancer: an inadequate indicator.

Screening programs show promise in increasing the rate of early detection of head and neck cancers in high-risk populations. Prout et al (Otolaryngol Head Neck Surg 1997;116:201-8) examined the usefulness of a large-scale screening program for head and neck cancer in an inner city population by primary care physicians. Symptom assessment was based on the American Cancer Society's "Seven Warning Signs for Cancer," (Cancer manual. 8th ed. Boston: American Cancer Society, Massachusetts Division; 1990. p. 40-64) 4 of which are relevant to the head and neck. However, these signs may be insufficient for detection of early head and neck cancer. We analyzed these and other typical symptoms to determine their role in early detection. Coincident medical problems, tobacco abuse, and alcohol abuse were also analyzed. Our findings indicate that no symptom or symptom complex is strongly correlated with early head and neck cancer for any subsite except the glottis. Symptom duration is an unreliable indicator of the duration of disease. However, patients under medical supervision are more likely to have their cancers detected early, supporting the value of surveillance by the primary care physician. The absence of definite early warning signs for most head and neck cancers suggests the need to develop essential screening criteria. Defining the population that is at high risk for head and neck cancer and subjecting it to an aggressive screening protocol is essential.

Inactivation of p53 and amplification of cyclin D1 correlate with clinical outcome in head and neck cancer.

The authors have investigated whether genetic abnormalities in two genes, loss of heterozygosity (LOH) of p53 and amplification of the cyclin D1 gene, correlate with clinical outcome in 56 matched pairs of blood and tumor from patients with squamous cell carcinoma of the head and neck (SCCHN). Frequency of p53 LOH was 47.4%, of cyclin D1 amplification 33.9%, and of both abnormalities together 23.7%. p53 LOH was associated with T4 (P = 0.003) and stage IV (P = 0.015) tumors. Cyclin D1 amplification was associated with recurrences and/or metachronous tumors (P = 0.007). The total number of p53 and cyclin D1 abnormalities (scored as zero, one, and two) show a pattern that seems to be additive; the increase in the number of these abnormalities is associated with a proportional increase in the frequency of T4, stage IV, presence of recurrences and/or metachronous tumors, and possibly a proportional decrease in the disease-free interval in the sample. The association of the markers with recurrences and/or metachronous tumors persists if the tumor stage effect is mathematically removed. The combined analysis of the p53 and cyclin D1 abnormalities seems to be more informative than either of them individually and may have predictive value in SCCHN.

Head and neck cancer screening among 4611 tobacco users older than forty years.

We implemented screening for squamous cell carcinomas of the oral cavity, pharynx, and larynx with symptom assessment and systematic inspection of the oral mucosa by primary care practitioners at health care sites serving inner-city residents of Boston; 4611 tobacco users older than 40 years were screened, and 313 with specific criteria were referred to otolaryngology for diagnostic evaluations. In these screened patients, the prevalence of oral mucosal lesions was almost 13% and prevalence of persistent hoarseness was more than 11%. Although the identification of these cancers was rare (nearly 3%), abnormal findings were seen in more than 70% of referred patients. These clinical and histologic diagnoses are described. We have documented the range of pathologic conditions in high-risk patients screened for upper aerodigestive tract malignancy.

"External counterpressure" and "internal distention" for optimal laryngoscopic exposure of the anterior glottal commissure.

External laryngeal counterpressure and internal laryngeal distention produce forces that are helpful for enhancing laryngoscopic exposure of the anterior glottis. These principles were formally described in the early 20th century, but are seldom used today. Hand pressure has been the typical source for external counterpressures. Since this maneuver is unstable if provided by an assistant and wasteful if provided by the surgeon, it is often neglected. Current phonomicrosurgical techniques require wider glottal exposure; therefore, a reexamination of the value of external counterpressure and internal distention is worthwhile. During the last 2 years, 125 microlaryngoscopic procedures were performed for a variety of benign, premalignant, and malignant lesions. All patients were placed in the Boyce-Jackson position and sustained with a modified Killian gallows, with resulting elevated-vector suspension. Internal distention was achieved by placing the largest-lumen glottiscope possible between the endotracheal tube and the infrapetiole region. Exposure was also improved by using silk adhesive tape to apply external counterpressure to the lower laryngeal framework. The use of both external counterpressure and internal distention as an adjunct to microlaryngoscopy was most helpful for the surgical management of lesions located near the anterior commissure. Seemingly, the two resultant forces are in opposition to each other, but in fact they are complementary, both to each other and to the orthodox laryngoscopic principle of elevated-vector suspension.

Tongue-base-cancer resection with partial supraglottic laryngectomy.

INTRODUCTION: Cancer in the tongue base, which is adjacent to or invading the lingual epiglottis, requires resection of part or all of the larynx to assure adequate surgical margin. Based on whole mount laryngeal sections, a tongue base-partial supraglottic laryngectomy procedure was designed for tumors adjacent to or minimally invading the lingual epiglottis. METHODS: A group of five patients with carcinoma of the tongue base adjacent to or minimally invading the lingual epiglottis was identified. This technique requires excision of the epiglottis, hyoepiglottic ligament, and pre-epiglottic space with the lesion. The structural physiological integrity of the false vocal cords with or without the hyoid bone is preserved. RESULTS: Clear tumor margins were obtained in all five patients. In three patients who required up to 50% resection of the tongue base, decannulation and resumption of a full oral diet was achieved. Two patients with more extensive lesions required 70% resection of the tongue base. Both patients underwent completion laryngectomy months later because of persistent aspiration. CONCLUSION: This preliminary report suggests that partial supraglottic laryngectomy may be used with acceptable functional results in patients with limited tongue base lesions.

Endoscopic treatment of supraglottic and hypopharynx cancer.

Transoral excision of supraglottic and hypopharynx cancer as a single modality is effective when lesions are selected for small size and endoscopic accessibility. Excisional biopsy with clear margins of larger supraglottic tumors in combination with postoperative radiotherapy provides an excellent treatment alternative for selected lesions in patients who are not candidates for open surgery. In this preliminary report, 45 cases using this minimally invasive approach are reviewed outlining oncologic rationale and functional advantages. A large bore tubed laryngoscope or the adjustable bivalve supraglottiscope was used along with a carbon dioxide laser in all cases. In 22 of the 45 patients (mostly T1), local en bloc excision of the primary cancer was performed as sole treatment on selected lesions of the supraglottis and hypopharynx. There were no local recurrences, however, 1 patient developed a neck recurrence and was salvaged by neck dissection. Twenty-three of the 45 patients had more extensive primaries (mostly T2, T3) and N0 necks. Transoral excisional biopsy was followed by full-course radiation therapy to the primary site and both necks. All 23 were followed a minimum of 2 years, and the median follow-up period was 58 months. Clear margins were obtained in 16 of 23, and there were no recurrences in the larynx. Two of 16 did fail in the neck and died despite neck dissection. Seven of 23 patients had positive margins and, despite full-course radiotherapy to the primary site and both necks, 5 of 7 failed locally or regionally. Two of the 7 died of their disease despite open salvage surgery. Therefore, 4 of 23 patients who underwent transoral excision of larger lesions followed by full-course radiotherapy died of recurrent cancer.

Vocal fold exposure in phonosurgery.

A difficult laryngeal exposure is made easier by placement of the patient's head and neck into the Boyce-Jackson "sniffing position" and then flexing them further if necessary, by selection of a laryngoscope appropriate to the patient and to the triangular glottic shape, by placement of the laryngoscope along the path of least resistance, by use of a true suspension device in order to apply the force for laryngoscopy towards the larynx and away from the teeth and gums, and by allowing time for the force to work. With these techniques, an easy exposure is made almost perfect. The true vocal folds are exposed from vocal process to anterior commissure without the need for external pressure, the endotracheal tube remains out of sight between the arytenoids, and there is no risk to the teeth, gums, and cervical spine.

A model for multidisciplinary data collection for cervical metastasis.

A system for multidisciplinary data collection for metastatic neck disease is discussed. Information from 87 neck dissections and 3218 lymph nodes is reported to illustrate the strength of the model. Clinical (endoscopic) assessment under general anesthesia, surgical assessment during the neck dissection, and radiographic (computed tomographic scan) assessment were compared with the pathological evaluation. All disciplines stratified the necks by region and node size. This model provides an effective stratagem for multi-institutional studies.

Preepiglottic space invasion in "early" epiglottic cancer.

The tendency of epiglottic cancer to invade the preepiglottic space and the significance of this invasion was evaluated in 36 surgical specimens of epiglottic carcinoma originally staged T1 or T2. None of the 9 lesions originating above the hyoepiglottic ligament invaded the preepiglottic space. Twenty-four of the 27 (89%) lesions originating below the hyoepiglottic ligament showed invasion of the preepiglottic space and were clinically understaged. Of the 3 infrahyoid lesions showing no invasion of the preepiglottic space, 1 was a verrucous carcinoma and another was a mucoepidermoid carcinoma arising on the petiole. All other lesions were squamous cell carcinoma. In 12 of the 24 patients (50%) with preepiglottic space invasion, cervical node metastasis was present despite the preoperative staging of T1 or T2.

A submucosal true vocal fold infusion needle.

This simple, inexpensive device for submucosal true vocal fold saline infusion into Reinke's space improves the diagnosis and treatment of small vocal cord lesions and is a useful addition to our microlaryngoscopy instrumentation.

Larynx preservation using induction chemotherapy plus radiation therapy as an alternative to laryngectomy in advanced head and neck cancer. A long-term follow-up report.

Since 1977, we have used induction chemotherapy (CT) plus radiation therapy (RT) with curative intent in 35 advanced head and neck cancer (Ca) patients who otherwise would have required total laryngectomy. Fourteen patients had advanced Ca of the larynx or supraglottic larynx (SGL); 21 patients had Ca of the hypopharynx. In six patients the Ca was Stage III; in 26 patients it was Stage IV. Three patients had Stage II disease--2 with cancer of the pyriform sinus and one patient with Stage II SGL Ca who refused surgery. Chemotherapy consisted of platinum (P) + bleomycin in 18 patients until 1982, then P + fluorouracil in the next 17 patients. Total response rate was 77%--complete (CR) in 26% and partial (PR) in 51%. There were two toxic deaths. Surgery was limited to tracheostomy in 4 patients prior to CT and to radical neck dissection after CT in 4 others. Two patients required salvage laryngectomy at 11 and 31 months, respectively. One patient underwent partial laryngectomy with voice preservation. Thirty-two patients were evaluable for overall response after RT. Final disease-free status was achieved in 20/34. One long-term survivor was lost to follow-up (44 months) and 8 patients remained alive at 13+ to 109+ months. Median failure-free survival for all patients was no less than 24 months. Not counting 4 early deaths free of disease, 2-year local control using only chemotherapy plus radiation was 52% (16:31). Overall, 33 of 35 patients retained their voices. Sixteen patients (46%) have survived 2 years or longer. Survival of patients who achieved CR after induction chemotherapy was 48 months versus 14 months for those with less than a CR (p = 0.001). Patients with a hypopharyngeal primary had only a 33% 2-year local control rate with chemotherapy and radiation and a median survival of only 12 months versus 77% control and a minimum 39-month survival for those whose tumor arose in the larynx (p = 0.009). Induction chemotherapy plus radiation therapy is an effective strategy which can produce a high rate of larynx preservation, local control, and long-term survival in patients with advanced cancer of the larynx. Patients with hypopharyngeal primaries have a lesser rate of long-term survival and local control, despite similar overall response rates.

Suprahyoid pharyngotomy for oropharynx cancer including the tongue base.

Suprahyoid pharyngotomy has been utilized as the standard approach to tongue base cancer not involving the larynx or mandible for the last 6 years at the Department of Veterans Affairs Medical Center, Boston, Mass. Review of 15 patients revealed that all had advanced disease (stage III and stage IV); 14 cases involved the tongue base, and one was on the posterior pharyngeal wall. By following the hyoepiglottic ligament, precise entry into the vallecula was routine. No injuries of vital neurovascular structures or compromised tumor margins were present; one tracheotomy was performed. Primary closure without the use of flaps was accomplished in 14 of 15 patients. No locoregional recurrences were found, with a median follow-up of 25 months. However, two patients died of another unrelated cancer, and two patients died of a myocardial infarction unrelated to their surgery. Suprahyoid pharyngotomy is a familiar approach often utilized during laryngectomy. In our experience, it provides excellent exposure of the oropharynx, can be combined with a transoral approach to avoid mandibulotomy without precluding this option, allows for simple reconstruction, and has a low complication rate.

A precision technique for suprahyoid pharyngotomy.

This technique of suprahyoid pharyngotomy is very useful for excision of selected laryngeal and pharyngeal neoplasms. By identifying and following the hyoepiglottic ligament, precise entry into the pharynx is accomplished easily and rapidly at the median glossoepiglottic fold.

A rare cause of nasal obstruction: a solitary neurofibroma.

This case represents a peripheral nerve sheath tumor as a cause of nasal obstruction. Nerve sheath tumors are relatively uncommon; however, most otolaryngologists will encounter them. These tumors develop from cranial and spinal nerve roots and from peripheral nerves. In total, approximately 25% to 44% of nerve sheath tumors occur in the head and neck region. Although the most important are cranial nerve tumors--the majority being acoustic neuromas arising from the vestibular nerve--they may also develop in the nasal cavity.

Endoscopic management of early supraglottic cancer.

An initial endoscopic surgical approach to early supraglottic cancer provides the surgeon with the ability to accurately stage these lesions, avoiding possible undertreatment while allowing for a valuable treatment option for those supraglottic cancers with histologically incontrovertibly superficial disease. Early invasion of the preepiglottic and paraglottic spaces can be determined accurately without altering or delaying any treatment option (open surgical excision, radiotherapy, or chemotherapy). The tendency of supraglottic cancers to transgress the natural foramina of the epiglottis is well established, and the concern about this depth of invasion is reflected by the 1977 revised staging criteria, which required assessment of the preepiglottic space (PES). Along with the microscope and the carbon dioxide laser, the adjustable supraglottiscope facilitates the determination of PES invasion and facilitates en bloc excision of superficial supraglottic cancers. The resulting morbidity typically is no different from that with routine direct endoscopy and biopsy.

Laser epiglottectomy: endoscopic technique and indications.

Endoscopic epiglottectomy (epiglottidectomy) may be performed with relative ease and minimal morbidity by using standard microlaryngoscopy techniques and the CO2 laser. Depending on the indications, the removal may be partial or complete. Indications for 51 epiglottectomies included treatment of supraglottic airway obstruction--30 cases; discovery of benign or malignant neoplasm (diagnosis and staging)--20 cases; treatment of malignant neoplasm--7 cases; glottic visualization--4 cases; and treatment of chronic inflammatory conditions--1 case. It is not unusual for a patient to have more than one indication for this procedure. Some epiglottic cancers invade the pre-epiglottic space. This crucial information may not be detectable by MRI or CT scanning techniques. Laser epiglottectomy provides a method to explore and perform a biopsy of the pre-epiglottic space and thereby stage these lesions accurately. There are no significant problems with postoperative alimentation, airway, or voice. Any form of primary or adjuvant therapy can be started without delay.