Epidermal growth factor receptor-targeted immunophotodiagnosis and photoimmunotherapy of oral precancer in vivo.

Immunophotodiagnosis uses a fluorescence-labeled monoclonal antibody (MAb) that recognizes a tumor-associated antigen to image the fluorescence emitted from the fluorophore-bound MAb that has localized in the tissue. It may be used to diagnose malignant or precancerous lesions, to delineate the margins for tumor resection, or as a feedback mechanism to assess response to treatment. In oral precancer, the epidermal growth factor receptor (EGFR) is overexpressed and could be used as a marker for early detection or as a target for therapy. The goal of this study was to test an anti-EGFR MAb (C225) coupled to either the near-infrared fluorescent dye N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid for detection or a photochemically active dye (chlorin(e6)) for therapy of early premalignancy in the hamster cheek pouch carcinogenesis model. Fluorescence levels in the carcinogen-treated tissue correlated with the histological stage of the lesions when the C225-N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid conjugate was used but did not do so with the irrelevant conjugates. Discrete areas of clinically normal mucosa with high fluorescence (hot spots) were subsequently shown by histology to contain dysplastic areas. The best contrast between normal and carcinogen-treated cheek pouches was found at 4-8 days after injection. To test the potential of immunophotodiagnosis as a feedback modality for therapeutic intervention, experiments were conducted with the same MAb conjugated to chlorin(e6) followed by illumination to reduce expression of the EGFR by a photodynamic effect. Subsequent immunophotodiagnosis showed that this treatment led to a significant reduction in fluorescence in the carcinogen-treated cheek pouch compared with nonilluminated areas. This difference between illuminated and dark areas was not seen in the normal cheek pouch. Taken together, the results demonstrate the potential for development of immunophotodiagnosis as a diagnostic tool and as a method of monitoring response to therapy and that the EGFR may be an appropriate target in head and neck cancer.

A novel, noninvasive imaging technique for intraoperative assessment of parathyroid glands: confocal reflectance microscopy.

BACKGROUND: Successful surgical management of primary hyperparathyroidism requires the ability to identify and distinguish normal from abnormal parathyroid tissue. Microscopic pathologic confirmation often helps with the diagnoses and decisions regarding the extent of parathyroid resection. Confocal reflectance microscopy (CRM) is an optical method of noninvasively imaging tissue without fixation, sectioning, and staining as in standard histopathology. The goal of this study was to determine if CRM imaging could be used to distinguish normal from diseased parathyroid tissue intraoperatively. METHODS: In this study, 44 parathyroid glands from 21 patients undergoing operations for primary hyperparathyroidism were imaged immediately after excision. CRM images were compared with conventional hematoxylin-and-eosin stained sections obtained from the same gland. The percentage area occupied by fat cells was calculated in images of both normal and diseased glands. RESULTS: Characteristic microscopic features of parathyroid glands were distinguishable by CRM and correlated well with histopathology. The stromal fat content of normal and diseased glands could easily be determined. The percentage area occupied by fat cells differed significantly (P <.00001) in normal glands (average, 23.0% +/- 10.9%) and adenomatous glands (average, 0.4% +/- 0.7%). CONCLUSIONS: CRM imaging rapidly revealed microscopic features that reliably differentiated normal and diseased parathyroid glands. The success of this preliminary ex vivo study promotes interest in further development of an in situ probe for in vivo clinical diagnostic use.

Dedifferentiated chondrosarcoma of the larynx.

A 74-year-old man with a history of a chondroid lesion of the larynx noted an enlarging neck mass. Axial CT showed a large expansile lesion arising from the left thyroid cartilage. Multiple rings and arcs with relatively intact cortex indicated a chondroid lesion. Irregularity of the anterolateral margin abutted a prominent soft-tissue component. The specimen obtained from fine needle aspiration was suggestive of a malignant fibrous histiocytoma. After further resection, the final diagnosis was dedifferentiated chondrosarcoma. A new soft-tissue component or rapid growth of the mass can be indicative of a diagnosis of dedifferentiated chondrosarcoma.

Optical integrating balloon device for photodynamic therapy.

BACKGROUND AND OBJECTIVES: It is difficult to deliver light uniformly and efficiently over the complex shapes presented by various organs for photodynamic therapy (PDT). A balloon delivery device for photodynamic therapy was designed and tested for treatment of various anatomic tissues. The device uses the principle of optical integration by multiple internal diffuse reflections to achieve uniform output illumination. STUDY DESIGN/MATERIALS AND METHODS: Soft, white, medical-grade silicone balloons were made in various shapes and tested for optical output, uniformity, efficiency, and power capabilities. Balloons were cast to be approximately the shape of the target tissue surface, organ, or cavity. Laser power was introduced into the saline-filled balloon by one or more fiber optics. Devices were constructed and used to illuminate oral mucosa and uterine endometrium for PDT. RESULTS: The balloon walls had low optical absorption, high diffuse reflectivity (80-95%), and low diffuse transmittance (5-20%) in the 500- to 900-nm wavelength region. Optical efficiencies of 65% were typical with emitted light over complex, nonspherical surfaces. Efficiency increased with inflation of the device, such that irradiance (power/area) at the balloon surface was nearly constant with inflation. CONCLUSION: Optically integrating balloons can provide highly uniform, efficient light exposure over complex tissue surfaces. Uniformity and irradiance were not strongly affected by balloon inflation, and these robust devices are easy to produce in essentially any shape.

Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy.

OBJECTIVES/HYPOTHESIS: To study the microscopic anatomy of normal oral tissues in vivo using confocal reflectance microscopy (CRM). This novel and noninvasive imaging modality can define and characterize healthy oral mucosa and thus this work serves as the foundation for studying oral diseases in vivo. STUDY DESIGN: This was a pilot observational cohort study comparing noninvasive CRM images with histology. MATERIALS AND METHODS: Lip and tongue mucosa were imaged by CRM in six healthy human subjects. In CRM living tissue is illuminated by a laser source and backscattered (or reflected) light is collected by a detector. Image contrast is determined by natural differences in refractive indices of organelles and other subcellular structures within the tissues. Gray-scale images were displayed in real-time on a video monitor and represented horizontal (en face) optical sections through the tissue. Motion of the oral tissue relative to the objective lens was minimized with a tissue stabilizer. After imaging, biopsies were taken from the same site of lip mucosa to correlate noninvasive confocal images with conventional histology. RESULTS: Confocal images correlated well with conventional histology, both qualitatively (visual analysis) and quantitatively (stereology). Imaging was possible up to depths of 490 and 250 microm in the lip and tongue, respectively. Cells and organelles including nuclei, circulating blood cells, and extracellular matrix were clearly observed. CONCLUSION: CRM provides details of normal human oral mucosa at the cellular level without the artifacts of histological processing, and thus has the potential for further development and use in clinical practice as a diagnostic tool for the early detection of oral cancer and precancer.

Manometric study of paranasal sinus mucoceles.

A paranasal sinus mucocele is a chronic cystlike lesion characterized by slowly progressive remodeling and expansion of the surrounding osseous walls. If left untreated, it may cause significant facial deformity, ophthalmic disturbances, and, in the worst instance, intracranial complications. According to a review of the literature, there is a long-held view that positive pressure exists within paranasal sinus mucoceles; however, to our knowledge, pressure measurements have not been recorded in humans. In this study, pressure measurements were taken of 4 paranasal sinus mucoceles by means of an 18-gauge needle probe and an amplified pressure transducer. The average value was +15 cm H2O with a range of +4 to +39 cm H2O. This study confirms the long-standing assumption that positive pressure exists within paranasal sinus mucoceles. The magnitude of the pressure was comparable to that which was found to be associated with bone resorption in several previously published studies. Further studies are needed to determine whether positive pressure and osseous remodeling are causally related in this condition.

Extent of lymphadenectomy achieved by various modifications of neck dissection: a pathologic analysis.

OBJECTIVES: Quantify the extent of lymphadenectomy achieved by the various modifications of neck dissection based on microscopic pathologic analysis. STUDY DESIGN: Retrospective review of neck specimens of patients who underwent neck dissection for head and neck malignancies at our institution over a 5-year period. METHODS: Charts and pathology report findings on patients who underwent neck dissection were reviewed. Patients who received preoperative chemotherapy or radiation therapy to the neck were excluded. The number of lymph nodes documented by pathologic microscopic examination for each specimen was recorded. RESULTS: There were 164 neck specimens on 135 patients (29 patient had simultaneous bilateral neck dissection). Those were divided into four groups based on the nonlymphatic structures preserved. There were 58 radical neck dissections (radical neck dissections) (group 1), 50 modified radical neck dissections sparing the eleventh cranial nerve (group 2), 15 modified radical neck dissections sparing the eleventh cranial nerve and internal jugular vein (group 3), and 33 modified radical neck dissections sparing the eleventh cranial nerve, internal jugular vein, and sternocleidomastoid muscle (group 4). The remaining 8 had other modifications of radical neck dissection. The mean number of lymph nodes found per specimen was 34 in group 1, 27 in group 2, 31 in group 3, and 22 in group 4. We performed one-way between-group analysis of variance (ANOVA). Pair-wise comparisons of means were carried out subsequent to ANOVA utilizing the Fisher Exact Test. Group 4 was significantly different from all other groups. Additionally, group 2 significantly differed from group 1. CONCLUSIONS: The extent of lymphadenectomy achieved by neck dissection decreases as the number of nonlymphatic structures preserved in the neck increases. The impact of this finding on the pathologic staging or prognosis needs further analysis.

Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial.

PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

Treatment of recurrent head and neck cancer with cisplatin and 5-fluorouracil vs. the same plus bleomycin and methotrexate.

A prospective randomized trial of 62 patients with recurrent squamous cell carcinoma of the head and neck was conducted to compare the effectiveness of our standard chemotherapy program with that of our test regimen. The standard chemotherapy regimen consisted of cisplatin 80 mg/M2 on day 1 followed by 5-fluorouracil 800 mg/M2 days 2 through 6. Our test regimen consisted of the same two drugs plus 15 U bleomycin on day 1 and methotrexate 100 mg/M2 on day 16 followed in 24 hours with 15 mg leucovorin every 6 hours for six doses. One patient in each arm of the study was not evaluated. Among 29 patients receiving the two-drug regimen, there was 1 complete response and 10 partial responses (38% response rate). Among 31 patients receiving the four-drug regimen, there were 3 complete responses and 16 partial responses (61% response rate; two vs. four-drug regimen, P = .06). The failure-free survival in the four-drug group was better than the two-drug group, median 4.5 vs. 2.3 months (P = .02). The overall survival for both groups was the same (median of 7.8 months). A detailed analysis of toxicity did not reveal any important differences between the two regimens. The addition of bleomycin and methotrexate to our cisplatin and 5-fluorouracil regimen resulted in an increase in effectiveness without adding toxicity.

The current surgical management of carotid body paragangliomas.

To determine if recent trends in evaluation and therapy have contributed to the successful surgical management of carotid body paragangliomas, we reviewed our experience over the past decade. Nineteen carotid body paragangliomas were identified in 17 patients. Eleven patients underwent complete, preoperative embolization of their afferent arteries with one complication. Calculated carotid body paragangliomas surface areas did not differ between the embolized 64.6 +/- 43.3 cm2 and nonembolized 63.0 +/- 57.9 cm2 lesions. Intraoperative blood loss was lower (p = 0.02) in the patients treated with embolization (372 +/- 213 ml) compared with their cohorts (609 +/- 564 ml). However, the operative times were equivalent 4.1 hours versus 4.5 hours in both groups. Intraoperative electroencephalographic (EEG) monitoring was used in 10 patients; in one patient the EEG indicated intraoperative thrombosis of the carotid artery, which was successfully treated by thrombectomy without complications. Two patients required carotid bifurcation resection and vascular reconstruction to remove the entire tumor; a late stroke manifested by contralateral hand weakness developed in one of these patients. The incidence of cranial nerve injury was low at 16%, with one transient ramus mandibularis paresis and two instances of vocal cord dysfunction. Two additional patients had a postoperative Horner's syndrome. We conclude that by diminishing intraoperative blood loss through complete and careful preoperative embolization and use of intraoperative EEG monitoring along with careful surgical technique, the complications associated with this challenging operation are facilitated and diminished.

Acute and chronic effects of bone ablation with a pulsed holmium laser.

A pulsed holmium laser transmitted through a quartz fiber was used to create osteotomies in the facial bones and sinuses of rabbits. The ablation process was quantified and residual thermal injury was assessed by light microscopy. Adjacent thermal damage was determined to vary between 130 and 220 microns and was independent of radiant exposure and pulse repetition rate. In other studies, large osteotomies were made to examine the biological response and to assess the technical feasibility of using fiber-delivered laser pulses in an operative setting. The animals tolerated the procedure without obvious problems and postoperative follow-up revealed a vigorous healing response. Because it can ablate both bone and soft tissue and can be transmitted through readily available, flexible quartz fibers, the holmium laser may prove to be a useful adjunct to endoscopic sinus surgical procedures.

Adaptation to surgery for head and neck cancer.

We examined the postoperative adjustment of 45 patients who underwent surgery for cancers of the head and neck: 23 who had laryngeal cancer, 18 who had oral cavity/oropharyngeal cancers, and 4 who had cancers of other sites. Patients were assessed preoperatively, and at 3 months and 9 to 12 months postsurgery. Interviews and questionnaires were used to assess depression, body image, limitations, pain, financial problems, need for help at home, and social interaction. Results revealed that pain, fatigue, weakness, and loss of speech were major concerns. Pain and financial concerns were worst at 3 months and then improved. Physical limitations increased steadily with time. Depression was a major factor in patients with oral cavity and oropharyngeal cancers. Of note, patients who underwent postoperative radiation therapy had the most difficulty adapting to their illness and treatment, with persistent limitations in function and social isolation. The implications of these findings are discussed.

Preliminary clinical results with low flip angle spin-echo MR imaging of the head and neck.

A new approach for producing primarily T2- and proton-density-weighted MR images in less time than the conventional long TR, long TE imaging is to reduce the TR of a double spin-echo pulse sequence and to also reduce the RF excitation flip angle to minimize the resulting T1 sensitivity. In preliminary studies with a human volunteer and five patients with various diseases of the head and neck, conventional long TR, long TE and short TR, short TE images were compared with short TR, long TE images with reduced flip angles (45 degrees, 30 degrees), which required only 40% of the imaging time of the long TR images. The latter images showed a similar contrast pattern to the conventional T2-weighted image, and contrast-to-noise measurements indicated an increase in contrast between the lesion and nearby tissue when the flip angle was reduced. Furthermore, the maximum contrast/noise per unit imaging time on the short TR, long TE image was comparable to that on the long TR, long TE image. Optimization of the flip angle with short TR allows a substantial reduction in imaging time but with a reduction in multislice capability. This technique will be most useful in areas of complex anatomy where two or more orthogonal imaging planes are required, such as the head and neck.

Plasma-mediated excimer laser ablation of bone: a potential microsurgical tool.

A pulsed ultraviolet excimer laser was used to ablate bone in vitro at 193, 248, 308, and 351 nm and in vivo at 193 nm. Ablation was dependent on sufficient fluence (energy delivered per unit area per pulse) for plasma formation at the target site at all wavelengths. Adjacent tissue damage at various fluences for each wavelength was examined using a light microscope. Damage was minimal at 193 nm (1 to 3 microns) and most extensive at 351 nm (60 to 75 microns). This is in sharp contrast to the 1 to 3 mm of adjacent thermal damage produced when carbon dioxide lasers are used to ablate bone. Differences in the degree and type of damage to adjacent tissues among the wavelengths studied indicated that other ablation mechanisms and tissue interactions are involved in addition to simple plasma vaporization of bone. Bleeding during and after ablation demonstrated that the use of this laser does not cause thermal damage, which would cauterize adjacent vessels. Pre- and post-mortem lesions made at identical power and pulse settings were of equal depth, indicating that bleeding does not affect the ablation rate. The excimer laser has potential as a microsurgical instrument for the precise removal of bone with minimal damage to adjacent structures.

Sports Injury to the Larynx and Trachea.

In brief: Athletes in contact sports frequently sustain trauma to the upper aerodigestive system. However, because of the slow progression and/or lack of symptoms relating to injuries of the larynx and associated structures, an early diagnosis is often not made. Complications may follow shortly after such injuries or later, so athletes, coaches, and team physicians should have a working knowledge of the pathophysiology of these injuries. This article discusses the anatomy of this part of the body, as well as the diagnosis and treatment of injuries to the larynx and upper aerodigestive system. Principles of treatment of upper airway trauma in general and of specific injuries are also addressed.

Pectoralis major myocutaneous flap reconstruction of the laryngopharynx and cervical esophagus.

Advanced carcinoma of the hypopharynx and cervical esophagus is a formidable challenge to the skills of the head and neck surgeon. Radiation therapy is valuable as adjunctive therapy when combined with curative surgery, which is the primary treatment modality. The extent of anatomical disease associated with extensive neoplasia of the hypopharynx and cervical esophagus is frequently not amenable to total laryngectomy with local tissue repair. Surgical ablation usually requires an extended laryngectomy, which does not permit primary local repair. A previous report by this author, comparing all techniques historically and chronologically, indicated that the present impetus is toward procedures characterized by a one-stage primary repair with shorter completion times. Presently, the three most promising procedures that meet these criteria are the gastric transposition, free microvascular bowel transfer, and regional myocutaneous flap repair. Theogaraj, et al. reported the use of a partially tubulated pectoralis muscle flap over preserved posterior wall cervical esophageal mucosa in cases of short segment stenosis. Encouraged by these results, a technique using partial tubulation for long-segment stenosis was reported. The use of this technique was expanded to include the repair of the defect left after total ablation of the laryngopharynx and cervical esophagus. Over the past 40 months, 22 patients have undergone repair using partial tubulation of the pectoralis myocutaneous flap. This paper will discuss the technical aspects of the procedure and analyze the procedure as it relates to mortality, morbidity, and completion time. Low morbidity and a completion time of 18 days competes favorably with gastric transposition and free jejunal transfer. A rational approach to reconstruction using all procedures will be discussed.

Infrared laser bone ablation.

The bone ablation characteristics of five infrared lasers, including three pulsed lasers (Nd:YAG, lambda = 1,064 micron; Hol:YSGG, lambda = 2.10 micron; and Erb:YAG, lambda = 2.94 micron) and two continuous-wave lasers (Nd:YAG, lambda = 1.064 micron; and CO2, lambda = 10.6 micron), were studied. All laser ablations were performed in vitro, using moist, freshly dissected calvarium of guinea pig skulls. Quantitative etch rates of the three pulsed lasers were calculated. Light microscopy of histologic sections of ablated bone revealed a zone of tissue damage of 10 to 15 micron adjacent to the lesion edge in the case of the pulsed Nd:YAG and the Erb:YAG lasers, from 20 to 90 micron zone of tissue damage for bone ablated by the Hol:YSGG laser, and 60 to 135 micron zone of tissue damage in the case of the two continuous-wave lasers. Possible mechanisms of bone ablation and tissue damage are discussed.

Giant cell reparative granuloma of the ethmoid sinus.

This article represents the fourth and fifth reported cases of GCRG that involve the ethmoid sinus. The problems encountered in establishing the diagnosis are emphasized, as are the features that differentiate it from the giant cell tumor, aneurysmal bone cyst, and hyperparathyroidism, the conditions with which it is most commonly confused. The unusually aggressive behavior, as demonstrated by these two cases, is highlighted.