Neurotic effects of doxycycline sclerotherapy.

A patient experienced phrenic nerve paralysis after doxycycline sclerotherapy for treatment of chylous fistula at our institution. The purpose of this study is to use physiologic testing to determine whether doxycycline is capable of inducing defects in neural function. A nonrandomized, controlled trial was performed with nerve-conduction studies to determine possible deleterious effects of doxycycline sclerotherapy. Thirty-eight CD rats were used and separated into four groups. Doxycycline was applied to the sciatic nerves of rats by either topical application directly on the nerve or by intraneural injection. Nerve-conduction studies were done before surgery and at 1,7, and 21 days after surgery. The results showed a statistically significant decrement in nerve-conduction velocity and strength of transmitted impulse in those nerves injected with doxycycline solution. Complete nerve block was seen frequently. This effect was not seen with topical application of doxycycline or normal saline solution or with intraneural injection of normal saline solution. This study demonstrates that doxycycline can induce a marked decrement in neural function when applied to the subepineural layers of the sciatic nerve in the rat. Therefore doxycycline sclerotherapy should be used with great caution in situations in which it could become exposed to nerves that have sustained surgical trauma.

Osseointegrated implants in the head and neck cancer patient.

BACKGROUND: Osseointegrated implants allow patients with oromandibular defects to obtain complete or partial dentition via implant-assisted or implant-borne prostheses. Implants restore masticatory and occlusal function, improving oral intake and articulation. However, use of implants in head and neck cancer patients has been discouraged due to lack of data supporting their utility in these patients. This study attempts to establish the validity of using osseointegrated implants for dental restoration in head and neck cancer patients. METHODS: Six patients who underwent resection/reconstruction for head and neck cancer received osseointegrated implants. Integration was assessed clinically, radiographically, and mechanically at 4-8 months; oral intake, mastication, and articulation were evaluated 6-12 months after receiving the dental prosthesis. RESULTS: Osseointegration occurred in 92% (24/26) of the implants: 100% (14/14) in neomandibles and 83% (10/12) in native mandibles. One patient had implants (2/5) that failed to integrate. The remaining patients' implants were immobile, free of infection, with no osteoradionecrosis. These patients tolerated a regular diet and experienced weight gain and improved articulation. CONCLUSIONS: The advent of osseointegrated implants and their compatibility with native and neomandible allows the restoration of functional dentition in patients undergoing ablative surgery for head and neck cancer.

Basal cell carcinoma metastatic to the salivary glands: differential diagnosis in fine-needle aspiration cytology.

A disparate group of salivary gland neoplasms is characterized by small, uniform, hyperchromatic, basaloid cells. This "small blue cell" pattern is most common in non-Warthin's types of monomorphic adenoma, or in adenoid cystic carcinoma. Small cell anaplastic carcinoma (primary or metastatic), metastatic basaloid squamous cell carcinoma, basal cell adenocarcinoma, and metastatic nasopharyngeal carcinoma are rarely encountered but may present a cytologically similar appearance. We report one female and two male patients (median age = 84 yr) with cutaneous-type basal cell carcinoma (BCC) aspirated from metastatic deposits in the parotid (2 cases) or the submandibular (1 case) gland. One was correctly classified at the time of aspiration, based on a previous history of multiple facial BCC. One was interpreted as carcinoma, the previous history being unavailable at the time of FNA. Smears in these two cases show necrosis and rare keratotic cells. The third cases was mistaken for pleomorphic adenoma (PA); the smears showed metachromatic fragments of collagenous tumor stroma that were misinterpreted as the matrix material typical PA. Similar material was identified in the other two cases. When the "small blue cell" pattern is encountered in salivary bland cytology, one should consider BCC, especially if necrosis is identified. The desmoplastic tumor stroma of BCC may mimic the chondroid matrix of PA. Careful consideration of previous history is very important.

Sialolithiasis. Differential diagnostic problems in fine-needle aspiration cytology.

Sialolithiasis with obstruction of major salivary gland ducts can lead to clinical tumefaction related to cystic dilatation. In addition to mucus accumulation, these pseudoneoplasms feature hyperplasia and squamous metaplasia of the ductal lining epithelium, with varying degrees of inflammation. The authors report five examples of this lesion aspirated from two males and three females ranging in age from 45 to 80 years (median 65 years). Three were in the submaxillary gland, and two were in the parotid. In three cases, stone fragments were identified, and diagnoses of sialolithiasis were rendered; two of these patients underwent surgical excision. The remaining two cases showed prominent foam cells and metaplastic squamous cells in a mucoid background that mimicked low grade mucoepidermoid carcinoma. Stone fragments were not identified and a differential diagnoses of sialolithiasis versus low grade mucoepidermoid carcinoma were suggested. Surgical excision revealed sialolithiasis in both instances. When stone fragments are identified in aspirated material, these cases pose little diagnostic difficulty. However, when this material is not present, epithelial changes and mucus accumulation may be difficult to distinguish from low grade mucoepidermoid carcinoma. Cautious interpretation is suggested in this setting.

Basal cell (monomorphic) and minimally pleomorphic adenomas of the salivary glands. Distinction from the solid (anaplastic) type of adenoid cystic carcinoma in fine-needle aspiration.

Cytologic features of the cell-stroma interface are useful in distinguishing between monomorphic adenomas of the basal cell type and adenoid cystic carcinoma. In basal cell adenomas, the collagenous stroma interdigitates with adjacent cells, whereas in adenoid cystic carcinoma, the two are separated by a sharp smooth border. Furthermore, the stroma of basal cell adenomas can contain rare spindle cells or capillaries, but the cylinders of adenoid cystic carcinoma are acellular. The authors review their experience with five cases of basal cell adenoma, and three cases that were designated "minimally pleomorphic adenomas." The latter group showed the small blue cell pattern of basal cell adenoma at the time of fine-needle aspiration, and histology revealed only small foci of typical pleomorphic adenoma. With the exception of one cystic case, the cell-stroma interface of basal cell adenoma was observed in all eight cases. These cases are contrasted with three adenoid cystic carcinomas with extensive solid (anaplastic) areas. All showed the small blue cell pattern and cell-stroma interface features of basal cell adenoma. Neither showed the smooth-bordered cylinders of adenoid cystic carcinoma. Two of these three were incorrectly interpreted as benign at the time of fine-needle aspiration. The authors suggest that the stroma aspirated from solid adenoid cystic carcinoma represents desmoplastic tumor stroma that mimics the pattern of basal cell adenoma in smear material. Distinction between basal cell adenoma and the solid type of adenoid cystic carcinoma at the time of fine-needle aspiration remains a very difficult problem.

Cytochrome P-450 and acetyltransferase expression as biomarkers of carcinogen-DNA adduct levels and human cancer susceptibility.

Carcinogen-DNA adducts are generally regarded as relevant biomarkers of carcinogen exposure and their levels in target tissues have often been predictive of tumor incidence in experimental animals. Thus, human risk assessment procedures have utilized dose-response models that assume proportional relationships between carcinogen exposure and cancer susceptibility, even though wide inter-individual variations in human metabolic activating enzymes have now been clearly established. To evaluate these approaches, we have examined the relationship between carcinogen exposure, DNA adduct levels, metabolic activation phenotypes, and cancers of the larynx, urinary bladder, and colon. Cigarette smoking is a strong risk factor for cancers of the larynx and urinary bladder. In the larynx, the DNA adducts appear to be derived predominantly from polycyclic aromatic hydrocarbons (PAHs) and are evident only in tissue from smokers. However, adduct levels appear to be determined primarily by expression of cytochrome P450 (CYP) 2C9/10, which varies > 10-fold in different individuals. This CYP catalyzes the metabolic activation of benzo (alpha) pyrene (BP) to a 9-hydroxy-BP-DNA adduct that accounts for up to 25% of the putative PAH adducts formed in vivo. For the urinary bladder, putative aromatic amine (AA)-DNA adducts are predominant and are significantly elevated in current smokers. Rapid CYP1A2 and slow acetyltransferase (NAT2) phenotypes have been previously implicated in the activation (N-oxidation) and detoxification (N-acetylation) of AAs for human bladder carcinogenesis. Data now indicate that NAT1, which is expressed in human urothelium and catalyzes the O-acetylation of N-hydroxy arylamines, is significantly correlated with DNA adduct levels and is bimodally distributed in this tissue. Colo-rectal cancer risk, which has been associated with exposure to heterocyclic amines (HAs) in cooked foods, is strongly elevated in individuals with the combined rapid phenotypes for CYP1A2 and NAT2. These enzymes are uniquely responsible for HA N-oxidation and subsequent O-acetylation, forming DNA adducts that are found in human colon. These studies indicate that cancer risk assessment procedures should be redesigned to include biomarkers of susceptibility, especially those involved in carcinogen bioactivation.

Metabolic activation and carcinogen-DNA adduct detection in human larynx.

Putative carcinogen-DNA adducts in human larynx tissues (n = 25) from smoker and non/ex-smoker patients were examined by 32P-postlabeling and compared with the metabolic activation capacity of larynx microsomes and cytosols from the same tissues. Hydrophobic DNA adducts were evident only in smokers, and chromatographic profiles of the adducts were similar using either the butanol extraction or nuclease P1 enhancement method, which suggested that the adducts may be derived from polycyclic aromatic hydrocarbons but not aromatic amines. Immunoblots of larynx microsomes using anti-cytochrome P450 1A1/1A2, 2C, 3A4, 2E1, and 2A6 antibodies showed intensities ranging from 1-10% of that typically observed with human liver microsomes. Enzymatic assays of larynx microsomes showed appreciable activity for benzo(a)pyrene hydroxylation (P450 1A1 and 2C) but not for 4-aminobiphenyl N-oxidation (P450 1A2), which indicated that the observed immunoreactivity was for P450 1A1; this represents the highest level of this P450 yet detected in human extrahepatic tissues. Accordingly, total DNA adduct levels in the larynx correlated strongly with levels of P450 2C, 1A1, and 3A4 but not with P450 2E1 or 2A6. Larynx cytosols also showed appreciable aromatic amine N-acetyl-transferase activity for p-aminobenzoic acid (NAT-1) but not for sulfamethazine (NAT-2); however, NAT-1 activity was not correlated with total DNA adducts, which is again consistent with the lack of aromatic amine-DNA adducts detected by 32P-postlabeling. Thus, these results suggest that the DNA adducts detected in human larynx are largely derived from metabolic activation of polycyclic aromatic hydrocarbons in cigarette smoke by P450 2C, 3A4, and/or 1A1.

Sinusitis in bone marrow transplantation.

Bone marrow transplantation has become a beneficial and curative technique used in treatment of patients with different hematologic conditions. It has become widely used at our institution for hematologic malignancies and certain resistant solid tumors. However, this treatment can result in immunosuppression, with an increased chance of infection. The purpose of this study was to review the causes of infections and determine the number of patients diagnosed with sinusitis. In the retrospective study, we evaluated the cases of bone marrow transplant patients for incidence and cause of fever. Sixty-eight percent of patients had fever after transplant; of these, 59% had fever of unknown origin. Only 1% of the patients with fever were diagnosed with sinusitis. In the evaluation of fever, sinusitis was not usually suspected and therefore was not included in the differential diagnosis. With such a high percentage of fever of unknown origin in this growing patient population, appropriate pretreatment evaluation of each case to rule out sinusitis should be considered.

Squamous cell carcinoma of the maxillary sinus.

Eighty-five patients with squamous cell cancer of the maxillary sinus received all of their treatment at The University of Texas M.D. Anderson Cancer Center between the years 1971 and 1986. Their records were evaluated according to stage, disease at presentation, symptoms and signs at presentation, treatment, and outcome. There were no differences in locoregional control or survival between groups treated with surgery alone vs surgery plus radiotherapy. Careful analysis of the data indicates that there was almost certainly some selection bias for the patients undergoing combination therapy, as most of this group had historically adverse prognostic factors identified. Those patients who underwent radiotherapy alone or chemotherapy presented with either metastatic or locally advanced disease and were treated with palliative intent; therefore, comparison between this group and standard therapy groups was impossible in this retrospective review. Although it is tempting to speculate that combination therapy improved locoregional control and survival in patients with more advanced disease, none of the data presented in this review reach statistical significance. Furthermore, there is no difference in survival in this population compared with a study at this institution 20 years ago. Squamous cell cancer of the maxillary sinus continues to be a challenging neoplasm. Radiotherapy may improve locoregional control and survival in a group of patients with more advanced disease and may have its greatest utility in earlier-stage disease. A multi-institutional prospective trial is needed to find ways to improve outcome in this patient population.

Orbital preservation in maxillectomy.

Twenty-eight previously untreated patients with squamous carcinoma of the maxillary sinus underwent maxillectomy with preservation of the orbital contents at the M. D. Anderson Cancer Center between 1971 and 1986. Eighteen patients had part or all of the orbital floor resected; nine patients were treated with radiotherapy, and nine had surgery only. Only 3 of 18 patients in this group (17%) retained significant function in the ipsilateral eye. Furthermore, local recurrence in this group was common (44%), regardless of whether postoperative radiotherapy was used. Ten patients retained the bony orbital floor; if the radiation fields did not include the eye, problems were minimal. Strong consideration should be given to orbital exenteration at the time of surgery, when the orbital floor is resected--especially if postoperative radiation fields will include the eye.

Salivary gland tumors.

Salivary gland cancers continue to pose both diagnostic and treatment dilemmas. Over the past year, a great deal has been written concerning salivary gland tumors in children, fine needle aspiration for salivary gland neoplasms, prognostic factors, and pathologic evaluation and treatment. Some of the more important findings include imaging studies and approaches to the human immunodeficiency virus-positive patient with parotid enlargement, the molecular biology of salivary cancer, and the pitfalls of fine needle aspiration cytology. The necessity of facial nerve sacrifice in parotid surgery for malignancy is debated, and the classification of tumors is clarified.

Tumor specific response to photodynamic therapy.

The exact mechanism by which photodynamic therapy (PDT) causes tumor destruction has not been elucidated. Early reports indicated that PDT causes direct cellular effects probably mediated by unstable oxygen species, resulting in cellular oxidation and death. More recently, PDT effects on tumor blood flow have been implicated, and there are questions as to whether the PDT response is specific to tumor tissue. Rats were implanted with a window chamber containing either a mammary adenocarcinoma or a piece of inert surgical sponge. After growth of the tumor was ascertained, all rats were given 5 mg/kg Photofrin intraperitoneally, and then were irradiated with 630 nm light 24 hours post-injection. Caliper thickness and reflectance measurements were performed before and after irradiation; all animals were sacrificed 72 hours post-PDT and the chambers submitted for histologic analysis. Animals implanted with tumors demonstrated marked edema of the chamber with an associated decrease in reflectance. No edema response was noted in the chambers containing inert sponge, or in any controls. Nonselective PDT effects (characterized by a marked foreign body response) in chambers containing sponge was not seen. Histologic analysis of treated specimens corroborate the above data.

Metabolic activation, DNA adducts, and H-ras mutations in human neoplastic and non-neoplastic laryngeal tissue.

Metabolic activation, DNA adducts, and H-ras mutations were examined in human laryngeal tissue (n = 16) from both smoker and non/ex-smoker patients with laryngeal cancer. DNA adducts detected by 32P-postlabelling were evident only in smokers (n = 13); in fact, smoking cessation for as little as 10 months resulted in no DNA adducts detected (n = 3). Total DNA adduct levels in these samples were significantly correlated with levels of cytochromes P-4502C and 1A1 in laryngeal microsomes. Moreover, the P-4501A1 levels represent the highest yet found in human tissues. In contrast, laryngeal microsomes did not have detectable P-4501A2 activity, while laryngeal cytosols showed appreciable N-acetyltransferase activity for p-aminobenzoic acid (NAT1) but not sulfamethazine (NAT2). DNA was extracted from laryngeal specimens and amplified by PCR. Nylon filter dot or slot blots were hybridized with 32P-labelled probes for codons 12, 13, and 61 of the H-ras gene. Sixty percent of specimens demonstrated mutations in either codon 12, 13, or 61; a single common and specific mutation was a Gln-->Glu transversion in codon 61. This mutation appeared in 5 laryngeal specimens, all from smokers. These results implicate cigarette smoke components, bioactivated by CYP1A1 and/or CYP2C, in DNA adduct formation. These results also demonstrate a probable smoking-related H-ras Gln-->Glu transversion in codon 61.

Cholesteatoma in the pediatric population: prognostic indicators for surgical decision making.

A review of surgical therapy for pediatric cholesteatoma at the Arkansas Children's Hospital was performed. Fifty-three children treated surgically for cholesteatoma were studied over a 10-year period. Primary acquired, or attic retraction cholesteatomas, were generally treated with a canal up tympanomastoidectomy; there were very few complications or secondary procedures in this group. Middle ear or secondary acquired cholesteatomas were initially treated by both canal up and canal down procedures; however, a large percentage of these patients eventually required an open cavity procedure. The presence of cholesteatoma in the sinus tympani strongly predicted failure to control disease with a canal up procedure (P < .05); conversely, the absence of matrix in the sinus tympani was predictive for success when a canal up procedure was used for attic cholesteatoma (P < .05). Finally, it was determined that follow-up was not adequate in our patient population. With this in mind, guidelines for the management of pediatric cholesteatoma will be presented.

Anatomy of the lateral pharyngotomy approach.

The pace of progress in head and neck surgery is rapid and can be bewildering to practitioners and students alike. As education is one of the major missions of Head & Neck, this new series is devoted to a comprehensive discussion of basic anatomical concepts manifested in the diagnosis, treatment, and care of patients with diseases of the head and neck. Although the anatomy of the head and neck region as related to surgical procedures will certainly be discussed, this will by no means be the only subject addressed. Other topics include the anatomic basis for specific pain syndromes encountered in patients with cancer of the head and neck, structural and lymphatic anatomy demonstrating patterns of disease spread, and constraints to standard surgical procedures because of anatomic "barriers." As medical illustration is an extremely important aspect of anatomy education, a concerted effort will be made to present material with illustrations that are understandable, clear, and concise. It is hoped that these subjects will not only educate but will also engender other topics of interest to readers. I welcome your suggestions for appropriate topics, as well as original contributions in keeping with the series guidelines.

Effect of aspirin on photodynamic therapy utilizing chloroaluminum sulfonated phthalocyanine (CASP).

The efficacy of photodynamic therapy (PDT) is mediated through a direct vascular effect. Interference with platelet function and resulting vascular stasis have been recently demonstrated utilizing the photosensitizer dihematoporphyrin ether (DHE). We examined the effect of aspirin, a known inhibitor of both cyclooxygenase and platelet activity, on PDT using chloroaluminum sulfonated phthalocyanine (CASP). Thirty-six rats implanted with a window chamber were given either 0.1 mg/kg (low dose) or 10 mg/kg (high dose) aspirin immediately before, immediately after, or 6 hours after the completion of CASP-PDT. Aspirin in either dosage did not appear to have any effect on the window vasculature when given immediately after light exposure. A moderate inhibition of vascular response was seen in animals treated with aspirin pre-PDT, whereas high-dose aspirin completely abrogated the CASP-PDT vascular response when given 6 hours post-PDT. These data indicate that aspirin can effect CASP-PDT in both time-dependent and dose-dependent fashions.

Chloroaluminum sulfonated phthalocyanine versus dihematoporphyrin ether: early vascular events in the rat window chamber.

The development of a simple and well-tolerated rat window chamber has allowed direct comparison of the vascular effects of two photosensitizers, chloroaluminum sulfonated phthalocyanine (CASP) and dihematoporphyrin ether (DHE). CASP and DHE were given 4 days after the implantation of the window chamber. Photodynamic therapy (PDT) with CASP was performed 24 hours after intravenous injection (10 mg/kg) with light at 675 nm (power density 200 mW/cm2, incident energy 100 J). DHE was given in a similar fashion (5 mg/kg intraperitoneally; light at 630 nm with matching power density and energy settings 24 hours after injection). Using videomicroscopic and integrating sphere measurements, marked differences were noted in the vascular effects of these photosensitizers. DHE caused immediate hemorrhage and disruption of the postcapillary venules, while CASP induced vascular spasm starting 4 hours after the completion of PDT. Forty-eight hours after PDT, both systems demonstrated a loss of chamber-induced neovascularization.

An implantable tumor-window chamber model for the study of photodynamic therapy.

In order to study both the anti-tumor effects and early vascular events in photodynamic therapy, a useful animal model has been developed. A window chamber is surgically placed on the dorsum of the Fischer-344 rat, and 500-microns fragments of the rat mammary adenocarcinoma 13672 are placed under direct vision into the subcutaneous tissue. Implantation of the chamber has been successfully completed in more than 50 rats. The operative procedure is straightforward and is accomplished in less than 1 hour. Using tumor fragments, tumor viability has been 60%. We have demonstrated obvious and reproducible neovascularization occurring as soon as 1 day after implantation. The application of this system to an experimental protocol comparing the photosensitizers dihematoporphyrin ether (DHE) and chloraluminum sulfonated phthalocyanine (CASP) has yielded important information on early vascular events resulting from photodynamic therapy.