[Immunocorrection in the treatment of diffuse peritonitis in aged patients].

The results of treatment of 161 patients with diffuse forms of peritonitis with, using of the immunostimulators are analyzed. The algorithm of staged complex immunocorrection for patients with acute pancreatitis, including aged patients, is worked out. The use of it improves the results of treatment and allows decrease the morbidity.

[Prediction of surgical infections severity at elderly and old patients].

Clinical and immunological characteristics of generalized peritonitis in different age group at complicated and non-complicated postoperative period were analyzed at 246 patients with abdominal purulent infection. Prognostic criteria of complicated postoperative period at elderly and old patients have been determined. It is concluded that interpretation of immune characteristics permits to determine the prognostic criteria of disease course and outcome at various age group, and to use the rational immunocorrection.

Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers.

PURPOSE: Epidermal growth factor receptor (EGFr) is overexpressed in a majority of head and neck squamous cell carcinomas, and this overexpression is associated with a poor prognosis. Therefore, EGFr has become the target of investigations aimed at disabling the receptor to determine whether this process leads to improved tumor kill with conventional treatment. MATERIALS AND METHODS: C225 is an anti-EGFr monoclonal antibody that inhibits receptor activity by blocking the ligand binding site. A panel of human head and neck squamous cell carcinoma cell lines was used to study the combination of C225 and radiation. RESULTS: It was determined that the combination of C225 (5 microgram/mL) delivered simultaneously with radiation (3 Gy) resulted in a greater decrement in cellular proliferation than either treatment alone. This reduction in proliferation correlated with reduced EGFr tyrosine phosphorylation and a reduction in phosphorylated signal transducer and activator of transcription-3 (STAT-3) protein (known to protect cells from apoptosis). Also, the decrement in proliferation correlated with increased apoptotic events, thereby indirectly linking C225/radiation-induced regulation of STAT-3 protein to apoptosis. CONCLUSION: This preclinical work serves as important support for the ongoing clinical investigation of C225 and radiotherapy for patients with head and neck carcinomas. The initial results of these clinical studies have been promising.

Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector.

In vivo cancer gene therapy approaches for squamous cell carcinoma of the head and neck (SCCHN) based on adenoviral vector-mediated gene delivery have been limited by the suboptimal efficacy of gene transfer to tumor cells. We hypothesized that this issue was due to deficiency of the primary adenoviral receptor, the coxsackie-adenovirus receptor (CAR), on the tumor targets. Studies of CAR levels on SCCHN cell lines confirmed that their relative refractoriness to the adenoviral vector was based on this deficiency. To circumvent this deficiency, we applied an adenoviral vector targeted to a tumor cell marker characteristic of SCCHN. In this regard, integrins of the alpha2beta1 and alpha3beta1 class are frequently overexpressed in SCCHN. Furthermore, these integrins recognize the RGD peptide motif. On this basis, we applied an adenoviral vector genetically modified to contain such a peptide within the HI loop of the fiber protein as a means to alter viral tropism. Studies confirmed that the CAR-independent gene delivery achieved via this strategy allowed enhanced gene transfer efficiencies to SCCHN tumor cells. Importantly, this strategy could achieve preferential augmentation of gene transfer in tumor cells compared with normal cells. The ability to achieve enhanced and specific gene transfer to tumor cells via adenoviral vectors has important implications for gene therapy strategies for SCCHN and for other neoplasms in general.

Treatment of recurrent head and neck cancer with 5-fluorouracil, hydroxyurea, and reirradiation.

Head and neck cancer locally recurrent after previous irradiation and surgery presents a difficult management problem. Conventional treatment alternatives include chemotherapy, reirradiation with interstitial implant, and hyperthermia. Reirradiation with external beam is generally not considered because of previous high radiation dose and limited tissue tolerance. In this study, 21 patients with recurrent and previously irradiated head and neck cancer were treated in a Phase I-II fashion. Patients received 5 days of 5-fluorouracil, 300 mg/m2/day IV bolus, Hydroxyurea 1.5 or 2 g/day by mouth and external beam radiation therapy every 2 weeks for up to four courses. Of 20 evaluable patients, 9 have attained a complete response (CR) and 6 a partial response (PR). Fifteen patients completed all planned therapy, eight on time, seven patients with delays. With a median follow-up of 7 months, 13 patients are alive, 7 disease-free (3 after salvage surgery) and 6 with recurrence. Eight patients have died. The 1-year survival is 56%. Treatment toxicity was mainly neutropenia. No major early or late radiation related side effects have been observed at a median follow-up of 7 months. Neither previous radiation dose, time since first radiation, prior chemotherapy, or site of recurrence was predictive of response or treatment tolerance. Patients with a performance status of at least 80 had a significant higher CR rate, with 7/10 patients in this group, as compared to 2/10 patients in patients with a performance status less than 80, achieving a CR. Reirradiation with 5-fluorouracil and hydroxyurea is a well tolerated outpatient treatment program for patients with recurrent and previous irradiated head and neck cancer that produces a high response rate and can provide significant palliation of symptoms.

A phase I study of prolonged infusion 5-fluorouracil and concomitant radiation therapy in patients with squamous cell cancer of the head and neck.

The radiosensitization properties of 5-FU are well documented, and clinical trials have suggested improved local control and survival in head and neck cancer. Clinical trials to date have used bolus injection or short term (less than or equal to 5 days) 5-FU infusions. To determine the maximum tolerated dose (MTD) of 5-FU given as continuous intravenous infusion for 12 weeks concomitant with conventional radiation therapy, 18 patients with advanced inoperable head and neck cancers were treated with conventional irradiation and 100, 200, 250, or 300 mg/m2/day of 5-FU. A dose of 250 mg/m2/day was determined to be the maximum tolerated dose and is recommended for Phase II studies.

Bupropion-induced erythema multiforme.

The high rate of dermatologic adverse effects associated with bupropion use may extend to its sustained-release preparation, currently prescribed extensively for smoking cessation as well as for treatment of depressive conditions. We report what we believe to be the first case, in a 31-year-old woman, of erythema multiforme after administration of sustained-release bupropion (Wellbutrin SR) for treatment of depression. This report emphasizes that prescribers must aggressively follow up their patients who have rashes or urticaria, discontinuing the medication as soon as erythema multiforme is suspected and watching closely for the emergence of potentially life-threatening dermatologic conditions.

Paragangliomas of the neck.

Between 1967 and 1990 inclusive, 28 patients with paragangliomas of the neck were diagnosed at the University of Alabama at Birmingham Affiliated Hospitals. There were 11 men and 17 women, whose ages ranged from 12 to 76 years (mean, 47 years). Tumor locations included the carotid bodies (19 cases), the vagus nerves (three), supraglottic larynx (two), the left lateral pharyngeal wall (one), posterior to the right jugular vein (not otherwise defined) (one), subcutaneous neck tissue (one), and a cervical lymph node with unknown primary (one). Diagnostic workup included angiography (23 cases) with preoperative embolization (three), computed tomography (one), magnetic resonance imaging (two), and urinary catecholamine assay (four). All 28 patients underwent resection of the lesions. Cranial nerve damage occurred in 11 patients (39%). There were no perioperative deaths or cerebrovascular accidents, although one of two saphenous vein grafts became thrombotic after carotid body tumor resection.

Distribution and metabolism of exogenous somatostatin in the rat.

The mechanisms of clearance and degradation of injected [3H]somatostatin have been studied in the rat using octadecasilyl-silica extraction and HPLC separation methods.. Three apparent consecutive plasma half-lives of 1, 3 and 20 min were estimated following administration of a pharmacological dose. The initial rapid clearance was due to uptake by various tissue beds, mainly the large peripheral tissue masses muscle, skin and intestine which together accounted for 70% injected radioactivity at 1 min. By contrast the amounts taken up by liver and kidney were relatively small (less than 10%) despite the accumulation of higher concentrations. Massive degradation occurred following uptake and small fragments and amino acids were released into the circulation almost immediately. Inactivation by blood itself was negligible. A slow phase of decline observed at later times suggested a return of intact peptide from extravascular storage sites to sustain plasma concentrations.

The mechanism of degradation of cyclo(-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-) and the relative stabilities of this and other octapeptide somatostatin analogues in rat intestinal juice.

The mechanism of degradation of the somatostatin analogue cyclo(-Asn-Phe-4-[3H]-Phe-D-Trp-Lys-Thr-Phe-Gaba-) in rat intestinal juice in vitro has been studied by isolation and identification of cleavage products. The analogue is much more stable than somatostatin but is nevertheless degraded in minutes in dilute intestinal juice. There is a single primary cleavage site at Lys-Thr and the linear peptide thus formed is subsequently rapidly degraded to smaller peptides. Analogues with a modified lysine are markedly stabilised relative to the octapeptide analogue.

Pharmacokinetics, distribution and elimination of a synthetic octapeptide analogue of somatostatin in the rat.

The in vivo fate of a long acting somatostatin analogue [des-AA1,2,3,4,13,14,D-Trp8,Gaba12]-somatostatin has been studied in the rat using biochemical and autoradiographic techniques. The analogue has a longer plasma half-life than somatostatin. This is due to its greater metabolic stability which renders it resistant to enzymic attack in the tissues. The primary route of elimination is by biliary excretion following clearance from the circulation by the liver. Evidence of enterohepatic circulation was found, but only to a very limited extent. When administered s.c., high plasma concentrations of intact peptide persist for a period of hours due to slow release from a stable depot at the injection site.

Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity.

An octapeptide and a protein, of molecular weights 800 and 34,000, respectively, were found to have nasal bioavailabilities of 73 and 0.6%, respectively, in the rat. This data, combined with reported values for 23 other compounds, indicated good availability without adjuvants for all molecules up to 1000 molecular weight (mean 70%, SD between compounds 26%, n = 15) with a decline in availability above this value. The relationship between absorption and molecular weight was modeled assuming competition between constant clearance from the nasal cavity and molecular weight-dependent transport through the mucosa. Deviations of absorption from values predicted by this model did not correlate with factors such as charge, hydrophobicity, or susceptibility to aminopeptidases, but the relative absorption of cyclic and cross-linked peptides and proteins was significantly greater than that of linear peptides. It is argued that the most likely route for transport is through junctions between cells and that surface-active adjuvants (MW 6000) which markedly enhance insulin uptake may act by rendering hydrophobic areas of contact of the junctional proteins temporarily hydrophilic. The nasal route is suitable for efficient, rapid delivery of many molecules of molecular weight less than 1000. With the use of adjuvants, this limit can be extended to at least 6000 and possibly much higher.

Effects of sodium 5-methoxysalicylate on macromolecule absorption and mucosal morphology in a vascularly perfused rat gut preparation in vivo.

The effect of sodium 5-methoxysalicylate on absorption was assessed by measurement of the appearance of test compounds in the portal blood output of a perfused rat gut model. The test compounds were a hexapeptide analogue of somatostatin, insulin, and horseradish peroxidase. Considerable amounts of sodium 5-methoxysalicylate were present in the portal blood 10 min after intraduodenal administration. When co-administered with sodium 5-methoxysalicylate (60 mg), a marked increase in the concentrations of the test substances occurred at t = 15 min which lasted for a further 15 min. Quantities of less than 60 mg had much reduced adjuvant effects. In control experiments with no adjuvant, the concentrations of the test substances remained low throughout the 1-h period of blood collection. After the administration of 60 mg of sodium 5-methoxysalicylate, slight mucosal damage was apparent at 10 min. This became progressively worse with time and, at 1 h, extensive mucosal stripping had occurred. The results suggest, although they do not prove, that apparent adjuvant effects in the small intestine may be a direct consequence of serious mucosal damage. This means that care must be taken in the investigation of adjuvant properties to exclude the possibility that an observed increase in transport is due to gross loss of integrity of the membrane.

Pseudocarcinomatous hyperplasia of the larynx due to Candida albicans.

A female patient presented with hoarseness. Findings on physical examination showed whitish true vocal cords. Laryngeal biopsies were performed on two two occasions. On the first biopsy a histopathological diagnosis of Candida albicans and acanthosis was controversial because the acanthosis resembled squamous cell carcinoma. On the second biopsy, several months later, the diagnosis of acanthosis was again controversial, but a diagnosis of pseudocarcinomatous hyperplasia was not determined until several months later. Finally, we can point out that pseudocarcinomatous hyperplasia can be associated with primary candidiasis and state that hoarseness, whitish true vocal cords, and pseudocarcinomatous hyperplasia can masquerade as squamous cell carcinoma of the larynx.

Molecular differences in mucoepidermoid carcinoma and adenoid cystic carcinoma of the major salivary glands.

OBJECTIVE/HYPOTHESIS: Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), the most common malignancies of the major salivary glands, are clinically and pathologically different. To determine whether MEC and ACC have different molecular characteristics, we examined the expression of erbB-2, erbB-3, epidermal growth factor receptor (EGFR), and transforming growth factor-alpha (TGF-alpha), important molecular features in other malignancies. STUDY DESIGN/METHODS: Archival tissue sections of 22 MEC and 6 ACC tumors of the major salivary glands were evaluated immunohistochemically for expression of erbB-2, erbB-3, EGRF, and TGF-alpha. A differential immunostaining score, reflecting the difference in immunostaining between carcinoma and uninvolved salivary gland tissue, was calculated for cytoplasmic and membranous staining. RESULTS: Positive immunostaining for all biomarkers was observed in the cytoplasm and membrane of both tumors. However, expression was higher in MEC than in ACC tumors and was statistically significant for cytoplasmic EGFR (P =.009), TGF-alpha (P =.041), and membranous EGFR (P =.004). A significantly higher percentage of MEC cells also demonstrated positive immunostaining for cytoplasmic erbB-3 (P =.022), EGFR (P =.005), membranous erbB-3 (P =.022), and EGFR (P =.013). The differential immunostaining score was significantly higher for MEC compared with uninvolved alveolar tissue and the membranes of uninvolved ductal tissue. There were no statistically positive differential immunostaining scores for ACC. CONCLUSIONS: There is a clear difference in the molecular phenotypes of MEC and ACC. The lack of statistically significant expression in ACC, when compared with similar uninvolved salivary gland tissue, suggests minimal involvement for these molecular structures in the pathogenesis of ACC. Conversely, erbB-2, erbB-3, EGFR, and TGF-alpha may have a role in the development and progression of MEC. These results have therapeutic implications for MEC of the major salivary glands.

Poststernotomy infections presenting as deep neck abscess.

A review of the world literature has failed to reveal any published reports of poststernotomy mediastinitis presenting as a deep neck infection. This article presents two such cases. Since the fascial layers of the mediastinum are a direct continuation of the cervical fascia, a number of potential pathways between the neck and mediastinum exist. Descending infection from the neck into the mediastinum is well documented. The reverse situation, an ascending infection from the mediastinum into the neck, is not described despite the potential natural pathways available for spread of infection. Our proposed mechanism for these two cases is that a surgically created pathway from the mediastinum to the lower neck allows for mediastinitis to point in the intercommunicating fascial spaces of the neck. Recognition of this clinical presentation will allow the surgeon to use prompt intervention for such a serious complication.

Nasal inverted papilloma with involvement of middle ear and mastoid.

Inverted papillomas of the paranasal sinuses have been characterized by their unusually benign histologic features, their ability to grow rapidly with bony destruction, and their tendency to recur if not adequately treated. The association of inverted papilloma with squamous cell carcinoma is well described, but malignant transformation is relatively rare. We report a case of a multiply recurrent inverted papilloma that spread to the middle ear and mastoid and eventually underwent malignant transformation with skull base invasion. Pathologic examination demonstrated many of the characteristics associated with malignant transformation. In addition, progesterone receptors were demonstrated that may have stimulated this tumor during the patient's pregnancy. To our knowledge, no similar cases have been reported in the literature.

Retargeting to EGFR enhances adenovirus infection efficiency of squamous cell carcinoma.

BACKGROUND: Adenovirus-mediated gene therapy has been used for squamous cell carcinoma of the head and neck (SCCHN), but the in vivo efficacy has been limited by a lack of tissue specificity and low infection efficiency. We are interested in improving cancer gene therapy strategies using targeted adenovirus vectors. OBJECTIVE: To determine if the infection efficiency of adenovirus-mediated gene transfer to SCCHN cells could be enhanced by retargeting to the epidermal growth factor receptor (EGFR), which is known to be overexpressed in these tumors. DESIGN: Epidermal growth factor receptor retargeting in SCCHN cells was accomplished with a bispecific antibody that recognized the knob domain of adenovirus as well as EGFR. Using this retargeting schema, we compared the infection efficiency and specificity of unmodified and EGFR-retargeted adenovirus. RESULTS: Squamous cell carcinoma of the head and neck cell lines were shown to be infected by adenovirus with low efficiency, which is likely because of the low level of adenovirus receptor expressed in the SCCHN cells. Epidermal growth factor receptor retargeting markedly enhanced transduction in both SCCHN cell lines and primary tumor tissue, as indicated by the elevated levels of reporter gene expression. Furthermore, retargeting enhanced infection of tumor tissue compared with normal tissue from the same patient. CONCLUSIONS: Epidermal growth factor receptor retargeting enhanced adenovirus infection of SCCHN cells and, in doing so, augments the potency of the vector. This modification makes the vector potentially more valuable in the clinical setting.

A phase I study of high-dose cisplatin, prolonged infusion 5-fluorouracil, and concomitant conventional fraction radiation therapy in patients with inoperable squamous cell carcinoma of the head and neck.

Cisplatin (CDDP) and 5-fluorouracil (5-FU) have been used alone, in combination, and in various doses and sequences with radiation therapy in attempts to improve local control and survival of patients with advanced head and neck cancer. This study was undertaken to determine the toxicity and maximum tolerated dose of high-dose CDDP plus prolonged infusion 5-FU with concomitant conventional radiation therapy. Twenty-two patients with inoperable Stage III and IV squamous cell cancer were treated with CDDP (30 or 35 mg/m2 for 5 days every 4 weeks for three courses) and 5-FU (200 or 300 mg/m2 per day continuous i.v. infusion for 12 weeks) with concomitant conventional radiation therapy. This aggressive treatment regimen is accompanied by severe mucositis, myelosuppression, and chronic neuropathy. CDDP, 35 mg/m2/day x 5, and 200 mg/m2/day of 5-FU infused over 12 weeks were identified as potential doses for future Phase II studies.

Concomitant chemotherapy and reirradiation as management for recurrent cancer of the head and neck.

Thirty-five patients with inoperable recurrent head and neck cancer previously treated with definitive irradiation were treated with reirradiation and concomitant chemotherapy. Patient records were retrospectively reviewed to assess toxicity, response, and survival. Patients received one of three regimens: 1) 40 Gy total (2 Gy daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 2 g hydroxyurea orally daily for 5 days; 2) 48 Gy total (1.2 Gy twice daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 1.5 g hydroxyurea orally daily for 5 days; 3) 60 Gy total (1.5 Gy twice daily), 300 mg/m2 5-fluorouracil intravenous bolus, and 1.5 g hydroxyurea orally daily for 5 days. For all regimens, treatment was given only on weeks 1, 3, 5, and 7. Acute toxicity was mainly hematologic and was less severe with the lower hydroxyurea dose. Acute mucosal and skin toxicity was acceptable for all regimens. Late toxicity was noted in 4 of 17 patients who survived 12 months or more. Late effects were Radiation Therapy Oncology Group grade 3 or less. Fifteen of 35 patients achieved a complete response, and 11 of 35 patients achieved a partial response. The median survival rate was 10.5 months. There was no significant difference in responses or median survival between the groups. Reirradiation of head and neck cancer with 5-fluorouracil and hydroxyurea offers acceptable acute toxicity and minimal late effects. The clinical response rates and median survival are encouraging. Further investigation is warranted.