Organization and activity in the pre- and postovulatory follicle of Necturus maculosus.

The established follicle envelope of Necturus maculosus consists of a layer of follicle cells (granulosa) surrounding the developing oocyte, a layer of theca comprised of connective tissue cells, fibers, and matrix, and a layer of serosal cells. The changes in shape and fine structure of these layers during differentiation accompanying oogenesis are described. The cells and capillaries of the follicle envelope are engaged in an extensive pinocytotic activity, the details of which are described. We used cytochemical techniques to analyze the activity of the follicle envelope with respect to lipid accumulation and alkaline phosphatase activity. Radioautographic results indicate that cells of the follicle envelope are capable of incorporating tritium-labeled uridine and amino acids at certain times during oocyte growth. A comparative analysis was made of the soluble proteins in follicle envelopes isolated from immature oocytes and of those in follicle envelopes isolated from nearly mature oocytes and in postovulatory follicles. After the oocyte is ovulated, the cells of the follicle envelope are converted into a postovulatory follicle. The cells of the postovulatory follicle undergo further differentiation resulting in their becoming actively engaged in the formation of a secretion, the details of which are described at the electron microscope level. Analysis of the postovulatory follicle by thin-layer chromatography and cytochemistry demonstrated the presence of a wide variety of lipid substances and the possible presence of steroid. That the postovulatory follicle may be engaged in steroid biosynthesis is also suggested by studies involving the demonstration of 3 beta-hydroxysteroid dehydrogenase activity with cytochemical techniques applied to frozen sections and to soluble proteins separated by gel electrophoresis.

Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer.

BACKGROUND: The majority of patients with head and neck cancer die of locoregional recurrence of disease following surgery and/or radiotherapy. PURPOSE: Our purpose was to administer induction chemotherapy, perform surgery, and administer concomitant chemoradiotherapy in rapid sequence and to evaluate their impact on locoregional and distant tumor control. METHODS: Sixty-four patients with previously untreated, locoregionally advanced head and neck cancer received two cycles of cisplatin, bleomycin, and methotrexate (PBM) (33 patients) or cisplatin, fluorouracil (5-FU), and leucovorin (PFL) (31 patients). PFL was given to patients who were unable to receive bleomycin. Local therapy consisted of surgery and/or concomitant chemoradiotherapy with 5-FU, hydroxyurea, leucovorin, and radiotherapy (FHX-L), all administered every other week. RESULTS: Complete and overall induction response rates were 21% and 79%, respectively, for PBM and 29% and 81%, respectively, for PFL. At completion of local therapy, 81% of the patients were disease-free. With a median follow-up of 35 months, the median survival and time to progression are 22 and 17 months, respectively, for PBM and have not been reached for PFL. Locoregional recurrence of disease is 30% for PBM and 26% for PFL. Distant disease progression is 24% for PBM and only 3% for PFL. CONCLUSIONS: The sequencing of induction chemotherapy and concomitant chemoradiotherapy is feasible and results in a high local control rate and in an encouraging survival rate with PFL. The high distant failure (i.e., outside the head and neck area) rate of PBM suggests insufficient systemic activity for that regimen. IMPLICATIONS: Concomitant FHX-L chemoradiotherapy may improve regional control rates of advanced head and neck cancer. Effective systemic therapy may be needed to control systemic micrometastases. PFL, but not PBM, appears to be suitable to accomplish that goal.

Cisplatin and fluorouracil chemotherapy does not yield long-term benefit in locally advanced head and neck cancer: results from a single institution.

Fifty-one patients with locally advanced head and neck cancer were treated with three cycles of cisplatin at 100 mg/m2 followed by 5-day continuous infusion fluorouracil (5-FU) at 1,000 mg/m2/d as induction chemotherapy. Subsequent local therapy consisted of surgery for patients with resectable disease and/or radiotherapy. Three cycles of adjuvant chemotherapy were administered to patients with partial response (PR) or complete response (CR) to induction chemotherapy. Twenty-two patients (43%) had a clinical CR that was pathologically confirmed in 12 patients (24%), and 24 patients (47%) had a PR for an overall response rate of 90%. Local therapy included surgery in 24 patients (47%) and radiotherapy alone in 22 patients (43%). Adjuvant chemotherapy was administered to 32 patients (63%) frequently at great dose reduction. At a median follow-up of 90 months, the median survival is 22 months (95% confidence interval, 15 to 36 months), and the 5-year survival is 25%, with only five patients known to be alive and disease-free at this time. The median time to progression is 14 months, with 29 patients (57%) having documented progression of their head and neck cancer and eight (16%) having progression of a second neoplasm. Seven patients died of intervening medical events. This high incidence of second malignancies supports the continued investigation of chemoprevention for patients in CR. Despite the known high response rates achieved with cisplatin and 5-FU induction chemotherapy, the overall poor survival data reported here should lead to a thorough reexamination of the frequent administration of this regimen in the community.

Neoadjuvant and adjuvant methotrexate, cisplatin, and fluorouracil in multimodal therapy of head and neck cancer.

To increase the complete response (CR) rate of patients with locally advanced head and neck cancer after three cycles of neoadjuvant chemotherapy, we added sequential methotrexate to the combination of cisplatin and continuous infusion fluorouracil (5-FU). We also evaluated the feasibility of administering three additional cycles of the same regimen as adjuvant chemotherapy. Thirty-eight patients were treated; the median age was 53 years and 36 patients had stage IV disease. Chemotherapy consisted of methotrexate 120 mg/m2 followed 24 hours later by cisplatin 100 mg/m2 and a five-day continuous infusion of 5-FU at 1,000 mg/m2/d. Of 34 patients evaluable for response to neoadjuvant chemotherapy, nine had a CR, 21 a partial response (PR), two a minimal response (MR), and one patient each stable disease (SD) and no response (NR). Of 31 patients who received local therapy, 15 were treated with surgery and radiotherapy and 16 with radiotherapy alone. Of 25 patients eligible to receive adjuvant chemotherapy only ten received all three intended cycles, while 15 received less or no adjuvant chemotherapy because of patient refusal, cumulative toxicity, or early disease progression. With a median follow-up time of 39 months, the median survival is estimated to be 20 months. Of eight patients with nasopharyngeal or paranasal sinus cancer, none has had disease recurrence. Patients with good initial performance status and low N-stage also had a significant survival advantage. Chemotherapy-related toxicities consisted mainly of mucositis, requiring 5-FU dose reduction in the majority of patients; similar toxicities were exacerbated in the adjuvant setting. The addition of methotrexate did not increase the CR rate over what has been reported for the combination of cisplatin and 5-FU alone. Certain subsets of patients appear to have a good prognosis when treated in this fashion. The administration of adequate adjuvant chemotherapy in patients with head and neck cancer remains difficult due to toxicity and poor patient compliance.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis.

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.

Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer.

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.

Cisplatin, fluorouracil, and leucovorin augmented by interferon alfa-2b in head and neck cancer: a clinical and pharmacologic analysis.

PURPOSE: To increase the activity of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) through further biochemical modulation and study the pharmacologic interaction of 5-FU and interferon alfa-2b (IFN). PATIENTS AND METHODS: Escalating doses of IFN (0.5 to 4.0 x 10(6) U/m2/d x 6) were added to cisplatin 100 mg/m2, continuous infusion 5-FU 800 or 640 mg/m2/d x 5, and leucovorin 100 mg orally every 4 hours. Forty-eight previously untreated patients with locoregionally advanced head and neck cancer received up to three cycles of PFL-IFN. RESULTS: Twenty-one patients were treated during a phase I cohort study. Dose-limiting mucositis was seen with 800 mg/m2/d of 5-FU and 0.5 x 10(6) U/m2/d of IFN. After decreasing the 5-FU dose to 640 mg/m2/d, the maximally tolerated dose (MTD) of IFN was 2.0 x 10(6) U/m2/d. Mucositis and myelosuppression were dose-limiting. Of 34 patients treated at this MTD, 56% (95% confidence interval, 39% to 73%) had a complete remission. There was no correlation between 5-FU clearance and IFN dose. Pharmacodynamic analyses at the MTD showed that older age, female sex, and higher 5-FU area under the time versus concentration curve (AUC) were associated with lower nadir counts and/or increased mucositis. Seven patients with diabetes mellitus had significantly increased myelosuppression, serum creatinine, hypocalcemia, higher 5-FU concentrations, and lower 5-FU clearance compared with nondiabetics. CONCLUSION: The recommended doses for PFL-IFN are 640 mg/m2/d for 5-FU and 2.0 x 10(6) U/m2/d for IFN. Sex, age, 5-FU AUC, and diabetes mellitus may have an impact on the pharmacodynamics of this regimen.

Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.

Hydroxyurea with concomitant radiotherapy for locally advanced head and neck cancer.

Hydroxyurea is an active single agent in squamous cell cancer of the head and neck. It has been used clinically, most frequently as a radiation-enhancing agent with concomitant radiotherapy. Pilot trials testing hydroxyurea in this setting reported encouraging results. Two randomized trials have been conducted with inconclusive results, possibly relating to study cohort size and short period of follow-up. More recently, hydroxyurea has been investigated with 5-fluorouracil and concomitant radiotherapy. A sound theoretic rationale can be made for this approach and data derived from a phase I/II study are presented. These support the further investigation of this regimen.

Perspectives on combination chemotherapy with concomitant radiotherapy for poor-prognosis head and neck cancer.

Concomitant chemoradiotherapy has resulted in small increases in disease-free or overall survival for patients with advanced head and neck cancer when single-agent chemotherapy is used. To increase the efficacy of this approach, combination chemotherapy also has been explored. In this setting, acute toxicities are frequently increased, necessitating interruption or protraction of radiotherapy. Despite this fact, pilot trials using 5-fluorouracil-based chemotherapy have indicated high response and encouraging survival rates. Some of these trials will be reviewed, with a focus on studies with 5-fluorouracil, hydroxyurea, and cisplatin conducted at the University of Chicago.

Radiobiological characterization of head and neck and sarcoma cells derived from patients prior to radiotherapy.

The radiobiological parameters of 33 tumor cell lines were studied in biopsy samples obtained from patients prior to radiotherapy. Epithelial tumor cells derived from head and neck cancer patients were more radioresistant than tumor cell lines derived from patients with sarcoma regardless of method of analysis. The presence of radioresistant tumor cell lines was associated with local failure in some patients. However, the presence of radiosensitive tumor cells did not necessarily predict local control. Our data suggest radiocurability is complex and inherent radiobiological parameters of tumor cells may be only one factor in radiotherapy outcome.

Cyanoacrylate adhesive used to stop CSF leaks during orbital surgery.

Butyl-2-cyanoacrylate (Histoacryl Blue) tissue adhesive successfully sealed three cases of CSF leaks encountered during orbital surgery. The application of tissue adhesive was followed by prompt cessation of leak. We have found this tissue adhesive to be a valuable technical adjunct in the intraoperative management of this difficult problem and have not seen any general or local toxic reaction to the material.

New concepts in head and neck surgery.

New methods in head and neck cancer treatment have enabled the oncologic surgeon to pursue the goals of conservation of head and neck physiologic function, reduce the morbidity and mortality associated with advanced head and neck cancers, and increase the cure rates for cancers once considered inoperable. Advances in multimodality therapy may lead in the next decade to less surgical mutilation and higher cure rates.

Myocutaneous trapezius flap.

A random pattern flap, such as the nape-of-the-neck flap, is a delayed cutaneous flap that relies on collateral circulation based on the skin pedicle. The myocutaneous trapezius flap, however, is a cervical flap that does not need to be delayed since it receives its blood supply from a musculocutaneous artery. The author has radiographic and clinical evidence that demonstrates that the upper one-half of the trapezius muscle is primarily, and abundantly, supplied by the transverse cervical artery. If this artery is kept intact during resection and reconstruction, a flap as large as 12 x 42 cm may be maintained. This flap has been used in various types of reconstruction on 23 patients, and it has been successful in terms of viability, versatility, safety, and cosmesis.

Melanoma of the upper aerodigestive tract: a review of 21 cases.

In this report 21 cases of primary malignant melanoma arising from the mucosa of the upper aerodigestive tract are reviewed. The patients ranged in age from 30 to 86; mean age was 67 years. There were 10 men and 11 women. All but one patient were white. Sites of involvement were: nose and paranasal sinuses, oral cavity and labial mucosa, parotid duct, and larynx. Surgery was the primary method of treatment. The 2-year survival rate was 44% (7/16) and the 5-year survival rate was 13% (2/15). Regional metastases were seen in 19% (4/21) while distant metastases was seen in 55% (11/21). The local recurrence rate was 69% (11/16). Distant metastases were usually associated with uncontrolled disease at the primary site. This fact as well as the low incidence of regional metastases lead us to conclude that better local control rather than regional lymphatic control is necessary if decreased distant metastases and increased survival are to be achieved.

Fluorescein test in the prediction of viability of skin flaps on pigs.

The fluorescein test is widely used in clinical and experimental studies for prediction of the viability of skin flaps. A thorough search of the literature revealed that the accuracy of this test had never been studied. Therefore, this study was designed to evaluate the accuracy of the fluorescein test in predicting the viability of skin flaps. A total of 212 unipedicle porcine skin flaps were used in this study. Statistical analysis demonstrated that the surviving area of the flap was significant greater than the staining area of the flap. We suggest that caution be exercised when the fluorescein dye test is used to assess skin flap viability and that the test be used for an approximate indication and not for an accurate prediction of the surviving flap area.

Nasofacial defect following fibrosarcoma excision and radiotherapy.

For initial reconstruction, Dr. Burget suggests that he would have advanced the cheek flap medially toward the nasal septum and, subsequently, reconstructed the missing right half of the nose with a forehead flap and cartilage grafts. Dr. Panje suggested early prosthetic rehabilitation, while Dr. Krause's concepts were similar to Dr. Burget's, with forehead flap nasal reconstruction, after cheek reconstruction to the nasofacial and nasolabial lines with a medially advanced cheek flap. Dr. Panje recommended an immediate maxillary denture prosthesis, as did Dr. Krause (who supplemented this with foam rubber). Dr. Burget placed the prosthesis 3 weeks after tumor ablation. For skin grafts, Drs. Panje and Burget suggested split thickness grafts to all new surfaces to decrease wound contracture, while Dr. Krause used dermis grafts for the same purpose. Other reconstructive methods mentioned were the (1) cervical tubed flap, (2) free scapular flap, (3) Washio flap, (4) tissue expansion, and (5) nasolabial flap. Suggestions for isolated defects included: Lower eyelid--increase internal support by building up the prosthesis; release lower lid from deltopectoral flap and V-Y advancement; support graft or irradiated cartilage (1-2 mm sheet) under orbicularis oculi. Nasal ala--bring present ala down and insert cartilage graft; turn internal skin down and fill the resulting defect with a composite graft. Upper lip--multiple Z-plasty. Retrodisplacement of cheek due to maxillectomy--release buccal scar; skin graft the raw internal surface and build up prosthesis.

Evidence for orbital deformation that may contribute to monocular blindness following minor frontal head trauma.

Traction injury to the optic nerve and vasa nervorum is the suggested etiology for monocular blindness following trivial frontal trauma. Holographic interferometry was used on human skulls to demonstrate orbital deformation in response to nondestructive frontal loading. The findings suggest an additional mechanism for energy dissipation and therefore for optic nerve injury following frontal impact.

Osteochondroma presenting as a neck mass: a case report.

Osteochondromas are benign bone tumors which rarely present as neck masses. This report reviews the literature and presents the case of a 10-year-old girl with a neck mass and hoarseness due to an osteochondroma of the cervical spine. An extensive diagnostic evaluation and partial surgical excision were necessary. Although rare, osteochondromas should be considered in the differential diagnosis of a firm neck mass. Surgical excision of these lesions is recommended.

Murine subrenal capsule assay: prediction of chemoresponsiveness in head and neck cancer.

If chemotherapy is to be used with the greatest efficacy in head and neck cancer, a predictive test that will indicate tumor sensitivity or resistance in individual patients may be desirable. This report demonstrates that the in vivo murine subrenal capsule assay was an efficient, sensitive method for retrospectively predicting the clinical response of squamous cell carcinomas of the head and neck to chemotherapy. Twenty-five courses of chemotherapy in 22 patients were compared to responses in the in vivo assay. The assay correctly identified sensitivity to chemotherapy in 86% of clinically responding patients. The specificity of the assay was 78%. A 60% efficiency for predicting clinical response and a 93% efficiency for predicting clinical resistance were demonstrated. Eighty percent of the results were correctly classified. The murine subrenal capsule assay has potential in planning of chemotherapy for selected patients.