The role of omentectomy during the surgical staging of uterine serous carcinoma.

Uterine serous carcinoma (USC) has a propensity for extrauterine spread, and some suggest that this disease be staged as an ovarian cancer, and thus include omental sampling. However, given the primary organ involved, the staging recommendations do not include omental sampling. The aim of this study is to evaluate the role of omental sampling during the surgical staging of USC. We retrospectively identified cases of USC at our institution from January 1990 to June 2000 and abstracted surgical procedures, stage, and sites of metastasis. Fisher's exact test was used to calculate sensitivity, specificity, and positive and negative predictive value. We identified 65 women with USC, of which 52 underwent omental evaluation. Thirty four of the omentums were visually normal and benign on histologic review. Two were visually negative and histologically positive for metastatic serous carcinoma. The remaining 16 specimens were grossly involved with histologic confirmation of disease. The sensitivity of a visually negative omentum is 0.89 (P < 0.0001). Microscopic omental metastasis from USC is rare. When the omentum is involved, thereby upstaging the patient to stage IVB disease, the disease is generally diagnosed by gross visualization. We conclude that omental sampling does not need to be included in the routine surgical staging of USC.

Introital stenosis requiring pelvic resection and soft tissue reconstruction.

BACKGROUND: Introital stenosis from both bony and soft tissue contracture is an unusual clinical problem not well addressed in the literature. CASE: A woman with a history of pelvic irradiation at age 1 for malignancy presented with severe introital stenosis unresponsive to conservative topical and dilatational therapy. She ultimately required staged bony resection of her infantile pelvis and soft tissue reconstruction to reestablish her introital aperture to an adequate and functional size. CONCLUSION: Introital stenosis from childhood requires a different treatment because development of the pelvis may not have been normal, and bony narrowing may exist in conjunction with soft tissue contracture. A staged multispecialty approach is recommended to treat this interesting variant of introital stenosis.

Corneoscleral rim cultures: lack of utility and implications for clinical decision-making and infection prevention in the care of patients undergoing corneal transplantation.

PURPOSE: To assess the utility of donor corneoscleral rim cultures. METHODS: A retrospective review of the culture results of 774 corneoscleral rims that remained after trephination of corneas for transplantation into patients at our academic medical center between January 1992 and November 1997. RESULTS: Forty-one (5.3%) corneoscleral rim cultures yielded microorganisms, mostly coagulase-negative staphylococci. Two patients developed endophthalmitis (one with Staphylococcus aureus and one with Pseudomonas aeruginosa) within 3 months after transplantation; each had a negative corneoscleral rim culture and neither patient's infection was temporally related to the transplant procedure. CONCLUSIONS: Preoperative donor corneoscleral rim cultures are unreliable predictors of endophthalmitis complicating corneal transplantation and, therefore, are not useful in the clinical management of patients having corneal transplants. Moreover, the discrepancy between the results of corneoscleral rim cultures and subsequent endophthalmitis renders them invalid as a quality assurance procedure. Instead, for patients with suspected endophthalmitis after corneal transplantation, we recommend that corneal surgeons select antimicrobial therapy based on current guidelines and the results of directed sampling. Furthermore, eye banks should prospectively track recipients who develop clinical endophthalmitis, immediately notify the corneal surgeon who transplanted the matched cornea of that used for the index case, and, in selected situations, attempt to identify a possible source of contamination.

Multilamellar bodies as potential scattering particles in human age-related nuclear cataracts.

PURPOSE: To characterize within human age-related nuclear cataracts rare spherical objects covered by multiple membranes, termed multilamellar bodies (MLBs). METHODS: Adult human normal, transparent lenses were obtained from eye bank donors and age-related nuclear cataracts were obtained immediately after extracapsular extraction. Each sample was Vibratome sectioned fresh into 200 microm thick sections that were fixed and embedded for light or electron microscopy. Confocal images were recorded from sections stained with the lipid soluble dye, DiI. RESULTS: Light micrograph montages of the equatorial plane containing the fetal and embryonic nuclei were examined. Rare, but distinct, circular 1-3 microm diameter objects were observed consistently in the cataracts. These objects did not appear to be components of the complex intercellular interfaces. Serial sections indicated that the objects were spherical, or contained a spherical component. For about 20,000 fiber cell cross-sections in each lens, the frequency of MLBs was 10 times higher in cataracts than in the normal lens nuclei. Although extensive searching with the electron microscope was necessary, the size, circular profile and multiple layers of thin (5 nm) membranes easily identified the MLBs. Interiors of the MLBs displayed variable textures. Confocal images indicated that the coverings were enriched in lipid compared to the adjacent plasma membranes. The calculated density of the MLBs in the cataractous nuclei was about 3800/mm3, which represents a volume fraction of 0.00003. CONCLUSIONS: Because the MLBs are large compared to the wavelength of light, display interiors with variable staining textures and have lipid-rich coverings, they appear to be ideal candidates for large scattering particles that may contribute to the forward light scattering in nuclear cataracts.

Paclitaxel, an active agent in nonsquamous carcinomas of the uterine cervix: a Gynecologic Oncology Group Study.

PURPOSE: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m(2) (135 mg/m(2) for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m(2) and de-escalation to 110 mg/m(2) were allowed based on adverse effects. RESULTS: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.

Noninvasive papillary serous carcinoma of the endometrium.

OBJECTIVE: To determine the clinical course of noninvasive uterine papillary serous carcinoma and whether it indicates advanced metastatic disease. METHODS: We reviewed the charts of women with noninvasive uterine papillary serous carcinoma who were treated at our institution and abstracted surgical stage, sites of metastases, disease progression, and length of follow-up. RESULTS: There were 595 cases of endometrial adenocarcinoma between January 1990 and February 2000, 69 of which had papillary serous histology. Sixteen were noninvasive tumors. Six were confirmed stage IA by complete surgical staging and ten were associated with metastasis at staging. Two of the six women with stage IA tumors had disease recurrence. CONCLUSIONS: Noninvasive papillary serous carcinoma is often widely metastatic. In our experience, approximately two thirds of patients had metastasis, indicating the need for complete surgical staging. Even in those with disease limited to the endometrium, a significant percentage will have disease recurrence.

Expression of Ki-67 in vulvar carcinoma and vulvar intraepithelial neoplasia III: correlation with clinical prognostic factors.

OBJECTIVES: In vulvar carcinoma, the expression of Ki-67 has been previously found to correlate with patient outcome. The objective of the study was to determine whether a specific pattern of expression was associated with occult vulvar cancer in patients with vulvar intraepithelial neoplasia (VIN) III and whether patterns of Ki-67 expression correlated with other clinical prognostic factors. METHODS: 19 women with only VIN III, 16 women with both vulvar cancer and VIN III, and 15 women with only vulvar cancer were identified. Immunostaining, using a monoclonal antibody for Ki-67, was then performed on representative tissue blocks and slides were assessed for diffuse or localized patterns of expression. For the patients with vulvar cancer, the type of staining was correlated with FIGO stage, tumor grade, lymph nodes status, and associated VIN III. RESULTS: All 35 patients with VIN III exhibited a diffuse staining pattern. In the 31 patients with vulvar carcinoma, 11 (35%) expressed a diffuse staining pattern while 20 (65%) showed a localized pattern. Poorly differentiated tumors were associated with a diffuse staining pattern (P = 0.013, RR 3.59, CI 1.59-7.60). For vulvar carcinoma, there were no statistically significant relationships between Ki-67 expression pattern and stage, associated VIN III, or lymph node involvement. CONCLUSION: VIN III, regardless of a concomitant vulvar cancer, always expressed a diffuse pattern; thus Ki-67 staining was not useful as a marker for occult cancer. In women with vulvar carcinoma, however, a diffuse Ki-67 expression was significantly associated with poorly differentiated tumors.

Vaginal adenosarcoma arising from endometriosis.

OBJECTIVE: Malignant transformation of endometriosis has been well documented. Endometrioid adenocarcinoma is the most common malignancy to occur in this setting, although other carcinomas and rarely stromal tumors can be seen. We present the first case in the literature of adenosarcoma, a rare mixed mullerian or mesodermal tumor, arising in extrauterine vaginal endometriosis. CASE: A 42-year-old woman underwent multiple medical therapies and surgeries for aggressive endometriosis. A pelvic exenteration was abandoned secondary to severe fibrosis, and low-dose radiotherapy was used to control bleeding from vaginal endometriosis. The pathologic diagnosis of recurrent endometriosis was confirmed multiple times over her 4-year course. Excision of a recurrent vaginal mass revealed adenosarcoma with heterologous elements. CONCLUSION: It is important to biopsy or excise recurrent endometriosis, as malignant transformation can occur, giving rise to epithelial, stromal, or mixed epithelial-mesenchymal tumors.

Ovarian capillary hemangioma presenting as an adnexal mass with massive ascites and elevated CA-125.

OBJECTIVE: Ovarian hemangiomas are very rare with the majority being cavernous hemangiomas. We report a case of a capillary ovarian hemangioma. METHODS: A case report of a woman with a capillary ovarian hemangioma with massive ascites and an elevated CA-125 is presented. RESULTS: A 39-year-old woman presented with an enlarged ovary containing two ovarian cysts. Her CA-125 was elevated to 872 U/ml. On surgical exploration, she had 1500 cc of clear yellow ascitic fluid and a 7.9 x 6.5 x 4.5 cm left ovarian mass. Frozen section revealed marked stromal edema with luteinized cells and no evidence of malignancy. Histologically, the tumor was a cellular capillary hemangioma with an anastomosing vascular pattern. CONCLUSIONS: This is the first case, reported in the literature, of an ovarian capillary hemangioma presenting with an elevated CA-125 and massive ascites.

Hyperfractionated radiation therapy plus chemotherapy in locally advanced cervical cancer: results of two phase I dose-escalation Gynecologic Oncology Group trials.

OBJECTIVE: The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix. METHODS: The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions. RESULTS: Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used. CONCLUSIONS: The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare.

Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: possible explanation for failure of combination therapy.

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown significant efficacy over previous drug combinations in ovarian cancer, 20-30% of patients fail to respond to this combination. These patients are deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available to ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we assessed the efficacy of combination drug therapy on cisplatin-resistant (cisplatinR) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatinR cells as well as in the cisplatin-sensitive parental cell lines. In cisplatinR C-13 cells, the concomitant addition of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel-induced multimininucleation was also inhibited when the cells were exposed sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel-induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 expression in cisplatinR cells. Conversely, paclitaxel did not inhibit p53 protein accumulation by cisplatin. These results suggest that cisplatin blocks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cisplatin can inhibit the effectiveness of paclitaxel in cispatinR cell lines. Therefore, the establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.

A phase II trial of isotretinoin and alpha interferon in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

From January 1993 through January 1996, 37 patients with unresectable squamous carcinoma of the cervix were entered on study and scheduled to receive oral isotretinoin 1 mg/kg per day with subcutaneous alpha interferon 6,000,000 units/day. A course was defined as 4 continuous weeks of therapy. The mean number of four-course cycles delivered was 1.8. One patient was ineligible because of wrong cell type and two were never treated. Thus, 34 patients were evaluable for toxicity. Eight patients were inevaluable for response. Five did not receive a complete 4-week course and three did not have additional tumor measurements; thus 26 were evaluable for response. Prior radiotherapy had been given to 25 patients and prior chemotherapy to 23 patients. There was no grade 4 neutropenia. The incidence of Gynecologic Oncology Group (GOG) grade 3 granulocytopenia and thrombocytopenia was 8.8% and 5.8%, respectively. Six patients (17.6%) developed grade 3 or worse nausea and vomiting. Four (11.7%) patients developed grade 3 neurologic symptoms. There were no complete responses and one partial response. The overall response rate was 3.8% (95% confidence interval, 0.1-19.6%). In this pretreated population, isotretinoin and alpha interferon in the dose and schedule employed exhibit minimal activity.

Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence.

OBJECTIVE: To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision. METHODS: Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III. RESULTS: The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both). CONCLUSION: A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.

Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma.

BACKGROUND: Tumor hypoxia may be associated with treatment resistance, cell proliferation, and metastatic potential, which contribute to poor prognosis. Complementary techniques for detecting hypoxia, cell growth, and metastases are required to study these relationships. OBJECTIVES: The purpose of this study was to demonstrate the clinical feasibility of quantitative hypoxia detection with pimonidazole, a novel hypoxia marker, and to correlate hypoxia with S-phase markers of tumor proliferation. METHODS: Pimonidazole binds to thiol-containing proteins specifically in hypoxic cells. Ten patients with cervical carcinoma received 0.5 g/m2 pimonidazole intravenously followed by biopsy of the cervical carcinoma the next day. Hypoxic cells were recognized by immunohistochemical detection of pimonidazole using a mouse monoclonal antibody. Cell proliferation was detected with a commercially available monoclonal antibody for proliferating cell nuclear antigen (PCNA). Assessment of hypoxia and cell proliferation was made qualitatively with light microscopy and quantitatively using point counting and image analysis software methods. RESULTS: No clinical toxic effects were associated with pimonidazole administration. Immunostaining with pimonidazole antibody was observed in 9 of 10 tumors, suggesting that hypoxia is a common occurrence in cervical carcinoma. Quantitatively, tumors that had large numbers of hypoxic cells had the greatest percentage of S-phase cells, but some tumors with smaller amounts of hypoxia also had substantial numbers of S-phase cells. CONCLUSION: Pimonidazole can be used for qualitative and quantitative assessment of tumor hypoxia.

Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker.

Hypoxia in human tumors is associated with poor prognosis, but the molecular mechanisms underlying this association are poorly understood. One possibility is that hypoxia is linked to malignant progression through vascular endothelial growth factor (VEGF) induction and the associated angiogenesis and metastasis. The present clinical study measures hypoxia and VEGF expression on a cell-by-cell basis in human squamous cell carcinomas to test the hypothesis that hypoxia and VEGF protein expression are coupled in human tumors. Eighteen patients with invasive squamous cell carcinoma of the uterine cervix and head and neck have been investigated by a quantitative image analysis of immunostained sections from their tumors. The hypoxia marker pimonidazole was used to measure tumor hypoxia, and a commercially available antibody was used to measure VEGF protein expression. A quantitative immunohistochemical comparison of hypoxia and VEGF protein expression revealed no correlation between the two factors.

Use of a saline breast implant to cover the pelvic floor.

Pelvic exenteration is one of the most radical procedures in the repertoire of gynecologic oncology procedures. Postoperative complications include sepsis, hemorrhage, formation of adhesions resulting in bowel obstruction, and fistulas resulting from large denuded pelvic surfaces. To date there is no clear consensus as to the best way to cover the pelvis after the destructive phase of an exenteration. Herein, we present a different approach to pelvic coverage by placement of a 300 cc saline breast implant. Use of a saline-filled breast implant to fill the pelvis represents a possible approach to addressing the denuded pelvic space created during extensive gynecologic surgery.

Distribution and type of morphological damage in human nuclear age-related cataracts.

The distribution and type of fiber cell damage was evaluated in human age-related nuclear cataracts and in aged normal (non-cataractous) lenses. Ten age-related nuclear cataracts (53 to 89 years old) and four normal lenses (59 to 67 years old) were examined by electron microscopy of fixed Vibratome sections. Images from the adult, juvenile, fetal and embryonic nuclear regions were compared. Each cataractous lens contained a central region of increased light scattering which involved the embryonic and fetal regions with progressively less involvement in the juvenile and adult nuclear regions. Some damaged fiber cells were observed in all specimens, although damage was minor and infrequent in the normal lenses. Degeneration of single or groups of fiber cells was noted in all the adult nuclei of the cataractous lenses, becoming less frequent in the juvenile nuclei. The types of damage included localized voids, multilamellar membrane aggregates, globular bodies, enlarged cells and regions of highly convoluted membranes. The fetal and embryonic nuclei of the cataractous lenses exhibited rare and minor morphological defects, and were virtually identical to the equivalent regions of the normal aged lenses. Examination of cell interfaces in opaque regions of cataractous lenses revealed that the oldest fiber cells sustained apparent membrane loss. Extracellular spaces in the embryonic, fetal and juvenile regions of the cataractous lenses often contained dense deposits, presumably cytoplasmic material lost from adjacent fibers. The results indicate that the region of greatest nuclear opacity, located in the lens center, does not contain any significant cellular damage. This suggests that older fiber cells respond differently to pathological and senescent changes than younger cells made after fetal development. The observed loss of membranes and cytoplasmic material from the oldest fiber cells may be a contributory mechanism in the formation of age-related human nuclear cataracts.

A phase I study of intraperitoneal interferon-alpha 2b and intravenous cis-platinum plus cyclophosphamide chemotherapy in patients with untreated stage III epithelial ovarian cancer: a Gynecologic Oncology Group pilot study.

Previous clinical investigations using interferons (IFNs) have shown activity against epithelial ovarian cancer. The objective of this study was to determine the maximum tolerated dose of intraperitoneal (ip) IFN-alpha 2b which could be administered in combination with intravenous (iv) cis-platinum plus cyclophosphamide chemotherapy. After comprehensive surgical staging and maximal cytoreduction, previously untreated patients with primary ovarian adenocarcinoma were entered at one of five IFN dose levels. IFN-alpha 2b (5-30 x 10(6) units) was administered ip on Day 1 (+/- Day 8). cis-Platinum (75 mg/m2) plus cyclophosphamide (750 mg/m2) were administered iv on Day 2 with prophylactic hydration and anti-emetics. Courses were repeated every 3 weeks for 8 cycles. Adverse effects were recorded using standard Gynecologic Oncology Group toxicity scales. Fifteen patients with mean age 56 years (range 43-73) were entered and received a combined total of 100 treatment cycles. Catheter-related complications occurred in 8 patients, and in three cases lead to catheter removal and discontinuation of ip therapy. Two patients experienced grade 2-3 nephrotoxicity and 1 experienced grade 2 peripheral neuropathy. There was a single episode of chemical peritonitis. Myelosuppression was the dose-limiting toxicity with grade 3-4 leukopenia complicating 6, 5, 12, 11, and 17 cycles at dose levels 1-5, respectively. No patient completed planned treatment without interruption or dose reduction. Planned cis-platinum dose intensity was most compromised at the fifth IFN-alpha 2b dose level. The maximum tolerated dose of IFN-alpha 2b was determined to be 20 x 10(6) units repeated on Days 1 and 8 of this 21-day cis-platinum plus cyclophosphamide chemotherapy cycle.

Immunohistochemical analysis of alpha 1-integrins in cervical cancer.

OBJECTIVE: The purpose of this study was to determine and compare the expression of the alpha 2-, alpha 3-, alpha 4- and alpha 5-subunits of the beta 1-family of integrins in both the normal and the carcinomatous cervix. STUDY DESIGN: A total of 22 solid tissue specimens (18 cancer and 4 normal) were analyzed immunohistochemically. The double-stain technique used an avidin-biotin complex kit to identify the various integrins and alkaline phosphatase-anti-alkaline phosphatase kit to identify the epithelial cells. Staining intensity, the main outcome measured, was graded as absent, weak, moderate, or strong. Statistical analysis was performed with the Wilcoxon rank sum test for nonparametric data. RESULTS: The alpha 2- and alpha 3-integrins stained the normal cervix epithelium more intensely than the stroma (p = 0.03). The alpha 4- and alpha 5-integrins stained both the stroma and the normal epithelium similarly. The alpha 2-integrin was absent in the stroma of all 18 cancer specimens despite being present in the epithelial regions of 14 to 18 cancers. The alpha 3-integrin had a greater staining intensity in the stroma of the cancers than in the epithelial regions (p = 0.002). Both alpha 4- and alpha 5-integrins were absent in the epithelial regions of the cancers but present in the stroma. CONCLUSIONS: The distribution and intensity of integrin expression in cervical cancer differ from their expression in the normal cervix. In particular, the fibronectin receptors, alpha 4 and alpha 5, were absent in the epithelial regions of the cervical cancers, and alpha 3 also had diminished expression in the malignant epithelium. These changes correlate well with the changes expected in malignant transformation.