The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients.

The aim of the study is to determine the role of lymphadenectomy in advanced epithelial ovarian cancer. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) program reported between 1988 and 2001. Kaplan-Meier estimates and Cox proportional hazards regression models were used for analysis. Of 13 918 women with stage III-IV epithelial ovarian cancer (median age: 64 years), 87.9% were Caucasian, 5.6% African Americans, and 4.4% Asians. A total of 4260 (30.6%) underwent lymph node dissections with a median number of six nodes reported. For all patients, a more extensive lymph node dissection (0, 1, 2-5, 6-10, 11-20, and >20 nodes) was associated with an improved 5-year disease-specific survival of 26.1, 35.2, 42.6, 48.4, 47.5, and 47.8%, respectively (P<0.001). Of the stage IIIC patients with nodal metastases, the extent of nodal resection (1, 2-5, 6-10, 11-20, and >20 nodes) was associated with improved survivals of 36.9, 45.0, 47.8, 48.7, and 51.1%, respectively (P=0.023). On multivariate analysis, the extent of lymph node dissection and number of positive nodes were significant independent prognosticators after adjusting for age, year at diagnosis, stage, and grade of disease. The extent of lymphadenectomy is associated with an improved disease-specific survival of women with advanced epithelial ovarian cancer.

Ovarian cancer in younger vs older women: a population-based analysis.

To compare the clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with epithelial ovarian cancer. Demographic, clinico-pathologic, treatment, and surgery information were obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001 and analysed using Kaplan-Meier estimates. Of 28 165 patients, 400 were <30 years (very young), 11 601 were 30-60 (young), and 16 164 were >60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4664 (40.2%), and 3643 (22.5%) had stage I-II disease, respectively (P<0.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% vs 58.8 and 35.3%, respectively (P<0.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment. Reproductive age (16-40 years) women with stage I-II epithelial ovarian cancer who received uterine-sparing procedures had similar survivals compared to those who underwent standard surgery (93.3% vs 91.5%, P=0.26). Younger women with epithelial ovarian cancer have a survival advantage compared to older patients.

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers.

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan-Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III-IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I-II (74, 82, and 86%; P<0.0001) and stage III-IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

Differential expression of CD40 and CD95 in ovarian carcinoma.

PURPOSE: The role of CD95 (Fas) as a mediator of apoptosis has been well documented. CD40 ligation has been recently shown to initiate apoptosis and modulate CD95 mediated apoptosis in normal and some neoplastic tissues. Here we report the expression of CD95 and CD40 in cryopreserved cell suspensions from ovarian cancer associated ascites, fresh primary and recurrent ovarian carcinoma (OVCA) specimens, and ten established ovarian cancer cell lines. The effect of CD95 and CD40 receptor binding on apoptosis is described in two cell lines. EXPERIMENTAL DESIGN: Ascites specimens, fresh primary and recurrent OVCA specimens were dissociated to single cell suspensions. Expression of CD95 and CD40 was analyzed using flow cytometry. Apoptosis was determined via annexin uptake by flow cytometry following incubation with anti-CD95 antibody, CH11 and trimeric CD40L. RESULTS: Ascites showed the highest expression of both CD95 and CD40. Recurrent OVCA, in contrast, expressed low levels of CD95 and CD40. Primary OVCA showed moderate expression of both receptors. CD40 expression in ascites was significantly greater when compared to solid specimens (p < 0.05). Both CD40 and CD95 were strongly expressed in eight of ten cell lines studied. Binding of CD40L did not influence CD95 mediated apoptosis. CONCLUSIONS: CD40 is ubiquitously expressed in ovarian carcinomas and expression differs between ascites and solid tumor. There may be differential expression of both CD40 and CD95 in recurrent vs primary ovarian carcinoma, which may contribute to increased clinical malignancy of recurrent disease. In contrast to other epithelial malignancies, CD40 ligation does not appear to modulate CD95 mediated apoptosis.

Susceptibility of B-cell lymphoma to human antibodies encoded by the V4-34 gene.

Our previous studies have shown that mAbs derived from the human V4-34 gene bind and kill human B-lymphocytes via membrane disruption. This study demonstrates the cytotoxicity of two V4-34 encoded mAbs, 216 and Z2D2, towards human B-cell lymphoma. In vitro, 216 and Z2D2 are cytotoxic to a variety of B-cell lymphomas obtained from patient biopsies. In vivo, increased survival was observed with both mAbs in a lymphoma model developed in scid mice with human B-cell line Nalm-6. Studies in mice show that these mAbs are well tolerated with minimum side effects. Since 216 and Z2D2 show increased toxicity towards cycling cells, V4-34 mAb-based therapy can be additive with drugs that block cell-cycle progression. Stem cells that are V4-34 mAb ligand negative would not be depleted. Together, these studies recommend an evaluation of the two completely human mAbs in a phase I trial for B-cell lymphoma.

Treatment of high-risk uterine cancer with whole abdominopelvic radiation therapy.

PURPOSE: To evaluate the treatment outcomes in patients with optimally debulked Stage III and IV endometrial adenocarcinoma (ACA) or Stages I-IV uterine papillary serous (UPSC) or clear cell (CCC) carcinoma of the uterus, treated postoperatively with whole abdominopelvic irradiation (WAPI). METHODS AND MATERIALS: Between 1979 and 1998, 48 patients received postoperative WAPI at our institution. Twenty-two patients had FIGO Stage III or Stage IV ACA and 26 patients had FIGO Stages I-IV UPSC or CCC. The median dose was 30 Gy to the upper abdomen and 49.8 Gy to the pelvis. Mean follow-up was 37 months (2.4-135 months). RESULTS: The 3-year estimated disease-free survival (DFS) and overall survival (OS) rates for the entire group were 60% and 77%, respectively. Patients with ACA had 3-year DFS and OS of 79% and 89%, respectively, compared with 47% and 68% in the UPSC/CCC group. Early-stage patients (I and II) with UPSC/CCC had 3-year DFS and OS of 87% compared with 32% and 61% in those with advanced (Stage III and IV) disease. The 3-year actuarial major complication rate was 7%, with no treatment-related deaths. All 4 failures in the ACA group were extra-abdominal and 6 of the 11 in the UPSC/CCC group had an extra-abdominal component. Age and UPSC/CCC histology were significant prognostic factors for DFS and OS. In addition, stage and number of extrauterine sites of disease were significant predictors for DFS in UPSC/CCC. CONCLUSION: WAPI is a safe, effective treatment for patients with optimally debulked advanced-stage uterine ACA or early-stage UPSC/CCC. Survival was significantly worse in advanced-stage UPSC/CCC patients. We recommend future trials of WAPI with concurrent, or subsequent systemic therapy in patients with advanced-stage UPSC or CCC.

Recognition of auto- and exoantigens by V4-34 gene encoded antibodies.

The antigenic specificities of 24 V4-34-encoded monoclonal antibodies were compared with the amino acid sequence. The specificities were divided into three categories, red blood cells, B lymphocytes and auto/exoantigens. Six anti-I monoclonal antibodies, with multiple substitutions in their VH region, did not bind B lymphocytes or auto/exoantigens. Reactivity to these two antigens segregated with the 16 anti-i monoclonal antibodies, which were derived from the near germline V4-34 gene. All anti-i monoclonal antibodies bound B lymphocytes, albeit with varying intensities. B-cell binding correlated with basic amino acids in the VH-CDR3. Reactivity to auto/exoantigens was demonstrated only by a subset anti-i monoclonal antibodies and did not correlate with B-lymphocyte or i-antigen binding. These anti-ssDNA reactive monoclonal antibodies had basic amino acids in the VH-CDR3, strongly supporting the suggested role of arginine in DNA binding. However, an arginine-rich CDR3 was not enough to ensure DNA reactivity, since six other anti-i monoclonal antibodies that fulfilled this criteria did not bind ssDNA. Thus it is possible that the anti-DNA reactivity of V4-34-encoded monoclonal antibodies is mediated by the classic antigen-binding groove generated by the CDRs of the heavy/light chains. In contrast, anti-B-cell/i-antigen reactivity is mediated, unconventionally, by the V4-34 protein with a dominant influence of the VH-CDR3.

Primary leiomyosarcoma of the vagina. A case report and literature review.

Primary vaginal leiomyosarcoma is a rare tumor. We report a unique case of a 27-year-old woman with stage I, high-grade primary leiomyosarcoma of the vagina treated with surgical resection and adjuvant radiation therapy. She returned within 6 months with an abdominal-pelvic recurrence and lung metastases. The patient died of disease 9 months after diagnosis. A comprehensive review of primary vaginal leiomyosarcoma was performed and factors affecting survival were analyzed. A Medline search of the English-language literature revealed 66 previously reported cases. Forty-eight of these had follow-up data. Survival probabilities were calculated using the Kaplan-Meier method, and the effects of age, stage, grade, tumor location, and treatment modality were analyzed. Stage III and IV data were combined. The overall 5-year survival rate was 43%. Patients more than 50 years of age had a 5-year survival rate of 26% compared with 51% for those less than 40 years. Five-year survival for stage I and II tumors was 55% and 44%, respectively. Patients with stage III/IV disease had 25% survival at 18 months. No patient treated primarily with chemotherapy or radiation therapy survived beyond 36 months. In contrast, patients treated primarily with surgery had a 5-year survival rate of 57%. Only stage remained an independent predictor of survival on Cox regression analysis. We continue to recommend surgical resection as primary treatment. Exenteration may be an option for select patients, but ultimately management should continue on a case-by-case basis.

Malignant granular cell tumor of the vulva in a 17-year-old: Case report and literature review.

Granular cell tumors are uncommon soft tissue tumors. Although the majority of these tumors are benign, a rare malignant variant exists which is aggressive, with local recurrence rates up to 70% and 3-year survival rates of less than 50%. We present a case of malignant granular cell tumor of the vulva in a 17-year-old, the sixth such case to be reported at this site. She was treated with a left hemivulvectomy and ipsilateral groin node dissection followed by postoperative radiation therapy. She remains free of disease at 16 months. Patients with malignant granular cell tumor or granular cell tumor of malignant potential are best managed with wide local excision and regional lymph node dissection.

VH4-34 encoded antibodies in systemic lupus erythematosus: a specific diagnostic marker that correlates with clinical disease characteristics.

OBJECTIVE: To determine the clinical significance of elevated serum levels of VH4-34 encoded antibodies (VH4-34 Ab) with respect to the diagnosis and clinical characteristics of systemic lupus erythematosus (SLE). METHODS: Ninety-five patients with SLE and 344 controls were studied. The controls included 34 healthy individuals, 282 patients with nonautoimmune diseases, and 28 patients with autoimmune diseases other than SLE. VH4-34 Ab levels were measured by inhibition ELISA using anti-idiotope monoclonal antibody (9G4). SLE disease activity, severity, and damage were assessed by visual analog scales, Systemic Lupus Activity Measure, Lupus Severity of Disease Index, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. RESULTS: Fifty-two of 95 patients with SLE had elevated levels of VH4-34 Ab compared to 18 of 344 controls (5%), giving a sensitivity of 55% and a specificity of 95% for elevated VH4-34 Ab as a serologic test for SLE. The positive predictive value of elevated VH4-34 under these conditions was 74-85%. In this study, anti-dsDNA was not VH4-34 encoded. Significant correlations between VH4-34 and disease activity and severity indices were observed (r = 0.29-0.50). The relative risk for severe disease in SLE patients with VH4-34 antibody level in the highest tertile compared to the lowest tertile was 5.25. Twenty-five of 29 patients with lupus nephritis and 6 of 6 patients with central nervous system (CNS) lupus had elevated VH4-34 Ab. CONCLUSION: With a specificity of 94-95%, the VH4-34 antibody assay may prove valuable as a confirmatory diagnostic test for SLE. In patients with known SLE, serum VH4-34 Ab levels correlate with overall disease severity and activity, but not damage, and with nephritis and CNS lupus.

Clinical practice guidelines in the management of gynecologic malignancies.

The need for guidelines in managing gynecologic cancer is addressed in the first part of this article. Second, the guideline development process that enables the practitioner to judge the validity and usefulness of proffered guidelines is detailed. An important element in this discussion is an exploration of the shortcomings, either real or perceived, of the process. The last section focuses on issues relating to the implementation of guidelines and some of the obstacles that one may encounter as the programs evolve.

Cytotoxicity of murine B lymphocytes induced by human VH4-34 (VH4.21) gene-encoded monoclonal antibodies.

We have previously described specific binding and cytotoxicity of human B lymphocytes by VH4-34 gene-derived anti-i cold agglutinin (CA) mAbs. Here we demonstrate that the carbohydrate ligand recognized by human VH4-34 anti-i CA mAbs is also expressed on murine B lymphocytes. Similar to human B cells, binding of murine B lymphocytes by VH4-34-derived anti-i CA mAbs leads to rapid cytotoxicity of target cells as tested both in vitro and in vivo. Moreover, the mechanism leading to murine B cell death is also similar to human B cells, since morphologically identical membrane pores were detected within 15 min of mAb exposure by scanning electron microscopy. The conservation of the carbohydrate ligand across species provides an ideal system to study the function of human VH4-34 gene derived Abs in immune regulation.

Rapid cytotoxicity of human B lymphocytes induced by VH4-34 (VH4.21) gene-encoded monoclonal antibodies, II.

We have previously described complement-independent killing of human B lymphocytes by two IgM MoAbs derived from the VH4-34 (VH4.21) gene. Analysis of 17 independently derived VH4-34-encoded MoAbs shows that B cell toxicity is not limited to the two described MoAbs, but is a general property shared by a subset of MoAbs derived from the VH4-34 gene. As observed by two independent microscopy techniques, giant membrane pores were formed on target B cells within 10-15 min of exposure to cytotoxic VH4-34-derived MoAbs. Toxicity by individual MoAb correlated directly to its B cell binding intensity measured by FACS, i.e. stronger the binding greater the killing. Sequence analysis showed that V(H) region in germ-line or in near germ-line configuration was necessary but not sufficient for B cell binding. In addition, a particular sequence motif enriched in basic amino acids in the CDR3 may be required to supplement the reactivity mediated by the V(H) region of the MoAb molecule. VH4-34-encoded antibodies that fulfil the above sequence requirements have cold agglutinin activity towards the i antigen of cord erythrocytes. In vivo, such anti-i/anti-B cell antibodies are rarely detected in healthy adults, but serum levels are dramatically elevated in selective pathological conditions, such as systemic lupus erythematosus and infectious mononucleosis. This strict regulation may be related to the novel and rapid mechanism of human B cell toxicity demonstrated by antibodies encoded by a single human V(H) gene.

Heavy chain variable gene usage by human B-1 lymphocytes and polyreactive autoantibodies.

To evaluate the role of B-1 cells and polyreactive autoantibodies in the development of adult immune repertoire, it is necessary to assess their immunoglobulin heavy chain variable-gene usage. We thus screened 28 independently derived human polyreactive MAbs from fetal and adult splenic B lymphocytes for their VH-region usage. We demonstrate that the polyreactivity of the IgM antibodies secreted by B-1 cells is not the result of the expression of particular variable region gene families. All six VH families are represented roughly in proportion to their estimated family size. Furthermore, the representation of the six families appears similar in polyreactive MAbs derived from fetal or adult lymphocytes.

Lymphangioleiomyomatosis of the uterus simulating high-stage endometrial stromal sarcoma.

Symptomatic uterine lymphangioleiomyomatosis (LAM) simulating high-stage uterine sarcoma in a patient with tuberous sclerosis complex is reported. A 49-year-old female presented with abdominal pain and anemia. Preoperative workup revealed a uterine mass and a large amount of peritoneal free fluid and possible metastatic implant along the lateral edge of the liver. The patient also had a large right pleural effusion. A fungating anterior uterine fundal mass with apparent perforation and intraabdominal hemorrhage was found on laparotomy. A portion of the mass was excised and initially interpreted as an endometrial stromal sarcoma. Microscopic examination revealed multiple vascular epithelioid smooth muscle proliferations in the uterus and serosal surface of the fallopian tube and periaortic lymph node lymphangioleiomyomas. The uterine, fallopian tube, and nodal lesions were positive for smooth muscle actin, desmin, and HMB-45, findings characteristic of LAM. Additional examination of the patient revealed stigmata of tuberous sclerosis complex. Although uterine LAM is uncommon, it may be associated with pelvic and/or abdominal symptoms and may simulate a primary uterine mesenchymal neoplasm.

VH4-34 (VH4.21) gene expression in the chronic arthritides of childhood: studies of associations with anti-lipid A antibodies, HLA antigens, and clinical features.

OBJECTIVE: To determine if the germ line gene VH4-34 (VH4.21) encodes the antimonophosphoryl lipid A (MPL) polyspecific antibodies found in oligoarticular arthritis of childhood. METHODS: Sera from a range of rheumatic diseases of childhood were assayed for VH4-34 derived antibodies by ELISA using the antiidiotype monoclonal antibody 9G4. Results were compared to assays for anti-MPL antibodies, C4d, and Bb, and for HLA type, joint count, and sedimentation rate. RESULTS: VH4-34 derived antibodies were elevated in all diseases studied except rheumatoid factor positive polyarticular disease. In oligoarticular arthritis, VH4-34 gene expression correlated with C4d concentration, and VH4-34 encoded globulins were more concentrated in synovial fluid than in blood. No association was found with HLA type. An association between VH4-34 expression and IgG anti-MPL was found in sera from patients from Cincinnati but not from Stanford. No other evidence supported a direct association between VH4-34 derived and anti-MPL antibodies in these children. CONCLUSION: The expression of VH4-34 is increased in several rheumatic diseases of childhood, but, as in adults, not in rheumatoid arthritis. VH4-34 expression is not associated with HLA type. The polyspecific autoantibody nature of some VH4-34 derived antibodies may explain the wide range of the unusual antibodies found in oligoarticular arthritis.

Rapid cytotoxicity of human B lymphocytes induced by VH4-34 (VH4.21) gene-encoded monoclonal antibodies.

We have previously described two human cold agglutinin MoAbs 216 and A6(H4C5), that are derived from the VH4-34 (VH4.21) gene that bind specifically to a cell surface ligand on human B lymphocytes. In this study, we report that binding of 216 and A6(H4C5) leads to rapid killing of target B cells. This complement-independent cytotoxicity was measured by three independent assays, cell viability dye uptake on FACS, 3H-thymidine uptake, and the 3(4,5)-dimethylthiazol-2,5-diphenyl tetrazolium bromide (MTT) assay. Cytotoxicity was specific for CD20+ mononuclear cells in human spleen and peripheral blood. The MoAbs were also cytotoxic to human B cell lines Nalm-6, OCI-LY8, Arent and SUP-B8, but not to T cell lines HuT 78 and PEER. As observed by scanning electron microscopy, membrane pores were formed within 15 min of exposure to the MoAbs. Cytotoxic activity was dependent on MoAb concentration and temperature of exposure. Killing with greater at 4 degrees C than 37 degrees C. Sodium azide and EDTA did not block the cytotoxic activity. No DNA fragmentation typical of apoptosis was observed. This rapid cytotoxic activity, independent of physiologic cellular process and independent of complement, suggests a novel mechanism of all death via membrane perturbations.

Operative laparoscopy in the management of ovarian cancer.

Advances in operative laparoscopic techniques have made possible the extension of this technology to the treatment of women with ovarian cancer. We present a detailed case series of eight patients with ovarian cancer who underwent a total of 11 operative laparoscopies for treatment of ovarian cancer ranging in stage from IA to IIIC. Three patients underwent initial laparoscopic staging and therapeutic debulking procedures. In three other cases that were incompletely staged via laparotomy, laparoscopy was used to complete the staging. Interval laparoscopic tumor debulking combined with second-look laparoscopy was performed in four cases. We describe our experience with these new applications of evolving techniques with particular regard to potential advantages, disadvantages, and complications. This detailed preliminary case series suggests the need for prospective clinical studies to establish the safety and efficacy of the approach.

Anti-endotoxin human monoclonal antibody A6H4C5 (HA-1A) utilizes the VH4.21 gene.

Human IgM monoclonal antibody A6H4C5 was manufactured by Centocor (Malvern, PA) and used in clinical trials as HA-1A (Centoxin). In vitro, A6H4C6 binds to lipid A and rough-strain, gram-negative bacteria endotoxin. Further analysis of A6H4C5 has shown that it is a polyreactive, cold agglutinin that utilizes the VH4.21 gene segment in germline configuration. It is also a human antibody that binds to human B cells. We have characterized several other independently derived VH4.21 human monoclonal antibodies with the same characteristics as A6H4C5. This group of antibodies may represent a conserved host immune response.