A phase II study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage IC-IV (AGO-OVAR protocol OVAR-8).

PURPOSE: A multicenter, nonrandomized, phase II study was initiated to evaluate the tolerability, toxicity, and activity of paclitaxel, carboplatin, and gemcitabine combination in previously untreated ovarian cancer. PATIENTS AND METHODS: Chemonaive patients who had radical debulking surgery for primary epithelial ovarian cancer International Federation of Gynecology and Obstetrics (FIGO) IC-IV received sequentially paclitaxel 175 mg/m(2), carboplatin AUC 5, and gemcitabine 800 mg/m(2) on day 1 and gemcitabine 800 mg/m(2) on day 8, every 3 weeks. RESULTS: From October 2001 to July 2002, 55 patients were treated and evaluated. Main toxicities were hematological with NCI-CTC grade 3/4 anemia 12.7%, leukopenia 70.9%, neutropenia 76.3%, and thrombocytopenia 45.5. However, febrile neutropenia occurred only in 1.8%. Grade 3/4 nonhematological toxicities were rare and occurred in less than 10% of patients. Toxicity-induced treatment delays occurred in 3.1% of cycles and resulted in early treatment cessation in four patients. Dose intensity reached 90.8% for carboplatin and paclitaxel, and 73.3% for gemcitabine. Objective response was observed in 10 of 14 patients with measurable disease. CONCLUSIONS: The triplet combination of paclitaxel-carboplatin-gemcitabine is feasible and active, with manageable hematological toxicity and no unexpected nonhematological toxicity. This regimen has proceeded to phase III evaluation.

Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer.

BACKGROUND: The majority of patients with ovarian cancer are not cured by first-line treatment. Until now, no study could demonstrate any substantial benefit when exposing ovarian cancer patients to second-line chemotherapy. However, most treatment regimens induce toxicity, thus negatively influencing the quality of rather limited life spans. Here we evaluate whether a second-line chemotherapy can offer any benefit compared with a less toxic hormonal treatment. PATIENTS AND METHODS: Patients with ovarian cancer progressing during platinum-paclitaxel containing first-line therapy or experiencing relapse within 6 months were eligible. Patients were stratified for response to primary treatment (progression versus no change/response), and measurable versus non-measurable disease. Treatment consisted of either treosulfan 7 g/m5 infused over 30 min or leuprorelin 3.75 mg injected subcutaneously or intramuscularly. Both regimens were repeated every 4 weeks. RESULTS: This study began in late 1996, and after 2.5 years accrual an interim analysis was performed when several investigators reported their concern about a suspected lack of efficacy. Following this analysis the recruitment was stopped early and the 78 patients already enrolled were followed up. The majority of patients received treatment until progressive disease was diagnosed or death occurred. Treatment delay was observed rarely and dose reduction was performed only in the treosulfan arm in 5% of 150 courses. Overall, both treatment arms were well tolerated. No objective responses were observed. The median survival time was 36 and 30 weeks in the treosulfan and leuprorelin arms, respectively. Overall survival did not differ between patients with relapse 3-6 months after first-line chemotherapy compared with patients with progressive disease within 3 months. CONCLUSIONS: The selected patient population represents a subgroup with extremely poor prognosis. Accordingly, results were not impressive. Both treatment arms showed favourable toxicity data, but failed to show remarkable activity, thus adding only limited evidence to the issue of whether patients with refractory ovarian cancer might benefit from second-line chemotherapy. Even stratified analysis did not identify any subgroup of patients in whom the administration of second-line chemotherapy could demonstrate a clinically relevant survival benefit.

[Electrophysiological studies in breast carcinoma patients with tamoxifen retinopathy]. / Elektrophysiologische Untersuchungen bei Mammakarzinompatientinnen mit Tamoxifen-Retinopathie.

PURPOSE: Crystalline plaques in the cornea or the retinal nerve fiber layer are well-known side effects of tamoxifen therapy. We investigated whether electrophysiological methods for determining the function of the retinal nerve fiber layer and retinal pigment epithelium demonstrate changes in tamoxifen retinopathy. PATIENTS AND METHODS: We compared the right eyes of four women with breast cancer and mono- or bilateral tamoxifen retinopathy to ten right eyes of age-matched, eyehealthy patients who had not received tamoxifen by means of electrophysiological investigations (e.g., pattern-reversal electroretinography, flash electroretinography for the maximal combined response, electrooculography; ISCEV standard conditions). RESULTS: No significant differences were observed between patients with tamoxifen retinopathy and controls regarding mean visual acuity, basal level of the electro-oculographic standing potential, basal level on the Arden index, or any of the other electrophysiological potentials. CONCLUSIONS: Pattern-reversal electroretinographic measurements revealed no damage of retinal ganglion cells in the presence of crystalline plaques in the retinal nerve fiber layer. Electro-oculography did reveal differences, but these were not statistically significant, possibly due to the small number of cases.

Uterussarkome--eine retrospektive Analyse von 78 Fallen.

OBJECTIVE: The objective of the study was to analyse the prognostic impact of several criteria for median survival and recurrence free interval in patients with uterine sarcomas. Factors included to our analysis were the staging according to FIGO, DNA content (ploidy), mitotic index, histology, the kind of primary therapy, grading and menopausal status. MATERIAL AND METHODS: Retrospectively, clinical data of 78 patients (41 leimyosarcomas, 23 carcinosarcomas = homologous malignant mixed Mullerian tumors, 14 endometrial stromal sarcomas--10 low grade, 4 high grade) were analysed. Additionally, in 36 of the cases mitoses were counted. Furthermore, DNA ploidy was determined using image cytometry on paraffine sections stained according to the Feulgen method. Receptor status was determined using immunohistochemical staining. Two and five year survival rates were 22% and 15%. There were 21 cases with local relapse and 27 cases with metastasis. RESULTS: The staging according to FIGO was the main prognostic factor, significantly influencing median survival time (p = 0.001) as well as the recurrence free interval (p = 0.03). There was a significant difference between median survival time compared to mitotic index (p = 0.014) and DNA ploidy (p = 0.02). A mitotic index < 10/10 HPF and diploidy were related with a better prognosis. Receptor status did not have an impact on median survival time. CONCLUSIONS: As our results suggest, DNA ploidy and mitotic index are likely to provide additional information for prognosis in patients with uterine sarcomas and could be used as criteria for selecting patients for adjuvant therapy.

Immunocytochemical detection of somatostatin receptors sst1, sst2A, sst2B, and sst3 in paraffin-embedded breast cancer tissue using subtype-specific antibodies.

The long-acting somatostatin analogue octreotide (SMS 201-995) inhibits growth of certain breast cancer cell lines in vivo and in vitro. Because the antiproliferative action of octreotide depends on at least the presence of somatostatin receptors, it is crucial to determine the pattern of somatostatin receptor protein expression on the tumor cells. In the present study, we have raised polyclonal antibodies to somatostatin receptor subtypes (ssts) sst1, sst2A, sst2B, and sst3 using peptides corresponding to their COOH-terminal sequences. These antisera were used for immunocytochemical staining of paraffin sections of 33 primary breast cancers. Somatostatin receptor-like immunoreactivity (Li) was predominantly localized to the plasma membrane of the tumor cells. In the vast majority of positively stained tumors, somatostatin receptor-Li was uniformly present on nearly all tumor cells. Both the level and the pattern of expression of ssts varied greatly between individual carcinomas. sst2A-Li and/or sst2B-Li was detectable in 28 tumors (85%); among these, 14 tumors (42%) showed particularly high levels of sst2-Li. sst1-Li was found in 17 (52%) cases and sst3-Li in 16 (48%) cases. The expression of ssts was independent of patient age, menopausal status, diagnosis, histological grade, and levels of estrogen and progesterone receptors. The immunocytochemical determination of somatostatin receptor status allows direct detection of receptor protein on the tumor cells and, hence, may provide more precise information than reverse transcription-PCR for predicting response to octreotide therapy in breast cancer.

Nodular hidradenoma. A report of three cases and review of the literature.

BACKGROUND: Nodular hidradenoma is a rare adnexal tumor most likely arising from the eccrine gland. OBJECTIVE: We describe three cases of a nodular hidradenoma presenting as an expanding nodule on the forehead (case 1), left lower extremity (case 2), and left neck (case 3). We discuss the clinical and histologic features of this tumor and present a review of the literature. CONCLUSIONS: This report highlights the salient histologic findings that distinguish nodular hidradenomas from other adnexal tumors and emphasizes the benefit of complete local excision to prevent recurrence of these tumors.

Carboplatin/paclitaxel versus cisplatin/paclitaxel as first-line chemotherapy in advanced ovarian cancer: an interim analysis of a randomized phase III trial of the Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group.

Since publication of the results of the Gynecologic Oncology Group III study, the combination of cisplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been widely adopted as standard treatment for advanced ovarian cancer. Further attempts to optimize first-line chemotherapy with platinum and taxanes include the substitution of cisplatin with carboplatin, individualization of the carboplatin dose by calculating it according to the area under the concentration-time curve, and reduction of paclitaxel infusion duration. These attempts have led to the initiation of several phase I/II trials evaluating the combination of carboplatin/paclitaxel. The promising results of these small studies have prompted the initiation of three phase III trials comparing carboplatin/paclitaxel with the standard combination of cisplatin/paclitaxel. The interim analysis after 15 months' accrual of the prospectively randomized German Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study is presented here. As of January 1997, 518 of 660 planned patients have been recruited. The interim analysis is based on data from 449 evaluable patients. The preliminary data indicate that hematologic toxicity occurred more frequently in arm A (carboplatin/paclitaxel), whereas nonhematologic toxicity occurred slightly more frequently in arm B (cisplatin/paclitaxel). Dose-intensity analysis did not reveal cumulative dose reductions or an increased need for colony-stimulating factors over subsequent courses in both arms. Forty-four patients with measurable disease following surgery completed chemotherapy and were evaluable for response, which remains blinded at this time and is reported for the group as a whole. So far, there have been 18 complete responses (41%) and 15 partial responses (34%), for an overall response rate of 75%. Retrospective comparison reveals no significant difference in response rates between patients in the cisplatin/paclitaxel arm of Gynecologic Oncology Group III and those in the Arbeitsgemeinschaft Gynäkologische Onkologie study. Overall, this interim analysis did not reveal any reason for an early termination of this study. Accrual is ongoing and is expected to be completed this year.

Weekly paclitaxel with epirubicin as second-line therapy of metastatic breast cancer: results of a clinical phase II study.

Phase I/II trials have shown that combination of an anthracycline with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) represents a high-potency therapy for treatment of patients with metastatic breast cancer, with response rates exceeding 90%. This phase II trial was conducted to test the tolerability and efficacy of weekly epirubicin plus paclitaxel as second-line therapy for patients with pretreated metastatic breast cancer. In this study, 35 patients with previous hormone therapy and/or chemotherapy were treated at a weekly dose of paclitaxel 80 mg/m2 with epirubicin 35 mg/m2 (10 patients, 123 cycles) or paclitaxel 80 mg/m2 with epirubicin 25 mg/m2 (25 patients, 218 cycles). The dose reduction of anthracyclines became necessary due to severe hemotoxicity (neutropenia World Health Organization grade 3 to 4 in 30.2% of cycles). The therapy schema included a 2-week therapy interval after each treatment period of 6 weeks, with treatment continued until response or disease progression. Overall, 18 patents (51.4%) presented with responses (complete response or partial response) to therapy, with seven (20%) achieving a complete response after six to 18 cycles. In three cases (8.6%), tumor state was unchanged for a median interval of 11 weeks (range, 5 to 20 weeks). Progressive disease was observed in seven cases (20%), and seven patients (20%) were not evaluable. Following epirubicin dose reduction, neutropenia World Health Organization grade 3 to 4 occurred in only 18.1% of cycles. Referring to nonhematologic toxicity, alopecia exceeded World Health Organization grade 2. Other nonhematologic toxicities exceeding grade 2 were observed in only a few courses and were not statistically relevant. No clinically relevant deterioration of cardiac function was observed at a median cumulative dose of epirubicin 285 mg/m2 (maximum cumulative dose, 630 mg/m2). This study has substantiated that the schedule used is highly efficient and well tolerated as second-line chemotherapy for patients with metastatic breast cancer.

Immunohistochemical characterization of dermatofibrosarcoma protuberans with practical applications for diagnosis and treatment.

Dermatofibrosarcoma protuberans (DFSP) is a rare, clinically challenging, soft tissue tumor. The main histologic differential of DFSP is usually a dermatofibroma. In 1990, the first report appeared demonstrating that cells of DFSP express the human progenitor antigen CD34 on their surface. Since then, there have been increasing reports of the usefulness of immunohistochemical staining with CD34 to differentiate DFSP from dermatofibroma and other soft tissue tumors. This literature is reviewed with special emphasis on the insights studies have provided into the histogenesis of DFSP. The literature demonstrating the practical applications of CD34 staining in the diagnosis and treatment of DFSP is also discussed.

Carboplatin plus paclitaxel as first-line chemotherapy in previously untreated advanced ovarian cancer. German AGO Study Group Ovarian Cancer. Arbeitsgemeinschaft Gynäkologische Onkologie.

Since publication of the results of the Gynecologic Oncology Group (GOG) III study, the combination of cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been adopted widely as the new standard for treating advanced ovarian cancer. Further attempts to optimize first-line chemotherapy with platinum and taxanes include substituting carboplatin for cisplatin, individualizing the carboplatin dose by calculating it according to the area under the concentration-time curve, and reducing the length of the paclitaxel infusion. Attempts to optimize platinum/paclitaxel combinations have led to the initiation of several small phase I/II trials evaluating the carboplatin/paclitaxel combination. The promising results of these studies have prompted the initiation of three phase III trials comparing carboplatin/paclitaxel with the standard combination of cisplatin/paclitaxel. An interim analysis after 1 year's accrual to the prospectively randomized German Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study is presented. Treatment consists of paclitaxel 185 mg/m2 infused over 3 hours on day 1 followed directly by either cisplatin 75 mg/m2 (arm B) or carboplatin dosed to an area under the curve of 6 (arm A). Treatment is repeated every 3 weeks for six courses. Eligibility criteria are epithelial ovarian cancer International Federation of Gynecology and Obstetrics stage IIB through IV, age of consent, written informed consent, Eastern Cooperative Oncology Group performance status < or =2, life expectancy of more than 12 weeks, adequate bone marrow function defined as neutrophil count 1.5 x 10(9)/L and platelet count > or =100 x 10(9)/L, adequate renal function defined as glomerular filtration rate (GFR) > or =60 mL/min, and adequate liver function defined as serum bilirubin levels within 1.25 x upper limit of normal. From October 1995 to December 1996, 442 of 660 planned patients were recruited to the AGO study. The interim analysis is based on data from 353 patients who were enrolled within the first study year. These preliminary data indicate that hematologic toxicity occurred more frequently in arm A (carboplatin/paclitaxel), while nonhematologic toxicity occurred slightly more frequently in arm B. Dose-intensity analysis did not reveal cumulative dose reductions or increasing use of colony-stimulating factors over subsequent courses in either arm. In all, 44 patients with measurable disease following surgery completed chemotherapy and were evaluable for response. The data remain blinded at this time, and results are reported for the group as a whole. So far, there have been 18 (41%) complete responses and 15 (34%) partial responses, for an overall response rate of 75%. Retrospective comparison with the GOG results reveals no significant difference in response rates between patients in the cisplatin/paclitaxel arm of GOG III and those in the AGO study: the GOG study reported a 73% response rate, compared with a preliminary 75% response rate in the AGO study, resulting in a relative risk of 1.03 (95% confidence interval, 0.83 to 1.27). Overall, this interim analysis did not reveal any reason to terminate this study early. Accrual is ongoing and is expected to be completed in 1997.

Dermatofibrosarcoma protuberans (DFSP): growth characteristics based on tumor modeling and a review of cases treated with Mohs micrographic surgery.

Dermatofibrosarcoma protuberans (DFSP) is a relatively rare cutaneous tumor that is clinically challenging since it is locally highly invasive and aggressive, although it rarely metastasizes. Traditionally, wide and deep local surgical excision has been regarded as the treatment of choice for DFSP. However, even 3-cm-wide local excision margins have resulted in a local recurrence rate of 11%. In recent years, reports of DFSPs successfully treated with Mohs micrographic surgery have been appearing in the literature. The DFSP literature is reviewed here, including worldwide experience reported to date in the use of Mohs surgery to excise DFSPs. Using this margin control technique, the recurrence rate is shown to be 2.4%, much lower than the best previously reported recurrence rate of 11% when wide local excision was used. Three-dimensional reconstructions of DFSPs, based on Mohs micrographic surgical technique, are also presented. These illustrations provide new insight into the growth characteristics of these tumors and why Mohs micrographic surgery is emerging as the treatment of choice for DFSP.

The dominant T cell clone is present in multiple regressing skin lesions and associated T cell lymphomas of patients with lymphomatoid papulosis.

This study was undertaken to determine the clonality of lymphomatoid papulosis (LyP), its clonal relationship to lymphomas, which occur at high frequency in LyP patients, and to define the cell lineage of Reed-Sternberg-like cells in type A lesions of LyP. Punch biopsies of skin of 11 adult patients with LyP were analyzed for morphologic subtype of LyP, surface antigens, and clonal T-cell receptor (TCR) gene rearrangements. Clonal rearrangements were identified by semiquantitative polymerase chain reaction amplification and sequencing of TCR-beta chain genes in nine patients and TCR-gamma chain genes in two patients. A single dominant clone was detected in multiple separate LyP lesions, often of different histologies, in nine patients. The same clone was detected in LyP lesions and the anaplastic large cell lymphoma (ALCL) of 2 patients and the mycosis fungoides (MF) of 2 other patients. No dominant clone could be detected in one patient with LyP uncomplicated by lymphoma or in a second patient with LyP and MF. A T-cell lineage was evident for RS-like cells in cell culture and in type A lesions. These results show that multiple regressing skin lesions and associated T cell lymphomas (MF and ALCL) are clonally related in most LyP patients, which suggest that the disease in these patients was initiated by a non-random genetic event.

Complications of cutaneous surgery in patients who are taking warfarin, aspirin, or nonsteroidal anti-inflammatory drugs.

BACKGROUND AND DESIGN: No controlled studies exist with regard to the risks of continuing therapy with warfarin sodium or platelet inhibitors or the benefits of briefly discontinuing therapy with these agents in patients who are undergoing cutaneous surgical procedures. Our objective was to determine the frequency of complications of cutaneous surgery in patients who were receiving warfarin or platelet inhibitors and to evaluate whether preoperative discontinuation reduces complications. A retrospective, controlled study was performed of complications of excisional and Mohs micrographic surgery in 653 patients who were being treated with warfarin or platelet inhibitors or with their medications being briefly withheld. RESULTS: Severe complications of cutaneous surgery in patients who are taking warfarin or platelet inhibitors are uncommon, occur in 1.6% of cases, and are not significantly increased compared with complications in control subjects. Furthermore, there was no statistically significant reduction in the rates of severe complications in patients who had their medications preoperatively held. CONCLUSION: Cutaneous surgery in patients who receive warfarin or platelet inhibitors is associated with a low risk of severe complications, not significantly reduced by brief preoperative discontinuation.

Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions.

Delayed hypersensitivity (DH) is a T cell-mediated form of immune response characterized by a predominantly perivascular, mononuclear cell infiltrate. The venules in DH reactions are hyperpermeable to plasma proteins, leading to extravasation of plasma fibrinogen and its extravascular clotting to form a fibrin gel that promotes induration and angiogenesis. The mechanisms responsible for microvascular hyperpermeability in DH are unknown. Recently, a cytokine named vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF) has been implicated in the chronic vascular hyperpermeability and angiogenesis of solid and ascites tumors, healing wounds, rheumatoid arthritis, and psoriasis. These findings suggested that VPF/VEGF might also have a role in the pathogenesis of DH. Two model systems were studied: allergic contact dermatitis to poison ivy in human volunteers and classical tuberculin hypersensitivity in rats. In both, in situ hybridization revealed that the mRNAs encoding VPF/VEGF were strikingly overexpressed in keratinocytes of the epidermis; scattered mononuclear cells infiltrating the dermis also overexpressed VPF/VEGF mRNA, to a greater extent in rat tuberculin than in human contact reactions. In contact reactions, mRNAs for two VPF/VEGF vascular endothelial cell receptors, flt-1 and KDR, were also strikingly overexpressed. Abundant fibrin deposition in both models confirmed that dermal microvessels were indeed hyperpermeable to plasma fibrinogen. These results implicate VPF/VEGF as a potentially important mediator in the pathogenesis of cell-mediated immunity and provide further evidence that products of epithelial cells may regulate the inflammatory response.

Use of the carbon dioxide laser in dermatologic surgery. A clinically relevant update for 1993.

BACKGROUND: The effective and safe use of the carbon dioxide (CO2) laser in the 1990s has been facilitated by technologic advances and widespread clinical use producing a better understanding of laser-tissue interactions, refinements in technique, and modifications of the list of indications. Safety guidelines have evolved from identification of complications. OBJECTIVE: To discuss the basic principles and applications of CO2 laser surgery. METHODS: Types of CO2 lasers and their applications are discussed. CONCLUSION: Today, use of the carbon dioxide laser simplifies many procedures, is reasonably safe, is effective for its intended usages, and is the preferred treatment of several cutaneous disorders.

Treatment of malignant cutaneous tumors.

Malignant cutaneous tumors, consisting primarily of basal cell carcinoma, squamous cell carcinoma, and melanoma, are exceedingly common. Diagnosis is made by visual examination of the skin surface and biopsy of any suspicious lesions. Treatment for most tumors is surgical (excision), although some basal cell and squamous cell carcinomas may be cured by field destructive techniques (cryosurgery, electrodesiccation and curettage, radiotherapy, and laser surgery). Chemotherapy and immunotherapy may be helpful in the control of advanced, multiple, and metastatic cancers. To decrease morbidity and mortality from malignant cutaneous tumors, effort should be directed toward identification of early lesions as well as prevention.

Periocular tumors.

Next to the fear of death from cancer, patients fear loss of sight more than anything else. They are especially fearful of the potential for visual impairment when confronted with the need to treat an eyelid neoplasm. Patients need reassurance that the treatment will not compromise vision and that their visual needs will be attended to. Optimally, the responsibilities for patient management are coordinated and shared in a team approach. Although many tumors around the eye are easily managed, a large proportion of them are significant by virtue of their size and location. These are best treated by a team that is prepared to provide optimal assessment, can deal with any size lesion and its repair, and is familiar with the spectrum of complications and their management.

Immunohistochemical distinction of lymphomatoid papulosis and pityriasis lichenoides et varioliformis acuta.

Lymphomatoid papulosis (LyP) and pityriasis lichenoides et varioliformis acuta (PLEVA) are benign self-healing cutaneous eruptions that may be clinically and histologically similar. However LyP has a 5% to 20% risk of associated lymphoid malignancy, whereas PLEVA does not. To determine whether the immunophenotype of lymphoid cells is useful in the distinction of these two disorders, the pattern of expression of lymphoid cell lineage and activation antigens in nine cases of LyP and seven cases of PLEVA were compared. In all cases of LyP most larger cells expressed the activation antigen Ki-1 (CD30) and lacked expression of the T-cell antigen CD7 and at least one other T-cell antigen (CD2, CD3, CD5). In contrast, CD30-antigen expression was rare or absent in PLEVA, CD3- and CD7-antigen expression was found in all cases, and diminished expression of T-cell antigens (CD2 and CD5) was seen in only one case. Diffuse expression of HLA-DR antigen by epidermal keratinocytes was found in a greater proportion of PLEVA cases (6 of 7) than LyP cases (3 of 6). In addition, CD8+ cells predominated at the dermal/epidermal junction in 3 of 6 cases of PLEVA but in only 1 of 7 cases of LyP. We conclude that LyP and PLEVA can be distinguished immunohistochemically in most, if not all, cases. Furthermore these results suggest that LyP and PLEVA are separate disorders, thus accounting for their variable prognoses.