Tumour cell-based vaccines for the treatment of melanoma.

Melanoma is generally resistant to chemotherapy and radiation therapy. Its unique immunological properties lend support to developing innovative new therapies via manipulation of the patient's own immune system. The use of whole-cell-based tumour vaccines, including autologous, whole-cell allogeneic and cytokine gene-modified vaccines, as well as tumour lysate vaccines, for active specific immunotherapy of melanoma, is discussed in detail with regard to rationale and available clinical data. Although phase II data on the use of melanoma vaccine in the adjuvant setting show promise, there is no randomised phase III trial demonstrating the efficacy of active specific immunotherapy for melanoma. The coming years will bring the results of several pivotal multicentre phase III trials testing the clinical utility of active specific immunotherapy in the management of melanoma.

Autologous peripheral blood stem cell transplantation for patients with malignancies: the Tri-Service General Hospital experience.

BACKGROUND: High-dose chemotherapy/radiotherapy followed by autologous peripheral blood stem cells transplantation (APBSCT) can be used to treat chemosensitive malignant diseases. We retrospectively studied the APBSCT treatment efficacy and safety of patients at Tri-Service General Hospital (TSGH). METHODS: From January 1994 to March 2000, 11 patients were treated with high doses of chemotherapy/radiotherapy followed by APBSCT. Nine patients were male and 2 were female. The median age was 26 years, with a range of 21 to 51. There were 7 acute myeloid leukemia (AML), 3 non-Hodgkin's lymphoma (NHL) and 1 ovarian cancer. All patients received both chemotherapy and granulocyte-colony stimulating factor to mobilize hematopoietic stem cells, and the most commonly used conditioning regimen was combined chemotherapy with Busulfan and Cyclophosphamide. RESULTS: The median numbers of infused mononuclear and CD34+ cells were 3.19 x 10(8)/kg and 9.2 x 10(6)/kg, respectively. Nine of the 11 patients engrafted successfully, but 2 patients with AML failed to engraft. The median times of WBC recovery (ANC > or = 500/uL) and platelet recovery (> or = 20 x 10(3)/uL) were 13 and 16 days, respectively. Four patients with AML survived after APBSCT and two of them were alive and disease-free for 36 and 51 months, respectively. One patient with AML and 3 patients with NHL died of relapse, and one patient with ovarian cancer was alive but with disease at 50 months. CONCLUSIONS: For patients with AML, APBSCT may be an alternative, safe and useful treatment modality. Further strategies for reducing relapse in lymphoma patients merit further investigation.

Lymphoscintigraphy and lymphatic mapping for identification of sentinel lymph nodes.

The recently introduced technique of sentinel lymph node dissection (SLND) may replace complete axillary lymph node dissection for axillary staging of early breast cancer. Successful SLND is predicated on meticulous delineation of the lymphatic pathway and sentinel node(s). Currently employed lymphatic mapping materials include vital blue dyes and radioactive tracers. Techniques of intraoperative lymphatic mapping and SLND using dye, tracer, or both have high success rates in the hands of experienced investigators, but their routine and widespread use awaits resolution of questions about the timing, dose, and type of radioactive tracer; the optimal lymphatic mapping technique; indications and contraindications for SLND; and certification of qualified surgeons, pathologists, and nuclear medicine physicians.

Serum TA90 antigen-antibody complex as a surrogate marker for the efficacy of a polyvalent allogeneic whole-cell vaccine (CancerVax) in melanoma.

INTRODUCTION: TA90 is a tumor-associated 90-kD glycoprotein antigen expressed on most melanoma cells, including those of CancerVax, a polyvalent allogeneic whole-cell vaccine. Previous studies have shown that a TA90 antigen-antibody immune complex (IC) in the serum of patients with melanoma is a marker of subclinical tumor burden and a strong prognostic factor. We hypothesized that the induction of TA90-IC during postoperative adjuvant CancerVax therapy might indicate vaccine-mediated immune destruction of subclinical melanoma cells with release of TA90, and thereby serve as a surrogate marker of vaccine efficacy. METHODS: From 1993 to 1997, 219 melanoma patients were enrolled in a prospective phase II trial of CancerVax plus bacille Calmette-Guerin (BCG) after complete tumor resection. Coded serum samples were prospectively collected and analyzed for TA90-IC before and 2, 4, 8, 12, and 16 weeks after initiation of CancerVax therapy. TA90-IC seroconverters were those patients whose negative TA90-IC values (< .410) became positive (> or = .410) after initiation of CancerVax treatment. RESULTS: Before CancerVax therapy, 51 patients had positive TA90-IC values and 168 patients had negative TA90-IC values. During CancerVax treatment, all 51 positive patients remained positive, 79 (47%) negative patients seroconverted to positive, and 89 (53%) negative patients remained negative. Seroconverters had higher 2-year rates of disease-free survival (59% vs. 32%; P < .006) and overall survival (78% vs. 63%; P < .02) than did patients whose TA90-IC values remained positive. CONCLUSIONS: CancerVax induces TA90-IC in melanoma patients with subclinical disease. TA90-IC seroconverted patients have significantly improved disease-free and overall survival compared with TA90-IC positive patients. TA90-IC is an important prognostic factor that can serve as a surrogate marker for the clinical efficacy of CancerVax.

Application of an [(18)F]fluorodeoxyglucose-sensitive probe for the intraoperative detection of malignancy.

BACKGROUND: Whole-body positron emission tomography (PET) has been shown to be a highly sensitive method for detecting malignancy not imaged by conventional modalities. We have adapted a hand-held gamma-ray-sensitive probe to detect the radiation emission from the [(18)F]fluorodeoxyglucose (FDG) used in PET imaging. This pilot study was devised to examine the feasibility of using a hand-held probe to intraoperatively differentiate normal from tumor-bearing tissue. MATERIALS AND METHODS: A commercially available gamma probe was adapted to detect the radioactivity released from FDG and examined to determine the in vitro sensitivity for localization of a FDG point source. Eight consecutive patients underwent resection of metastatic colon cancer or melanoma; each received a preoperative injection of 7--10 mCi of FDG. The gamma probe was used to determine radioactive counts per second from tumor and normal tissue, and ratios of tumor to adjacent normal background were calculated. RESULTS: In vitro studies with a FDG point source demonstrated the probe could identify the source with a 50% reduction in maximum counts 1.7 +/- 0.1 cm from the source (full-width half-maximum measurement). Based on the results of their preoperative PET scans 17 tumors were identified from the 8 patients. Of the 17 tumors assessed the in vivo tumor-to-background ratios varied from 1.16:1 to 4.67:1 for the melanoma patients (13 tumors) and from 1.19:1 to 7.92:1 for colon cancer patients (4 tumors). Thirteen tumors were resected; four (2 patients) were unresectable. CONCLUSIONS: This study demonstrates the use of a hand-held gamma-ray-sensitive probe to intraoperatively differentiate the radioactivity released from FDG from tumor-bearing and adjacent normal tissue. While further studies are necessary for us to optimize the use of this probe, the intraoperative detection of FDG-avid malignancies may ultimately improve our ability to completely resect patients with metastatic disease.

Tumor-associated antigen TA90 immune complex assay predicts recurrence and survival after surgical treatment of stage I-III melanoma.

PURPOSE: Immune complexes (IC) containing the tumor-associated antigen TA90 can be identified in the sera of melanoma patients. We have shown that an enzyme-linked immunosorbent assay for TA90-IC can detect subclinical metastasis before surgical treatment of early-stage melanoma. We assayed the TA90-IC levels of postoperative sera from patients with melanoma and evaluated their relationship to recurrence and survival. PATIENTS AND METHODS: Multiple archival serum samples prospectively collected during postoperative surveillance of 166 patients with American Joint Committee on Cancer stage I, II, or III melanoma were analyzed for TA90-IC in a blinded fashion. Results were correlated with disease recurrence and survival determined by database and chart review. RESULTS: TA90-IC status in the early postoperative period was strongly correlated with survival. Five-year overall survival rates were 84% for TA90-IC-negative patients and 36% for TA90-IC-positive patients (P =.0001). Respective 5-year disease-free survival rates were 74% and 24% (P =.0001). The TA90-IC assay was a significant predictor of survival for both stage II and III patients. Multivariate analysis identified TA90-IC status as the strongest independent prognostic factor for both overall and disease-free survival. The TA90-IC assay was elevated in 54 (77%) of 78 patients who developed recurrent disease, becoming positive 19 +/- 7 months before clinical evidence of recurrence. Overall, the assay detected recurrence with a sensitivity of 78% and specificity of 77%. Exclusion of patients receiving postoperative immunotherapy with a polyvalent melanoma cell vaccine increased sensitivity and specificity to 92% and 86%, respectively. CONCLUSION: The TA90-IC assay can accurately predict survival and detect the presence of subclinical disease after surgery for melanoma, which should be useful in selecting patients for adjuvant therapy. Because the TA90-IC assay detected recurrence on an average of 19 months sooner than did routine clinical and radiographic evaluation, it may allow more timely therapeutic interventions.

Intraoperative lymphatic mapping and sentinel lymph node dissection in breast cancer.

Because the tumor status of the regional lymph nodes is the most important prognostic factor in patients with early-stage breast cancer, accurate histopathologic assessment of these nodes is essential for optimal management, including the selection of candidates for adjuvant systemic therapies. Intraoperative lymphatic mapping using a vital blue dye, with or without a radiocolloid, can identify the first axillary node to receive lymphatic drainage from a primary breast carcinoma. Focused histopathologic assessment of this sentinel node can be used to determine the tumor status of the entire axillary basin. The minimal morbidity and high accuracy of sentinel lymph node dissection (SLND) in breast cancer have been validated by multiple independent investigators, and the data suggest that this surgical technique may eventually replace complete lymph node dissection as the preferred axillary procedure for the management of early-stage disease. In experienced hands, SLND can be successfully performed in more than 90% of eligible breast cancer patients; the tumor status of the sentinel node accurately predicts the status of all axillary nodes in more than 95% of cases. This article reviews the current status, controversies, and future directions of SLND as a staging technique for patients with primary breast carcinoma.

Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma?

BACKGROUND: Although the presence of tumor cells in the blood of patients with metastatic melanoma suggests widely disseminated disease, many of these patients enjoy prolonged survival or cure after surgical resection. Our previous study of adjuvant vaccine therapy after complete resection of metastatic melanoma revealed a strong correlation between postoperative survival and elevated antibody titers to a 90-kDa tumor-associated antigen (TA90) expressed by melanoma cells of the vaccine. We hypothesized a similar correlation between postoperative survival and endogenous anti-TA90 antibody titers induced by the patient's melanoma in the absence of postoperative adjuvant immunotherapy. METHODS: From 1970 to 1996, 64 patients underwent complete resection of distant melanoma metastases and did not receive postoperative adjuvant immunotherapy. Serum collected within 4 months after surgery was tested in a coded and blinded fashion for anti-TA90 IgG and IgM by enzyme-linked immunosorbent assay, and for total IgG and IgM (controls) by radial immunodiffusion. RESULTS: Median follow-up for the study population was 19 months (range, 3-147 months). There was no significant correlation between anti-TA90 IgG titer and total IgG level (P = .4785), or between anti-TA90 IgM and total IgM (P = .0989). Univariate analysis showed that postoperative anti-TA90 IgM titer as a continuous variable was significantly associated with overall survival (OS); i.e., the higher the anti-TA90 IgM titer, the longer the OS. Using an established cutoff titer of 800, median OS was 42 months for patients with high anti-TA90 IgM titers (n = 28) vs. 9 months for patients with low titers (n = 36) (P = .0001). There was no significant correlation between total IgG/IgM and survival (P = .4107 and .4044, respectively). Multivariate analysis identified anti-TA90 IgM as the most significant independent variable influencing OS after complete resection of distant melanoma metastases (P = .0001). CONCLUSIONS: We conclude that the endogenous immune response to metastatic melanoma determines the outcome after surgical therapy. Enhancement of this specific immune response may prolong the survival of patients with distant melanoma metastases.

Near-tetraploid minimally differentiated acute myeloid leukemia with extensive erythrophagocytosis by leukemic blasts.

Numerical change of chromosomes is common in acute myeloid leukemia (AML). However, a chromosome number as high as near-tetraploidy is very rare, especially in minimally differentiated AML (AML-M0). Erythrophagocytosis by reactive or malignant histiocytes is common in malignant hematological diseases; however, erythrophagocytosis by leukemic blasts is also very rare, especially in AML-M0. We report here the first case of AML-M0 with both of these unique characteristics: a near-tetraploid karyotype and erythrophagocytosis by leukemic blasts.

Radiofrequency ablation: a minimally invasive technique with multiple applications.

PURPOSE: Radiofrequency ablation (RFA) of soft tissue, which has recently been approved by the United States Food and Drug Administration, destroys tumor cells by delivering an electrical current through a 15-gauge needle. This study evaluated RFA for patients with hepatic malignancies considered unresectable because of their distribution, their number, and/or the presence of liver dysfunction. PATIENTS AND METHODS: Between November 1997 and February 1999, 50 patients with 132 unresectable hepatic metastases underwent RFA of tumors from 0.5 to 9 cm in diameter. There were 41 colorectal metastases in 22 patients, 13 hepatomas in seven patients, 37 neuroendocrine metastases in six patients, and 41 noncolorectal metastases in 15 patients. Real-time ultrasonography was used to guide RFA, and lesions were ablated by applying temperatures of approximately 100 degrees C for 8 minutes. Overlapping ablations were used for larger lesions. In patients with multiple lesions, RFA was performed simultaneously with cryosurgery, resection, and/or hepatic arterial infusion. RESULTS: RFA was undertaken percutaneously on an outpatient basis in 13 patients (25 lesions). The remaining patients underwent RFA via laparoscopy (21 patients; 58 lesions) or celiotomy (16 patients; 49 lesions); mean hospital stay was 1 and 5 days, respectively. RFA was the sole therapy in 28 patients and was additional therapy in 22 patients. At a median follow-up of 6 months, 27 patients were free of disease, 17 were alive with disease, and six had died of their disease (three colon, three melanoma). Three patients whose disease recurred at a prior RFA site underwent successful percutaneous RFA. Overall, there was a significant postoperative reduction in levels of carcinoembryonic antigen, alpha-fetoprotein, serotonin, and 5-hydroxyindoleacetic acid. Intraoperative ultrasonography identified unrecognized hepatic lesions in 12 of 37 patients (32%); these lesions were successfully ablated. When performed with cryosurgery, RFA reduced the morbidity of multiple freezes. DISCUSSION: RFA is a safe and effective alternative for the ablation of unresectable hepatic malignancies and when used adjunctively can reduce the morbidity of cryosurgery. Percutaneous and laparoscopic RFA can be performed effectively with less than 24 hours of hospitalization. Intraoperative ultrasonography is essential for accurate staging.

Metastasectomy for recurrent stage IV melanoma.

BACKGROUND AND OBJECTIVES: Many patients undergoing complete surgical resection of distant metastatic melanoma (American Joint Committee on Cancer [AJCC] stage IV) develop recurrent disease. We examined whether a second metastasectomy could prolong the survival of patients with recurrent stage IV melanoma. DESIGN AND PATIENTS: Retrospective review of our 8,750-patient melanoma database identified 211 patients who were rendered clinically free of disease by surgical resection of stage IV metastases during the 24-year study period (January 1971 through December 1995). Our study population comprised the 131 patients who developed recurrent stage IV disease and were followed for at least 24 months or until death. RESULTS: The median disease-free interval prior to recurrent stage IV disease was 8 months (range 0.6-91.8 months). There were 131 tumor-involved anatomic sites; the median number was one (range 1-3). Of these sites, 71 (54.2%) were soft tissue, 35 (26.7%) were pulmonary, 28 (21.4%) were gastrointestinal, 23 (17.6%) were cerebral, 13 (9.9%) were skeletal, and 2 (1.5%) were gynecologic. Median survival following treatment for recurrent stage IV melanoma was 18.2 months after complete metastasectomy, compared with 12.5 months or 5.9 months after a palliative surgical procedure or nonsurgical management, respectively. The 5-year survival rate was 20.0% (8/40) for patients in the complete surgical metastasectomy group, compared with 7.0% (3/43) and 2.1% (1/48) for those in the palliative surgical and nonsurgical groups, respectively. By multivariate analysis, the two most important prognostic factors for survival following diagnosis of recurrent stage IV melanoma were a prolonged disease-free interval to recurrence (P = 0.0001) and complete surgical metastasectomy of the recurrence (P = 0.0001). CONCLUSIONS: Metastasectomy can prolong the survival of patients with recurrent stage IV melanoma if all clinically evident tumor can be resected.

Nesidioblastosis, myelodysplastic syndrome and nodular diabetic glomerulosclerosis in an elderly nondiabetic woman: an autopsy report.

Nesidioblastosis as the cause of hyperinsulinaemic hypoglycaemia in an adult is rare. We report here an additional case of nesidioblastosis, which resulted in fatal hyperinsulinaemic hypoglycaemia in a 72-year-old woman with an underlying myelodysplastic syndrome. The diagnosis of nesidioblastosis was established only after post-mortem examination with a careful exclusion of minute insulinoma. To our surprise, the renal pathology disclosed typical diabetic nodular glomerulosclerosis in the same patient who had no previous history of diabetes mellitus (DM). Nesidioblastosis has been reported to cause 'reversal' of Type 1 DM and insulinoma causing 'reversal' of Type 2 disease. We therefore hypothesize that our patient might have had an undiagnosed DM in the past, which resulted in the typical diabetic nodular glomerulosclerosis. The nesidioblastosis caused a 'reversal' of DM and even the ultimate development of hyperinsulinaemic hypoglycaemia.

Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases.

BACKGROUND: This study was conducted to document the rate, duration, and type of objective response to active specific immunotherapy with a polyvalent melanoma cell vaccine (PMCV) for patients with in-transit melanoma metastases and to identify any acute or chronic toxic effects of PMCV treatment. METHODS: An analysis was conducted of all in-transit melanoma patients seen at the John Wayne Cancer Institute in Santa Monica, California, during the period 1985-1997 who were enrolled in prospective PMCV protocols in the absence of other therapies with possible antitumor activity (n = 54). Clinical response to PMCV was assessed by standard criteria. Survival curves were estimated by the Kaplan-Meier method. Toxicity was graded according to the Eastern Cooperative Oncology Group standard. RESULTS: PMCV produced a 17% (9 of 54 patients) objective response rate with a 13% rate (7 of 54 patients) of complete remission (CR). The median duration of CR was >22 months. Complete response lasting more than 1 year was observed in 4 patients (7.2%); 1 patient remained in remission over 9 years. Median survival was >53 months (i.e., not reached) for responders, 42 months for nonresponders, and 53 months overall. Salvage interventions allowed reinduction with PMCV in 23 of 25 patients, who subsequently remained clinically free of disease for a median of 14 months. Overall toxicity was mild, easily tolerable, and did not significantly change the quality of life. There were no toxic deaths. CONCLUSIONS: PMCV can cause objective complete regression of measurable intransit metastatic melanoma with minimal toxicity, and may prolong patients' median survival.

Survival of patients with melanoma of the lower extremity decreases with distance from the trunk.

BACKGROUND: Early stage melanoma of the lower extremity is generally associated with a favorable prognosis. However, several retrospective studies have suggested that melanoma on the foot portends poor survival. The authors hypothesized that the region of the lower extremity has prognostic importance. METHODS: Between January 1, 1971, and December 31, 1991, 652 patients were seen at the John Wayne Cancer Institute for a primary melanoma on the foot (92 patients), calf (336 patients), or thigh (224 patients). All patients had clinically or histopathologically negative regional lymph nodes. The duration of follow-up after first diagnosis was 9 -302 months, with a minimum of 6 years for survivors. Survival curves were estimated by the Kaplan-Meier method. Pearson chi-square test was used to test differences associated with the regional site of the lower-extremity melanoma. The log rank test was used for univariate analysis, and Cox proportional hazards regression was used for multivariate analysis. RESULTS: Univariate analysis identified regional site, gender, Breslow depth, Clark level, and age at diagnosis as significant for both overall survival (OS) and disease free survival (DFS) (P = 0.0001). Multivariate analysis confirmed regional site as an independent prognostic variable for OS (P = 0.0002) and DFS (P = 0.0005). Ten-year rates of OS and DFS were 71% and 66%, respectively, for patients with foot melanomas, compared with 92% and 87% for those with calf melanomas and 95% and 94% for those with thigh melanomas. CONCLUSIONS: The prognosis for patients with primary melanoma of the lower extremity is affected by the distance of the lesion from the trunk. Thus, distal (foot) lesions carry a higher risk than thigh lesions. This difference should be considered as a covariate when stratifying patients in clinical trials.

Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma.

Although patients with metastatic disease are usually not offered surgery as part of their comprehensive treatment plan, the authors suggest that surgical reduction of the tumor burden may enhance the host immune response and create a favorable setting for the use of active specific immunotherapy.

Oral ciprofloxacin as antibacterial prophylaxis after allogeneic bone marrow transplantation: a reappraisal.

The efficacy of ciprofloxacin as antibacterial prophylaxis for allogeneic bone marrow transplantation has been well documented, and it virtually eliminated bacteremias caused by gram-negative pathogens in early reports. Ciprofloxacin was therefore incorporated into the prophylactic antibiotic regimen during allogeneic bone marrow or peripheral blood stem cell transplantation at Veterans General Hospital, Kaohsiung from February 1997. In 12 consecutive patients receiving allogeneic bone marrow or peripheral blood stem cell transplantation, ciprofloxacin-resistant Escherichia coli bacteremia developed in three (25%). In addition to our data, increasing evidence suggests that the widespread use of a fluoroquinolone is associated with the emergence of resistant isolates as well as documented infections caused by these resistant strains. The incidence of Escherichia coli bacteremia in our transplant patients was 25%, which was similar to that in patients not receiving preventive therapy or in those receiving trimethoprim-sulfamethoxazole prophylaxis. The prophylactic efficacy of ciprofloxacin in allogeneic bone marrow transplant or peripheral blood stem cell transplant recipients should therefore be reassessed.

Enhancement of complement-dependent cytotoxicity by polyvalent melanoma cell vaccine (CancerVax): correlation with survival.

BACKGROUND: Case control studies have demonstrated that administration of CancerVax, a polyvalent melanoma cell vaccine (PMCV), after complete resection of melanoma metastases produces a significant improvement in disease-free survival (DFS). Because PMCV has no direct cytotoxic effect on melanoma cells, the authors hypothesized that it prolongs survival by enhancing antibody-mediated antimelanoma cytotoxicity. METHODS: One hundred melanoma patients participating in a trial of PMCV adjuvant therapy following complete resection of regional node metastases were randomly selected for study. Serum samples obtained immediately before (T0) and 4, 8, 12, and 16 weeks after initiation of PMCV adjuvant therapy were adsorbed with L-14 lymphoblastoid cells and then tested for in vitro complement-dependent cytotoxicity (CDC) against M-14 cells, a melanoma cell line not used in PMCV. CDC was expressed as percentage of total cells (n = 10,000) killed. Survival curves were estimated by the Kaplan-Meier method. Statistical analysis was performed by the signed rank sum test, Spearman test, log-rank test, and Cox proportional hazard regression. RESULTS: Median CDC at T0 was 4.5% (range, 0% to 40%). Within 16 weeks after initiation of PMCV therapy, CDC had increased in 82 (82%) patients. The median increase of 7.5% (range, -9% to 39%) represented a highly significant change (signed rank sum test; P = .0001). At a median follow-up of 29 months (range, 6 to 92 months), the maximum increase in CDC (deltaCDC) as a continuous variable was significantly correlated with DFS (P = .0001). Median survival and 5-year DFS were more than 54 months and less than 54%, respectively, for patients with deltaCDC > or =10% (n = 44) but only 7 months and 14%, respectively, for those with deltaCDC <10% (n = 56; P = .0001). Multivariate analysis confirmed deltaCDC as the most significant independent variable associated with DFS following initiation of PMCV therapy (P = .0001). CONCLUSION: PMCV therapy greatly enhances serum CDC against melanoma cells. This enhancement is directly correlated with DFS following initiation of vaccine therapy.

Acquired hemophilia A: report of two cases.

Two patients who presented with active bleeding and were diagnosed with acquired hemophilia A (AHA) are reported herein. One was a 27-year-old woman who experienced spontaneous oozing from an episiotomy wound six days after her second normal delivery. Bleeding became progressively worse, despite treatment with primary sutures and curettage of the uterus at a local hospital. She underwent emergency exploratory laparotomy because of intra-abdominal bleeding, during which perforations of the uterus were discovered. Unremitting bleeding from the surgical wound occurred after surgery. The patient was finally diagnosed with AHA when Factor VIII (FVIII) inhibitor (titer, 19 Bethesda units (BU)/ml) was detected in her plasma. She died of refractory hemorrhaging, despite intensive treatment with Factor IX concentrate infusion and cyclophosphamide therapy. The second patient was a 22-year-old man who sustained spontaneous and recurrent intramuscular hemorrhage in the right thigh for one month. Laboratory studies including complete blood count, biochemical evaluation, coagulation screening and immunologic assays were all within normal limits, except for a prolonged activated partial thromboplastin time. Idiopathic AHA was diagnosed after the detection of plasma FVIII inhibitor with a concentration of 5.9 BU/ml. The patient's coagulopathy was successfully managed with plasma exchange and subsequent treatment with oral prednisolone and cyclophosphamide.