[Complete remission after standard induction therapy in a patient with acute myeloid leukemia associated with double-minute chromosomes].

Acute myeloid leukemia (AML) associated with double-minute chromosomes (dmin) is a rare condition and has a poor prognosis. A 68-year-old man with leukocytosis and thrombocytopenia was admitted to our hospital. Bone marrow aspiration showed that 79.5% of myeloblasts were positive for myeloperoxidase. The patient was diagnosed with acute myeloid leukemia (French-American-British classification: M2, World Health Organization classification: AML, not otherwise specified, AML with maturation). Chromosomal analysis revealed the presence of dmin: 45, X, -Y, 5-33 dmin. Fluorescence in situ hybridization revealed multiple MYC signals, and spectral karyotyping showed that dmin was derived from chromosome 8. These findings indicated resistance to chemotherapy alone. After the standard induction therapy with daunorubicin and cytarabine, the number of myeloblasts in the bone marrow decreased, and the amplified MYC signals disappeared. Then, the patient achieved complete remission. Reportedly, most patients with AML correlated with dmin have a complex karyotype, except for this case. Owing to the absence of a complex karyotype, the patient had good sensitivity to chemotherapy. Further studies with a larger population of patients with AML associated with dmin, but without complex karyotypes, should be conducted to accurately predict prognosis in such cases.

Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms.

BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.

[A Case of FOLFOXIRI plus BV Therapy Responding to Liver Metastasis of Rectal Cancer with the Portal Venous Tumor Thrombi(Vp4)as Oncologic Emergency].

A 65-year-old woman was diagnosed with simultaneous hepatic metastasis of rectal cancer with portal venous tumor thrombi(Vp3)that developed in the bifurcation of the portal vein. Four days from the first visit, abdominal dynamic contrastenhanced CT image on the portal venous phase shows that the tumor thrombi progressed in the main trunk of the portal vein (Vp4). We decided that it was a condition of oncologic emergency and initiated FOLFOXIRI plus BV therapy. After 12 courses, tumor shrinkage and regression of the portal venous tumor thrombi were achieved, but conversion surgery was impossible because the collateral circulation of the hepatic portal region remained. The treatment target was changed to the extension of the survival period. The initiation and reinitiation of FOLFOXIRI plus BV therapy and maintenance of 5-FU/l-LV plus BV therapy contributed to disease control in 24 months and survival period of 36months.

Surgical Treatment of Rotational Vertebral Artery Syndrome Induced by Spinal Tumor: A Case Report and Literature Review.

Vertebrobasilar insufficiency (VBI) provoked by physiological head rotation is known as rotational vertebral artery syndrome (RVAS) or Bow Hunter syndrome. RVAS most often occurs at C1-2 level with head rotation and presents with symptoms of VBI. Several previously published studies have reported RVAS at subaxial sites (V2 segment), however, tumor-induced RVAS has never been reported. The authors report the first case of RVAS at V2 segment due to compression from a spinal tumor. A 71-year-old man presented with symptoms of dizziness provoked by head rotation or neck extension. computed tomography (CT) angiography and dynamic cerebral angiography revealed circumferential stenosis with neutral neck position and complete occlusion of the left dominant vertebral artery (VA) at C5 level with his neck extended or rotated to the left. Complete neurological recovery was achieved after removal of a spinal osteochondroma and surgical decompression of the left VA via an anterior approach. Spinal tumors should be included in the differential diagnosis in cases of RVAS. Spinal degenerations or sarcomatous transformation of the tumor could lead to clinical manifestations of RVAS in cases with spinal osteochondroma. Complete removal of the tumor with or without spinal fusion would be the treatment of choice, in addition to medical treatment in the cases of acute stroke.

Epstein-Barr virus-positive mucocutaneous ulcer arising in a post-hematopoietic cell transplant patient followed by polymorphic posttransplant lymphoproliferative disorder and cytomegalovirus colitis.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a newly described entity occurring in elderly or iatrogenically immunocompromised patients. We describe a case of EBVMCU arising in a post-hematopoietic cell transplant patient and followed by EBV-positive polymorphic posttransplant lymphoproliferative disorder (EBV+ polymorphic PTLD). The patient, a 52-year-old woman, received chemotherapy and autologous peripheral blood stem cell transplantation for relapsed diffuse large B-cell lymphoma (DLBCL). She achieved complete remission and was followed up in an outpatient clinic after discharge. One year later, EBVMCU appeared in the tongue and exhibited spontaneous regression. Six months after the regression of the EBVMCU, she had EBV+ polymorphic PTLD, analogous to EBV+ polymorphic DLBCL. The therapy for PTLD was not effective, and the patient finally died of disease progression. This was the first case of EBVMCU characterized by both an association with autologous peripheral blood stem cell transplantation and subsequent emergence of malignant lymphoma in a patient with relapsed DLBCL.

Kinetics of versican-expressing macrophages in bone marrow after cord blood stem cell transplantation for treatment of acute myelogenous leukaemia.

AIMS: To determine versican-producing cells in normocellular bone marrow and to evaluate chronological alteration in the number of versican-producing macrophages in bone marrow of patients with acute myelogenous leukaemia (AML) after cord blood stem cell transplantation (CBSCT) to gain insight in the significance of versican in recovery of haematopoiesis. METHODS: We enrolled seven age-matched unrelated patients with normocellular bone marrow for determining versican-producing cells in bone marrow, CBSCT-treated patients with AML, 18 with fine and other four with poor engraftment, for determining chronological alteration of versican-expressing and CD68-expressing cells in transplanted bone marrow in reference to the total cells. Clot samples of patients with AML were collected from the +16 to +55 day after transplantation and separated into four groups. We included an AML case whose specimen was obtained on the +9 day. Cells positive in immunohistochemistry using antibodies to versican and CD68 were counted to obtain the mean±SD in a unit area of the bone marrow, plotted chronologically and compared with the numbers from the age-matched normocellular group. RESULTS: We determined by a double immunohistochemistry that the versican-expressing cells in bone marrow are macrophages. The time-course curve demonstrated an inverse relationship between the versican-positive macrophages and the total cells in the transplanted bone marrow for over 55 days. In bone marrow of poor engraftment cases, versican-positive macrophages appeared to be decreased in comparison with age-matched and sampling day-matched patients. CONCLUSIONS: These results suggest that versican and/or versican-expressing macrophages positively contribute to bone marrow regeneration of patients with AML after CBSCT.

Activation of Yes-Associated Protein in Low-Grade Meningiomas Is Regulated by Merlin, Cell Density, and Extracellular Matrix Stiffness.

The NF2 gene product Merlin is a protein containing ezrin, radixin, and moesin domains; it is a member of the 4.1 protein superfamily associated with the membrane cytoskeleton and also interacts with cell surface molecules. The mammalian Hippo cascade, a downstream signaling cascade of merlin, inactivates the Yes-associated protein (YAP). Yes-associated protein is activated by loss of the NF2 gene and functions as an oncogene in meningioma cells; however, the factors controlling YAP expression, phosphorylation, and subcellular localization in meningiomas have not been fully elucidated. Here, we demonstrate that merlin expression is heterogeneous in 1 NF2 gene-negative and 3 NF2 gene-positive World Health Organization grade I meningiomas. In the NF2 gene-positive meningiomas, regions with low levels of merlin (tumor rims) had greater numbers of cells with nuclear YAP versus regions with high merlin levels (tumor cores). Merlin expression and YAP phosphorylation were also affected by cell density in the IOMM-Lee and HKBMM human meningioma cell lines; nuclear localization of YAP was regulated by cell density and extracellular matrix (ECM) stiffness in IOMM-Lee cells. These results suggest that cell density and ECM stiffness may contribute to the heterogeneous loss of merlin and increased nuclear YAP expression in human meningiomas.

Relapse of acute myeloid leukemia mimicking autoimmune pancreatitis after bone marrow transplantation.

We herein present the case of a 30-year-old man who developed recurrent pancreatitis and chronic graft-versus-host disease following unrelated bone marrow transplantation for acute myeloid leukemia (AML) with t(16;21)(p11;q22). Autoimmune pancreatitis was initially suspected due to the radiological findings and lack of response to gabexate mesilate and antibiotics. An examination of specimens successfully obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) demonstrated invasion of AML cells in the pancreatic tissue. EUS-FNA is a less invasive method and a particularly useful diagnostic tool in severely ill patients.

[On the correlation between histological and cytological diagnosis, and the intrinsic 5 subtypes].

Japanese General Rules presented by the Japanese Breast Cancer Society have been long time applied in Japan. This classification uniquely adds subtypes into the group of invasive ductal carcinomas (IDC) and reported to be correlated to patients' clinical course. The latest St. Gallen consensus meeting reported the use of 5 molecules, and introduced alternative definition in the breast cancer classification. The purpose of this study is to relate the Japanese subgrouping of IDC with the 5 subtypes and to investigate whether these classifications could predict early and late recurrence and whether cytological diagnosis is influenced by the tumor phenotypes. Analyzing 127 cases, we observed that the Ki-67 labeling index (LI) of the 5 subtypes, luminal A, luminal B-Her2--/- Her2+, Her2-subtype and basal-like, is increased in this order. Though the Japanese histological groups, papillotubular, solid-tubular and scirrhous, included more or less those subtypes, the luminal types were more represented in papillotubular and scirrhous subtypes, and the solid-tubular type in non luminal subtypes. The Ki-67 LI 14% served as a cutoff for differentiating invasive from non-invasive ductal carcinomas. Breast cancers recur within 5 years after the clinical onset when the Ki-67 LI exceeded 14%. These data suggest that, (1) the intrinsic subtyping is an accurate modality in diagnosing breast cancers, (2) it can predict the recurrence duration, (3) the solid-tubular type of the Japanese classification is likely an aggressive form among breast cancers, and (4) the cytological diagnosis is presently a powerful tool in determining malignancy.

Spinal intradural cystic venous angioma originating from a nerve root in the cauda equina.

A spinal intradural extramedullary venous angioma is extremely rare and has not been previously reported. In this paper, the authors report on this entity with morphological and immunohistochemical evidence, and discuss the surgical strategy for its treatment. A 54-year-old woman presented to Nagoya University Hospital complaining of left-sided pain in the hip, thigh, and inguinal and perianal regions, with progressive worsening during the previous 2 weeks. Lumbar spine MRI showed an intradural extramedullary cyst at the level of T12-L1, which extended from the conus medullaris to the cauda equina. The cyst wall was not enhanced on T1-weighted MRI with Gd. Intraoperatively, a midline dural opening allowed the authors to easily visualize a dark-reddish cyst behind the spinal nerve rootlets in the cauda equina adjacent to the conus medullaris. The cyst was believed to originate from one of the spinal nerve rootlets in the cauda equina and a cluster of veins was identified on the cyst wall. The cyst was resected with the affected nerve rootlet. The surgery left no detectable neurological deficit. Based on the morphological and immunohistochemical evidence, the lesion was diagnosed as a venous angioma. No tumor recurrence was confirmed based on MRI at the time of the 2-year follow up. This is the first report of an intradural extramedullary cystic venous angioma that was successfully resected.

Interferon-ß delivery via human neural stem cell abates glial scar formation in spinal cord injury.

Glial scar formation is the major impedance to axonal regrowth after spinal cord injury (SCI), and scar-modulating treatments have become a leading therapeutic goal for SCI treatment. In this study, human neural stem cells (NSCs) encoding interferon-ß (INF-ß) gene were administered intravenously to mice 1 week after SCI. Animals receiving NSCs encoding IFN-ß exhibited significant neurobehavioral improvement, electrophysiological recovery, suppressed glial scar formation, and preservation of nerve fibers in lesioned spinal cord. Systemic evaluation of SCI gliosis lesion site with lesion-specific microdissection, genome-wide microarray, and MetaCore pathway analysis identified upregulation of toll-like receptor 4 (TLR4) in SCI gliosis lesion site, and this led us to focus on TLR4 signaling in reactive astrocytes. Examination of primary astrocytes from TLR4 knockout mice, and in vivo inhibition of TLR4, revealed that the effect of IFN-ß on the suppression of glial scar formation in SCI requires TLR4 stimulation. These results suggest that IFN-ß delivery via intravenous injection of NSCs following SCI inhibits glial scar formation in spinal cord through stimulation of TLR4 signaling.

Intra-extradural dumbbell-shaped hemangioblastoma manifesting as subarachnoid hemorrhage in the cauda equina.

A 56-year-old man presented with a rare intra-extradural dumbbell-shaped hemangioblastoma in the lumbar spine associated with von Hippel-Lindau (VHL) disease manifesting as subarachnoid hemorrhage. The tumor, which was exiting at the right L2-3 intervertebral foramen, was removed successfully by total facetectomy and posterior spinal fusion at the L2-3 segment. Nine years later, a recurrent tumor due to VHL was also totally removed with minimal neurological complications. Accurate diagnosis of this vascular-rich lesion is essential for developing an adequate surgical strategy. The dumbbell-shaped tumor requires total facetectomy and spinal reconstruction, and care should be taken to preserve the entire nerve root origin by only identifying the affected nerve fascicles at the origin, if possible. Postoperative adhesion must be minimized for second surgery in patients with genetic disease such as VHL, who are likely to suffer recurrence.

Enhanced antitumor effect of combination intravesical mitomycin C and bacillus Calmette-Guerin therapy in an orthotopic bladder cancer model.

Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is currently the most successful adjuvant agent for the treatment and/or prophylaxis of non-muscle-invasive bladder cancer (NMIBC). However, NMIBCs recur in 60-70% of cases and 30% of these recurrent tumors present with a higher grade and more invasive properties. Patients that do not respond to intravesical BCG therapy are considered to be a challenge for urologists. Thus, novel conservative possibilities should be explored. To test the efficacy of a novel therapeutic approach, we examined the antitumor effect of combination therapy by intravesical administration of mitomycin C (MMC) plus BCG, infusing the two drugs simultaneously, in an orthotopic bladder cancer model. Intravesical BCG and MMC administration showed a dose-dependent survival (n=8 per group). The combination of MMC and BCG provided a significant survival advantage compared to the BCG-alone (p=0.035) and MMC-alone groups (p=0.040) (n=8 per group). The group with combined MMC/BCG exhibited a survival period similar to that achieved with an amount eight times higher that of BCG (n=10 per group). Ki-67 labeling index of cancer cells, showing tumor proliferation, was significantly lower in the combined group compared to the BCG-alone (p<0.05), MMC-alone (p<0.01) and control groups (p<0.01). No difference was detected between the combined group and the BCG-alone group with regard to CD3, T-cell infiltration and CD68 macrophage activity. The combined MMC/BCG treatment decreased the tumor appearance rate, improved the survival period and reduced the cellular proliferation rate in tumors compared to the BCG-alone treatment. The results suggest that the combined intravesical MMC/BCG treatment induced an enhanced antitumor effect against bladder tumors. The combined MMC/BCG treatment also showed a survival period similar to that achieved using a dose eight times higher of BCG-alone.

Enhanced antitumor effect of coincident intravesical gemcitabine plus BCG therapy in an orthotopic bladder cancer model.

OBJECTIVES: To evaluate the antitumor effect of the coincident administration of intravesical gemcitabine (Gem) plus bacillus Calmette-Guérin (BCG) in an orthotopic bladder cancer model. METHODS: We evaluated the cytotoxic effect of gemcitabine against MBT-2 cells in vitro. Orthotopic tumors were established by implanting MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical Gem administration was evaluated at various doses: 0 mg (control); 1, 2, 4, and 8 mg (n = 8 for each group). Next, a comparative evaluation of tumor growth among the control, Gem-alone, BCG-alone, and combined Gem + BCG groups was performed (n = 16 for each group). Therapy was administered at 3-day intervals starting on day 5 and repeated 6 times. To evaluate the proliferative activity among the groups, Ki-67 immunostaining of the tumor was performed. RESULTS: Gemcitabine exhibited a dose-dependent antitumor effect. Of the 8 mice in each group treated with a dose of 0, 1, 2, 4, or 8 mg of Gem, 1, 4, 4, 4, 5, and 4 mice failed to develop tumors and survived, respectively. The combination of Gem + BCG (54.1 ± 9.4 days) provided a significant survival advantage compared with BCG-alone (39.0 ± 16.4 days) (P = .02). Ki-67 expression, representing tumor proliferation, was significantly lower in the combined Gem + BCG group than in the BCG-alone group (P < .01). CONCLUSIONS: Our results suggest that intravesical Gem + BCG treatment induces an enhanced antitumor effect against bladder tumors.

Tumor thickness, depth of invasion, and Bcl-2 expression are correlated with FDG-uptake in oral squamous cell carcinomas.

High [(18)F]-2-fluorodeoxyglucose (FDG)-uptake of oral squamous cell carcinoma (OSCC), assessed by pretreatment positron emission tomography (PET), has indicated poor survival of patients. In this study, we sought to elucidate the underlying pathological and biological mechanisms of the close correlation in OSCC between high FDG-uptake and poor survival. Twenty-three patients who underwent both pretreatment FDG-PET and radical surgery were evaluated. We calculated the maximum standardized uptake value (SUVmax) as FDG-uptake. Tumor thickness and depth of invasion were quantitatively measured. Pathological specimens were immunohistochemically stained with antibodies to glucose transporter-1, E-cadherin, beta-catenin, vascular endothelial growth factor (VEGF), VEGF-C and Bcl-2, and their expressions were densitometrically assessed. SUVmax was significantly correlated with both tumor thickness and depth of invasion in simple regression analysis. Patients with SUVmax12 exhibited significantly shorter 3-year overall survival than patients with SUVmax < 12. Tumors with SUVmax > or =12 showed significantly greater tumor thickness, depth of invasion and average Bcl-2 intensity than those with SUVmax<12. Furthermore, tumor thickness> or =11.4mm, depth of invasion> or =11.8mm and average Bcl-2 intensity > or =50% were significantly correlated with poor survival. These results suggest that SUVmax in OSCC is significantly correlated with pathological features, and that it is both a non-invasive and useful parameter for predicting patients' prognosis.

BRMS1 contributes to the negative regulation of uPA gene expression through recruitment of HDAC1 to the NF-kappaB binding site of the uPA promoter.

The BRMS1 metastasis suppressor was recently shown to negatively regulate NF-kappaB signaling and down regulate NF-kappaB-dependent uPA expression. Here we confirm that BRMS1 expression correlates with reduced NF-kappaB DNA binding activity in independently derived human melanoma C8161.9 cells stably expressing BRMS1. We show that knockdown of BRMS1 expression in these cells using small interfering RNA (siRNA) leads to the reactivation of NF-kappaB DNA binding activity and re-expression of uPA. Further, we confirm that BRMS1 expression does not alter IKKbeta kinase activity suggesting that BRMS1-dependent uPA regulation does not occur through inhibition of the classical upstream activators of NF-kappaB. BRMS1 has been implicated as a corepressor of HDAC1 and consistent with this, we show that BRMS1 promotes HDAC1 recruitment to the NF-kappaB binding site of the uPA promoter and is associated with reduced H3 acetylation. We also confirm that BRMS1 expression stimulates disassociation of p65 from the NF-kappaB binding site of the uPA promoter consistent with its reduced DNA binding activity. These data suggest that BRMS1 recruits HDAC1 to the NF-kappaB binding site of the uPA promoter, modulates histone acetylation of p65 on the uPA promoter, leading to reduced NF-kappaB binding activity on its consensus sequence, and reduced transactivation of uPA expression.

Role of IKK and oscillatory NFkappaB kinetics in MMP-9 gene expression and chemoresistance to 5-fluorouracil in RKO colorectal cancer cells.

Nuclear factor kappa B (NFkappaB) is a central participant in the metastasis and chemoresistance of colorectal cancer (CRC). However, it is not fully understood to what extent NFkappaB contributes to induction of the metastasis-associated matrix metalloprotease-9 (MMP-9) gene and sensitivity to the commonly used chemotherapeutic 5-fluorouracil (5-Fu) in CRC. Using the RKO human CRC cell line and two NFkappaB signaling deficient RKO mutants, we investigated NFkappaB's role in the induction of MMP-9 and 5-Fu sensitivity in RKO CRC cells. NFkappaB plays a predominant role in MMP-9 gene induction in RKO cells, as evidenced by the failure of tumor necrosis factor alpha (TNFalpha) to induce MMP-9 in either of the NFkappaB signaling mutants. RKO cells exhibit a robust, oscillatory NFkappaB activity in response to TNFalpha not seen in either of the NFkappaB mutant cell lines, which instead demonstrate diminished, nonoscillatory NFkappaB activation. Analysis of TNFalpha-induced phosphorylation and MMP-9 promoter recruitment of the p65 NFkappaB subunit revealed a significant reduction in p65 phosphorylation as well as reduced and altered recruitment of p65 to the MMP-9 gene promoter in the mutants compared to the parental RKO cell line. 5-Fu only activated NFkappaB in the parental RKO cells through induction of IkappaB-kinase (IKK) activity and increased sensitivity to 5-Fu is observed in both NFkappaB mutant lines. Our results suggest that TNFalpha-dependent induction of MMP-9 gene expression is tightly regulated by oscillatory/cumulative activation of NFkappaB and that 5-Fu stimulates NFkappaB and RKO CRC cell survival through induction of IKK activity.

Novel enhanced lung-colonizing variant of murine MBT-2 bladder cancer cells.

OBJECTIVES: To develop an enhanced lung-colonizing variant of murine bladder cancer that will allow the mechanism of metastasis to be studied more readily. METHODS: We implanted murine bladder tumor cells (MBT-2) into the leg muscles of C3H mice. We developed variant cells from a lung metastasis nodule. We compared the MBT-2 cells and variant cells (MBT-2V) in vivo by evaluating lung nodule formation, survival, in vitro adhesion, and migration-invasion assays. Zymography and semiquantitative reverse transcriptase-polymerase chain reaction analyses were also performed to characterize the metastatic ability of both cells. RESULTS: MBT-2 and MBT-2V cells were tumorigenic when injected intramuscularly into C3H mice, but MBT-2 cells had little potential to metastasize compared with MBT-2V cells. Metastases were observed in the lungs of mice injected in the tail vein with MBT-2 and MBT-2V cells. Mice receiving MBT-2V cells had significantly shorter survival (P <0.01) and more lung nodules (245 versus 106, P <0.0001) than those receiving MBT-2 cells. In vitro study revealed that MBT-2V cells exhibited more adhesion, greater migration, and more invasiveness than did MBT-2 cells. Pathologic examination revealed the tumors from MBT-2V cells to be more aggressive than those from MBT-2 cells. MBT-2V also showed significantly greater matrix metalloproteinase-9 expression. CONCLUSIONS: We generated an enhanced lung-colonizing variant of MBT-2 cells. Our MBT-2V cells showed more aggressive and invasive metastatic ability than that of the MBT-2 cells. Zymography and reverse transcriptase-polymerase chain reaction analyses indicated that matrix metalloproteinase-9 might be associated with the metastatic ability of MBT-2V cells.

Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model.

OBJECTIVES: To evaluate the antitumor effect of intravesical cationic liposome-mediated interleukin-12 (IL-12) gene delivery in an orthotopic murine bladder cancer model, and to investigate the immunologic memory against tumors between IL-12 gene therapy and bacille Calmette-Guérin (BCG) therapy. METHODS: Orthotopic murine bladder tumors were established by implanting 5 x 10(5) MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical IL-12 gene therapy was evaluated at varying doses: 0 microg (control) and 3, 5, and 10 microg (n = 8 for each group). Intravesical treatments were performed every 3 days and repeated six times beginning 5 days after tumor implantation. To compare the long-term, tumor-specific immunity between IL-12-treated mice (n = 18) and BCG-treated mice (n = 20), the animals surviving at day 60 and 10 new control mice were rechallenged with MBT-2 cells and received no additional treatment. On day 120, all surviving mice were killed and underwent necropsy. RESULTS: In the IL-12 groups at doses of 0, 3, 5, and 10 microg, 0, 2, 3, and 3 mice survived, respectively. Mice in the 5-microg and 10-microg IL-12 groups survived significantly longer than did the control group. All mice cured by IL-12 treatment successfully rejected the rechallenge with MBT-2 cells; however, mice cured by BCG and the new control mice died of the rechallenged bladder tumors. CONCLUSIONS: Intravesical IL-12 gene therapy, which induced long-lasting tumor-specific immunologic memory compared with BCG therapy, improved survival in an orthotopic bladder cancer model.