A tumor endothelial cell-specific microRNA replacement therapy for hepatocellular carcinoma.

Current approved anti-angiogenic drugs (AAD) for hepatocellular carcinoma (HCC) inhibit tumor angiogenesis, but affect the hepatic vasculature resulting in adverse effects. Tumor endothelial cells (TECs) differ from normal endothelial cells. In this study, we aimed to detect TEC-specific miRNAs and develop an anti-angiogenic treatment specific for TECs. We established HCC orthotopic mouse models. TEC-specific miRNAs were detected using a microRNA array. Finally, we evaluated the therapeutic effects of the TEC-specific miRNA agonist cocktail. In total, 260 TEC-specific genes were detected. Among the top ten downregulated TEC-specific miRNAs, miR-139-3p and 214-3p were important for the TEC phenotype. The TEC-specific microRNA agonist cocktail showed significant anti-tumor effects by inhibiting tumor angiogenesis without affecting hepatic vasculatures in HCC orthotopic mouse models. Moreover, it significantly downregulated tip-cell sprouting-related genes. We identified two downregulated TEC-specific miRNAs; microRNA replacement therapy, which targets the downregulated TEC-specific miRNAs, is an effective and promising treatment for HCC.

Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors.

BACKGROUND: Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. METHODS: We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed. RESULTS: In the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5ß1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5ß1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment. CONCLUSIONS: Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5ß1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

The Clinical Impact of Hepatic Arterial Infusion Chemotherapy New-FP for Hepatocellular Carcinoma with Preserved Liver Function.

Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.

Subcutaneous Fat Thickness of the Lower Limb is Associated with Trunk Muscle Mass in Patients with Hepatocellular Carcinoma: A Simple Assessment for Sarcopenia Using Conventional Ultrasonography.

OBJECTIVE: Trunk muscle mass can be evaluated by skeletal muscle index (SMI), which is a prognostic factor in patients with hepatocellular carcinoma (HCC); however, this requires the use of computed tomography, and a simpler assessment for trunk muscle mass is urgently needed. We aimed to examine whether an association between SMI and lower extremity compartments including muscle and subcutaneous fat thickness of lower limbs (SFT-LL) could be identified by means of ultrasonography in patients with HCC. METHODS: We retrospectively enrolled male patients with HCC (n=30). Trunk muscle mass was evaluated by SMI using computed tomography. Ultrasonography was used for assessment of muscle and SFT-LL. Factors associated with SMI were evaluated by decision-tree analysis. RESULTS: There was no significant correlation between SMI and muscle thickness of lower limbs. However, a significant correlation was seen between SMI and left SFT-LL (r=0.406, P=0.026). In decision-tree analysis for SMI, left SFT-LL was selected as the initial split variable with an optimal cut-off value of 5 mm. In patients with left SFT-LL ≥ 5 mm, SMI was 39.4±3.4 cm2/m2, whereas SMI was 31.6±6.3 cm2/m2 in patients with left SFT-LL <5 mm. CONCLUSION: Left SFT-LL evaluated by ultrasonography was associated with SMI. Thus, ultrasonography may be a useful tool to evaluate trunk muscle mass. Moreover, left SFT-LL may be a useful indicator of sarcopenia in patients with HCC.

Clinical Importance of Regimens in Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Macrovascular Invasion.

Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the therapeutic effects between New FP (a fine-powder cisplatin suspended with lipiodol plus 5-fluorouracil) and low dose FP (LFP/cisplatin plus 5-fluorouracil) in the treatment of MVI-HCC patients with Child-Pugh class A. New FP is a regimen that consists of a fine-powder cisplatin suspended with lipiodol and 5-fluorouracil. Fifty-one patients were treated with LFP, and 99 patients were New FP. We compared the therapeutic effects of LFP and New FP and assessed factors that associated with the therapeutic effects. The median survival and progression-free survival times of LFP and New FP were 16.1/24.7 and 5.4/8.8 months, respectively (p < 0.05, p < 0.05). The complete response (29%) and objective response rate (76%) of New FP were significantly higher than those of LFP (p < 0.001, p < 0.01). Factors associated with better therapeutic response were better ALBI-grade and New FP treatment choice. New FP is a more powerful regimen than LFP in HAIC for MVI-HCC. New FP represents a recommended HAIC regimen for the treatment of patients with MVI-HCC.

Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice.

BACKGROUND: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC. MATERIALS AND METHODS: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs). RESULTS: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs. CONCLUSION: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

Increased Arterio-Portal Shunt Formation after Drug-Eluting Beads TACE for Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Conventional transcatheter arterial chemoembolization (C-TACE) and drug-eluting bead (DEB)-based TACE are current treatments for hepatocellular carcinoma (HCC). We compared the therapeutic efficacies and adverse events of these methods in a single-center retrospective cohort study. METHODS: We enrolled 174 patients treated between January 2010 and October 2016; 98 and 76 underwent C-TACE and DEB-TACE, respectively, with 76 and 22 of the former group and 49 and 27 of the latter group classified as Child-Pugh class A and B, respectively. Therapeutic outcomes, progression-free survival (PFS), and adverse events were evaluated. RESULTS: The PFS rates in the C-TACE and DEB-TACE groups were 8.1 and 6.1 months, respectively (p = 0.79). The response and disease control rates were 64 and 71% in C-TACE patients and 69 and 78% in DEB-TACE patients, respectively (p = 0.25). Postprocedural pain, vomiting, and fever were more frequent following C-TACE than DEB-TACE (p < 0.001). In contrast, the incidences of bilomas and arterio-portal shunts were significantly higher following DEB-TACE (p < 0.001); the incident rates of arterio-portal shunt formation were 8.1 and 48.7% in patients undergoing C-TACE and DEB-TACE, respectively. Child-Pugh class A was significantly associated with arterio-portal shunt formation after DEB-TACE on multivariate analysis. CONCLUSIONS: There were no significant differences in the therapeutic efficacies of C-TACE and DEB-TACE. However, the frequency of arterio-portal shunt formation was significantly higher in HCC patients with Child-Pugh class A undergoing DEB-TACE. Our findings imply that C-TACE should be selected for HCC patients with Child-Pugh class A and DEB-TACE should be chosen for those with Child-Pugh class B.

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability toward Adverse Events.

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Dose and Location of Irradiation Determine Survival for Patients with Hepatocellular Carcinoma with Macrovascular Invasion in External Beam Radiation Therapy.

AIM: Prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) is extremely poor. However, proper therapeutic strategies have not been established yet. The purpose of this study is to identify the effects of external beam radiation therapy (EBRT) for MVI of HCC. METHODS: We have analyzed and evaluated 80 consecutive patients with HCC with MVI who underwent EBRT, and factors associated with enhanced survival in EBRT were evaluated by univariate and multivariate analysis. RESULTS: The local response rate of radiotherapy for the irradiated MVI was 66.2%. The time to progression of the irradiated MVI was 5.8 months. Univariate and multivariate analyses showed that the higher irradiation dose (over 45 Gy) and the irradiation location (hepatic vein tumor thrombus - HVTT) were significant factors associated with survival benefits of EBRT. The response of EBRT for HVTT was significantly superior to that for portal vein or bile duct tumor thrombus. CONCLUSION: We conclude that a multidisciplinary therapeutic strategy based on EBRT should be proactively selected in the treatment of advanced HCC with MVI.

Epirubicin is More Effective than Miriplatin in Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a standard therapy used in the treatment of intermediate hepatocellular carcinoma (HCC). Recently, balloon-occluded TACE (B-TACE) has been developed. PURPOSE: This study aimed to clarify the effects of B-TACE in patients with HCC, with a focus on which drug is suitable to suspend in Lipiodol for B-TACE. METHODS: We retrospectively evaluated 35 patients with HCC treated with B-TACE. Factors associated with enhanced time to progression (TTP) after B-TACE were evaluated using univariate and multivariate analyses. RESULTS: A total of 35 patients with HCC (40 nodules) were treated with B-TACE between June 2013 and August 2016. Epirubicin was used in 25 nodules and miriplatin was used in 15 nodules. Epirubicin (15.1 months) was significantly better than miriplatin (3.2 months) in prolonging the local TTP after B-TACE (p = 0.0293). Epirubicin showed a positive tendency in TE4 (100% tumor necrosis) rate when compared with miriplatin (p = 0.058). Achievement of TE4 was the only significant factor associated with better TTP after B-TACE. Epirubicin- and TACE-naïve statuses were significant factors in achieving TE4 with B-TACE. CONCLUSION: To enhance the TTP with B-TACE, TE4 should be achieved. Epirubicin is a more optimal anticancer drug (as a Lipiodol suspension) than miriplatin for achieving TE4 with B-TACE.

Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation.

Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication that significantly reduces a patient's quality of life. We retrospectively analysed the incidence of and risk factors for BO in allo-SCT recipients. In 2087 patients who underwent allo-SCT between January 1994 and June 2005 and survived >90 days after transplantation, 57 patients developed BO with a 5-year cumulative incidence of 2.8%. The median time interval from transplantation to BO diagnosis was 335 days (range 83-907 days). The 5-year cumulative incidence of BO was 1.62% in bone marrow transplantation (BMT) from related donors, 3.83% in peripheral blood stem cell transplantation (PBSCT) from related donors (R-PBSCT), 2.91% in BMT from unrelated donors and 2.65% in unrelated cord blood transplantation. The incidence of BO after R-PBSCT was significantly higher than that after any other type of allo-SCT (p = 0.02). R-PBSCT (p = 0.019) and preceding chronic graft-versus-host disease (GVHD) (p < 0.001) were BO-associated risk factors. Overall 5-year survival of patients with BO from the time of diagnosis was 45.4%, significantly less than those without (77.5% from day 335, p < 0.001). R-PBSCT recipients with existent chronic GVHD have a high risk of developing BO, and need extensive care and repeated pulmonary function tests.

[Second transplantation for graft failure after allogeneic hematopoietic stem cell transplantation--a retrospective survey by Kanto Study Group for Cell Therapy].

We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.

[Hepatitis B virus reactivation in patients with HBs antibodies after allogeneic hematopoietic stem cell transplantation].

We retrospectively investigated the clinical characteristics of reactivation of hepatitis B (HB) virus after allogeneic hematopoietic stem cell transplantation (HSCT). Of 2002 patients who received transplantation between January 1994 and December 2004, seven patients who were anti-HB surface antibody (anti-HBs) positive and HB surface antigen (HBs-Ag) negative developed reactivation of the HB virus after allogeneic HSCT. The patients' median age was 49 years, and they consisted of 5 males and 2 females. Six of 7 recipients received hematopoietic stem cells from HLA-identical sibling donors. All donors were negative for HBs-Ag. Six donors were negative for anti-HBs and one donor was not investigated for anti-HBs. HB reactivation occurred 5 to 29 (median 15) months after HSCT. Chronic graft-versus-host-disease (GVHD) was observed in 5 cases. The peak value of GPT during HB reactivation varied from 83 to 1930 (median 318) IU/l. Lamivudine was given to 5 patients. One patient was treated with supportive therapy and other one patient was observed without treatment. Two patients developed fulminant hepatitis and died of hepatic dysfunction. Clinicians should consider the possibility of HB reactivation in anti-HBs-positive patients. The establishment of a preventive method for HB reactivation would be desirable.

Immune-mediated myelopathy following allogeneic stem cell transplantation.

We report a case of immune-mediated myelopathy occurring 4 months after unrelated bone marrow transplantation for myelodysplastic syndrome. After the tapering of cyclosporine for graft-versus-host disease prophylaxis, the patient developed several neurological symptoms mimicking the clinical features of multiple sclerosis (MS). Although neurological exacerbation was well stabilized with a bulk dose of corticosteroid, sustained improvement of neurological deficits occurred after the patient developed hematopoietic mixed chimerism (HMC). This experience may provide clinical evidence supporting the current therapeutic concept, in which HMC induction can potentially cure several immune diseases, including MS.

[Successful treatment with voriconazole for disseminated cutaneous and visceral infection by Fusarium solani in a patient with acute myeloid leukemia].

We report the successful treatment of a disseminated Fusarium infection with skin manifestations in a severely neutropenic patient. A 51-year-old man with acute myeloblastic leukemia (M4) underwent two courses of remission induction therapy with cytarabine and daunorubicin. Despite prophylactic treatment with tosufloxacin and micafungin, the patient developed a febrile scrotal ulcer. Eight days later, we noted the appearance of painful and diffuse cutaneous nodules and a plain chest X-ray disclosed multiple nodular lesions. Microbiological examination of the scrotal ulcer revealed infection by Fusarium solani, which was also confirmed by both histological and microbiological examination of the skin nodules. Although the patient was treated with amphotericin B (AMPH-B), the clinical symptoms worsened. After AMPH-B was replaced with voriconazole (VRCZ), the patient's symptoms and chest radiographic findings dramatically improved. Thus, VRCZ might be an alternative therapy for patients with neutropenia who have fusariosis that is refractory or unresponsive to AMPH-B.

Effect of blood cyclosporine concentration on the outcome of hematopoietic stem cell transplantation from an HLA-matched sibling donor.

We retrospectively evaluated the effect of the blood cyclosporine (CsA) concentration on the outcome of allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor in 171 patients who received a continuous infusion of CsA and short-course methotrexate to prevent graft-versus-host disease (GVHD). CsA was started at 3.0 mg/kg/day and the dose was adjusted to maintain the blood CsA concentration between 250 and 350 ng/ml. The actual dose of CsA averaged 1.9 mg/kg/day at the 3rd week after transplantation. The incidence of grade II-IV acute GVHD was 29.9%. Patient age and sex were identified as independent significant risk factors for acute GVHD. The CsA concentration during the 3rd week after transplantation most strongly affected the incidence of grade II-IV acute GVHD (RR 0.995 for an increase in CsA concentration by 1 ng/ml, P = 0.037) adjusted for other risk factors. The incidence of acute GVHD was significantly lower in patients with a 3rd-week CsA concentration higher than 300 ng/ml than in those with values between 200 and 300 ng/ml (20% vs. 35%, P = 0.036). We concluded that the blood CsA concentration at peri-engraftment period may be important in preventing acute GVHD.

Meningeal hematopoiesis following radiation myelitis in a hematopoietic stem-cell transplant recipient.

Extramedullary meningeal hematopoiesis (EMH) represents an uncommon finding after stem-cell transplantation. We describe the case of an allogeneic bone marrow transplantation (BMT) recipient who developed EMH 1 month after radiation myelitis had been diagnosed. A 39-year-old man with multiple myeloma underwent matched unrelated BMT following a myeloablative conditioning regimen of cyclophosphamide and total-body irradiation (200 cGyx6). This was followed by delivery of 40 Gy of involved-field radiation to an extramedullary plasmacytoma compressing the spinal cord. Although transplantation went extremely well, the patient developed radiation myelitis 7 months after transplantation, and EMH ensued 1 month later. Because the patient was not in a disease state known to cause EMH, it is tempting to speculate that radiation-related neural injuries might cause donor cells to migrate to the central nervous system.

Chest computed tomography of late invasive aspergillosis after allogeneic hematopoietic stem cell transplantation.

Computed tomography (CT) is a powerful diagnostic tool for invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT); however, little information is available concerning CT findings of late IA after allo-SCT. To characterize CT findings of late IA, we retrospectively examined medical records and high-resolution CT findings of 27 allo-SCT recipients with late IA. Either acute or chronic GVHD was diagnosed in 24 patients. All 27 patients were given corticosteroids at IA diagnosis. High-resolution CT findings included halo (n=12), centrilobular nodules (n=12), ill-defined consolidation (n=13), ground-glass attenuation (n=8), pleural effusion (n=7), pleural-based consolidation (n=4), and cavitation (n=4). CT findings showing centrilobular nodules and either halo or cavitation were classified into bronchopneumonia type and angioinvasive type, respectively. Angioinvasive-type, bronchopneumonia-type, and combination-type IA were diagnosed in 11, 8, and 4 patients, respectively. CT findings were nonspecific in the other 4 patients. One bronchopneumonia-type case and 2 angioinvasive-type IA cases were subsequently diagnosed as combination type. Although there were no significant differences in patient characteristics between the 2 types of IA, bronchopneumonia-type IA had a poorer prognosis than angioinvasive IA ( P=.022). Halo is a useful diagnostic marker in late IA as well as early IA, and late IA frequently manifests as bronchopneumonia.