Differential diagnosis of infectious diseases, drug-induced lung injury, and pulmonary infiltration due to underlying malignancy in patients with hematological malignancy using HRCT.

PURPOSE: To differentiate among infectious diseases, drug-induced lung injury (DILI) and pulmonary infiltration due to underlying malignancy (PIUM) based on high-resolution computed tomographic (HRCT) findings from patients with hematological malignancies who underwent chemotherapy or hematopoietic stem cell transplantation. MATERIALS AND METHODS: A total of 221 immunocompromised patients with hematological malignancies who had proven chest complications (141 patients with infectious diseases, 24 with DILI and 56 with PIUM) were included. Two chest radiologists evaluated the HRCT findings, including ground-glass opacity, consolidation, nodules, and thickening of bronchovascular bundles (BVBs) and interlobular septa (ILS). After comparing these CT findings among the three groups using the χ2test, multiple logistic regression analyses (infectious vs noninfectious diseases, DILI vs non-DILI, and PIUM vs non-PIUM) were performed to detect useful indicators for differentiation. RESULTS: Significant differences were detected in many HRCT findings by the χ2 test. The results from the multiple logistic regression analyses identified several indicators: nodules without a perilymphatic distribution [p = 0.012, odds ratio (95% confidence interval): 4.464 (1.355-11.904)], nodules with a tree-in-bud pattern [p = 0.011, 8.364 (1.637-42.741)], and the absence of ILS thickening[p = 0.003, 3.621 (1.565-8.381)] for infectious diseases, the presence of ILS thickening [p = 0.001, 7.166 (2.343-21.915)] for DILI, and nodules with a perilymphatic distribution [p = 0.011, 4.256 (1.397-12.961)] and lymph node enlargement (p = 0.008, 3.420 (1.385-8.441)] for PIUM. CONCLUSION: ILS thickening, nodules with a perilymphatic distribution, tree-in-bud pattern, and lymph node enlargement could be useful indicators for differentiating among infectious diseases, DILI, and PIUM in patients with hematological malignancies.

[Resolution of dasatinib-associated lymphadenopathy following discontinuation of dasatinib in patients with chronic myeloid leukemia].

This study reports two cases of dasatinib-associated lymphadenopathy (DAL). Case 1 involved a 58-year-old man diagnosed with chronic myelogenous leukemia (CML). After 13 months of starting on dasatinib treatment, a molecular response (MR) 4.5 was achieved. Due to the loss of MMR, dasatinib was discontinued at 39 months but restarted at 42 months. Right cervical lymphadenopathy appeared 51 months after starting the treatment. DAL was diagnosed based on the findings of a cervical lymph node biopsy. After dasatinib was switched to ponatinib, the lymphadenopathy disappeared without recurrence. In case 2, a 54-year-old man was diagnosed with CML. He was started on dasatinib and MR 4.5 was achieved after 6 months. Left cervical lymph node adenopathy appeared 21 months later, and a diagnosis of DAL was made based on the findings of a cervical lymph node biopsy. After discontinuation of dasatinib, cervical lymph node adenopathy disappeared without recurrence. The possibility of DAL should be considered if lymphadenopathy is observed during dasatinib treatment.

High-resolution CT findings of pulmonary infections in patients with hematologic malignancy: comparison between patients with or without hematopoietic stem cell transplantation.

PURPOSE: To evaluate the high-resolution CT (HRCT) findings of pulmonary infections in patients with hematologic malignancy and compare them between patients with or without hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: A total of 128 patients with hematologic malignancy and pulmonary infection were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (37 non-HSCT cases and 14 HSCT cases), pneumocystis pneumonia (PCP) (29 non-HSCT cases and 11 HSCT cases), and fungal infection other than PCP (20 non-HSCT cases and 17 HSCT cases). Two chest radiologists retrospectively evaluated the HRCT criteria and compared them using chi-squared tests and a multiple logistic regression analysis. RESULTS: According to the multiple logistic regression analysis, nodules were an indicator in HSCT patients with PCP (p = 0.025; odds ratio, 5.8; 95% confidence interval, 1.2-26.6). The centrilobular distribution of nodules was the most frequent (n = 4, 36%) in HSCT patients with PCP. A mosaic pattern was an indicator of PCP in both HSCT and non-HSCT patients. There were no significant differences in other infections. CONCLUSION: The mosaic pattern could be an indicator of PCP in both HSCT and non-HSCT patients. Nodules with centrilobular distribution might be relatively frequent HRCT findings of PCP in HSCT patients.

Effective Treatment of a Malignant Breast Phyllodes Tumor with Doxorubicin-Ifosfamide Therapy.

Malignant phyllodes tumors of the breast occur infrequently and are difficult to treat with chemotherapy. Here, we present an effective chemotherapy strategy for recurrent malignant breast phyllodes tumors. A 48-year-old woman was diagnosed with a malignant phyllodes tumor in her right breast and underwent total right mastectomy. One year later, the tumor recurred in the right (a 2.2 cm mass) and left (a 10 cm mass) lungs; pleural effusion was also observed in the left lung. Eight courses of doxorubicin-ifosfamide (AI) therapy were administered. After treatment, the right lung mass and pleural effusion regressed completely and the left lung mass regressed to 2 cm. In conclusion, AI therapy is useful for treating recurrent malignant breast phyllodes tumors.

Efficacy of Glutaraldehyde-Treated Leaflets for Mitral Valve Repair to Treat Active Infective Endocarditis: A Case Report.

We report the use of glutaraldehyde (GA) in a case of valve repair for mitral valve prolapse associated with active infective endocarditis. GA scrubbed at the site of infection decontaminates and reinforces infected fragile tissue, avoids excessive debridement, and strengthens the edges of valve leaflets to facilitate suturing.

Takotsubo Cardiomyopathy in a Patient with Previously Undiagnosed Hypertrophic Cardiomyopathy with Latent Obstruction.

A 62-year-old woman with takotsubo cardiomyopathy (TCM) accompanied by cardiogenic shock due to the obstruction of left ventricular outflow tract (LVOT) and massive mitral regurgitation (MR) was admitted to the emergency department. After successful treatment with intensive care, dobutamine stress-echocardiography was performed, which reproduced a dynamic LVOT gradient, severe MR and cardiogenic shock. A histological examination obtained from the right ventricular septum demonstrated hypertrophied and bizarre myocytes, with myocyte disarray. Besides TCM, a diagnosis of preexisting hypertrophic cardiomyopathy with latent obstruction was made. She was discharged with medical therapy including a beta-blocker, which would not be routinely employed in the treatment of a patient with TCM.

[Case of abdominal wall malignant peripheral nerve sheath tumor which is difficult to distinguish from a urachal disease].

Malignant peripheral nerve sheath tumors (MPNST) are highly malignant soft tissue sarcomas. It is very rare for MPNST to arise in the abdominal wall. We report a case of abdominal wall MPNST that was difficult to distinguish from a urachal disease. A 72-year-old woman found a mass of the umbilicus in October 2011. She visited a digestive surgery department in November because it gradually enlarged. Diagnostic imaging suggested a urachal tumor. She was then referred to our clinic. Contrast enhanced CT showed that the 5-cm cystic tumor extended from the umbilicus to abdominal wall. The tumor showed low uptake value in PET-CT. We diagnosed her with a urachal cyst, but could not deny urachal carcinoma. Therefore, we performed surgical resection in January 2012. The pathological diagnosis was MPNST. She has not experienced recurrence for 9 months. MPNST mostly occur in the retroperitoneum close to the spine, extremities, head, and neck. It is very rare for them to occur in the abdominal wall. This is the sixth case including overseas reports. In addition, this is the first case in which it was difficult to distinguish from a urachal disease.

[Malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma of the penis: a case report].

We report the case of a malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (MFH/UPS) of the penis in a 78-years-old-man who had undergone previous radical prostatectomy, external beam radiation therapy for prostatic adenocarcinoma. The mass was a 9-cm firm lesion at the base of the penis predominantly composed of malignant spindle cells arranged in sweeping fascicles and storiform pattern. The tumor cells stained for vimentin, beta-smooth muscle actin, S-100, and were negative for keratin, desmin, Melan A, PSA. Despite total penectomy, he developed a local reccurence 4 months after surgery, and died from dissemination 6 months after surgery. This is the 8th case of penile MFH/UPS.

Preoperative evaluation of early colorectal cancer using an ultrasound mini probe.

BACKGROUND/AIMS: We investigated whether endoscopic ultrasonography (EUS) can assess the depth of invasion of early colorectal cancer exhibiting the V pit pattern on magnifying endoscopy with submucosal invasion of 1,000 µm or deeper. METHODOLOGY: Among 38 colorectal tumors exhibiting the V pit pattern on magnifying endoscopy, the findings on EUS with a mini-probe (15 MHz) were compared with histopathological findings. The diagnostic accuracy, sensitivity and specificity of EUS were examined separately in tumors exhibiting the Vi or V5 pit pattern. RESULTS: Diagnostic accuracy of EUS for cancers exhibiting the Vi pit pattern on magnifying endoscopy with submucosal invasion of 1,000 µm or deeper was 9/15 (60%). Sensitivity was 90%, specificity 14.3%, positive predictive value 31.7% and negative predictive value 76.3%. Diagnostic accuracy of EUS for cancers exhibiting the VN pit pattern on magnify-ing endoscopy with submucosal invasion of 1,000 µm or deeper was 13/18 (72%). The sensitivity and specificity of EUS were 100% and 37.5%, respectively. CONCLUSIONS: EUS tended to diagnose the invasion depth of cancer with submucosal invasion exhibiting the V pit pattern as deeper than it actually was. EUS accurately diagnosed early colorectal cancer with shallow invasion exhibiting the VN pit pattern and surgery was avoided.

Mucosa-associated lymphoid tissue (MALT) lymphoma arising in the esophagus, stomach, and lung.

A 62-year-old woman was referred to our hospital for further investigation of slow-growing gastrointestinal submucosal tumors (SMTs) and multiple lung nodules. Esophageal SMTs had been identified 6 years earlier, following which lung tumors and gastric SMTs had subsequently developed. Despite repeated endoscopic biopsies, these SMTs could not be diagnosed definitively. Moreover, we were unable to detect any serological abnormalities or radiologic findings such as lymph node swelling. Thoracoscopic excision of a lung nodule led to the definitive diagnosis of mucosaassociated lymphoid tissue (MALT) lymphoma. Cytological findings of aspiration biopsy specimens from the esophagus and stomach were compatible with that of the lung nodule. To our knowledge, this is the first case report of esophageal MALT lymphoma with lung and gastric involvement. We discuss this extremely rare disease with reference to the relevant literature.

Transplantation of neurospheres derived from bone marrow stromal cells promotes neurological recovery in rats with spinal cord injury.

Previous studies have revealed that cell therapy using bone marrow stromal cells (BMSCs) could promote motor functional recovery in animals with spinal cord injury (SCI). We describe here the development of cell biology technique and the experimental study of regeneration in SCI. The aim of this study was to investigate the potential for neurological recovery by transplantation neurospheres (NS) derived from BMSCs into thoracic SCI. Adult Fisher rats were used: 45 were subjected to complete thoracic SCI performed by the balloon compression method. BMSCs were cultured in vitro to obtain NS. Seven days after thoracic SCI, groups of 15 rats each received transplants of BMSCs-NS (group A), BMSCs (group B), or injection of medium only (group C) into the SCI lesion. Rats from each group were evaluated and compared longitudinally for motor function recovery. The spinal cords (SC) of injured rats were harvested at day 21 or day 42 and prepared for histological analysis. Five weeks after transplantation, many neuronal or axonal sproutings were observed and replaced by host cells in the SCI lesion of group A. Also, transplanted BMSCs-NS expressed neuronal lineage markers. Transplanted rats could walk with weight bearing and showed recovered motor evoked potentials (MEPs).

High-resolution computed tomography of chest complications in patients treated with hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) has become a standard method for treating patients with hematological malignancies. Preconditioning chemotherapeutic drugs, total body irradiation (TBI), or chronic graft-versus-host disease (GVHD) can cause several chest complications after HSCT. Because immunosuppression is marked after HSCT, it takes at least 1 year for the immune system to recover completely. Therefore, several infectious and noninfectious complications may occur within the year after HSCT. HSCT-specific complications occur in a characteristic temporal sequence associated with the period following HSCT. During the neutropenic phase, bacterial pneumonia, fungal infection, pulmonary edema, and diffuse alveolar hemorrhage may occur. During the early phase, pneumocystis pneumonia, cytomegalovirus pneumonia, engraftment syndrome, and idiopathic pneumonia syndrome are the common complications. During the late phase, constrictive bronchiolitis and organizing pneumonia may occur probably associated with chronic GVHD. Although high-resolution CT findings lack specificity, the frequency and likelihood of occurrence of certain complications in certain phases and sometimes characteristic features (such as a CT halo sign for fungal infection) facilitate early detection of a life-threatening complication.

A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice.

BACKGROUND/AIM: A European randomized trial showed biochemical effects of 6-month treatment with Stronger Neo-Minophagen C (SNMC), a glycyrrhizin-containing preparation, in patients with chronic hepatitis C, but its underlying mechanisms remain elusive. We reported previously that SNMC exhibits an anti-oxidative effect in hepatitis C virus (HCV) transgenic mice that develop marked hepatic steatosis with mitochondrial injury under iron overloading. Hepatic steatosis and iron overload are oxidative stress-associated pathophysiological features in chronic hepatitis C. The aim of this study was to investigate whether long-term treatment with SNMC could prevent the development of hepatic steatosis in iron-overloaded HCV transgenic mice. METHODS: C57BL/6 transgenic mice expressing the HCV polyprotein were fed an excess iron diet concomitantly with intraperitoneal injection of saline, SNMC, or seven-fold-concentrated SNMC thrice weekly for 6 months. RESULTS: Stronger Neo-Minophagen C inhibited the development of hepatic steatosis in a dose-dependent manner without affecting hepatic iron content, attenuated ultrastructural alterations of mitochondria of the liver, activated mitochondrial ß-oxidation with increased expression of carnitine palmitoyl transferase I and decreased the production of reactive oxygen species in the liver in iron-overloaded transgenic mice. However, SNMC hardly affected the unfolded protein response, which post-transcriptionally activates sterol regulatory element-binding protein 1, a transcription factor involved in lipid synthesis, even though we reported previously the activation of the unfolded protein response in the same iron-overloaded transgenic mice. CONCLUSIONS: These results suggest that SNMC prevents hepatic steatosis possibly by protecting mitochondria against oxidative stress induced by HCV proteins and iron overload.

Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice.

BACKGROUND/AIM: Hepatic iron overload and steatosis play critical roles in the progression of hepatitis C virus (HCV)-associated chronic liver disease. However, how these two pathophysiological features affect each other remains unknown. The aim of this study was to investigate how hepatic iron overload contributes to the development of hepatic steatosis in the presence of HCV proteins. METHODS: Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or a control diet. Mice in each group were assessed for the molecules responsible for fat accumulation in the liver. RESULTS: Hepatic iron levels were positively correlated with triglyceride concentrations in the liver for all mice. As compared with the livers of nontransgenic mice fed the control diet, the livers of transgenic mice fed the excess-iron diet showed a lower expression of carnitine palmitoyl transferase I, a higher expression of sterol-regulatory element-binding protein 1 and fatty acid synthetase and an activated unfolded protein response indicated by a higher expression of unspliced and spliced X-box DNA-binding protein 1 (XBP-1), phosphorylated eukaryotic initiation factor-2alpha (p-eIF2alpha), CCAAT/enhancer-binding protein homology protein (CHOP) and abundant autophagosomes concomitant with increased production of reactive oxygen species. Six-month treatment with the anti-oxidant N-acetyl cysteine dramatically reduced hepatic steatosis in transgenic mice fed the excess-iron diet through decreased expression of unspliced and spliced XBP-1, p-eIF2alpha, and CHOP. CONCLUSIONS: The iron-induced unfolded protein response appears to be one of the mechanisms responsible for fat accumulation in the liver in transgenic mice expressing the HCV polyprotein.

Gemtuzumab ozogamicin therapy for isolated extramedullary AML relapse after allogeneic hematopoietic stem-cell transplantation.

The treatment of isolated extramedullary relapse (IEMR) after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) poses a challenge for which no standard approach exists. Gemtuzumab ozogamicin (GO) is a recombinant humanized monoclonal antibody, conjugated to calicheamicin, which targets the CD33 antigen that is expressed in acute myelogenous leukemia (AML) blasts. The selectivity of GO for CD33-positive leukemic cells makes it an attractive agent for use in patients with multiple sites of IEMR after allo-HSCT, because GO does not suppress cells responsible for the putative graft-versus-leukemia (GVL) effect. Herein, we describe a 54-year-old male patient who developed AML with multiple sites of extramedullary (EM) relapse after allo-HSCT, and who exhibited apparent donor-derived hematopoiesis in the bone marrow. At approximately 120 days after allo-HSCT, the patient complained of severe lumbago. T2-weighted magnetic resonance images and fluorodeoxyglucose-positron emission tomography showed multiple mass lesions in soft tissue and bone. A biopsy specimen from a lumbar soft tissue mass confirmed EM relapse, and revealed that donor T lymphocytes were present in the relapse site and that leukemic cells expressed CD33. Therefore, to maintain the GVL effect of donor T lymphocytes, the patient was treated with GO as a single agent. He achieved complete hematological remission, and has remained in remission, with only mild liver injury, for more than 10 months since GO treatment. GO can be an effective therapy for IEMR after allo-HSCT, especially when cytotoxic T lymphocytes react to leukemic cells at the site of EM relapse.

Does chromoendoscopy improve the colonoscopic adenoma detection rate?

BACKGROUND/AIMS: It is not clear whether chromoendoscopy with indigo carmine improves the rate of detection of colorectal polyps compared to: detection via standard colonoscopy. The aim of our study was to determine whether chromoendoscopy with indigo carmine significantly improves the detection of adenomas in the distal colon and rectum. METHODOLOGY: Using back-to-back sigmoidoscopies in each study patient, we prospectively evaluated whether chromoendoscopy with indigo carmine picked up more adenomatous polyps than standard colonoscopy. In all patients, standard high-resolution complete colonoscopy without indigo carmine was performed at the first examination. The second examination was restricted to colonoscopy distal to the splenic flexure of the colon. For the second examination, patients were randomized to chromoendoscopy with indigo carmine or colonoscopy without indigo carmine application. The second examination's detection rate was compared between the two groups. RESULTS: In the 60 patients in the chromoendoscopy with indigo carmine group, 38 adenomas were found in the first examination and 14 adenomas in the second examination. In the 70 patients in the standard colonoscopy group, 66 adenomas were found in the first examination and 32 adenomas in the second examination. The detection rates in the two groups were 26.9% and 32.7%, re spectively, which were not significantly different (p = 0.47). CONCLUSION: Chromoendoscopy did not detect more adenomatous polyps in comparison to standard colonoscopy.

Constitutively lower expressions of CD54 on primary myeloma cells and their different localizations in bone marrow.

To evaluate nuclear factor-kappaB (NF-kappaB) activity in primary myeloma cells from myeloma patients, we confirmed that the expression levels of CD54 showed a good correlation with the levels of DNA binding activity for NF-kappaB in human myeloma cell lines, and thus analyzed the expression levels of CD54 on CD38(++) plasma cell fractions as one of NF-kappaB activity. Primary myeloma cells unexpectedly showed constitutively lower expressions of CD54 than normal bone marrow (BM) plasma cells. Furthermore, the expression levels of CD54 on these plasma cells showed a significant correlation with the plasma levels of CXCL12 stromal cell-derived factor-1alpha (SDF-1alpha) in their BM aspirates, and the expressions of CXCR4, the receptor for CXCL12, decreased on primary myeloma cells compared with normal BM plasma cells. It was also confirmed that the addition of CXCL12 to the in vitro culture significantly induced the up-regulation of CD54 expression in primary myeloma cells. In addition, myeloma cells with lower expressions of CD54 were more unstable in the in vitro culture, resulting in a marked reduction of the viable cell number. In the immunohistochemical analysis of BM aspirates, myeloma cells with lower CD54 expression resided in the perivascular regions. Therefore, these data suggest that primary myeloma cells exhibit constitutively lower CD54 that might be partially regulated by CXCL12, and their localizations in the BM may be associated with the expression levels of CD54.

Increased serum levels of matrix metalloproteinase-9 in acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Matrix metalloproteinases (MMPs) have been implicated in a variety of normal and pathological conditions that involve matrix degradation and remodelling. We investigated the role of MMPs in acute graft-versus-host disease (aGVHD) in 29 patients who had undergone allogeneic haematopoietic stem cell transplantation. The present study showed that the serum levels of MMP-9, but not those of MMP-2, significantly correlated with the occurrence and severity of aGVHD. Moreover, immunohistochemical analysis of the cutaneous lesions of patients with aGVHD revealed an increased number of inflammatory cells positive for MMP-9. These results suggest that MMP-9 might play an important role in the pathogenesis of aGVHD.

Risk of concomitant carcinoma in situ determining biopsy candidates among primary non-muscle-invasive bladder cancer patients: retrospective analysis of 173 Japanese cases.

OBJECTIVES: To determine candidates for bladder biopsies among Japanese primary non-muscle-invasive bladder cancer patients according to the risk of concomitant carcinoma in situ (CIS). METHODS: Between January 1992 and August 2006, 173 primary non-muscle-invasive bladder cancer cases underwent transurethral resection of the bladder tumor with bladder biopsies for the detection of CIS. Correlations between biopsy results and preoperative/pathological features were retrospectively analyzed. RESULTS: Positive cytology was statistically associated with the presence of concomitant CIS in multivariate analysis (P < 0.01). Abnormal cystoscopic appearance outside the tumor almost achieved statistical significance in multivariate analysis among preoperative factors (P = 0.06). In our series, one (12.5%) of eight low-risk, 18 (24.7%) of 73 intermediate-risk and 41 (59.4%) of 69 high-risk cases had CIS in normal-looking sites, respectively. In cases with a single papillary tumor and negative cytology, one of 16 (6.3%) had concomitant CIS in their biopsy specimens at the normal-looking sites. CONCLUSIONS: All non-muscle-invasive bladder cancer patients with positive cytology are candidates for additional random biopsies. Targeted biopsies should be performed for all suspicious areas in the bladder mucosa. Random biopsies should be considered in cases with the macroscopic types of cancer for predicting intermediate- and high-risk cancer.

Discrepancies between cytology, cystoscopy and biopsy in bladder cancer detection after Bacille Calmette-Guerin intravesical therapy.

OBJECTIVES: To evaluate discrepancies in the detection of Bacille Calmette-Guerin (BCG)-resistant bladder cancer by cystoscopy, bladder biopsy and urinary cytology. METHODS: Between January 1992 and August 2006, 127 bladder cancer patients underwent a cycle of eight weekly BCG instillations. Four weeks after the last BCG instillation, urinary cytological analysis and cystoscopy with targeted biopsy in addition to eight-nine selected-site biopsies were performed. RESULTS: Biopsy-proven cancer was found in 11/27 (40.7%), 5/42 (11.9%), and 11/58 (19.0%) of positive, suspicious, and negative cytology cases, respectively. Abnormal and normal cystoscopic findings correlated with a biopsy-proven cancer in 13/53 (24.5%) and 14/74 (18.9%) cases, respectively. The combination of a macroscopic cystoscopic suspicion and a positive cytology missed malignant cases in 15.9% of the cases. In 100 cases without biopsy-proven cancer, the rates of denuded urothelium at biopsy in the cases with positive and non-positive cytology were 7/16 (43.8%) and 16/84 (19.0%), respectively. CONCLUSIONS: According to our study, routine biopsy is recommended in the evaluation of BCG treatment, even if the timing, limitations and disadvantages of the procedure should be taken into account.