Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity

AIM: To evaluate the role of N-myc downstream-regulated gene 1 (NDRG1) expression in prognosis and survival of colorectal cancer patients with different ethnic backgrounds. METHODS: Because NDRG1 is a downstream target of p53 and hypoxia inducible factor-1α (HIF-1α),we examined NDRG1 expression together with p53 and HIF-1α by immunohistochemistry. A total of 157 colorectal cancer specimens including 80 from Japanese patients and 77 from US patients were examined. The correlation between protein expression with clinicopathological features and survival after surgery was analyzed.in colorectal tumor compared with normal epithelium in both Japanese and US patient groups. Expression of NDRG1 protein was significantly correlated with lymphatic invasion,venous invasion,depth of invasion,histopathological type,and Dukes' stage in Japanese colorectal cancer patients. NDRG1 expression was correlated to histopathological type,Dukes' stage and HIF-1α expression in US-Caucasian patients but not in US-African American patients. Interestingly,Kaplan-Meier survival analysis demonstrated that NDRG1 expression correlated significantly with poorer survival in US-African American patients but not in other patient groups. However,in p53-positive US cases,NDRG1 positivity correlated significantly with better survival. In addition,NDRG1 expression also correlated significantly with improved survival in US patients with stages Ⅲ and Ⅳ tumors without chemotherapy. In Japanese patients with stages Ⅱ and Ⅲ tumors,strong NDRG1 staining in p53-positive tumors correlated significantly with improved survival but negatively in patients without chemotherapy. CONCLUSION: NDRG1 expression was correlated with various clinicopathological features and clinical outcomes in colorectal cancer depending on the race/ethnicity of the patients. NDRG1 may serve as a biological basis for the disparity of clinical outcomes of colorectal cancer patients with different ethnic backgrounds.     

Eigenspace Template Matching for Detection of Lacunar Infarcts on MR Images

Detection of lacunar infarcts is important because their presence indicates an increased risk of severe cerebral infarction. However, accurate identification is often hindered by the difficulty in distinguishing between lacunar infarcts and enlarged Virchow-Robin spaces. Therefore, we developed a computer-aided detection (CAD) scheme for the detection of lacunar infarcts. Although our previous CAD method indicated a sensitivity of 96.8 % with 0.71 false positives (FPs) per slice, further reduction of FPs remained an issue for the clinical application. Thus, the purpose of this study is to improve our CAD scheme by using template matching in the eigenspace. Conventional template matching is useful for the reduction of FPs, but it has the following two pitfalls: (1) It needs to maintain a large number of templates to improve the detection performance, and (2) calculation of the cross-correlation coefficient with these templates is time consuming. To solve these problems, we used template matching in the lower dimension space made by a principal component analysis. Our database comprised 1,143 T₁- and T₂-weighted images obtained from 132 patients. The proposed method was evaluated by using twofold cross-validation. By using this method, 34.1 % of FPs was eliminated compared with our previous method. The final performance indicated that the sensitivity of the detection of lacunar infarcts was 96.8 % with 0.47 FPs per slice. Therefore, the modified CAD scheme could improve FP rate without a significant reduction in the true positive rate.     

An inducible lambdoid prophage encoding cytolethal distending toxin (Cdt-I) and a type III effector protein in enteropathogenic Escherichia coli

Cytolethal distending toxins (CDTs) are inhibitory cyclomodulins, which block eukaryotic cell proliferation and are produced by a diverse group of Gram-negative bacteria, including Escherichia coli strains associated with intestinal and extraintestinal infections. However, the mode of transmission of the toxin gene clusters among diverse bacterial pathogens is unclear. We found that Cdt-I produced by enteropathogenic E. coli strains associated with diarrhea is encoded by a lambdoid prophage, which is inducible and infectious. The genome of Cdt-I converting phage (CDT-1Phi) comprises 47,021 nucleotides with 60 predicted ORFs organized into six genomic regions encoding the head and tail, virulence, integrase, unknown functions, regulation, and lysis. The genomic organization of CDT-1Phi is similar to those of SfV, a serotype-converting phage of Shigella flexneri, and UTI89, a prophage identified in uropathogenic E. coli. Besides the cdtI gene cluster, the virulence region of CDT-1Phi genome contains sequences homologous to a truncated cycle inhibiting factor and a type 3 effector protein. Mutation analysis of susceptible E. coli strain C600 suggested that the outer membrane protein OmpC is a putative receptor for CDT-1Phi. CDT-1Phi genome was also found to integrate into the host bacterial chromosome forming lysogens, which produced biologically active Cdt-I. Furthermore, phage induction appeared to cause enhanced toxigenicity of the E. coli strains carrying lysogenic CDT-1Phi. Our results suggest that CDT-1Phi is the latest member of a growing family of lambdoid phages encoding bacterial cyclomodulins and that the phage may have a role in horizontal transfer of these virulence genes.     

Dipylidium caninum infection in an infant

Dipylidium caninum, the dog tapeworm, is a common intestinal cestode of domestic dogs and cats, but few cases have been reported of human infection by this parasite in Japan. We repot a case of D. caninum infection in a 17 month-old girl, who sometimes had symptoms of abdominal pain, diarrhea, and dysphoria at night. Her mother noted the appearance of small white worms in her stool, and she was seen by a local pediatrician. Despite antiparasitic therapy wiht pyrantel pamoate, the problem persisted and was eventually referred for further workup to Kurume University Hospital. The diagnosis was made by microscopic examination of the excreted proglottids, which contained characteristic egg capsules. She was successfully treated with a singledose of praziquantel and four adult parasites were recovered. The longest intact worm was 32cm. Her family had household pets (a dog and a cat). The pets were seen by the local veterinary and both were evidenced D. caninum. Humans, primarily children, become infected when they accidentally ingest fleas. Parents usually find proglottids as multiple white objects, often described as cucumber, melon, or pumpkin seeds, in stool, diapers, or on the perineum. Most general practitioners and pediatricians may treat children with enterobiasis (pinworm) infection, and in case the treatment fails, other parasite infection should be considered such as this worm. A history of dog or cat pets, fleas, and flea bites may be important clues to diagnosis. Pets found to be infected should also be treated.     

Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome

A role for gamma-aminobutyric acid (GABA)ergic inhibition in cortical sensory processing is one of the principle concerns of brain research. Angelman syndrome (AS) is thought to be one of the few neurodevelopmental disorders with GABAergic-related genetic involvement. AS results from a functional deficit of the imprinted UBE3A gene, located at 15q11-q13, resulting mainly from a 4-Mb deletion that includes GABA(A) receptor subunit genes. These genes are believed to affect the GABAergic system and modulate the clinical severity of AS. To understand the underlying cortical dysfunction, we have investigated the primary somatosensory-evoked responses in AS patients. Subjects included eleven AS patients with a 15q11-q13 deletion (AS Del), two AS patients without a 15q11-q13 deletion, but with a UBE3A mutation (AS non-Del), six epilepsy patients (non-AS) and eleven normal control subjects. Somatosensory-evoked fields (SEFs) in response to median nerve stimulation were measured by magnetoencephalography. The N1m peak latency in AS Del patients was significantly longer (34.6+/-4.8 ms) than in non-AS patients (19.5+/-1.2 ms, P<0.001) or normal control subjects (18.4+/-1.8 ms, P<0.001). The next component, P1m, was prolonged and ambiguous and was only detected in patients taking clonazepam. In contrast, SEF waveforms of AS non-Del patients were similar to those of control individuals, rather than to AS Del patients. Thus, GABAergic dysfunction in AS Del patients is likely due to hemizygosity of GABA(A) receptor subunit genes, suggesting that GABAergic inhibition plays an important role in synchronous activity of human sensory systems.     

Predictive value of QT dispersion for acute heart failure after autologous and allogeneic hematopoietic stem cell transplantation

The aim of our study was to evaluate whether corrected QT dispersion (QTc dispersion), an electrocardiographic marker, is a good predictor of the development of acute heart failure after high-dose chemotherapy followed by autologous or allogeneic hematopoietic stem cell transplantation. We enrolled 50 consecutive patients, from age 15 to 63 years, with hematopoietic diseases scheduled to undergo autologous or allogeneic hematopoietic stem cell transplantation, and compared QTc dispersion with other markers before transplantation conditioning. In univariate logistic analysis, QTc dispersion was a significant factor for acute heart failure after hematopoietic stem cell transplantation (odds ratio, 3.7 per 10 msec; confidence interval, 1.6-8.5; P = 0.002). There were no significant differences as age, sex, systolic or diastolic echocardiographic function markers, cumulative anthracycline dose, or QTc before transplantation between patients with and without acute heart failure. After multiple adjustments for left ventricular ejection fraction, cumulative anthracycline dose, cyclophosphamide conditioning dose, QTc dispersion was a significant and independent factor for acute heart failure after hematopoietic stem cell transplantation (odds ratio, 48.0 per 10 msec; confidence interval, 1.4-1666.3; P = 0.03). This study demonstrated that QTc dispersion could be used as a powerful noninvasive predictor of the development of acute heart failure after hematopoietic stem cell transplantation.