Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome.

Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2KD/KDEzh2Δ/Δ). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2. Hyper-differentially methylated regions (hyper-DMRs) in Tet2KD/KDEzh2Δ/Δ MDS hematopoietic stem/progenitor cells were largely distinct from those in each single mutant and correlated with transcriptional repression. Although Tet2 hypomorph was responsible for enhancer hypermethylation, the loss of Ezh2 induced hyper-DMRs that were enriched for CpG islands of polycomb targets. Notably, Ezh2 targets largely lost the H3K27me3 mark while acquiring a significantly higher level of DNA methylation than Ezh1 targets that retained the mark. These findings indicate that Ezh2 targets are the major targets of the epigenetic switch in MDS with Ezh2 insufficiency. Our results provide a detailed trail for the epigenetic drift in a well-defined MDS model and demonstrate that the combined dysfunction of epigenetic regulators cooperatively remodels the epigenome in the pathogenesis of MDS.

Successful treatment of cytomegalovirus enteritis after unrelated allogeneic stem cell transplantation by the infusion of ex vivo-expanded CD4+ lymphocytes derived from the recipient's peripheral blood donor cells.

Adoptive immunotherapies have been developed for antiviral agent-refractory cytomegalovirus (CMV) disease after stem cell transplantation (SCT). However, the application of such strategies is limited, particularly in terms of need for donor cooperation regarding blood sampling and inaccessibility in the setting of cord blood transplantation. Herein, we describe the first successful treatment of antiviral agent-refractory CMV enteritis after allogeneic SCT by the infusion of ex vivo-expanded donor-derived CD4(+) lymphocytes obtained from the recipient's peripheral blood.

Comparison of preoperative whole-body positron emission tomography with MDCT in patients with primary colorectal cancer.

OBJECTIVE: Preoperative use of emission tomography with(18)F-fluorodeoxyglucose (FDG-PET) in patients with primary colorectal cancer remains controversial. This study evaluated the additional value of FDG-PET in comparison with routine multidetector row computed tomography (MDCT) in patients with primary colorectal cancer. METHOD: Retrospective analysis was performed in 65 patients with colorectal cancer who underwent whole-body FDG-PET. Results of FDG-PET were compared with routine preoperative evaluation by MDCT regarding detection of primary tumour, lymph node involvement and distant metastases. All images were evaluated before surgery. RESULTS: Tumour detection rate was 100% (63/63) for MDCT and 98% (62/63) for FDG-PET. Lymph node involvement was pathologically confirmed in 35 patients. MDCT and FDG-PET displayed sensitivities of 89% (31/35; 95% CI: 73-97%) and 43% (15/35; 95% CI: 26-61%) and specificities of 52% (11/21; 95% CI: 30-74%) and 95% (20/21; 95% CI: 76-100%), respectively. Liver metastases were present in 22 patients. MDCT and FDG-PET showed accuracies of 98% (64/65; 95% CI: 92-100%) and 97% (63/65; 95% CI: 89-100%), respectively. FDG-PET detected additional extrahepatic metastatic lesions and affected treatment plan compared with MDCT in 10 patients. CONCLUSION: Preoperative FDG-PET is not superior to MDCT for detection of primary tumour, lymph node involvement or liver metastases, but may have potential clinical value in patients with advanced colorectal cancer by detecting extrahepatic distant metastases.

Effect of bilateral sagittal split ramus osteotomy setback on the soft palate and pharyngeal airway space.

To evaluate the effect of bilateral sagittal split ramus osteotomy setback on the morphology of the pharyngeal airway, especially the structures of the soft palate and pharyngeal airway space (PAS), lateral cephalograms obtained from 49 women before treatment and 1 year after surgery were traced and compared. All patients underwent this osteotomy to correct mandibular hyperplasia. The data were corrected with the use of regression equations for the PAS, taking into account head posture. On average, the SNB angle decreased by 3.9 degrees, resulting in an increase of 4.1 degrees in OPT/NSL (head posture, defined as the craniocervical angulation at the uppermost part of the cervical spine). The morphology of the PAS and soft palate changed significantly (p<0.01). The mean reduction in the PAS was 2.6mm retropalatinally and 4.0mm retrolingually. On average, the soft-palate length increased by 3.2mm and the soft-palate angle increased by 4 degrees. These results show that mandibular setback surgery markedly decreases the PAS and changes the morphology of the soft palate.

A cephalometric evaluation of the pharyngeal airway space in patients with mandibular retrognathia and prognathia, and normal subjects.

The antero-posterior diameter of the pharyngeal airway space (PAS) at the level of the soft palate and base of the tongue was assessed in age-matched females with a normal mandible (n=31), mandibular retrognathism (n=30) or mandibular prognathism (n=38). All subjects were examined by lateral cephalometry. Measured variables were corrected with the use of appropriate regression equations to eliminate the effects of head posture on the PAS. The corrected data showed more clear-cut differences in the PAS among the three groups than did the measured data. Pharyngeal airway diameter was largest in the group with mandibular prognathism, followed by the normal mandible and mandibular retrognathism groups. These results indicate that the antero-posterior dimension of the PAS is affected by different skeletal patterns of the mandible.

The significance of the aberrant left hepatic artery arising from the left gastric artery at curative gastrectomy for gastric cancer.

BACKGROUND: An aberrant left hepatic artery (ALHA) is occasionally encountered during esophagogastric surgery. However, at curative gastrectomy for gastric cancer, it is questionable as to whether the ALHA need to be divided in order to maximize lymph node clearance and the issue requires clarification. METHODS: We encountered 50 patients with an ALHA during curative gastrectomy for gastric cancer between 1997 and 2001. Data concerning operative feasibility, postoperative liver function and therapeutic value of nodal dissection were analyzed retrospectively. RESULTS: For 27 patients, we preserved the ALHA, and for the remaining 23 patients, we divided the ALHA at the origin of the left gastric artery (LGA). Serum levels of aspartate aminotransferase and alanine aminotransferase were statistically significant higher on postoperative day (POD) 1 (P=0.0008 and P=0.0007), and on POD 3 (P=0.001 and P=0.008), respectively, in the ALHA-divided group. Patients who underwent a total gastrectomy predominated in the ALHA-divided group, the total number of dissected lymph nodes being higher in the ALHA-divided group (P=0.018). However, the total numbers of dissected lymph nodes and metastatic lymph nodes around the LGA were similar in the 2 groups (P=0.447 and P=0.128), respectively. No significant differences were seen between the 2 groups in morbidity and mortality. The overall 5-year survival rates were also comparable. CONCLUSIONS: Although a prospective study is required, this study suggested that routine division of the ALHA may not always be required for curative gastrectomy.

Surgical management of only hearing ears with positive indications.

Positive surgical indications for an only hearing ear were evaluated in order to improve patients' quality of life. Fifteen cases of surgery involving an only hearing ear over the past eight years were retrospectively reviewed. Of eight perforated chronic otitis media cases, seven underwent type one tympanoplasty and one underwent simple underlay myringoplasty regardless of otorrhoea at the time of surgery. Of six cholesteatoma cases, two received the canal wall up method and four received the canal wall down method. Ossiculoplasty was carefully performed in six cases. Hearing was improved in seven cases, whereas it remained unchanged in seven cases and deteriorated in one case. Of nine patients, two did not need a hearing aid after surgery. Five patients with severe combined hearing loss (>90 dB) were able to communicate with a hearing aid, alleviating their anxiety regarding hearing loss. Only hearing ears with chronic otitis media and cholesteatoma can be successfully treated by tympanoplasty with or without ossiculoplasty.

Clinical outcome of high segmental gastrectomy for early gastric cancer in the upper third of the stomach.

BACKGROUND: Reflux oesophagitis is commonly encountered in the surgical treatment of cancer of the upper third of the stomach. The aim of this study was to describe a novel surgical technique and evaluate the clinical outcome of high segmental gastrectomy for early-stage proximal gastric cancer. METHODS: Thirty consecutive patients with early gastric cancer located in the upper third of the stomach were included, of whom 12 underwent high segmental gastrectomy and 18 underwent proximal gastrectomy with jejunal interposition. The incidence of reflux oesophagitis and nutritional parameters were compared between the two groups at 1 year after operation. RESULTS: One patient had mild reflux symptoms and two had endoscopic evidence of oesophagitis 1 year after high segmental gastrectomy. Half of the patients who had proximal gastrectomy had reflux symptoms of varying severity and 14 had endoscopic evidence of oesophageal changes at 1 year after surgery. There were significant differences between groups in the incidence of reflux symptoms (P = 0.016) and endoscopically detected gastro-oesophagitis (P < 0.001). There were no adverse events in either group, and the survival rate after high segmental gastrectomy appeared favourable. CONCLUSION: Selected patients with early-stage proximal gastric cancer benefit from high segmental gastrectomy in terms of reduced reflex oesophagitis, without jeopardizing curability.

Relationship between the pharyngeal airway space and craniofacial morphology, taking into account head posture.

This study assessed the relationship between craniofacial characteristics and the size of the pharyngeal airway space (PAS), taking into account head posture. Sixty dental students 25-30 years of age (30 men and 30 women) were examined by lateral cephalometry. The data were corrected with the use of appropriate regression equations for the PAS. The PAS significantly correlated with hyoid position, maxillary and mandibular size, maxillary and mandibular prognathism, and mandibular inclination. A large, anteriorly positioned mandible was associated with a large PAS-TP (the most proximal distance between the posterior pharyngeal wall and the tongue base). Uvula length and PNS-Ba (the distance between the most posterior point of the hard palate and the most inferior point of the anterior foramen magnum) correlated with PAS-UP (the most proximal distance between the posterior pharyngeal wall and uvula). Our results suggest that the anteroposterior dimension of the PAS is substantially affected by the size of the enclosure surrounding the PAS, including the maxilla, mandible and soft palate.

Pharyngeal narrowing as a common feature in pycnodysostosis--a cephalometric study.

We report on pycnodysostosis presenting as severe snoring caused by pharyngeal narrowing in two siblings. Cephalograms showed pharyngeal narrowing at the level of the soft palate and the base of the tongue caused by the long soft palate and mandibular hypoplasia. From the literature review and our results, we suggest that respiratory insufficiency such as snoring or obstructed sleep apnea are common and under-appreciated symptoms of pycnodysostosis.

Clinical value of multidetector row computed tomography in detecting lymph node metastasis of early gastric cancer.

AIMS: To evaluate the clinical value of multidetector row computed tomography (MDCT) as a pre-operative staging tool for lymph node metastasis in patients with early gastric cancer (EGC). METHODS: In 278 consecutive patients with EGC, lymph node metastasis was evaluated pre-operatively with MDCT at a slice thickness of 2.5mm (n=57), 5.0mm (n=188), or 7.5mm (n=33). RESULTS: Overall accuracy of nodal category from N0 to N3 was 86% for MDCT and 95% for operative assessment. Regarding accuracy in detecting at least one metastatic lymph node, area under curves (AUC) of receiver operating characteristics for 2.5, 5.0, and 7.5-mm slices and assessment during surgery were 0.87, 0.67 and 0.47, and 0.70, which were significantly different (P<0.0001). MDCT image with 2.5-mm could discriminate the presence of lymph node metastasis with diagnostic accuracy: sensitivity 80%; specificity 92%; positive predictive value (PPV) 50%; negative predictive value (NPV) 98%, whereas assessment during surgery was as follows: sensitivity 65%; specificity 98%; PPV 72%; and NPV 97%. CONCLUSIONS: These results suggest that pre-operative assessment with MDCT using thinner slices may detect at least one lymph node metastasis as accurately as assessment during surgery for patients with EGC.

Incidence and prognostic significance of lateral lymph node metastasis in patients with advanced low rectal cancer.

BACKGROUND: Lateral lymph node metastases occur in some patients with low rectal cancer and may cause local recurrence after total mesorectal excision. The aims of this study were to identify risk factors for lateral node metastases in patients with pathological tumour (pT) stage 3 or pT4 low rectal adenocarcinoma, and to evaluate the prognostic significance of lateral node metastases. METHODS: A retrospective analysis was performed of the outcome of 237 patients with pT3 or pT4 low rectal adenocarcinoma who underwent R0 resection with systematic lateral node dissection. RESULTS: Lateral lymph node metastases were found in 41 patients (17.3 per cent). Increased risk of lateral lymph node metastases was associated with a distal tumour margin close to the anal margin, histological type other than well or moderately differentiated adenocarcinoma, and the presence of mesenteric lymph node metastases. Patients with lateral node metastases had a significantly shorter postoperative survival (5-year survival rate 42 versus 71.6 per cent; P < 0.001) and an increased risk of local recurrence (44 versus 11.7 per cent; P < 0.001) compared with those without lateral node metastases. CONCLUSION: Tumour site, histological type and the presence of mesenteric lymph node metastasis are factors predicting the risk of lateral node metastasis. The poor prognosis of patients with lateral lymph node metastases after systematic lateral dissection suggests the need for adjuvant therapy.

Computed tomographic analysis of the position and course of the mandibular canal: relevance to the sagittal split ramus osteotomy.

The aim of this study was to investigate the position and course of the mandibular canal through the mandibular ramus using computed tomographic (CT) imaging and to relate the findings to performing sagittal split ramus osteotomies. The mandibles of 35 patients with skeletal Class III prognathism with symmetry (12 males and 23 females) were observed on transaxial computed tomograms acquired with a slice thickness of 2 mm. The position and course of the mandibular canal from the mandibular foramen to the mandibular body at the level of the second molar were measured at four specific locations in the same plane. Among the 70 rami examined, lack of a bone marrow space on the buccal side, including a fusion type anatomy with no buccal side cortical bone of the mandibular canal, were observed at the CT location between the mandibular foramen and mandibular angle. Our results suggest that special care must be taken when sagittal splitting is performed, and the safest location for the buccal corticotomy is anterior to the mandibular angle.

Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population.

Patients with long-standing ulcerative colitis (UC) are known to have an increased risk for the development of colorectal cancer (CRC). The aim of this study was to clarify the cumulative risk for the development of dysplasia or invasive cancer and the effectiveness of surveillance colonoscopy in the Japanese population. A total of 217 patients received a total of 1027 surveillance colonoscopies between January 1979 and December 2001 at the University of Tokyo hospital. Patients with invasive cancer found in the surveillance group were compared to those referred to our hospital from the other hospitals without surveillance colonoscopy. Surveillance colonoscopy confirmed 15 patients with definite dysplasia. Of these, five were proved to have invasive cancer in the resected specimens. The cumulative risk for the development of invasive cancer at 10, 20, and 30 years was 0.5, 4.1, and 6.1%, respectively, while that for the development of definite dysplasia at 10, 20, and 30 years was 3.1, 10.0, and 15.6%, respectively. All the patients with invasive cancer in the surveillance group remained alive, while three out of four patients in the nonsurveillance group died. Our surveillance programme is useful for detecting UC-associated CRC, and survival may be improved by surveillance colonoscopy.