A solitary rod-shaped intertrabecular metastasis in the femur.

Intertrabecular metastasis (ITM) is a type of bone metastasis characterized by tumour growth without significant trabecular changes. ITM is most commonly found in vertebral bodies, and rarely in long bones. We report a solitary rod-shaped ITM of lung adenocarcinoma in the femur.

In-depth proteomics reveals the characteristic developmental profiles of early lung adenocarcinoma with epidermal growth factor receptor mutation.

INTRODUCTION: Lung adenocarcinoma progresses stepwise from atypical adenomatous hyperplasia to adenocarcinoma in situ (AIS), followed by minimally invasive adenocarcinoma (MIA), and then obvious invasive adenocarcinoma. In this study, we examined the protein expression profiles of early and epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinomas. METHODS: Fifteen cases of small and EGFR mutation-positive adenocarcinomas were collected, including AIS, MIA, and small invasive adenocarcinoma (SIA). We examined their protein expression profiles by tandem mass tag (TMT)-labeling liquid chromatography-mass spectrometry (LC-MS/MS) and compared the results between AIS and MIA versus SIA. The differentially expressed proteins were then verified by Western blot analysis and immunohistochemistry (IHC). The clinicopathological implications of the proteins were also examined by IHC. RESULTS: A total of 4220 proteins were identified by LC-MS/MS analysis. Pathway analysis of the differentially expressed proteins revealed that pathways related to interferon α/ß signaling, glutamate and glutamine metabolism, and gluconeogenesis were upregulated in SIA relative to AIS. Among the 13 differentially expressed proteins, cellular retinoic acid binding protein 2 (CRABP2), delta(24)-sterol reductase (DHCR24), and adenylate kinase 4 (AK4) were expressed significantly more strongly in SIA than in AIS. Patients with high expression of CRABP2, DHCR24, and AK4 showed a significantly poorer outcome than those with low expression. CONCLUSION: In comparison with AIS, SIA shows differences in several different protein expression pathways. Furthermore, CRABP2, DHCR24, and AK4 are useful IHC markers for diagnosis of lung adenocarcinoma invasiveness and may be associated with malignant progression of AIS.

The prognostic significance of N-myc downregulated gene 1 in lung adenocarcinoma.

It has been reported that N-myc downstream regulated gene 1 (NDRG1) is related to the prognosis of non-small cell lung cancer (NSCLC), and associated with c-Myc degradation in NSCLC cell lines. However, the relationship of NDRG1 to prognosis or c-Myc expression in lung adenocarcinoma has not been well clarified. The present study was designed to investigate the prognostic significance of NDRG1 and/or c-Myc expression in lung adenocarcinoma using immunohistochemistry with a tissue microarray. We examined 184 lung adenocarcinomas and observed low expression of NDRG1 in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), whereas high expression of NDRG1 was seen in invasive adenocarcinoma. Each of the clinicopathological features except age was significantly correlated with NDRG1 expression. Kaplan-Meier curves indicated that high expression of NDRG1 was significantly correlated with poor prognosis in comparison with low expression (log-rank, P < 0.001). Univariate and multivariate analyses indicated that vascular invasion (P = 0.012), lymphatic permeation (P = 0.038), and NDRG1 expression (P = 0.026) were independent prognostic factors. Expression of NDRG1 and positivity for c-Myc were significantly correlated (P = 0.005). These findings indicate that NDRG1 expression is associated with both prognosis and c-Myc expression in lung adenocarcinoma.

[A Case of Gastrointestinal Metastases of Breast Cancer Effectively Treated with Gemcitabine and Paclitaxel Combination Chemotherapy].

A 55-year-old woman was admitted to our hospital complaining of constipation and abdominal distention. She had a history of right breast surgery for cancer at the age of 48 years. An abdominalCT scan revealed tumors at the antrum of the stomach and the ascending colon, and the tumor at the ascending colon caused obstruction of the colon. She was diagnosed with breast cancer recurrence and was administered combination chemotherapy consisting of gemcitabine and paclitaxel. Ileus improved after this treatment, and she was discharged from the hospital and was able to receive outpatient chemotherapy. After 8 months, she experienced symptoms of ileus again, and conservative treatment was considered impossible. Therefore, she underwent distal gastrectomy and right hemicolectomy. Histological and immunohistological analyses confirmed that the tumors were breast cancer metastases. Chemotherapy with gemcitabine and paclitaxel helped our patient to return to daily life and improved her prognosis.

Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.

Somatic hypermethylation of the O6-methylguanine-DNA methyltransferase gene (MGMT) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing. No significant association of MGMT methylation with G > A mutations in KRAS, TP53 or in the whole exome was found (p > 0.5 in all comparisons). The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas (TCGA) consortium dataset. Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic. We also found a significant clustering (p = 0.001) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients. This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci, including MGMT or ADAMTS14, that may lead to predictive biomarkers for CRC. Methylation of these loci in normal mucosa was more frequent in elder (p = 0.001) patients, and particularly in African Americans (p = 1 × 10-5), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.

Collagenous gastroduodenitis coexisting repeated Dieulafoy ulcer: A case report and review of collagenous gastritis and gastroduodenitis without colonic involvement.

Collagenous gastritis (CG) is a rare disorder characterized by the thick collagenous subepithelial bands associated with mucosal inflammation. There have been approximately fifty reports in the literature since it was first described in 1989. According to previous reports, CG is heterogeneous and classified into two groups-(1) cases limited to the gastric mucosa in children or young adults, and (2) CG associated with collagenous colitis in elderly adults presenting with chronic watery diarrhea. In Japan, only nine previous cases were reported, and all of them were young adults. We report a case of CG with collagenous duodenitis in a 22-year-old female. She had repeated upper gastrointestinal bleeding from a Dieulafoy lesion of the fornix, but had no symptoms of malabsorption or diarrhea. Endoscopic findings revealed striking nodularity with a smooth islet-shaped normal area in the antrum and the body. The pathological findings of nodular mucosa showed the deposition of collagen bands just under the mucoepithelial lesion. In addition, she had collagenous duodenitis in part of the bulbs, and a colonoscopy showed no abnormalities. We provide a literature review of CG and collagenous gastroduodenitis without colonic involvement.

[Two cases of ileocecal carcinoid found by total colonoscopy and a review of the literature on 16 cases].

We report 2 cases of ileocecal carcinoid with review of the literature recently reported in Japan. Both cases were diagnosed as carcinoid by colonoscopic biopsy after ileocecal tumors had been pointed out by computed tomography. We performed curative operation with lymph node dissection. Since multiple lymph node metastases were shown in both cases pathologically, they were closely followed after surgery, but no recurrence has been shown. Since SSTR2a stain was strongly positive in both cases, octreotide, the effectiveness of which was verified in the PROMID study might be administered if necessary. As ileocecal carcinoid has a tendency to metastasize to other organs, careful surveillance by colonoscopy and early detection are required. Furthermore, development of effective drugs following octreotide and further investigation including biological and histopathological analysis of neuroendocrine tumors including carcinoid are necessary.

Down-regulation of epidermal growth factor receptor by selective expansion of a 5'-end regulatory dinucleotide repeat in colon cancer with microsatellite instability.

PURPOSE: The epidermal growth factor receptor (EGFR) is overexpressed in several tumor types, and its expression is influenced by the length of a 5'-end microsatellite repeat (CA)n: the longer the repeat, the lower the expression. Dinucleotide repeats accumulate insertion/deletion types of mutations in tumors with microsatellite instability. We designed this study to estimate the occurrence of these mutations in EGFR(CA)n and their relevance in carcinogenesis of microsatellite instability-positive colon and gastric tumors. EXPERIMENTAL DESIGN: We analyzed the frequency of EGFR(CA)n mutations in vivo in 55 colorectal and 14 gastric microsatellite instability-positive cancers, and in vitro in single-cell clone cultures of microsatellite instability-positive colon tumor cell line LS174. Single-cell clone cultures with different repeat lengths were analyzed by fluorescent-activated cell sorter for EGFR cell-surface expression. A correlation analysis was done between EGFR(CA)n mutations and mutations in KRAS, BRAF, and p53. RESULTS: Unlike single-cell clone cultures, which exhibited higher rate of deletions compared with insertions, most of EGFR(CA)n mutations in colon and gastric tumors were insertions. Longer EGFR(CA)n correlated with lower EGFR cell-surface expression in single-cell clone cultures. In colon cancers, the elongation of the repeat was associated negatively with mutations in KRAS and BRAF, but not in p53. CONCLUSIONS: The EGFR(CA)n elongation observed in tumors cannot be explained by an intrinsic property of this repeat favoring insertions versus deletions. Instead, a selection for repeat elongation occurs in microsatellite instability-positive tumors, leading to EGFR down-regulation. These findings suggest that in microsatellite instability-positive tumors current therapies targeting EGFR overexpression may have either no effect or an opposite to the expected effect.

Solitary peripheral ciliated glandular papillomas of the lung: a report of 3 cases.

We report 3 cases of solitary papillomas located in peripheral regions of the lung that are extremely rare in the literature. The patients were 75-year-old and 72-year-old men and a 53-year-old woman. One patient complained of recurrent hemoptysis. The other 2 had no symptoms, but abnormal nodular shadows were revealed by chest radiographs during a health check. The maximum diameters of the tumors were 1.0, 1.4, and 1.1 cm, respectively. The 3 tumors gave almost the same histologic findings. Papillomatous fronds lined by a stratified columnar epithelium were seen in the lumens of peripheral bronchi, bronchioles, or alveoli. The stratified columnar epithelium consisted of ciliated, mucous, and basal cells. The neoplastic epithelium extended to the alveolar region and showed a similar appearance to bronchioloalveolar or papillary type adenocarcinomas. For differential diagnosis, it is noteworthy that endobronchiolar papillomatous fronds constantly exist and spreading along alveolar walls is limited in adjacent alveoli in peripheral papillomas. The presence of ciliated cells and basal cells is considered an important finding to suggest benign character of the lesion.

Genetics supersedes epigenetics in colon cancer phenotype.

A CpG island DNA methylator phenotype has been postulated to explain silencing of the hMLH1 DNA mismatch repair gene in cancer of the microsatellite mutator phenotype. To evaluate this model, we analyzed methylation in CpG islands from six mutator and suppressor genes, and thirty random genomic sites, in a panel of colorectal cancers. Tumor-specific somatic hypermethylation was a widespread age-dependent process that followed a normal Gaussian distribution. Because there was no discontinuity in methylation rate, our results challenge the methylator phenotype hypothesis and its hypothetical pathological underlying defect. We also show that the mutator phenotype dominates over the gradual accumulation of DNA hypermethylation in determining the genotypic features that govern the phenotypic peculiarities of colon cancer of the mutator pathway.

Low mutation incidence in polymorphic noncoding short mononucleotide repeats in gastrointestinal cancer of the microsatellite mutator phenotype pathway.

Frameshifts in short mononucleotide tracts (SMT) in genes, such as TGFbetaRII and BAX, are common in gastrointestinal tumors of the microsatellite mutator phenotype (MMP). The significance of less common mutations has been recently challenged because frequencies as high as 50% were reported in some noncoding SMTs in MMP colon cancer cell lines (L. Zhang, et al., Cancer Res., 61: 3801-3805, 2001). We did not confirm these findings after examining >50 MMP gastrointestinal cancers for mutations in eight SMT loci with the highest reported frequencies. In three of these loci, no clonal mutations were detected, and they were infrequent (2.9-6.7%) in the other five. Length polymorphisms are frequent (25.7-43.9%) in one-half of these SMTs, suggesting an explanation for the discrepancy. Because of the peculiar features of MMP tumors, low prevalence of mutations in cancer genes may not be a disqualifying criterion for their functionality.