World J Gastroenterol 2006 May 28; 12(20): 3155-61 (Read article online)

Roberts KE, Duffy AJ, Bell RL

The immense success of laparoscopic surgery as an effective treatment of gastroesophageal reflux disease (GERD) and achalasia has established minimal invasive surgery as the gold standard for these two conditions with lower morbidity and mortality, shorter hospital stay, faster convalescence, and less postoperative pain. One controversy in the treatment of GERD evolves around laparoscopic antireflux surgery (LARS) as the preferred treatment for Barrett's esophagus and the procedure's potential to reduce the risk of adenocarcinoma of the esophagus. GERD has also been associated with respiratory symptoms, asthma and laryngeal injury, and a second controversy prompts discussions about whether total or partial fundoplication is the more appropriate treatment for GERD. A new and promising alternative in the treatment of GERD is endoluminal therapy. Three types of this new treatment option will be discussed: radiofrequency energy delivered to the lower esophageal sphincter, the creation of a mechanical barrier at the gastroesophageal junction, and the direct endoscopic tightening of the lower esophageal sphincter. Laparoscopic surgery is discussed not only as a very effective treatment for GERD but also as permanent cure for achalasia. This review analyzes the three most important treatment options for achalasia: medications, pneumatic dilatation, and surgical therapy. Medications as the only true non-invasive option in the treatment of achalasia are not as effective as LARS because of their short half-life and variable absorption due to the poor esophageal emptying. The second treatment option, pneumatic dilatation, involves the stretching of the lower esophagus and is still considered the most effective non-surgical treatment for achalasia. Finally, surgical therapy for achalasia and the two major controversies concerning this laparoscopic treatment are discussed. The first involves the extent to which the myotomy is extended onto the stomach, and the second concerns the necessity and type of antireflux procedure to prevent GERD after myotomy. LARS and laparoscopic Heller myotomy are the agreed upon as the gold standards for surgical treatment of GERD and achalasia, respectively. In the hands of an experienced laparoscopic surgeon both are safe and effective treatments for patients with excellent subjective and objective long-term results with at least 90% patient satisfaction.

World J Gastroenterol 2006 May 28; 12(20): 3180-5 (Read article online)

Mulkeen AL, Yoo PS, Cha C

Recently, there has been an increased recognition of neoplasms of the pancreas other than ductal adenocarcinoma. Although not as well studied or characterized as pancreatic adenocarcinoma there are many distinct lesions which exhibit diverse biological behaviors and varying degrees of malignancy. These lesions include: endocrine neoplasms, cystic tumors, solid pseudopapillary tumors, acinar cell carcinoma, squamous cell carcinoma, primary lymphoma of the pancreas, and metastatic lesions to the pancreas. These less common neoplasms are being diagnosed more frequently as the number and sensitivity of diagnostic imaging studies increase. This review article discusses the clinical course, diagnosis, and treatment of these less common, but quite relevant, neoplasms of the pancreas.

Ann Surg Oncol 2006 May 22; (Read article online)

Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW, Tan D, Brattain MG, Javle MM

BACKGROUND: Long-term survival of surgically resectable pancreatic cancer patients is uncommon. The epidermal growth factor receptor (EGFR) and the phosphoinositol-3-kinase pathways are often activated in pancreatic cancer, and an understanding of their role in resected cases may help refine adjuvant therapy. METHODS: We investigated the expression of EGFR, Erk, Akt, and their phosphoforms (p-) in pancreatectomy specimens and correlated these with survival. Thirty-nine consecutive surgically resected pancreatic adenocarcinoma cases were included. Immunohistochemical staining of paraffin-embedded blocks was performed by using monoclonal antibodies against EGFR, Erk, p-Erk, Akt, and p-Akt. A standard immunoperoxidase technique was used to detect the avidin-biotin peroxidase complex. Immunostaining was visually scored with the histoscore method by two surgical pathologists. RESULTS: Patient characteristics were as follows: 17 men and 22 women; median age, 66 years; and American Joint Committee on Cancer stage I, 5 patients; stage II, 4 patients; stage III, 27 patients; and stage IV, 3 patients. The tumor was World Health Organization grade 1 in 4, grade 2 in 17, and grade 3 in 18 cases. Adjuvant therapies were chemotherapy (n = 6), radiotherapy (n = 1), and chemoradiotherapy (n = 17). Immunohistochemistry revealed positive expression of EGFR in 30.8%, Erk in 92.3%, p-Erk in 45.9%, Akt in 71.8%, and p-Akt in 20.5% of cases. On univariate analyses, tumor grade (P = .0098), p-Akt (P = .0003), and p-Erk (P = .0052) expression correlated with survival. On multivariate analyses, age (P = .0002; hazard ratio [HR], 1.8), grade (P = .00318; HR, 3.0), Akt (P = .0433; HR, .4), p-Akt (P = .0002; HR, .2), and p-Erk (P = .0003; HR, 3.5) expression correlated significantly with survival. CONCLUSIONS: p-Erk and p-Akt expression may have prognostic and therapeutic implications in pancreatic cancer.

Kyobu Geka 2006 May; 59(5): 387-91 (Read article online)

Segawa M, Kusajima Y, Saito K

Pleomorphic carcinoma of the lung is a type of carcinoma with spindle and/or giant cells with a poor diagnosis. A 73-year-old male was referred to our hospital because of the pulmonary tumor. Lung biopsy revealed that the tumor was poorly differentiated adenocarcinoma. No distant metastasis were observed by systemic examination. A right middle lobectomy with partial resection of the right upper lobe and lymph node dissection were performed, because the tumor (5.3 x 4.0 x 4.0 cm) was located in peripheral S' and invaded S3 via the interlobular space. Histological findings showed adenocarcinoma comprised of spindle cell components that reacted positively to epithelial membrane antigen (EMA) and no lymph node metastasis. Therefore, he was diagnosed with pleomorphic carcinoma of the lung, pT2N0M0, stage IB. But metastatic lesions newly appeared in the thoracic skin, the liver, the diaphragm, the bilateral adrenal glands, and the retroperitoneal space on the 30th postoperative day. He died of peritonitis and pleuritis on only 60 days after the operation.

Phytother Res 2006 May 23; (Read article online)

Kundaković T, Stanojković T, Juranić Z, Kova�ević N

The cytotoxicity of naphthazarin derivatives isolated from the roots of Onosma arenaria on human cervix adenocarcinoma cells (HeLa) and leukaemia K562 cells, as well on non-malignant peripheral blood mononuclear cells (PBMC) was studied. The results show that beta-hydroxyisovalerylalkannin, acetylalkannin and the pigment fraction exhibited high cytotoxicity in vitro against the tested cell lines, as well the healthy PBMC before or after activation with phytohaemagglutinin. Copyright (c) 2006 John Wiley & Sons, Ltd.

Radiat Med 2006 Feb; 24(2): 150-3 (Read article online)

Beşe NS, Ozgüroğlu M, Dervişoğlu S, Kanberoğlu K, Ober A

Gastric cancer metastatic to skeletal muscle is an unusual entity. Surgery, systemic chemotherapy, or radiotherapy to the metastatic mass can be treatment options for achiving palliation. Case Report: A patient with multiple skeletal muscle metastases that occurred during follow-up after gastrectomy and adjuvant chemo-radiotherapy is reported. Magnetic resonance imaging (MRI) demonstrated soft-tissue masses involving the posterior right paralumbar and posterior left paradorsal muscles. Biopsy showed metastatic infiltrating adenocarcinoma. The patient did not respond to palliative chemotherapy. Palliative radiotherapy was administered to the painful mass. Based on this case, the diagnosis of muscle metastases and treatment options for palliation are discussed.

Kyobu Geka 2006 May; 59(5): 394-8 (Read article online)

Nishida T, Shoji S, Itoh T, Minami K, Akizuki K, Umekawa K, Nishiyama N

A 47-year-old man was admitted to our hospital for treatment of massive hemoptysis. He was intubated and underwent bronchial arterial embolization because of this deteriorating respiratory state and uncontrollable hemoptysis. Computed tomography (CT) of the chest showed a 1-cm nodular shadow in the peripheral apical lobe (S1) of the right lung. He underwent right upper lobectomy for the purpose of preventing re-hemorrhage as well as making the definitive diagnosis of nodular shadow in S1 of the right lung. Intraoperative pathological examination revealed the nodule as adenocarcinoma, and mediastinal lymphadenectomy was added to the right upper lobectomy. The patient recovered uneventfully, and there has been no sign of recurrence for 15 months after the operation.

Korean J Gastroenterol 2006 May; 47(5): 394-6 (Read article online)

Choi SY, Lee JI, Noh TJ, Jang JY, Nam KD, Kim NH, Lee SK, Joo KR, Dong SH, Kim HJ, Kim BH, Chang YW, Chang R

Gastrectomy is known to be a risk factor for adenocarcinoma in remnant stomach. It is suggested that reflux of bile juice or duodenal secretion to remnant stomach induces atrophic gastritis, intestinal metaplasia, and gastric adenocarcinoma. Malignant lymphoma in remnant stomach after gastrectomy is very rare. Only about thirty cases are reported in the world, and there is no case report in Korea. Gastric MALT (mucosa-associated lymphoid tissue) lymphoma is associated with Helicobacter pylori infection but the mechanism of lymphoma development in remnant stomach is still unknown. We report a case of low grade gastric MALT lymphoma of gastric stump after 10 years from partial gastrectomy.

Surg Today 2006; 36(6): 559-62 (Read article online)

Higuchi R, Yamamoto M, Hatori T, Shimizu K, Imai K, Takasaki K

Intrahepatic cholangiocarcinoma (ICC) with lymph node (LN) metastasis is generally associated with a poor prognosis. However, we treated ICC with LN metastasis successfully by surgery and postoperative immunotherapy in a 59-year-old woman. The immunotherapy consisted of CD3-activated T cells and tumor lysate- or peptide-pulsed dendritic cells. Pathological examination confirmed a diagnosis of moderately differentiated adenocarcinoma with LN metastasis and portal vein invasion. The patient has been alive without recurrence for 3 years 6 months since her operation.

World J Gastroenterol 2006 May 14; 12(18): 2958-61 (Read article online)

Boutis AL, Andreadis C, Patakiouta F, Mouratidou D

Breast metastases from gastric cancer are extremely rare. A case report of a 37-year-old female with breast inflammatory invasion and ascites is described. Breast biopsy revealed carcinomatous invasion of the lymphatics from adenocarcinoma cells with signet-ring features. Estrogen (ER) and progesterone receptors (PR) and c-erb-B2 were negative. Upper gastrointestinal endoscopy revealed a prepyloric ulcerative mass. Histopathologic examination of the lesion showed infiltration from a high-grade adenocarcinoma, identical with that of the breast. Immunostaining was positive for cytokeratins CK-7 and CK-20 and CEA and negative for ER and PR. Ascitic fluid cytology was positive for adenocarcinoma cells. Mammography was not diagnostic. Abdominal CT scanning revealed large ovarian masses suggestive of metastases (Krukenberg's tumor). A cisplatin-based regimen was given but no objective response was observed. The patient died six months after initial diagnosis. A review of the literature is performed.

Clin Nucl Med 2006 Jun; 31(6): 355-6 (Read article online)

Sharma R, Bhatnagar P, Mondal A, Sawroop K, Datta M, Kashyap R

Tc-99m sestamibi is known to concentrate in bronchogenic cancer but it lacks the anatomic details for proper management of the patient. Tc-99m MIBI SPECT imaging can detect bronchogenic cancer with high specificity and high positive predictive value. Tc-99m sestamibi SPECT/CT was performed with a gamma camera mounted anatomic x-ray tomography (GMAXT-GE Medical Systems, Millenium VG with Hawkeye). For comparison with GMAXT, additional high-resolution CT of the mediastinum was performed. Correct preoperative localization was achieved. The lesions found on the MIBI scan were found to be located in the right lung. Apart from this, another lesion was noted on the MIBI scan. On fusion images, this lesion was found to be in the right anterior axillary fold. CT-nuclear medicine fusion imaging guided fine needle aspiration cytology done from the lesion in the axillary fold gave a diagnosis of metastatic adenocarcinoma. This was later confirmed by surgical biopsy of the lymph node. Later biopsy reports on bronchoscopy confirmed the lung lesion to be adenocarcinoma.

Clin Nucl Med 2006 Jun; 31(6): 359-360 (Read article online)

Roscoe KJ, Raja S, Tronic B, Dou Y

A 64-year-old woman presented with hoarseness, and her workup revealed an RUL mass. FDG PET revealed a corresponding single hypermetabolic focus in the RUL with additional thyroid-hypermetabolic focus. The RUL mass resection revealed a primary lung, moderately differentiated scarring adenocarcinoma. Contained within the RUL mass were multiple foci of metastatic papillary thyroid carcinoma. Subsequent thyroid resection revealed papillary thyroid carcinoma of identical histology. This is a rare report of a single positive FDG PET focus containing metastatic papillary thyroid within a primary lung cancer. This case highlights the necessity of histologic confirmation of FDG PET-positive lesions in subsequent patient management.

Eur Arch Otorhinolaryngol 2006 May 23; (Read article online)

Barbeaux A, Duck L, Weynand B, Desuter G, Hamoir M, Gregoire V, Baurain JF, Machiels JP

Combined small cell carcinoma (SMCC) of the larynx consists of SMCC admixed with a component of squamous cell carcinoma or adenocarcinoma. These tumors are very rare and, to date, only a few cases have been fully described. This points out the lack of information available about the correct management of these patients. Here, we describe two additional cases of combined SMCC of the larynx that illustrate the difficulties that we can encounter to diagnose correctly these patients and, by consequence, to treat them adequately.

Oncogene 2006 May 22; (Read article online)

Rodrigues S, Rodrigue CM, Attoub S, Fléjou JF, Bruyneel E, Bracke M, Emami S, Gespach C

TFF1 is overexpressed in inflammatory diseases and human cancers of the digestive and urogenital systems. To examine the transforming potential of TFF1 in human colon epithelial cells, premalignant PC/AA/C1 adenoma cells (PC) derived from a patient with familial adenomatous polyposis (FAP) were transformed by the TFF1 cDNA and used as a model of the adenoma-carcinoma transition. Constitutive expression of TFF1 increased anchorage-independent cell growth in soft agar, and induced or potentiated the growth of colon PC-TFF1 and kidney MDCKts.src-TFF1 tumor xenografts in athymic mice. This resulted in reduction of thapsigargin-induced apoptosis and promotion of collagen type I invasion through several oncogenic pathways. Using the differential display approach to identify TFF1 target genes, we found that the dual specific phosphatases Cdc25A and B implicated in cell cycle transitions are strongly upregulated under active forms in both PC-TFF1 and HCT8/S11-TFF1 colon cancer cells. Accordingly, TFF1 expression is absent in normal human colon crypts but is induced in correlation with Cdc25a and b transcript levels and tumor grade in familial and sporadic colon adenomas and carcinomas. We propose that TFF1 and Cdc25A-B cooperate with other dominant oncogenic pathways to induce the adenoma and adenocarcinoma transitions. Agents that target TFF1/Cdc25 signaling pathways may be useful for treating patients with TFF1-positive solid tumors.Oncogene advance online publication, 22 May 2006; doi:10.1038/sj.onc.1209665.

Dig Surg 2006 May 23; 23(1-2): 74-79 (Read article online)

Bloomston M, Bhardwaj A, Ellison EC, Frankel WL

Background: The effect of overexpression of epidermal growth factor receptor (EGFR) in pancreatic carcinoma is not clear. Utilizing tissue microarrays, we evaluated EGFR expression in pancreatic cancer to determine the association of EGFR expression with histopathologic characteristics and patient outcome. Methods: 71 cases of pancreatic adenocarcinoma and 18 cases of chronic pancreatitis were retrieved from archival files. Tissue cores from donor blocks were arrayed to create a tissue microarray. Sections were stained with EGFR and the intensity of membranous staining and percentage of tumor cells showing immunoreactivity were determined. At least 1% membranous staining and 1+ intensity were considered positive. Results: EGFR was present in 49 of 71 (69%) cases of pancreatic adenocarcinoma and 7 of 18 (39%) cases of chronic pancreatitis (p = 0.03). There was no statistically significant correlation between intensity or extent of EGFR expression and tumor grade, size, or lymph node status. While median survival was nearly twice as long when EGFR was expressed (15.2 vs. 8.3 months), this did not reach statistical significance. Conclusions: EGFR is overexpressed in pancreatic cancers independent of histopathologic characteristics and does not predict survival. Immunohistochemical analysis of EGFR staining may help in identifying candidates for EGFR inhibitor therapy. Copyright (c) 2006 S. Karger AG, Basel.

Biosci Biotechnol Biochem 2006 May; 70(5): 1076-81 (Read article online)

Katakura Y

Although dysfunctional telomeres and oncogenic or stressful stimuli are known to trigger cellular senescence in normal human diploid cells, the molecules and signaling network involved in the cellular senescence program are not fully understood. We have been trying to identify cellular senescence-inducing factors by various means. First, we screened for an extrinsic signal that can induce cellular senescence in human lung adenocarcinoma cell line A549, and identified transforming growth factor-beta (TGF-beta) as the cellular senescence-inducing factor. Cancer cells senesced by treatment with TGF-beta impaired tumorigenicity both in vitro and in vivo, suggesting that cellular senescence functions as a tumor suppression mechanism. Next, we identified 86 independent senescence-associated genes by subtractive screening using A549-derived cell lines. Thirdly, we established novel cell lines (AST cells) from A549 cells exposed to mild oxidative stress. AST cells demonstrated functional impairment of telomerase due to perturbed subcellular localization of human telomerase reverse transcriptase, suggesting that mild oxidative stress might affect the cell fate of cancer cells. These results should provide insight into the molecular basis of the cellular senescence program.

Surg Today 2006; 36(6): 554-8 (Read article online)

Mokuno Y, Katayama M, Ogura Y, Kimura K, Koh K

We report a case of metachronous bilateral adrenal metastases from mucinous adenocarcinoma of the stomach. A 68-year-old man who had undergone surgery for advanced gastric cancer 5 months earlier had a follow-up computed tomography (CT) scan, which showed a right adrenal tumor. We performed a right adrenalectomy, and histopathological examination revealed a mucinous adenocarcinoma with features consistent with those of gastric cancer. A routine follow-up CT scan done 41 months after the right adrenalectomy showed a left adrenal mass. Chemotherapy had no apparent effect, and left adrenalectomy was performed 65 months after the right adrenalectomy. Histopathological examination also revealed a metastasis from gastric cancer. The patient was alive without recurrence 40 months after the left adrenalectomy. This case suggests that resection of adrenal metastasis from gastric cancer is an effective treatment option that may prolong survival in selected patients.

Cancer Gene Ther 2006 May 19; (Read article online)

Oshikiri T, Miyamoto M, Hiraoka K, Shichinohe T, Kawarada Y, Kato K, Suzuoki M, Nakakubo Y, Kondo S, Dosaka-Akita H, Kasahara N, Katoh H

Squamous cell carcinoma antigens SCCA1 and SCCA2 are highly homologous serine proteinase inhibitors which have been widely utilized as serological markers for squamous cell cancers, but it has recently been demonstrated that only SCCA2 is truly specific for certain forms of lung cancer. Using a construct containing the 5'-flanking region of the SCCA2 gene between -460 and +0 bp and the luciferase reporter gene, SCCA2 promoter activity was detected in SCCA2-producing SCC cell lines (LK-2, LC-1), but not in SCCA2-nonproducing lung adenocarcinoma cell lines (A549, ABC-1, and RERF-LC-MS) or normal cells (WI-38, SAEC, and NHEK-Adult). Infection with a recombinant adenovirus vector, Ad-SCCA2-DsRed, resulted in cell-specific expression of the SCCA2 promoter-driven DsRed marker gene only in LK-2 and LC-1 cells. The same strategy was used for SCCA2-driven expression of a proapoptotic gene, (KLAKLAK)2, which can cause mitochondrial disruption by triggering mitochondrial permeabilization and swelling, resulting in the release of cytochrome c and induction of apoptosis. Infection with Ad-SCCA2-KLAKLAK2 specifically reduced the growth of the two human lung SCC cell lines compared to the SCCA2 nonproducing cell lines both in vitro and in vivo, suggesting that the SCCA2 promoter had a tumor-specific effect. These results suggest that transduction of SCCA2 promoter-controlled suicide genes by adenoviral vectors can confer transcriptionally targeted cytotoxicity in SCCA2-producing lung SCC cells, and represents a novel strategy for gene transfer specifically targeted to SCC in the lung.Cancer Gene Therapy advance online publication, 19 May 2006; doi:10.1038/sj.cgt.7700953.

J Biol Chem 2006 May 17; (Read article online)

Fu X, Beer DG, Behar J, Wands J, Lambeth D, Cao W

Gastro-esophageal reflux disease complicated by Barrett's esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). The mechanisms whereby acid reflux may accelerate the progression from BE to EA are not known. We therefore investigated the role of NADPH oxidases in acid-induced changes in Barrett's SEG1-EA cells. NOX1 and NOX5-S were the major isoforms of NADPH oxidase in SEG1-EA cells. The expression of NOX5-S mRNA was significantly higher in these cells than in esophageal squamous epithelial cells. NOX5 mRNA was also significantly higher in Barrett's tissues with high-grade dysplasia than without dysplasia. Pulsed acid treatment significantly increased H(2)O(2) production in both SEG1-EA cells and BE mucosa, which was blocked by the NADPH oxidase inhibitor apocynin. In SEG1 cells, acid treatment increased mRNA expression of NOX5-S, but not NOX1, and knockdown of NOX5 by NOX5 siRNA abolished acid-induced H(2)O(2) production. In addition, acid treatment increased intracellular calcium and phosphorylation of CREB. Acid-induced NOX5-S expression and H(2)O(2) production were significantly inhibited by removal of extracellular calcium and by knockdown of CREB using CREB siRNA. Two novel CREB binding elements TGACGAGA and TGACGCTG were identified in the NOX5-S gene promoter. Overexpression of CREB significantly increased NOX5-S promoter activity. Knockdown of NOX5 significantly decreased (3)H-thymidine incorporation, which was restored by 10(-13)M H(2)O(2). Knockdown of NOX5 also significantly decreased retinoblastoma protein phosphorylation, and increased cell apoptosis and caspase-9 expression. In conclusion, in SEG1 EA cells NOX5-S is overexpressed and mediates acid-induced H(2)O(2) production. Acid-induced NOX5-S expression depends on an increase in intracellular calcium and activation of CREB. NOX5-S contributes to increased cell proliferation and decreased apoptosis.

Carcinogenesis 2006 May 18; (Read article online)

Manjanatha M, Shelton S, Bishop M, Lyn-Cook L, Aidoo A

The major constituents of isoflavones, daidzein (DZ) and genistein (GE) interact with the and estrogen receptors in several tissues including mammary. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE, or 17-estradiol (E2) exposures on chemically-induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue transgenic rats. The rats were fed control diet containing the isoflavones and E2 and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND 50. Animals were euthanized at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E2 supplementation alone resulted in the lacI MFs that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lacI MFs in the mammary of both OVX and INT rats and Hprt MFs in spleen lymphocytes (p 0.01). In general, feeding the isoflavones or E2 did not cause any significant changes in DMBA-induced mutagenicity in the mammary. However, feeding the isoflavone mixture (DZG) resulted in a significant reduction in the DMBA-induced lacI MFs (p 0.05). Cell proliferation as measured by PCNA immunohistochemistry was increased in both OVX and INT rats exposed to DMBA as compared with rats fed control diet (p 0.05). Mammary histology indicated that hyperplasia was induced in most of the treatment groups including control. Although DMBA did not induce mammary tumors in the OVX rats, adenoma and adenocarcinoma were detected in the mammary glands of INT rats.