Adenocarcinoma
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Pubmed
Journal: The EMBO journal
February/1/2004
Abstract

The CDK inhibitor p21waf1/cip1 is degraded by a ubiquitin-independent proteolytic pathway. Here, we show that MDM2 mediates this degradation process. Overexpression of wild-type or ring finger-deleted, but not nuclear localization signal (NLS)-deleted, MDM2 decreased p21waf1/cip1 levels without ubiquitylating this protein and affecting its mRNA level in p53(-/-) cells. This decrease was reversed by the proteasome inhibitors MG132 and lactacystin, by p19(arf), and by small interfering RNA (siRNA) against MDM2. p21waf1/cip1 bound to MDM2 in vitro and in cells. The p21waf1/cip1-binding-defective mutant of MDM2 was unable to degrade p21waf1/cip1. MDM2 shortened the half-life of both exogenous and endogenous p21waf1/cip1 by 50% and led to the degradation of its lysine-free mutant. Consequently, MDM2 suppressed p21waf1/cip1-induced cell growth arrest of human p53(-/-) and p53(-/-)/Rb(-/-)cells. These results demonstrate that MDM2 directly inhibits p21waf1/cip1 function by reducing p21waf1/cip1 stability in a ubiquitin-independent fashion.

Pubmed
Journal: Lancet (London, England)
January/6/1997
Abstract

BACKGROUND

Survival rates after surgery for rectal cancer remain at about 40% at 5 years from diagnosis. The aim of this study was to find out whether local recurrence rate could be reduced and survival increased by a moderately high dose of preoperative radiotherapy in patients with locally advanced, but otherwise operable, carcinoma of the rectum.

METHODS

We carried out a prospective randomised trial of surgery alone (n = 140) versus surgery preceded by 40 Gy radiotherapy (n = 139) given in 20 fractions of 2 Gy over 4 weeks. The patients, from 20 regional centres throughout the UK, were enrolled between 1981 and 1989, and followed up for a minimum of 5 years or to death.

RESULTS

217 patients died, 114 of 140 allocated surgery alone and 103 of 139 allocated preoperative radiotherapy: median survival times were 24 months and 31 months, respectively. The hazard ratio for overall survival was 0.79 (95% CI 0.60-1.04, p = 0.10). At 5 years' follow-up 65 patients allocated surgery alone and 50 who received preoperative radiotherapy had local recurrence (hazard ratio 0.68 [0.47-0.98], p = 0.04); the corresponding numbers of patients with distant recurrence were 67 and 49 (hazard ratio 0.66 [0.46-0.95], p = 0.02). There was a significant benefit of radiotherapy on disease-free survival (hazard ratio 0.76 [0.58-1.0], p = 0.05). There was no increase in postoperative or late complications in the radiotherapy group.

CONCLUSIONS

Our results provide further evidence that preoperative radiotherapy can reduce the rate of local recurrence of rectal cancer in patients with locally advanced disease. However, survival results are still equivocal, and so we must await the results of a meta-analysis of all radiotherapy trials from which precise and definitive results, particularly for survival, may be obtained.

Pubmed
Journal: Gut
July/26/2012
Abstract

OBJECTIVE

The detection of molecular markers in stool samples is a potential strategy for colorectal cancer (CRC) screening. This study evaluated the feasibility of detecting miR-21 and miR-92a in stool samples of patients with CRC or polyps.

METHODS

The reproducibility of detection and stability of stool-based microRNA were evaluated. Stool samples were collected from 88 patients with CRC, 57 patients with colorectal polyps and 101 healthy controls. MiRNA levels in CRC tissues and stool samples were detected by real-time quantitative reverse transcription PCR. Stool miR-21 and miR-92a levels were compared before and after the removal of tumour or advanced adenoma.

RESULTS

The study demonstrated that stool-based miRNA were stable with highly reproducible detection. The expression of miR-21 and miR-92a was significantly higher in CRC tissues compared with their adjacent normal tissues (p<0.0001). Patients with CRC had a significantly higher stool miR-21 level (p<0.01) and miR-92a level (p<0.0001) compared with normal controls. Stool miR-92a, but not miR-21, was significantly higher in patients with polyps than in controls (p<0.0001). At a cut-off value of 435 copies/ng of stool RNA, miR-92a had a sensitivity of 71.6% and 56.1% for CRC and polyp, respectively, and a specificity of 73.3%. In addition, the stool miR-92a level demonstrated a higher sensitivity for distal CRC than proximal CRC (p<0.05), and a higher sensitivity for advanced adenoma than minor polyps (p<0.05). Removal of tumour resulted in reduced stool miR-21 and miR-92a levels (p<0.01), and the removal of advanced adenoma resulted in a reduction of the stool miR-92a level (p<0.05).

CONCLUSIONS

Stool miRNA are useful for screening CRC and polyps.

Pubmed
Journal: Radiology
February/16/2004
Abstract

OBJECTIVE

To compare the performance of helical computed tomography (CT) and endoscopic ultrasonography (US) in the preoperative staging of gastric cancer.

METHODS

Fifty-one consecutive patients with a primary malignant gastric tumor (stage T2-T4) were preoperatively evaluated with both helical CT and endoscopic US within 3 days. Each tumor was staged according to the TNM classification system with both modalities. All patients subsequently underwent surgery. Results of CT and endoscopic US were compared with histologic staging of tumor invasion depth and regional lymph node metastasis. For comparison of CT and endoscopic US data, the marginal homogeneity test was used, and a P value of less than.05 was determined to indicate statistical significance.

RESULTS

In comparison with histologic results, CT achieved correct T staging in 39 patients (76%) and correct N staging in 35 patients (70%). The corresponding results for endoscopic US achieved correct T staging in 44 patients (86%) and correct N staging in 45 patients (90%). There was no significant difference between T staging (P =.55) and N staging (P >.99). Because of challenging detection of wall layers, correct T staging was difficult for CT and endoscopic US in the differentiation of T2 and T3 lesions.

CONCLUSIONS

Compared with endoscopic US, helical CT focused on the stomach provides valuable results regarding T and N staging in patients with gastric cancer.

Pubmed
Journal: The Journal of urology
September/11/2000
Abstract

OBJECTIVE

We report the findings of a transperineal magnetic resonance image (MRI) guided biopsy of the prostate in a man with increasing prostate specific antigen who was not a candidate for a transrectal ultrasound guided biopsy.

METHODS

Using an open configuration 0.5 Tesla MRI scanner and pelvic coil, a random sextant sample was obtained under real time MRI guidance from the peripheral zone of the prostate gland as well as a single core from each MRI defined lesion. The patient had previously undergone proctocolectomy for ulcerative colitis and, therefore, was not a candidate for transrectal ultrasound guided biopsy. Prior attempts to make the diagnosis of prostate cancer using a transurethral approach were unsuccessful.

RESULTS

The random sextant samples contained benign prostatic hyperplasia, whereas Gleason grade 3 + 3 = 6 adenocarcinoma was confirmed in 15% and 25% of the 2 cores obtained from the MRI targeted specimens of 2 defined lesions. The procedure was well tolerated by the patient.

CONCLUSIONS

Transperineal MRI guided biopsy is a new technique that may be useful in detecting prostate cancer in men with increasing prostate specific antigen who are not candidates for transrectal ultrasound guided biopsy.

Pubmed
Journal: International journal of cancer
August/23/2005
Abstract

Hypermethylation of secreted frizzled-related proteins (SFRP) genes frequently occurs with several cancers but has not been studied in esophageal adenocarcinoma or its precursor-Barrett's esophagus. To explore the role of SFRP methylation in the neoplastic progression of Barrett's esophagus and to evaluate methylated SFRP genes as biomarkers for Barrett's esophagus and cancer, methylation of SFRP genes was determined in esophageal adenocarcinomas, Barrett's esophagus and normal epithelia using methylation-specific PCR. Protein expression of SFRP genes was then assessed in these tissues by immunohistochemistry. The mRNA expression of SFRP genes was quantified by real-time reverse-transcription PCR in esophageal adenocarcinoma cell lines with and without demethylation by 5-aza-2'deoxycytidine and inhibition of deacetylation by trichostatin A treatment. Hypermethylation of SFRP1, 2, 4 and 5 was detected in 93%, 83%, 73% and 85% of 40 cancers; 81%, 89%, 78% and 73% of 37 Barrett's epithelia; 25%, 64%, 32% and 21% of 28 adjacent normal epithelia from Barrett's patients; and 10%, 67%, 0% and 13% of 30 normal esophagogastric epithelia from healthy individuals, respectively (p < 0.001 for SFRP1, 4 and 5; p < 0.05 for SFRP2). Protein expression of SFRP1, 2 and 4 was downregulated in 87%, 67% and 90% of cancers, and expression correlated inversely with grade and stage of cancers and with grade of dysplasia. Expression of SFRP2 and SFRP4 proteins was lower in cancers with corresponding gene methylation (p < 0.05). Demethylation treatment effectively re-expressed SFRP mRNA in cancer cell lines. Thus, hypermethylation of SFRP genes is a common early event in the evolution of esophageal adenocarcinoma, and methylation of SFRP1, 4 and 5 might serve as biomarkers for Barrett's neoplasia. Aberrant promoter methylation appears to functionally silence SFRP gene expression in esophageal adenocarcinoma.

Pubmed
Journal: Gastroenterology
March/3/1996
Abstract

OBJECTIVE

Contribution of transforming growth factor beta 1 (TGF-beta 1) to tumor progression has been suggested. However, little is known about the role of TGF-beta 1 in colorectal cancer. Plasma TGF-beta 1 levels and its expression were analyzed in patients with colorectal cancer.

METHODS

Plasma TGF-beta 1 levels were measured in 22 patients with colorectal cancer using a TGF-beta 1 enzyme-linked immunosorbent assay. Expression of TGF-beta 1 messenger RNA and immunohistochemical distribution of the protein in colorectal cancer tissues were examined.

RESULTS

Plasma TGF-beta 1 levels in patients with colorectal cancer (14.8 +/- 8.4 ng/mL) were significantly higher than in normal controls (1.9 +/- 1.4; n = 22) (P < 0.001). After curative surgical resection, plasma TGF-beta 1 levels decreased in examined patients from 11.9 +/- 6.7 to 3.8 +/- 1.2 ng/mL (P < 0.01). TGF-beta 1 messenger RNA was about 2 1/2 times more abundant in colorectal cancer tissues than in control (P < 0.01). TGF-beta 1 was detected in the cytoplasm of colorectal cancer cells immunohistochemically. Both TGF-beta 1 messenger RNA expression in colorectal adenocarcinoma tissues and its plasma levels were associated with tumor stage of Dukes' classification (P < 0.05).

CONCLUSIONS

These results suggest that plasma TGF-beta 1 levels may reflect overexpression of the gene in colon cancer tissues and are associated with disease progression.

Pubmed
Journal: Annals of oncology : official journal of the European Society for Medical Oncology
February/13/2008
Abstract

BACKGROUND

A phase 3 study demonstrated that panitumumab, a human monoclonal anti-epidermal growth factor receptor antibody, significantly prolonged progression-free survival versus best supportive care (BSC) in patients with chemorefractory metastatic colorectal cancer.

METHODS

This open-label extension study evaluated panitumumab monotherapy in BSC patients with radiographically documented disease progression in the phase 3 study. Patients received panitumumab 6 mg/kg every 2 weeks. The primary end point was safety; efficacy was also evaluated.

RESULTS

One hundred and seventy-six patients were randomly assigned to the BSC arm of the phase 3 study received >/=1 panitumumab dose in this extension study. Panitumumab was well tolerated. The most frequent treatment-related adverse events were skin toxic effects. Three (2%) patients had a grade 4 treatment-related adverse event. There were no infusion reactions. One (0.6%) patient had a complete response; 19 (11%) patients had a partial response; and 58 (33%) patients had stable disease. Median progression-free survival time was 9.4 [95% confidence interval (CI): 8.0-13.4) weeks. Median overall survival time was 6.3 (95% CI: 5.1-6.8) months. Anti-panitumumab antibodies were detected in 3 (4.2%) of 71 patients with a post-baseline sample.

CONCLUSIONS

These findings are comparable to those from the phase 3 study and support panitumumab monotherapy for chemorefractory colorectal cancer.

Pubmed
Journal: Histopathology
December/16/1983
Abstract

Based on histopathological examination of 264 exocrine pancreatic tumours (167 autopsy and 97 surgical) from the files of the Institute of Pathology, University of Hamburg, over a 15-yr period (1966-1980), a histogenetic classification is proposed. In addition to the more common neoplasms this also includes rarer and more recently defined entities. Of the 264 tumours, 250 were of duct origin, 10 acinar and four of uncertain histogenesis. Ductal adenocarcinoma, subdivided into a well-differentiated and a poorly-differentiated type, was most frequent (81.1%), followed by its variants: pleomorphic giant cell carcinoma 5.3%, adenosquamous carcinoma 3.8%, and mucinous carcinoma 1.1%. All these had a poor prognosis. Serous cystadenoma (1.1%), mucinous cystic tumour (1.5%) and intraductal papilloma (0.8%), which were rare tumours and mostly apparent in surgical material, proved to be benign or of only latent malignancy. The group of tumours of acinar cell origin consisted of the solid and cystic tumour (2.7%) with favourable prognosis and the acinar cell carcinoma (1.1%). No pancreatoblastoma was observed. The pleomorphic carcinomas of the small cell type (1.5%) were classed as tumours of uncertain histogenesis.

Pubmed
Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
March/10/2005
Abstract

OBJECTIVE

To determine if iridium implant (IM) and external-beam radiation therapy (EBRT) is better than standard EBRT in locally advanced prostate cancer.

METHODS

Patients with T2 and T3 prostate cancer with no evidence of metastatic disease were randomly assigned to EBRT of 66 Gy in 33 fractions during 6.5 weeks or to IM of 35 Gy delivered to the prostate during 48 hours plus EBRT of 40 Gy in 20 fractions during 4 weeks. The primary outcome consisted of biochemical or clinical failure (BCF). BCF was defined by biochemical failure, clinical failure, or death as a result of prostate cancer. Secondary outcomes included 2-year postradiation biopsy positivity, toxicity, and survival.

RESULTS

Between 1992 and 1997, 51 patients were randomly assigned to receive IM plus EBRT, and 53 patients were randomly assigned to receive EBRT alone. The median follow-up was 8.2 years. In the IM plus EBRT arm, 17 patients (29%) experienced BCF compared with 33 patients (61%) in the EBRT arm (hazard ratio, 0.42; P = .0024). Eighty-seven patients (84%) had a postradiation biopsy; 10 (24%) of 42 in the IM plus EBRT arm had biopsy positivity compared with 23 (51%) of 45 in the EBRT arm (odds ratio, 0.30; P = .015). Overall survival was 94% in the IM plus EBRT arm versus 92% in the EBRT arm.

CONCLUSIONS

The combination of IM plus EBRT was superior to EBRT alone for BCF and postradiation biopsy. This trial provides evidence that higher doses of radiation delivered in a shorter duration result in better local as well as biochemical control in locally advanced prostrate cancer.

Pubmed
Journal: Gastrointestinal endoscopy
October/18/2000
Abstract

BACKGROUND

Preoperative diagnosis of pancreatic adenocarcinoma can be difficult. Computed tomography (CT) is the standard, noninvasive imaging method for evaluation of suspected pancreatic adenocarcinoma, but it has limited sensitivity for diagnosis, local staging, and metastases. Endoscopic ultrasound (EUS) and fluoro-deoxyglucose/positron emission tomography (FDG-PET) are imaging methods that may improve diagnostic accuracy.

METHODS

Thirty-five patients with presumed resectable pancreatic adenocarcinoma were prospectively evaluated with helical CT, EUS, and FDG-PET.

RESULTS

Sensitivity for the detection of pancreatic cancer was higher for EUS (93%) and FDG-PET (87%) than for CT (53%). EUS was more sensitive than CT for local vascular invasion of the portal and superior mesenteric veins. EUS diagnosis of vascular invasion was associated with poor outcome after surgery. EUS-guided, fine-needle aspiration allowed tissue diagnosis in 14 of 21 attempts (67%). FDG-PET diagnosed 7 of 9 cases of proven metastatic disease, 4 of which were missed by CT. Two of three metastatic liver lesions suspected by CT were indeterminate for metastases. FDG-PET confirmed metastases.

CONCLUSIONS

EUS and PET improve diagnostic capability in pancreatic adenocarcinoma. EUS is useful in determining local vascular invasion and obtaining tissue diagnosis. FDG-PET is useful in identifying metastatic disease. Both techniques are more sensitive than helical CT for identification of the primary tumor. (Gastrointest Endosc 2000;52:367-71).

Pubmed
Journal: Cancer research
November/7/1995
Abstract

p53 and MTS1 are known to be mutationally inactivated in pancreatic adenocarcinoma. Other tumor suppressor genes are likely also to play a role. To define chromosomal arms which may harbor additional tumor suppressor genes, we performed an extensive allelotype on pancreatic cancer utilizing a xenograft enrichment technique. Eighty-eight percent (28/32) of primary tumors gave rise to xenografts. Eighteen cases were used in a PCR-based allelotype using 283 polymorphic markers, over 2800 informative assays, and an average coverage of 4.1 informative markers per chromosomal arm per case. Highly frequent allelic loss (> 60%) was seen at chromosomes 1p, 9p, 17p, and 18q. Moderately frequent allelic loss (40-60%) was seen at 3p, 6p, 6q, 8p, 10q, 12q, 13q, 18p, 21q, and 22q. The average fractional allelic loss was 0.36. Allelic and sequence stability was demonstrated among 64 parallel and second-passage xenografts derived from 12 cases of pancreatic adenocarcinoma with the ascertainment of over 3000 single alleles. The findings were confirmed in primary tumors. In only two instances were discrepancies revealed between the allelic loss data obtained from corresponding parallel xenografts, probably due to the xenografting of minor subpopulations, reflecting genetic heterogeneity of the primary tumor.

Pubmed
Journal: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
March/5/2007
Abstract

Pancreatic cancer has a poor prognosis with complete surgical resection being the only therapy to offer a realistic chance for long-term survival. The aim of this study is to identify surgery-related variables that influence long-term survival. Between 1990 and 2002, 226 consecutive patients (mean age of 64+/-11 years) had resection for pancreatic adenocarcinoma. Prognostic variables in these patients were analyzed using univariate and multivariate analysis. Two hundred four patients (90%) had pancreaticoduodenectomy, 13 patients (6%) had distal pancreatectomy, and 9 patients (4%) had a TP. Stage I disease was present in 50 (22%), stage II disease in 170 (75%), and stage III disease in 6 (3%). R0 resections were achieved in 70%. Operative morbidity was 36% and 30-day mortality was 6%. Actual 1-year, 3-year, and 5-year survival rates were 49% (n=111), 14% (n=31), and 4% (n=9). Using multivariate analysis: tumor size, tumor differentiation, obtaining an R0 resection, and lack of postoperative complications were variables associated with long-term survival. Long-term survival in patients with pancreatic cancer after resection remains poor. Achieving a margin negative resection (R0) with no postoperative complications are prognostic variables that can be affected by the surgeon.

Pubmed
Journal: Gastroenterology
July/4/2005
Pubmed
Journal: Genes & development
March/26/2003
Abstract

Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.

Pubmed
Journal: Cancer research
November/6/1986
Abstract

Oxygenation and development of necrosis were evaluated in multicellular spheroids of poorly differentiated (HT29) and moderately well-differentiated (Co112) human adenocarcinoma of the colon. Spheroids were grown in vitro under well-controlled oxygen and nutrient conditions in spinner flasks up to sizes of 2800-micron diameter after 5 wk of culture. Morphological studies showed that the Co112 spheroids contained pseudoglandular structures with lumen, very similar to the characteristics of the original tumor specimen from the patient and to the cells when grown as xenograft tumors in nude mice. Microelectrodes were used to measure the oxygen tension (PO2) profile within individual spheroids at different stages of growth. Histological sections through the centers of spheroids were measured to determine the thickness of the viable rim of cells surrounding spheroid necrotic centers in order to estimate the size of the severely hypoxic zone of cells by comparison with the PO2 profiles of the same spheroids. The data demonstrate significant differences between these two human colon tumor spheroid systems. Both spheroid types exhibited steep PO2 gradients at relatively small sizes of less than 600-micron diameter, but for any given size in this range, the more differentiated Co112 spheroids were more hypoxic. Although severe hypoxia (PO2, less than 10 mm of Hg) was present in both spheroid types at larger sizes, there was a significant difference in the central PO2 values which were between 5 and 10 mm of Hg in large Co112 spheroids but remained at or close to 0 mm of Hg in large HT29 poorly differentiated human colon tumor spheroids. The presence of pseudoglandular structures and lumen in the Co112 spheroids was associated with changes in the shape of PO2 profiles. Such profiles have not previously been seen in other poorly differentiated human or rodent tumor spheroids. Furthermore, the PO2 profiles of both of these human tumor spheroid types were often continuously curving with a very shallow gradient in the inner edge of the viable rim of cells surrounding the necrotic center. Regulation of oxygen consumption and/or diffusion in these inner regions of human spheroids could produce these continuously curving PO2 gradients.

Pubmed
Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
July/6/1989
Abstract

C57BL/6 mice bearing either a transplantable methylcholanthrene-induced sarcoma or Lewis lung adenocarcinoma were passively immunized every other day with a rabbit immunoglobulin fraction raised against murine cachectin/tumor necrosis factor-alpha. Mice bearing methylcholanthrene-induced sarcoma developed tumor-associated hypophagia that was attenuated by anticachectin immunoglobulin treatment. In the same tumor-bearing animals, anticachectin treatment also significantly reduced the extent of carcass protein and fat loss, and reduced tumor weight. Mice bearing Lewis lung adenocarcinoma did not develop significant anorexia or carcass lean tissue depletion as tumor growth progressed, but they lost carcass lipid. Treatment of Lewis lung adenocarcinoma bearing mice with anticachectin antibodies diminished the degree of carcass lipid depletion and prevented plasma hypertriglyceridemia. However, in both tumor models, anticachectin treatment did not affect either the development of anemia, hypoalbuminemia or the increase in serum amyloid P concentrations seen with increasing tumor burden. We conclude that an endogenous cachectin response, inhibitable by exogenously administered antibody, contributes to anorexia and to changes in body fat and protein metabolism in these tumor-bearing animals. Neutralizing endogenous cachectin production with antibodies offers the potential to reduce tissue wasting that is frequently associated with neoplastic disease, but it does not appear to affect all of the hematologic and acute phase responses in these murine tumor models.

Pubmed
Journal: The American journal of surgical pathology
April/6/2004
Abstract

Preoperative radiation (RT) and chemotherapy improve outcome in patients with locally advanced rectal adenocarcinoma and, therefore, have been used increasingly in patient management. The histopathologic alterations in postirradiated rectal adenocarcinoma and their prognostic significance have not been fully characterized. In this study, detailed analyses of morphologic alterations of stromal and tumor cells were performed in a series of 66 posttreatment rectal carcinomas, and the pathologic findings were correlated with long-term outcome. All tumors were locally advanced, with a bulky and/or tethered tumor or endorectal ultrasound or magnetic resonance imaging evidence of T3-4 and / or N1 disease. All patients were treated at one institution with preoperative RT to the pelvis (at least 4500 cGy) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy 4 to 7 weeks prior to surgical resection. Pathologic assessment showed some treatment response in all patients. Nine patients (13.4%) had complete response, and 8 (11.9%) had near-complete response (> 95% of the tumor replaced by fibroinflammatory tissue). Salient morphologic features included marked fibrosis with or without prominent inflammatory cells replacing neoplastic glands; lack of active tumor necrosis; increased mucin production and mucin pools; marked cytoplasmic eosinophilia, often in combination with marked nuclear atypia but without active mitoses in tumor cells showing treatment effect; endocrine tumor phenotype; and retention of mucosal adenoma in the presence of tumor regression within the bowel wall. With a median follow-up of 69 months, the estimated 5-year recurrence-free survival (RFS) for the entire group was 79%. By univariate analysis, the residual tumor stage (P < 0.05) and reduction of pretreatment T stage (P = 0.002) significantly correlated with RFS, as did pN stage (P = 0.002) and lymphovascular invasion (P = 0.008). The extent of treatment response did not correlate with RFS (P = 0.4). However, patients with a treatment response > or = 95% seemed to fare better than those with a treatment response < 95% (marginally significant difference in RFS, P = 0.057). Univariate and multivariate analyses identified the following morphologic patterns that were significantly associated with a reduced RFS independent of other risk factors: a fibrotic-type stromal response with minimal inflammatory infiltrates (P = 0.001) and absence of surface ulceration (P = 0.026). Our study represents the first detailed morphologic assessment of rectal carcinomas that have been subjected to long course preoperative RT and chemotherapy. Our results demonstrate distinct morphologic features in treated rectal carcinomas that are prognostically relevant.

Pubmed
Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
March/1/2004
Abstract

OBJECTIVE

To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer.

METHODS

Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed.

RESULTS

All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths.

CONCLUSIONS

Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.

Pubmed
Journal: Gastrointestinal endoscopy
October/23/2005
Abstract

BACKGROUND

Accurate staging of high-grade dysplasia and of early cancer in Barrett's esophagus is important in the selection of patients for endoscopic therapy.

METHODS

Patients with Barrett's esophagus and biopsy specimen proven high-grade dysplasia and adenocarcinoma in focal nodular lesions or in endoscopically unapparent flat lesions in short-segment Barrett's esophagus were initially staged with EUS. In patients with disease limited to the mucosa on EUS, cap-assisted EMR was performed. The depth of tumor invasion on EMR specimens was classified in a similar manner to squamous-cell cancer of the esophagus: m1 (epithelial layer, dysplasia), m2 (lamina propria invasion), m3 (muscularis mucosae invasion), sm (submucosal invasion).

RESULTS

EUS was performed in 48 consecutive patients (27 with focal nodular lesions and 21 with microscopic lesions), and submucosal invasion was diagnosed in 8 (confirmed in 7/8 at surgery). EMR was carried out in the remaining 40 patients without significant complications. In the 25 patients with high-grade dysplasia on prior biopsy specimens, EMR confirmed m1 disease in 19; whereas in 6 (24%), invasive adenocarcinoma was detected (to m2 in 4; to m3 in 2). In the 15 patients with invasive cancer on prior biopsy specimens and staged as intramucosal cancer on EUS, intramucosal carcinoma was confirmed in 9 (m2 in 3; m3 in 6); whereas, in 6 patients (40%), submucosal invasion was found. Overall, EUS provided accurate staging in 41/48 patients (85%) with one patient overstaged and 6 patients understaged compared with pathologic staging obtained by surgery or EMR. Of the 34 patients with m1 to m3 staging after EMR, 29 were treated endoscopically and had no evidence of cancer after a mean follow-up of 22.9 months(standard deviation 9.2 months).

CONCLUSIONS

EMR provides pathologic staging information that, in addition, may be helpful after EUS if a stage-determined approach is used in the management of high-grade dysplasia and of early cancer in Barrett's esophagus. EMR may be particularly useful for staging of focal nodules or in short-segment Barrett's esophagus with microscopic lesions when endoscopic therapy is an option.

Pubmed
Journal: Cancer research
February/3/1998
Abstract

Hyaluronan (HA) is a linear high molecular weight extracellular polysaccharide. It is thought to be involved in mitosis and the enhancement of wound healing, tumor invasion, and metastasis. Because its clinical relevance in cancer has not been explored, we scored HA in colorectal adenocarcinoma and studied its relationship with patient survival. A specific probe prepared from cartilage proteoglycan aggregates was used to stain paraffin-embedded tumor samples from 202 colorectal adenocarcinoma patients treated in Kuopio University Hospital and followed up for a mean of 14 years. The hypothesis that the percentage of HA-positive carcinoma cells (HA%) and HA intensity in cancer cells correlated with survival was tested with the log-rank test, hazard ratios, and their confidence intervals. Ninety-three % of tumors had at least a proportion of carcinoma cells positive for HA. HA intensity in tumor epithelium was stronger in Dukes' stages C and D tumors and in high-grade tumors. The cancer-related survival rate was lower among patients with strong HA intensity in tumor epithelium (P < 0.001) and high HA% (P < 0.001). Recurrence-free survival was also shorter in patients with an intense signal for HA (P = 0.001) and high HA% in tumor epithelium (P = 0.04). HA intensity in tumor epithelium independently predicted survival and recurrence-free survival (Cox's analysis). We conclude that a high proportion of HA-positive cancer cells and high intensity of the HA-signal predicts a poor survival rate. The abnormal expression of HA in the neoplastic colon epithelial cells is suggested to provide a distinct advantage for invasive growth and metastasis.

Pubmed
Journal: Annals of surgical oncology
December/2/1999
Abstract

BACKGROUND

Traditional teaching maintains that patients with primary colorectal adenocarcinoma require timely resection to prevent bleeding, perforation, or obstruction. The true benefits of primary tumor resection remain undocumented for patients presenting with metastatic disease, however. We postulated that resection of primary colorectal tumors could be avoided safely in a select population of asymptomatic colorectal cancer patients presenting with incurable stage IV disease.

METHODS

A retrospective review of the Vanderbilt University Hospital tumor registry was performed for the years 1985 to 1997. During this period, 955 patients presented for management of primary colorectal cancer. From this group, all patients with stage IV disease at the time of diagnosis were identified. Patients who initially underwent resection of their primary lesion were included in the resection group; those who underwent initial nonoperative primary tumor management were included in the nonresection group. Data were obtained regarding age, extent of disease, nonsurgical therapy, tumor-specific complications, and palliative surgical procedures. Surgery-free survival and overall survival were analyzed using the Kaplan-Meier method. For patients with liver metastases, hepatic tumor burden was defined as either H1 (<25% parenchymal replacement), H2 (25% to 50%), or H3 (>50%) disease.

RESULTS

Sixty-six patients were included in the resection group, and 23 patients with intact asymptomatic primary colorectal lesions were included in the nonresection group. Among patients with hepatic metastases, most of the patients in both groups had H1 disease. Ten patients in the resection group and 3 patients in the nonresection group presented with exclusively extrahepatic metastases. In the nonresection group, primary therapy included chemotherapy in 13 patients, external beam radiation therapy in 1 patient, and combination chemoradiation in 9 patients. The median survival in the nonresection group was 16.6 months. The 2-year actuarial survival was 18%, and the surgery-free survival was 91.3%. Only 2 of 23 patients (8.7%) managed without resection eventually developed obstruction at the primary tumor site requiring emergent diversion. There were no episodes of tumor-related hemorrhage or perforation. For the resection group, the operative morbidity was 30.3%, and the perioperative mortality rate was 4.6%. The median survival in the resection group was 14.5 months (P = 0.59, log-rank test vs. nonresection group).

CONCLUSIONS

Selected patients with asymptomatic primary colorectal tumors who present with incurable metastatic disease may safely avoid resection of their primary lesions, with an anticipated low rate of hemorrhage, perforation, or obstruction before death from systemic disease. No survival advantage is gained by resection of an asymptomatic primary lesion in the setting of incurable stage IV colorectal cancer.

Pubmed
Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
August/30/1998
Abstract

OBJECTIVE

To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma.

METHODS

A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive.

RESULTS

Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%.

CONCLUSIONS

This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

Pubmed
Journal: Gastroenterology
October/31/1994
Abstract

OBJECTIVE

Limited data are available regarding TP53 gene alterations in Barrett's esophagus. This study was undertaken to characterize TP53 mutations and p53 protein immunoreactivity in cancers and preinvasive lesions of Barrett's esophageal mucosa.

METHODS

Seventeen Barrett's adenocarcinomas were examined by polymerase chain reaction amplification, denaturant gradient gel electrophoresis, and sequencing for the presence of TP53 mutations in exons 5-8. In 9 cases, Barrett's epithelium adjacent to the cancer was investigated. p53 protein immunoreactivity was studied with PAb 1801.

RESULTS

Sixteen mutations were found in 15 adenocarcinomas, including 10 missense, 3 nonsense, 1 frameshift, and 2 mutations located within consensus splice donor and acceptor sequences. All nucleotide substitutions were transitions. Eight of the 12 transitions involving a GC base pair occurred within the context of a CpG dinucleotide. p53 immunostaining was present in all 10 cases with missense mutations and in 1 case without a detectable mutation. The surrounding Barrett's mucosa showed TP53 mutations identical to that observed in the carcinoma in only 3 of 5 specimens showing high-grade dysplasia.

CONCLUSIONS

TP53 gene mutations and p53 protein immunostaining are present in a majority of Barrett's adenocarcinomas. Our results suggest that these mutations are involved at an early stage during malignant transformation of Barrett's esophagus.

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