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D Klimstra

Publications and source records attributed to D Klimstra.

At least 19 recordsLinked to original sources
PubMed2003

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection.

The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 10(7) particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 10(5) tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with >90% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-gamma (IFN-gamma) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (P<.003) and 52% (P<.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8+/-11 (median=4) vs. 65.9+/-15 (median=66) in control animals, P<.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.

Animals↗
PubMed2001

Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes.

To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b(G12D) under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fall in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging.

Adenocarcinoma↗
PubMed2001

Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes.

Intrahepatic cholangiocarcinoma (IHC) is a rare primary hepatic tumor of bile duct origin for which resection is the most effective treatment. But resectability, outcomes after resection, and recurrence patterns have not been well described. Patients with IHC were identified from a prospective database. Demographic data, tumor characteristics, and outcomes were analyzed. From March 1992 to September 2000, 53 patients with hepatic tumors underwent exploration and were found to have pure IHC on pathologic analysis. Patients with mixed hepatocellular and cholangiocarcinoma tumors were excluded. At exploration, 20 patients were unresectable for an overall resectability rate of 62% (33 of 53). Median survival for patients submitted to resection was 37.4 months versus 11.6 months for patients undergoing biopsy only (p = 0.006; median followup for surviving patients, 15.6 months). Actuarial 3-year survival was 55% versus 21%, respectively. Factors predictive of poor survival after resection included vascular invasion (p = 0.0007), histologically positive margin (p = 0.009), or multiple tumors (p = 0.003). After resection, 20 of 33 patients (61%) recurred at a median of 12.4 months. Sites of recurrence included the liver (14), retroperitoneal or hilar nodes (4), lung (4), and bone (2). The median disease-free survival was 19.4 months, with a 3-year disease-free survival rate of 22%. Factors predictive of recurrence were multiple tumors (p = 0.0002), tumor size (p = 0.001), and vascular invasion (p = 0.01). About two-thirds of patients who appeared resectable on preoperative imaging were amenable to curative resection at the time of operation. Although complete resection improved survival, recurrence was common. The majority of recurrences were local or regional, which may help guide future adjuvant therapy strategies.

Actuarial Analysis↗
PubMed2001

Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.

OBJECTIVE: To analyze resectability and survival in patients with hilar cholangiocarcinoma according to a proposed preoperative staging scheme that fully integrates local, tumor-related factors. SUMMARY BACKGROUND DATA: In patients with hilar cholangiocarcinoma, long-term survival depends critically on complete tumor resection. The current staging systems ignore factors related to local tumor extent, preclude accurate preoperative disease assessment, and correlate poorly with resectability and survival. METHODS: Demographics, results of imaging studies, surgical findings, pathology, and survival were analyzed prospectively in consecutive patients. Using data from imaging studies, all patients were placed into one of three stages based on the extent of ductal involvement by tumor, the presence or absence of portal vein compromise, and the presence or absence of hepatic lobar atrophy. RESULTS: From March 1991 through December 2000, 225 patients were evaluated, 77% of whom were seen and treated within the last 6 years. Sixty-five patients had unresectable disease; 160 patients underwent exploration with curative intent. Eighty patients underwent resection: 62 (78%) had a concomitant hepatic resection and 62 (78%) had an R0 resection (negative histologic margins). Negative histologic margins, concomitant partial hepatectomy, and well-differentiated tumor histology were associated with improved outcome after all resections. However, in patients who underwent an R0 resection, concomitant partial hepatectomy was the only independent predictor of long-term survival. Of the 9 actual 5-year survivors (of 30 at risk), all had a concomitant hepatic resection and none had tumor-involved margins; 3 of these 9 patients remained free of disease at a median follow-up of 88 months. The rates of complications and death after resection were 64% and 10%, respectively. In the 219 patients whose disease could be staged, the proposed system predicted resectability and the likelihood of an R0 resection and correlated with metastatic disease and survival. CONCLUSION: By taking full account of local tumor extent, the proposed staging system for hilar cholangiocarcinoma accurately predicts resectability, the likelihood of metastatic disease, and survival. Complete resection remains the only therapy that offers the possibility of long-term survival, and hepatic resection is a critical component of the surgical approach.

Adult↗
PubMed2001

Multiple high-grade bronchial dysplasia and squamous cell carcinoma: concordant and discordant mutations.

Loss of heterozygosity (LOH) involving chromosomes 3p, 5q, 9p, or 17p and aberrant expression or mutation of p53 are reported previously in selected bronchial dysplasias and squamous cell cancers (SCCs). Yet, comprehensive analyses of LOH patterns at these chromosomal sites and of p53 alterations are not reported for histologically normal bronchial epithelium, high-grade bronchial dysplasia, and SCC present in the same pulmonary resections. Whether concordant or discordant genetic changes are detected in these bronchial tissues, especially when multiple high-grade dysplastic bronchial lesions are present, was studied. Genomic DNA was microdissected from eight pulmonary SCCs and high-grade dysplastic lesions that were associated with SCC. In four cases, two independent high-grade dysplastic bronchial lesions were identified. When available, histologically normal bronchial epithelium was microdissected. Germ-line genomic DNA was isolated from normal lymph nodes. LOH was assessed for 15 microsatellite markers on chromosomes 3p, 5q, 9p, or 17p, sites frequently deleted in lung cancers. Immunohistochemical p53 expression was studied and correlated with p53 DNA sequence analyses. Progressive LOH for these markers was found when SCCs were compared with high-grade dysplasia and histologically normal bronchial epithelium present in the same resections. Histologically normal bronchial specimens had LOH in up to 27% of informative markers. High-grade dysplastic lesions exhibited LOH for 18-45% and SCC had LOH for 18-73% of the markers. Common regions of LOH were found in some dysplasias compared with SCCs. In other dysplasias, discordance was found relative to SCCs, especially for p53 mutations. In cases with a single or second high-grade dysplasia associated with SCC, heterogeneity in LOH markers was detected. These concordant and discordant changes were consistent with convergent and divergent clonal selection pathways in pulmonary squamous cell carcinogenesis. Some histologically normal bronchial epithelial tissues had genetic changes more similar to those in the SCCs than in dysplastic lesions. DNA loss or mutations accumulate in SCC, but discordant genetic changes can exist in the same carcinogen-exposed bronchial tissues. These findings have implications for lung cancer prevention trials.

Bronchial Diseases↗
PubMed2000

Intra-abdominal fibrosis after systemic and intraperitoneal therapy containing fluoropyrimidines.

BACKGROUND: Intra-abdominal and retroperitoneal fibrosis has been described as secondary to intraperitoneal (IP) administration of several chemotherapeutic agents, including carboplatin, mitoxantrone, and the combination of 5-fluorouracil and cisplatin. The IP administration of floxuridine (FUDR) is an effective and minimally toxic treatment for patients with metastases to the peritoneum. An increasing number of patients with colorectal, gastric, or ovarian carcinoma are treated with IP chemotherapy. METHODS: The authors report two patients with metastatic colon carcinoma who experienced severe intra-abdominal fibrosis presenting as an intra-abdominal mass mimicking recurrence in one patient and diffuse encasement of the bowel in the other, after the administration of IP FUDR and leucovorin. RESULTS: Two patients with Stage III colon adenocarcinoma received postoperative adjuvant 5-fluorouracil and levamisole. They subsequently presented with a rise in carcinoembryonic antigen level and isolated liver metastasis. They underwent hepatic lobectomy with postoperative intra-arterial hepatic FUDR and systemic 5-fluorouracil and leucovorin. They each had an intra-abdominal recurrence, which was resected and treated with postoperative IP FUDR and leucovorin. They then presented with a diffuse pattern of IP fibrosis with no tumor identified. CONCLUSIONS: IP FUDR and leucovorin therapy can be associated with diffuse IP fibrosis, which in this study caused an intra-abdominal mass that was indistinguishable from recurrent malignancy in one patient and encasement of the bowel in the other.

Adenocarcinoma↗
PubMed2000

Levels of E2F-1 expression are higher in lung metastasis of colon cancer as compared with hepatic metastasis and correlate with levels of thymidylate synthase.

We recently reported that forced overexpression of the transcription factor E2F-1 in human HT-1080 fibrosarcoma cells resulted in corresponding high levels of thymidylate synthase (TS) and resistance to 5-fluoropyrimidines (D. Banerjee et al., Cancer Res., 58: 4292-4296, 1998). Because colorectal metastasis to the lung has higher TS levels than liver metastasis and is less responsive to treatment with 5-fluorouracil (R. Gorlick et al., J. Clin. Oncol., 16: 1465-1469, 1998), it was, therefore, of interest to measure E2F-1 expression in these tumors. In contrast to marginally increased levels of dihydrofolate reductase and topoisomerase I in lung metastasis as compared with liver metastasis, lung tumors had a 5-fold increase in E2F-1 expression as compared with liver tumors, corresponding to the relative levels of TS in these metastases. These data indicate that there exists a close correlation between E2F-1 and TS levels and provide a rationale for targeting this transcription factor, ie., E2F-1, for the treatment of certain cancers.

Adenocarcinoma↗
PubMed2000

Lymph node staging in gastric cancer: is location more important than Number? An analysis of 1,038 patients.

OBJECTIVE: To compare the impact of staging systems on the survival of 1,038 patients with gastric cancer undergoing resection for cure in a North American center. SUMMARY BACKGROUND DATA: In 1997, the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer redefined N stage in gastric cancer. The number of involved nodes rather than their location defines N, and a minimum of 15 examined lymph nodes is recommended for adequate staging. In the 1988 AJCC N-staging system, N1 and N2 node metastases were defined as within 3 cm or more than 3 cm of the primary; the 1997 AJCC N stages were defined as N1 = 1 to 6 positive nodes, N2 = 7 to 15 positive nodes, and N3 = more than 15 positive nodes. METHODS: Between 1985 and 1999, 1,038 patients underwent an R0 resection. Median and 5-year survival rates were compared and the Kaplan-Meier method was used to estimate median survival. RESULTS: The location of positive nodes did not significantly affect median survival when analyzed by the number of positive nodes. In contrast, the number of positive lymph nodes had a profound influence on survival. The new N categories served as a better discriminator of median survival when 15 or more nodes were examined. Survival estimates for stages II, IIIA, and IIIB were significantly influenced by examining 15 or more nodes. CONCLUSION: The number of positive nodes best defines the prognostic influence of metastatic lymph nodes in gastric cancer. Survival estimates based on the number of involved nodes are better represented when at least 15 nodes are examined.

Adult↗
PubMed2000

Solitary fibrous tumor of the liver: imaging findings.

OBJECTIVE: This study describes the imaging features of solitary fibrous tumor of the liver in three patients. CONCLUSION: A single large, well-circumscribed, heterogeneously enhancing hepatic mass was present in each patient. These imaging features are suggestive of, but not diagnostic for, solitary fibrous tumor of the liver. The two benign and one malignant solitary fibrous tumors of the liver in this series were indistinguishable from one another on imaging studies.

Female↗
PubMed1999

5-fluorouracil-induced small bowel toxicity in patients with colorectal carcinoma.

BACKGROUND: Diarrhea and oral mucositis are the most frequently reported gastrointestinal side effects caused by 5-fluorouracil (5-FU). Diarrhea may be severe in 10-30% of patients and is schedule-dependent. 5-FU-induced gastrointestinal toxicity predominantly affects the upper and the lower gastrointestinal tract. The current study describes 5-FU-induced small bowel toxicity as an entity that to the authors' knowledge has not been reported previously in patients with colon carcinoma receiving 5-FU-based therapy. METHODS: The authors report a series of six patients with colorectal carcinoma who developed acute small bowel toxicity after treatment with 5-FU and leucovorin. RESULTS: Six patients developed a clinical picture of acute abdominal pain and diarrhea. Small bowel damage was documented by laparotomy in two patients, by colonoscopy in one patient, and by abdominal computed tomography scan in three patients. The course was complicated by recurrence of symptoms in one patient who was rechallenged with 5-FU and leucovorin, but the remaining four patients were rechallenged safely with lower doses of 5-FU and leucovorin after the acute toxicity episode. A possible explanation for this toxicity is 5-FU-induced vasospasm and/or decrease in fibrinolytic activity that results in decreased mucosal blood flow. CONCLUSIONS: 5-FU-induced small bowel toxicity is a potentially severe toxicity that may occur in patients with colon carcinoma or other malignancies who are receiving 5-FU-based therapy. [See editorial on pages 1099-100, this issue.]

Adenocarcinoma↗
PubMed1999

In vivo interleukin-2 gene therapy of established tumors with herpes simplex amplicon vectors.

In vivo cytokine gene transfer may greatly simplify autologous tumor vaccine production. Herpes simplex viral amplicon vectors (HSV) are efficient gene-transfer vehicles and may overcome many limitations of prior gene-transfer methods. The interleukin-2 (IL-2) and beta-galactosidase genes (lac) were inserted into an HSV amplicon vector and tested in a subcutaneous squamous cell carcinoma of lung origin to determine the efficiency of in vivo gene transfer and the utility of such a direct gene transfer approach in cancer therapy. Gene transfer and expression were assessed by histochemical staining and enzyme-linked immunosorbent assay (ELISA). Growth of injected tumors as well as non-injected tumors remote from the site of injection was assessed. Assessment of lymphocytic infiltrates into tumors was performed by immunohistochemistry. Survival was recorded. Direct in vivo injection of established tumors with a HSVi12 resulted in efficient gene transfer and production of IL-2 in the injected tumor but not at tumors remote from the sites of injection. There was a significant suppression of growth of the tumors injected with HSVi12 (P<0.01) when compared with tumors injected with HSV without i12. Of note, growth of tumors remote from sites of HSVi12 injection was also retarded and treatment was associated with a significant (P<0.05) improvement in survival. Direct intratumoral administration of HSV amplicon vectors can result in efficient transfer of cytokine genes and have antitumor efficacy. HSV vectors are therefore potentially useful agents in such in vivo gene-therapy strategies and simplify cytokine antitumor gene-therapy strategies.

Animals↗
PubMed1999

Herpes simplex virus (HSV)-mediated ICAM-1 gene transfer abrogates tumorigenicity and induces anti-tumor immunity.

BACKGROUND: Costimulatory and cellular adhesion molecules are thought to be essential components of antigen presentation in the immune response to cancer. The current studies examine gene transfer utilizing herpes viral amplicon vectors (HSV) to direct surface expression of adhesion molecules, and specifically evaluate the potential of a tumor-expressing intercellular adhesion molecule-1 (ICAM-1) to elicit an anti-tumor response. MATERIALS AND METHODS: The human ICAM-1 (hICAM1) gene was inserted into an HSV amplicon vector and tested in a transplantable rat hepatocellular carcinoma and in a human colorectal cancer cell line. Cell surface ICAM-1 expression was assessed by flow cytometry. Lymphocyte binding to HSV-hICAM1-transduced cells was compared with that to cells transduced with HSV not carrying the ICAM gene. Tumorigenicity of HSV-hICAM1-transduced tumor cells were tested in syngeneic Buffalo rats. Additionally, immunization with irradiated (10,000 rads) HSV-hICAM1-transduced tumor cells was performed to determine its effect on tumor growth. RESULTS: A 20-min exposure of tumor cells at a multiplicity of infection (MOI) of 1 resulted in high-level cell surface expression of human ICAM in approximately 25% of tumor cells. Transduced rat or human tumor cells exhibited significantly enhanced binding of lymphocytes (p < 0.05). HSV-hICAM1-transduced cells elicited an increase in infiltration by CD4(+) lymphocytes in vivo and exhibited decreased tumorigenicity. Immunization with irradiated HSV-hICAM1-transduced cells protected against growth of subsequent injected parental tumor cells. CONCLUSIONS: HSV amplicon-mediated gene transfer is an efficient method for modifying the cell surface expression of adhesion molecules. Increased tumor expression of ICAM-1 represents a promising immune anti-cancer strategy.

Animals↗
PubMed1998

Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma.

PURPOSE: It has been observed previously that the pulmonary metastases of colorectal adenocarcinoma are less responsive to therapy with fluorouracil (FUra) as compared with other sites of metastasis (liver, local). To investigate the basis of this chemoresistance, the levels of thymidylate synthase (TS) mRNA and protein were measured, as TS expression has been shown to be predictive of response to therapy in colorectal cancer. MATERIALS AND METHODS: Tumors were obtained from 19 patients with metastatic colorectal cancer (12 hepatic and seven pulmonary). TS expression was measured by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and TS protein levels were measured by Western blotting. The presence of TS amplification was assessed by Southern blotting. Levels of p53 protein were determined using immunohistochemistry. RESULTS: TS mRNA expression was shown to be significantly higher in the pulmonary metastases (mean TS/beta-actin ratio, 19.7; n = 7) as compared with the hepatic metastases (mean TS/beta-actin ratio, 4.7; n = 11) of colorectal cancer. Lower TS expression was observed in patients with hepatic metastases who had received prior FUra versus patients who had not been treated. High levels of TS expression in some samples was associated with low-level (two to three gene copies) increases in TS gene copy numbers and this was observed more frequently in the pulmonary metastatic samples. The increased gene copy numbers occurred both in samples with wild-type p53 and those with mutant p53 tumor-suppressor gene as determined by immunohistochemistry. CONCLUSION: High levels of TS enzyme may be the basis of the lack of response of pulmonary metastases to FUra treatment.

Adenocarcinoma↗
PubMed1997

High telomerase activity in primary lung cancers: association with increased cell proliferation rates and advanced pathologic stage.

BACKGROUND: Telomerase enzyme activity is not detected in most normal cells, a phenomenon believed to be associated with limitations on cellular proliferation. Since this activity is detected in nearly all human tumors, including non-small-cell lung cancers, it has been suggested that telomerase activation may be coupled to acquisition of the malignant phenotype. In this study, we determined whether telomerase activity was associated with tumor pathologic stage, tumor cell proliferation rates, and clinical outcome in a cohort of patients with resected non-small-cell lung cancer for whom long-term follow-up was available. METHODS: Primary tumor specimens from 99 patients treated with surgery alone and six patients treated with surgery after chemotherapy were analyzed. Telomerase activity was measured by means of a modified Telomeric Repeat Amplification Protocol (TRAP) assay. Southern blot analysis of terminal restriction fragments was used to evaluate telomere length. Immunohistochemical analysis of Ki-67, a proliferation-associated nuclear antigen, was used to assess tumor cell proliferation. RESULTS: Telomerase activity was detected in 84 of the 99 tumors treated with surgery alone; this activity was not detected in specimens of adjacent, benign lung tissue. Telomerase was detected in only three of six tumors resected after chemotherapy. For the surgery-alone group, statistically significant positive associations were found between the level of telomerase activity and tumor stage, lymph node metastasis, pathologic TNM (tumor-node-metastasis) stage, and Ki-67 immunostaining; a statistically significant inverse association was found between telomerase activity and patient age. No statistically significant differences in telomere length were found in relation telomerase activity or pathologic stage. Telomerase activity was not found to be associated with clinical outcome in a multivariate Cox proportional hazards analysis adjusted for tumor stage and lymph node status. CONCLUSIONS: High telomerase activity is detected frequently in primary non-small-cell lung cancers that exhibit high tumor cell proliferation rates and advanced pathologic stage.

Adenocarcinoma↗
PubMed1997

Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.

Approximately 130,000 cases of colorectal cancer (CRC) are diagnosed in the United States each year, and about 15% of these have a hereditary component. Two well-defined syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), account for up to 5% of the total new cases of CRC. Truncating APC mutations are responsible for FAP, and defective mismatch repair genes cause HNPCC. However, the genes responsible for most of the familial cases are unknown. Here we report a mutation (T to A at APC nucleotide 3920) found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC. Rather than altering the function of the encoded protein, this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition.

Adenomatous Polyposis Coli↗
PubMed1997

Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression.

The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-alpha only in 10% (10 of 96), of both EGFR and TGF-alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

Adenocarcinoma↗
PubMed1996

Low grade salivary duct carcinoma. A distinctive variant with a low grade histology and a predominant intraductal growth pattern.

BACKGROUND: Salivary duct carcinoma (SDC) has been established as a morphologically distinct and highly aggressive (HG) malignancy of the major salivary glands. However, a low grade (LG) or intermediate grade salivary duct neoplasm has not been described. METHODS: We report the clinicopathologic findings of 10 cases believed to represent the (LG) counterpart of SDC. Immunoperoxidase stains were performed on five cases, and electron microscopy on three. RESULTS: All of the tumors occurred in adult patients with no sex predilection, and presented as slow growing parotid gland lesions. Four cases involved the superficial lobe, one the deep lobe, and one arose within an intraparotid lymph node. The exact location of the tumor within the parotid gland was not stated in four cases. The size of the tumors ranged from 0.7 to 4 cm in greatest dimension, with most measuring between 1 and 2 cm. The gross appearance was focally to predominantly cystic. Microscopically, the tumors were characterized by intraductal proliferative lesions exhibiting three main patterns: (1) cystic ducts with micropapillary, tufted, and plaque-like intraluminal projections; (2) ducts distended by a solid or pseudocribriform (fenestrated) cellular proliferation, with varied cystic dilatation; and (3) ducts exhibiting architectural atypia. The three patterns coexisted and merged in most tumors, in varying proportions. All tumors shared bland to LG cytologic features, with the exception of one that had focal high-grade cytologic ductal atypia. Despite gross circumscription, there was microscopic multifocality, and in one case, stromal invasion. By immunohistochemistry, the neoplastic cells expressed the conventional ductal and glandular epithelial cell markers in addition to strong positivity for S-100 with coexpression for CK-903. Electron microscopy confirmed the ductal phenotype of the tumors and supported an in situ process evidenced by the presence of native myoepithelial cells. Nine patients underwent total parotidectomy and one superficial parotidectomy. One patient received radiation therapy following total parotidectomy. Follow-up for 6 cases ranged from 2 to 12 years and revealed no evidence of disease. CONCLUSIONS: LG-SDC represents the LG end of the spectrum of salivary duct malignant neoplasms and exhibits differentiation towards an intercalated duct-like cell phenotype. Its relationship to HG-SDC should be further explored.

Adult↗