Tumor Poor Prognosis Research Articles

Organochlorines and breast cancer risk by receptor status, tumor size, and grade (Canada).

We evaluated the association between organochlorines and breast cancer subtype defined by the tumor characteristics: estrogen receptor status, progesterone receptor status, tumor size, and grade. A case-control study was conducted from 1995 to 1997 in Kingston and Toronto, Canada. Breast adipose tissue, taken from 217 cases and 213 biopsy controls frequency-matched on age, was analysed for 14 polychlorinated biphenyl (PCB) congeners and 10 pesticides. Adjusting for age, geometric means of several organochlorines differed by estrogen receptor status and tumor grade (p < 0.05). Odds ratios (ORs) for each organochlorine relative to the common control group for breast cancers of differing subtype were compared using polytomous logistic regression. Although the ORs did not differ significantly by subtype, the ORs of PCBs and p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were higher with risk of estrogen receptor-negative breast cancer than estrogen receptor-positive breast cancer. One of the most extreme differences was with DDE, where the OR for the association with risk of estrogen receptor-negative breast cancer was 2.4 (95% confidence interval (CI) 1.0-5.4) in the uppermost tertile relative to the lowest, whereas the corresponding OR for risk of estrogen receptor-positive breast cancer was 1.1 (95% CI 0.6-1.9). PCBs also tended to be more strongly positively associated with risk of larger and higher-grade tumors. The association between organochlorines and breast cancer risk did not significantly differ by subtype, but many PCBs were more strongly associated with tumors of poor prognosis.

Comparative genomic hybridization of postirradiation sarcomas.

Radiotherapy is a known risk factor for sarcoma development. Postirradiation sarcomas arise within the radiation field after a latency period of several years and usually are highly malignant. Very little is yet known about their genetic changes. Twenty-seven postirradiation sarcomas were analyzed by comparative genomic hybridization, which allows genome-wide screening of DNA sequence copy number changes. Copy-number aberrations were detected in 20 (74%) tumors. The mean number of aberrations per tumor was 5.3 with gains outnumbering losses. The most frequent gains affected the minimal common regions of 7q11.2-q21 and 7q22 in 30% and 7p15-pter in 26%. Gain of 8q23-qter was detected in 22%. The most frequent losses affected 11q23-qter and 13q22-q32 in 22%. In osteosarcomas, the most frequent aberration was loss of 1p21-p31, in malignant fibrous histiocytomas (MFH) gain of 7cen-q22, and in fibrosarcomas gain of 7q22. The findings in postirradiation osteosarcomas and MFHs were compared with findings in sporadic osteosarcomas and MFHs, reported previously by the authors. In sporadic osteosarcomas, gains outnumbered losses, but, in postirradiation osteosarcomas, losses were more frequent than gains. Loss at 1p was rare in sporadic osteosarcoma (3%) but frequent (57%) in postirradiation osteosarcomas. Gains at 7q were frequent both in postirradiation and sporadic MFH. According to previous studies on different types of sporadic sarcomas, gains at 7q or 8q are associated with poor prognosis or large tumor size. Thus, the frequent gains at 7q and 8q might have been responsible in part for the poor prognosis of postirradiation sarcomas. Also, however, some of their clinical features, i.e., high malignancy grade, late diagnosis, and central location, are associated with a poor prognosis.

Clinicopathological characteristics of breast carcinomas with allelic loss in the p73 region.

p73, a new member of the p53 family, has been mapped to chromosome 1p 36, a region where loss of heterozygosity (LOH) is frequently observed in primary human tumors. Allelic loss studies involving the 1p arm in breast carcinomas offer rates ranging from 13% to 75%, depending on the genetic interval being studied. We investigated LOH in an intragenic microsatellite marker, and those centromerically flanking the p73 gene, at 1p 36, and their correlations with patient age and 10 pathologic parameters in a series of 193 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using the five markers of the 1p 36 region (p73P1, D1S2694, D1S214, D1S2666 and D1S450). LOH was found in at least one of these markers in 27% of tumors. When we established the comparison between tumors with and without LOH and the distribution of the 10 pathologic parameters considered, we observed statistically significant differences in association with higher histologic grade (p = 0.02), more advanced pathological stage (p = 0.02), peritumoral vessel involvement (p = 0.04) and poorly differentiated carcinomas (p = 0.01), as well as in tumors that concomitantly exhibited lymph node metastases, peritumoral vessel involvement and absence of steroid receptors (p = 0.02). These data suggest that LOH in the p73 region could be pathogenically related to breast cancer and possibly to a poor tumor prognosis.

Lobe-specific extent of systematic lymph node dissection for non–small cell lung carcinomas according to a retrospective study of metastasis and prognosis

Background: Complete lymphadenectomy of the mediastinum is advised for patients with lung cancer to provide prognostic information and possible survival benefit. The proper extent of dissection should be further defined. Method: The lymphatic metastatic patterns according to the primary site and prognoses were retrospectively analyzed in 166 patients with non–small cell carcinoma who underwent at least lobectomy with hilar and mediastinal lymphadenectomy. All patients had histologically proven mediastinal metastasis (pN2). Results: Among 54 right upper lobe tumors the most common site of metastasis was the lower pretracheal station (74%), whereas metastases to the subcarinal station were seen only in 13%. Among 8 patients with right middle lobe tumors and 41 patients with right lower lobe tumors, both superior mediastinal and subcarinal stations were involved. The 34 left upper segment tumors metastasized to the aorticopulmonary window most commonly (71%) and to the subcarina only in 12% of cases. Inversely, the 10 left lingular tumors metastasized to the subcarina most commonly (50%) and to the aorticopulmonary window only in 20% of cases. Among 44 left lower lobe tumors the subcarinal station was most common for metastasis (58%), with infrequent metastases to the aorticopulmonary window. The 5-year survival for all 166 patients was 35%. Patients with single-station and single-node metastases had a significantly better prognosis than those with more extensive metastases. Right lower lobe tumors with superior mediastinal metastasis carried a particularly poor 5-year survival of only 4.1%. Comment: Subcarinal lymphadenectomy is not always necessary for tumors of the right upper lobe and left upper segment. For tumors of other lobes both superior mediastinal dissection and subcarinal dissection are advised. However, superior mediastinal metastasis should be recognized as an indicator of poor prognosis in tumors of both lower lobes. (J Thorac Cardiovasc Surg 1999;117:1102-11)

Carcino-sarcome bronchopulmonaire

Bronchopulmonary carcinosarcoma is an uncommon neoplasm consisting of mixed malignant epithelial and mesenchymal cells. We report a case of bronchopulmonary carcinosarcoma in a 62-year-old man illustrating some characteristics of this tumor of poor prognosis and unknown histogenesis. Bronchopulmonary carcinosarcoma has clinical and X rays features identical to those of bronchopulmonary epithelial malignant tumors. Most of the authors consider that a totipotential cell might be at the origin of this "mixed" tumor. Although 90% of bronchopulmonary carcinosarcomas are resectable, their prognosis is worse than that of other lung cancers, with a 6-month median survival.

Customized Gynecologic Interstitial Implants: CT-Based Planning, Dose Evaluation, and Optimization Aided by Laparotomy

Purpose: Interstitial perineal implants may be utilized to deliver a high local radiation dose in the treatment of advanced gynecologic malignancies. Lack of knowledge of the precise anatomic relationships between the implant and the target and critical organs may limit efficacy and increase complication risks. Computed tomography (CT)-based planning, dose evaluation, and optimization of customized interstitial implants, aided by laparotomy, have been developed to overcome these limitations. Methods and Materials: Twenty patients with locally advanced gynecologic malignancies treated between May 1990 to October 1996 with external irradiation and one or two implants. Interstitial implants were performed when intracavitary brachytherapy was judged to be inadequate or when the response to external radiation and an intracavitary implant was not satisfactory. Customized interstitial implants were planned using preimplantation CT to determine catheter angles and paths that best implanted the target while avoiding pelvic bones and organs. Laparotomy aimed at lysing bowel adhesions, placement of omental carpet, and refining needle placement. Postimplantation CT was used for loading optimization and dose evaluation. Results: Catheter angles 15–25° were found to adequately implant anteriorly laying targets while avoiding pubic bones and bladder. Adhesiolysis of bowel loops from the vaginal apex was required in patients with prior hysterectomy. Small modifications in catheter placements were made during laparotomy in all implants. Postimplantation CTs showed deviations of the catheter positions compared with the planning CTs and were essential in determining target and organ doses and loading optimization. At a median follow-up of 42 months (range: 9–80 months), local control rate is 55% and disease-free survival 40%. Late complications occurred in 2 of 11 of patients without local recurrence. Conclusions: CT-based planning, loading optimization, and dose evaluation of customized implants improve radiation dose delivery. Laparotomy enhances implant accuracy and safety. Local tumor control rate is still unsatisfactory. It reflects the shortcomings of technical advances alone in poor prognosis tumors like those selected for this series.

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

The Challenge of Developing New Therapies for Childhood Cancers

The Challenge of Developing New Therapies for Childhood Cancers

Entropy-based texture analysis of chromatin structure in advanced prostate cancer.

A new texture operator, gray-level entropy matrix (GLEM), was developed, and nine new textural features were extracted from this matrix. These textural features were applied to light microscopy images of nuclei taken from monolayers of advanced prostate cancer cells representing two different prognostic groups: hormone-sensitive (good prognosis) and hormone-resistant (poor prognosis) tumors. A comparison between the classification results obtained from GLEM features and those obtained from standard textural estimators is also discussed. Single features that gave correct classification rates better than 65% were included in a discriminant analysis in order to find the optimal set of features to discriminate between the two prognostic groups in the training data set. The best combination of features includes three GLEM features together with ENTROPY extracted from gray-level cooccurrence matrix, and this combination gave a correct classification rate of 95% using the leaving-one-out technique. The influences of image sharpness and number of cells were also investigated. The features based on entropy or degree of scatter of minute structures can be used to discriminate between hormone-sensitive and hormone-resistant prostate carcinomas.

Entropy‐based texture analysis of chromatin structure in advanced prostate cancer

A new texture operator, gray-level entropy matrix (GLEM), was developed, and nine new textural features were extracted from this matrix. These textural features were applied to light microscopy images of nuclei taken from monolayers of advanced prostate cancer cells representing two different prognostic groups: hormone-sensitive (good prognosis) and hormone-resistant (poor prognosis) tumors. A comparison between the classification results obtained from GLEM features and those obtained from standard textural estimators is also discussed. Single features that gave correct classification rates better than 65% were included in a discriminant analysis in order to find the optimal set of features to discriminate between the two prognostic groups in the training data set. The best combination of features includes three GLEM features together with ENTROPY extracted from gray-level cooccurrence matrix, and this combination gave a correct classification rate of 95% using the leaving-one-out technique. The influences of image sharpness and number of cells were also investigated. The features based on entropy or degree of scatter of minute structures can be used to discriminate between hormone-sensitive and hormone-resistant prostate carcinomas. © 1996 Wiley-Liss, Inc.

Transitional cell carcinoma of the upper urinary tract: Follow-up and prognostic factors

— Of the 176 patients treated in our Institute over the last 16 years for upper tract transitional cell carcinoma (UTTCC), 155 were included in this study, 97 of whom had undergone nephroureterectomy, 28 conservative surgery and 30 endourologic treatment. The overall survival rate at 5 and 10 years was 73% and 58%, respectively. Univariate analysis of overall survival rate (O.S.) and disease-free survival rate (D.F.S.) showed no difference between patients with superficial and with invasive tumours, while multivariate analysis highlighted a difference. No difference was evident upon univariate and multivariate analysis of the patients with superficial tumours who underwent conservative (19) vs. radical (45) surgery. The same can be said for the so-called good prognosis tumours (pTa-T1-G2) and poor prognosis tumours (pT1-G3, pT2-4, G2-3) submitted to radical surgery. Overall survival was better in patients with no recurrent tumours compared to those with recurrences; furthermore prognosis was worse for patients with more than 2 recurrences. Tumour site, mono or multifocality and associated bladder tumour did not influence prognosis. Our experience confirms the basic importance of grade as a prognostic factor for UTTCC and the favourable prognosis for patients with superficial tumours, regardless of surgical technique. A rigid follow-up is mandatory for patients with more than 2 recurrences.

Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma

Primary cutaneous neuroendocrine (Merkel cell) carcinoma is a rare neoplasm with aggressive behavior but potential for response to radiotherapy and chemotherapy. Optimal treatment regimens are evolving based on reports of case series and a growing understanding of the natural history. A retrospective analysis of 34 cases treated at two Australian Institutions over 13 years is presented, focusing on clinical features and response to therapy. The aggressive nature of this neoplasm is confirmed by the local recurrence rate of 22% following surgical excision, the development of regional node metastases in 76%, and of distant metastases in 70%. Overall median survival was 24 months with 65% of patients succumbing to metastatic disease. An association with B cell malignancies and immunosuppressive therapy is noted, with these patients having a poorer outcome, and one spontaneous remission was observed. Radiation therapy produced responses in 21 of 30 measurable sites (11 complete, 10 partial), and in 11 sites irradiated prophylactically there was only one infield relapse (9%). Responses to chemotherapy were observed in 8 of 20 applications (40%), particularly carboplatin and etoposide given in the setting of regional node disease. In this poor prognosis tumor, further investigation of adjuvant radiotherapy and chemotherapy is warranted, as responsiveness of recurrent disease is confirmed. Immunological factors appear important in the natural history, and their manipulation may offer additional therapeutic options.

Intensification thérapeutique et autotransplantation de cellules-souches hématopoïétiques dans le traitement des tumeurs solides de l'adulte : principes, réalisation et application au traitement des tumeurs germinales, trophoblastiques, mammaires, ovariennes et bronchiques à petites cellules. Première partie

Autologous bone marrow transplantation for the treatment of solid tumors in adults remains an uncommon therapeutic approach. The feasibility of such high-dose therapies is clearly proved, especially with the advent of hematopoietic growth factors and the rescue by the peripheral stem cells to reduce the duration of the chemotherapy-induced myeloid aplasia. The question is to exactly define the place of high-dose therapy in the land of solid tumors. For the treatment of primary chemoresistant gonadal germ-cell tumors, the possibility to cure the patients and the interest of high-dose therapy with autologous bone marrow transplantation are clearly demonstrated. As consolidation for the treatment of poor prognosis tumors, the place of high-dose therapies remains moot. For the treatment of chemoresistant extragonadal germ-cell tumors, especially for primary mediastinal tumors, the level of resistance to cisplatin-based chemotherapy regimens is generally too high to be overcome by intensive therapies given as single course or as tandem courses. However in association with debulking surgery, this therapeutic approach has to be considered for some patients. In the treatment of poor prognosis breast cancer, high-dose therapy with autologous bone marrow transplantation or with peripheral stem cells support is able to convert some patients with partial response into complete responders. However, the consequences on overall survival and on disease-free survival are not evident. For metastatic breast cancer and for poor-prognosis tumors (inflammatory breast cancer, axillary metastatic nodes > or = 8), the interest of high-dose therapy has to be determined by randomized studies. These studies are ongoing in USA and in Europe. For the treatment of poor-prognosis ovarian cancer, the situation is more difficult to appraise. Once again, randomized studies have to be done to precisely define the place of high-dose therapy. In the land of small-cell lung carcinomas, high-dose therapy is actually forsaken by most of authors, even for limited diseases. The results of previous studies are disappointing. Moreover, occult medullary micrometastases involvement is frequent, once again even in limited diseases. However new therapeutic associations, as the ICE regimen (IFM, Carboplatin, VP-16) delivered as single or tandem therapy, have to be studied, especially as early consolidation therapy for the treatment of limited small-cell lung carcinomas.

What's New in Breast Cancer?: Molecular Perspectives of Cancer Development and the Role of the Oncogene c- erbB-2 in Prognosis and Disease

The oncogene c-erbB-2 is frequently amplified in human breast carcinoma. The c-erbB-2 gene is present as a single copy in normal cells, and has been mapped to chromosome 17 in the region 17q 12-21.32. c-erbB-2 encodes a transmembrane glycoprotein known as p185. The intracellular component of p185 has tyrosine kinase activity; the extracellular domain has a structure resembling a growth factor receptor. c-erbB-2 amplification, p185 overexpression and levels of transcribed c-erbB-2 specific messenger RNA have been studied in a large number of breast carcinomas using a variety of techniques. In general, overexpression of p185 oncoprotein reflects various levels of DNA amplification, though in some cases amplification can be detected in the absence of overexpression of p185 and similarly overexpression of p185 can be present without detectable levels of c-erbB-2 amplification. This findings suggests that multiple mechanisms may be responsible for overexpression. c-erbB-2 amplification and/or overexpression occurs in almost all cases of high grade duct carcinoma in-situ, but has been reported in only 10%-40% of infiltrating duct carcinoma. c-erbB-2 amplification or overexpression occurs rarely in invasive lobular carcinoma, and has not been detected in ductal or lobular epithelial hyperplasia, or in atypical ductal or atypical lobular hyperplasia. It is generally believed that c-erbB-2 amplification/overexpression is an important independent prognostic indicator in breast carcinoma, identifying a subset of patients with poor prognosis tumours, particularly if axillary node metasases are present. However, many unanswered questions remain regarding c-erbB-2 and its role in breast cancer development and progression. The causes of c-erbB-2 amplification are unknown. There is no evidence of mutations in the human gene which might cause amplification or overexpression. The significance of the differences in levels of c-erbB-2 amplification/overexpression in in-situ duct carcinoma and associated invasive duct carcinoma has not been established. Amplification or overexpression have not been reported in atypical duct hyperplasia, a proposed precursor of duct carcinoma in-situ, yet overexpression occurs almost always in high grade duct carcinoma in-situ. c-erbB-2 may play a critical role in the development of a clonal in-situ, proliferation of high histological grade, yet does not obviously influence the acquisition of an invasive phenotype. We would postulated that this instability in amplification/overexpression is of biological significance, and if better understood may aid in the study of progression of human breast carcinoma.

Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: A pediatric oncology group study

Purpose : In September 1984, the Pediatric Oncology Group began accrual to a Phase I/II study designed to assess the efficacy and toxicity of sequentially escalated doses of hyperfractionated (twice daily) radiotherapy in children wit-h poor-prognosis brain stem tumors. Pediatric Oncology Group Study #849closed in June 1990 with a total of 136 patients on study. We report here the outcome of patients treated atthe third and final dose level (75.6 Gy), and compare the results to those obtained at the 66 and 70.2 Gy dose levels. Methods and Materials : Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the midbrain, pons or medulla. Histological confirmation of diagnosis was not mandatory provided that the clinical and radiological findings were typical for brain stem glioma. Treatment consisted of radiotherapy delivered to local fields. At the third dose level, fraction sizes of 1.26 Gy were given twice dally, with a minimum interfraction interval of 6 hr to a dose of 75.6 Gy in 60 fractions over 6 weeks. Between 5 89 and 6 90 , 41 patients were accrued to the study. Two were excluded from analysis leaving 39 evaluable patients, 21 male and 19 female, whose ages ranged from 3 to 15 years (median 7.5 years). Results : Following treatment, neurological improvement was reported in 30/39 (77%) of the patients. On central review of imaging studies in 29 patients, one patient was found to have had a complete response to radiotherapy, five a partial (> 50% response), and only three had non-responding or progressive disease. The median time to disease progression was 7 months; median survival time was 10 months; survival at 1 year was 39.9% (SE 8.3%) and at 2 years, 7% (SE 4.8%). The pattern of failure was local in all patients; in addition six had evidence of leptomeningeal seeding. Morbidity of treatment included an enhanced skin reaction (21%), otitis media and/or externa (26%) and steroid use > 3 months (62%). Intralesional necrosis was a frequent finding (45%) on imaging studies performed at a median time of 6 weeks post treatment. Conclusion : The results of treatment in terms of progression-free survival and overall survival are not significantly different (at p = .55 and p = .46, respectively) from those obtained at the two previous dose levels. There is no evidence that higher doses of hyperfractionated radiotherapy given as in this study improve the outlook of patients with poor-risk brain stem gliomas.

A comparison between the clinical behavior of neurilemmomas in the neck and oral and maxillofacial region

The records of 49 patients with neurilemmoma in the neck and oral and maxillofacial region (OMR) were reviewed. The results showed some location-related differences in clinical behavior, including six cases of recurrence and two cases of malignant change found in the OMR. It was suggested that anatomic factors play an important role in the poor prognosis of tumors in the OMR.

Immune stimulation with interleukin-2 after autologous stem cell transplantation in children and adolescents with solid tumors

Children with solid tumors of poor prognosis have benefitted from autologous bone marrow transplantation as a treatment modality. Adjuvant interleukin-2 (IL2) therapy has previously been shown to improve prognosis in adults with some solid tumors. In this setting improved survival probability has been attributed to IL2-mediated augmentation of antineoplastic activity of the immune system. In this study 8 pediatric patients in complete remission after autologous stem cell transplantation were treated with recombinant IL2 administered in 3 cycles of 5 days continuous intravenous infusions and a two week rest in between. We demonstrated that IL2 therapy increased transplantation-related activation of the immune system both on cellular and humoral levels. Peripheral blood T and NK cell number increased by the factors 1.7 and 6.0 respectively. NK and T cell activation were further enhanced as indicated by elevated levels of soluble IL2 receptor. The production of tumor cytotoxic cytokines like alpha TNF and gamma INF was stimulated. The elevated aTNF and gamma INF cytokine synthesis seemed to be mainly related to the activation and proliferation of NK cells, as T cells obtained from patients after IL2 therapy showed a definite cytokine production deficiency after T cell specific stimulation.

Immunohistochemical study of mucin carbohydrates and core proteins in human pancreatic tumors

Pancreatic cancer has a poor prognosis, and early diagnosis of carcinoma and discrimination between malignant and benign conditions are difficult. Many pancreatic cancer-associated antigens, such as CA 19-9, DU-PAN-2, YPan-1, and SPan-1, have been studied. However, expression of Tn, sialosyl-Tn, and T antigens in tissues of different types of pancreatic neoplasms has not been investigated systematically. Moreover, little is known about the distribution of different types of apomucins in the pancreas. The expression of Tn, sialosyl-Tn, and T antigens and DF3 (mammary type apomucin) and intestinal MRP (intestinal type apomucin) was examined immunohistochemically in 47 pancreatic tumors: 36 invasive ductal carcinomas, 5 intraductal papillary tumors, and 6 adenomas. In normal pancreatic tissues, neither Tn nor sialosyl-Tn antigen was expressed. In contrast, expression of both Tn and sialosyl-Tn antigens was observed in all the invasive ductal carcinomas and intraductal papillary tumors. None of the adenomas expressed both Tn and sialosyl-Tn. DF3 antigen was expressed in all invasive ductal carcinomas but not in intraductal papillary tumors, whereas intestinal MRP was expressed in all the intraductal papillary tumors but not in the invasive ductal carcinomas. The results from this study suggest that the expression of the mucin core protein and mucin carbohydrate antigens is correlated with the biologic behavior of pancreatic tumors. In particular, the expression of mammary type mucin core protein and intestinal type mucin core protein showed a striking contrast between invasive ductal carcinomas with a poor prognosis and intraductal papillary tumors with a favorable prognosis.

Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma

Most children with neuroblastoma presenting after infancy have metastatic, chemoresistant disease. Amplification of the MYCN proto-oncogene is a significant marker of these poor-prognosis neuroblastoma tumors. Recent studies suggest that MYCN may function in part by promoting angiogenesis via vascular endothelial growth factor (VEGF). VEGF blockade has been validated as a therapeutic strategy in adult cancers. In these studies, we asked whether inhibition of VEGF signaling via VEGFR2 blockade in established MYCN-amplified neuroblastoma xenografts would: 1) restrict tumor growth; 2) induce hypoxia; and 3) alter tumor vasculature. The MYCN-amplified neuroblastoma human cell line NGP was implanted intrarenally in athymic female mice. After 5 weeks, mice with established tumors were selected, a cohort euthanized to provide day 0 controls, and the rest assigned to receive biweekly injections of DC101 (anti-murine VEGFR2 antibody) or vehicle. DC101 treatment did not inhibit progressive tumor growth in established NGP xenografts. Although tumor vasculature was not significantly disrupted, a modest increase in tumor hypoxia was demonstrated by pimonidazole staining, and expression of a previously described hypoxia metagene was increased by gene set enrichment analysis (GSEA) in DC101-treated tumors. DC101 treatment elicited increased: 1) expression of VEGFR1 and its ligand placental growth factor; and 2) increased Notch activation in tumor vasculature concurrent with expression of the Notch ligand Jagged1. This result suggests that established MYCN-amplified neuroblastoma tumors are relatively VEGF-independent, and display the ability to rapidly up-regulate hypoxia-responsive alternative proangiogenic mechanisms that may stabilize vasculature when VEGF is deficient.

Is apocrine differentiation in breast carcinoma of prognostic significance?

Apocrine differentiation in human breast cancers has been assessed using immunohistochemistry to detect zinc alpha 2 glycoprotein and the findings related to standard prognostic factors, disease free interval (DFI) and survival in 145 women with early breast cancer. Breast tumour samples from women with a minimum follow-up of 5 years were assessed. Routinely fixed and processed tissue was used throughout. Sixty-six (45%) tumours did not stain with the antibody. Fifty-two (36%) exhibited positive apocrine staining while for 27 (19%) only a few cells were reactive. The presence of apocrine differentiation was unrelated to lymph node status, menstrual status, tumour grade or size, oestrogen receptor (E2R) or progesterone receptor status. However, patients whose tumours exhibited apocrine staining had a shorter disease-free interval (DFI) (P = 0.03) and survival (P = 0.03). A Cox's multiple regression analysis of the data found that the presence of staining added significantly (P = 0.047) to the predictive value of node status (P = 0.0001), menstrual status (P = 0.0001), tumour size (P = 0.0026) and E2R status (P = 0.0014) for patient survival. The other seven prognostic factors tested did not reach significance and were rejected from the model. Apocrine differentiation in breast cancer appears to be an independent predictor of poor prognosis tumours.