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Showing papers in "Cancer in 1997"


Journal ArticleDOI
15 Oct 1997-Cancer
TL;DR: Good prognostic factors for survival after the development of bone metastases are good histologic grade, positive estrogen receptor status, bone disease at initial presentation, a long disease free interval, and increasing age, while patients with disease that remains confined to the skeleton have a better prognosis than those with subsequent visceral involvement.
Abstract: The skeleton is the most common organ to be affected by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney possess a special propensity to spread to bone. Breast carcinoma, the most prevalent malignancy, causes the greatest morbidity. Of great clinical importance is the observation that metastatic bone disease may remain confined to the skeleton. In these patients, the decline in quality of life and eventual death is due almost entirely to skeletal complications and their subsequent treatment. Bone pain is the most common complication of metastatic bone disease, resulting from structural damage, periosteal irritation, and nerve entrapment. Recent evidence suggests that pain caused by bone metastasis may also be related to the rate of bone resorption. Hypercalcemia occurs in 5-10% of all patients with advanced cancer but is most common in patients with breast carcinoma, multiple myeloma, and squamous carcinomas of the lung and other primary sites. Pathologic fractures are a relatively late complication of bone involvement. The clinical courses of breast and prostate carcinoma are relatively long, with a median survival of 2-3 years. For patients with breast carcinoma, good prognostic factors for survival after the development of bone metastases are good histologic grade, positive estrogen receptor status, bone disease at initial presentation, a long disease free interval, and increasing age. In addition, patients with disease that remains confined to the skeleton have a better prognosis than those with subsequent visceral involvement. For patients with prostate carcinoma, adverse prognostic features include poor performance status, involvement of the appendicular skeleton and visceral involvement, whereas for patients with multiple myeloma, the levels of serum beta2-microglobulin and lactate dehydrogenase and the immunologic phenotype are the most important factors. These prognostic factors may be useful in planning the rational use of bisphosphonates in the treatment of advanced cancer.

1,479 citations



Journal ArticleDOI
15 Jun 1997-Cancer
TL;DR: Studies have shown that a higher accumulation of ALA‐derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALa‐based PDT and diagnosis, however, no review updating the clinical data has appeared so far.
Abstract: BACKGROUND Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25 years PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light Although several photosensitizers other than ALA-derived protoporphyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis However, no review updating the clinical data has appeared so far METHODS A review of recently published data on clinical ALA-based PDT and diagnosis was conducted RESULTS Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results However, the modality with present protocols does not, in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs CONCLUSIONS Promising results of ALA-based clinical PDT and diagnosis have been obtained The modality has advantages over conventional treatments However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue; improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems Cancer 1997; 79:2282-308 © 1997 American Cancer Society

1,000 citations



Journal ArticleDOI
15 Oct 1997-Cancer
TL;DR: Molecular mechanisms underlying each of the steps involved in the process of tumor metastasis are discussed and new anti‐metastasis therapies are being developed.
Abstract: In the present article, the steps involved in the process of tumor metastasis are discussed. Several events are required for malignant cells to leave the primary tumor and proliferate at a distant site: vessel formation (angiogenesis), cell attachment, invasion (matrix degradation, cell motility), and cell proliferation. Molecular mechanisms underlying each of these steps are described. Based on blocking these processes, new anti-metastasis therapies are being developed.

785 citations


Journal ArticleDOI
01 Feb 1997-Cancer
TL;DR: A number of prognostic factors for thyroid carcinoma have been identified, including sociodemographic characteristics such as age and gender, and tumor characteristics, such as histology and stage as discussed by the authors.
Abstract: BACKGROUND A number of prognostic factors for thyroid carcinoma have been identified, including sociodemographic characteristics, such as age and gender, and tumor characteristics, such as histology and stage. The relative importance of these factors as independent predictors of survival for patients with papillary, follicular, anaplastic, and medullary thyroid carcinoma has been extensively studied but remains uncertain. METHODS The authors used data collected by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute between 1973 and 1991 to investigate prognostic factors for each of the major histologic types of thyroid carcinoma in a population-based patient series and to assess the effect of these factors as predictors of survival. RESULTS Both tumor and sociodemographic characteristics were independently associated with survival. Patients with papillary carcinoma had the highest 10-year relative survival (0.98), followed by those with follicular carcinoma (0.92) and medullary carcinoma (0.80). Anaplastic tumors had the lowest 10-year relative survival (0.13). Stage at diagnosis and differentiation status were strong independent prognostic factors for each histologic type. Advanced stage at diagnosis was a stronger prognostic factor for medullary carcinoma than for other histologic types. Increasing age was associated with lower relative survival for each histologic type. Gender, marital status, and ethnicity were significant, but weaker, predictors of survival. CONCLUSIONS Survival varied markedly among patients with different histologic types of thyroid carcinoma. Stage at diagnosis and tumor differentiation were important prognostic factors for each histologic type. Age at diagnosis was a stronger predictor of survival for patients with follicular and medullary carcinoma than for patients with papillary carcinoma. Cancer 1997; 79:564-73. © 1997 American Cancer Society.

661 citations


Journal ArticleDOI
15 Jun 1997-Cancer
TL;DR: Natural killer cells have a spontaneous cytotoxic capacity against tumor cells and represent a small proportion of human colon carcinoma‐infiltrating lymphocytes.
Abstract: BACKGROUND Natural killer (NK) cells have a spontaneous cytotoxic capacity against tumor cells. These cells represent a small proportion of human colon carcinoma-infiltrating lymphocytes. Their prognostic significance in these tumors has yet to be determined. METHODS One hundred and fifty-seven patients who each had a colectomy for large bowel adenocarcinoma were studied. No patient received adjuvant therapy. Immunohistochemical stains were performed for NK cells using the monoclonal antibody CD57. The number of NK cells was counted using a MICRON image analyzer. The total area studied for each tumor was 1 cm2. In this area, 50 intratumoral fields of 0.173 mm2 were selected. The degree of NK infiltration was classified as little ( 150 NK cells). The Kaplan-Meier method was used to obtain survival figures. Multivariate analyses were performed using the Cox regression model. RESULTS At 5 years, patients with little and moderate NK infiltration showed significantly shorter survival rates (overall and disease free survival) than those with extensive infiltration (P < 0.01). Three significant factors affecting survival were selected in a stepwise fashion in increasing order as follows: TNM stage, NK infiltration, and lymphocytic infiltration. Patients with TNM Stage III disease and extensive NK infiltration showed significantly longer survival rates than those with little or moderate infiltration (P < 0.001). In these patients, multivariate analysis using the Cox regression model identified two significant variables: number of involved lymph nodes and NK cell infiltration. CONCLUSIONS In patients with colorectal carcinoma, an extensive intratumoral infiltration of NK cells is associated with a favorable tumor outcome. Intratumoral infiltration of NK cells can be used as a variable with prognostic value, especially in patients with TNM Stage III disease. Cancer 1997; 79:2320-8. © 1997 American Cancer Society.

601 citations


Journal ArticleDOI
15 Oct 1997-Cancer
TL;DR: Osteoclasts can be inhibited by drugs such as the new‐generation bisphosphonates; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia; and possibly even more importantly, there are also a reduction of tumor burden in bone.
Abstract: Solid cancers metastasize to bone by a multistep process that involves interactions between tumor cells and normal host cells. Some tumors, most notably breast and prostate carcinomas, grow avidly in bone because the bone microenvironment provides a favorable soil. In the case of breast carcinoma, the final step in bone metastasis (namely bone destruction) is mediated by osteoclasts that are stimulated by local production of the tumor peptide parathyroid hormone-related peptide (PTH-rP), whereas prostate carcinomas stimulate osteoblasts to make new bone. Production of PTH-rP by breast carcinoma cells in bone is enhanced by growth factors produced as a consequence of normal bone remodeling, particularly activated transforming growth factor-beta (TGF-beta). Thus, a vicious cycle exists in bone between production by the tumor cells of mediators such as PTH-rP and subsequent production by bone of growth factors such as TGF-beta, which enhance PTH-rP production. The metastatic process can be interrupted either by neutralization of PTH-rP or by rendering the tumor cells unresponsive to TGF-beta, both of which can be accomplished experimentally. The osteoclast is another available site for therapeutic intervention in the bone metastatic process. Osteoclasts can be inhibited by drugs such as the new-generation bisphosphonates; as a consequence of this inhibition, there is a marked reduction in the skeletal events associated with metastatic cancer to bone, such as pain, fracture, and hypercalcemia. However and possibly even more importantly, there is also a reduction of tumor burden in bone. In experimental situations, this has clearly been shown to affect not only morbidity but also survival. The precise mechanism by which bisphosphonates inhibit osteoclasts is still unclear and may represent a combination of inhibition of osteoclast formation as well as increased apoptosis in mature osteoclasts. However, studies with potent bisphosphonates such as ibandronate, pamidronate, and risedronate have clearly documented that reduction of bone turnover and osteoclast activity leads to beneficial effects not only on skeletal complications associated with metastatic cancer, but also on tumor burden in bone.

562 citations


Journal ArticleDOI
01 Apr 1997-Cancer
TL;DR: Diagnostic accuracy and reproducibility are compromised by the subjective histologic criteria currently used to classify and grade gliomas.
Abstract: BACKGROUND Accurate histologic diagnosis of gliomas is fundamental to proper patient management and to the interpretation of basic and clinical investigations. Diagnostic accuracy and reproducibility are compromised by the subjective histologic criteria currently used to classify and grade gliomas. METHODS The histologic features of 4 sets of gliomas (a total of 244 cases) were reviewed independently by 4 neuropathologists to determine interobserver diagnostic concordance rates. Cases wherein diagnostic disagreements arose were reviewed jointly to identify and refine the histologic criteria that were adversely affecting diagnostic reproducibility. Using the criteria developed in the study, a set of 315 gliomas with known survival data was evaluated in order to validate the usefulness of the criteria. RESULTS There was significant improvement in diagnostic concordance with each session (P = 0.02). For the first session, the concordance rates were as follows: all 4 reviewers, 52%; any 3 reviewers, 60%; 2 reviewers, 70%. For the fourth session, the respective rates were 69%, 75%, and 80%. Although features important in grading, particularly microvascular proliferation, were sometimes problematic, most disagreements related to the classification of tumors. Much of the improvement related to the refinement of criteria distinguishing diffuse astrocytomas from oligodendrogliomas/oligoastrocytomas and pilocytic astrocytomas. It was concluded that the presence of any typical oligodendroglioma was sufficient to remove a tumor from the astrocytoma category. CONCLUSIONS The authors' data indicate that oligodendroglial tumors comprise up to 25% of gliomas, a significantly higher proportion than was previously recognized. The data also suggest that the wide range of survival times reported for patients with anaplastic astrocytoma may reflect "contamination" resulting from misdiagnosis, particularly of oligodendroglial tumors and pilocytic astrocytomas. Cancer 1997; 79:1381-93. © 1997 American Cancer Society.

545 citations


Journal ArticleDOI
15 Dec 1997-Cancer
TL;DR: The authors focus on the specification of appropriate volumes of interest (VoI) using PET in association with computed tomography (CT) to quantitate accurately the activity and volume of lesions and organs with positron emissiontomography (PET).
Abstract: BACKGROUND It is common protocol in radionuclide therapies to administer a tracer dose of a radiopharmaceutical, determine its lesion uptake and biodistribution by gamma imaging, and then use this information to determine the most effective therapeutic dose. This treatment planning approach can be used to quantitate accurately the activity and volume of lesions and organs with positron emission tomography (PET). In this article, the authors focus on the specification of appropriate volumes of interest (VoI) using PET in association with computed tomography (CT). METHODS The authors have developed an automatic image segmentation schema to determine the VoI of metastases to the lung from PET images, under conditions of variable background activity. An elliptical Jaszczak phantom containing a set of spheres with volumes ranging from 0.4 to 5.5 mL was filled with F-18 activity (2-3 μCi/mL) corresponding to activities clinically observed in lung lesions. Images were acquired with a cold background and then with variable source-to-background (S/B) ratios of: 7.4, 5.5, 3.1, and 2.8. Lesion VoI analysis was performed on 10 patients with 17 primary or metastatic lung lesions, applying the optimum threshold values derived from the phantom experiments. Initial volume estimates for lung lesions were determined from CT images. Approximate S/B ratios were obtained for the corresponding lesions on F-18-fluoro-2-deoxy-D-glucose (18FDG)-PET images. From the CT estimate of the lesion size and the PET estimate of the S/B ratio, the appropriate optimum threshold could be chosen. The threshold was applied to the PET images to obtain lesion activity and a final estimate of the lesion volume. RESULTS Phantom data analysis showed that image segmentation converged to a fixed threshold value (from 36% to 44%) for sphere volumes larger than 4 mL, with the exact value depending on the S/B ratios. For patients, the use of optimum threshold schema demonstrated a good correlation (r = 0.999) between the initial volume from CT and the final volume derived from the 18FDG-PET scan (P < 0.02). The mean difference for those volumes was 8.4%. CONCLUSIONS The adaptive thresholding method applied to PET scans enables the definition of tumor VoI, which hopefully leads to accurate tumor dosimetry. This method can also be applied to small lesions (<4 mL). It should enable physicians to track objectively changes in disease status that could otherwise be obscured by the uncertainties in the region-of-interest drawing, even when the scans are delineated by the same physician. Cancer 1997; 80:2505-9. © 1997 American Cancer Society.

523 citations


Journal ArticleDOI
01 Oct 1997-Cancer
TL;DR: In this article, the authors provided an overview of aspects of the burden of cancer in the elderly, highlighting certain demographic and epidemiologic data, which served as a frame of reference for participants in the Oncology Geriatric Education Retreat, San Juan, Puerto Rico, February 21-26, 1997.
Abstract: Sixty percent of all cancer occurs in persons aged > or =65 years. This article provides an overview of aspects of the burden of cancer in the elderly, highlighting certain demographic and epidemiologic data. It served as a frame of reference for participants in the Oncology Geriatric Education Retreat, San Juan, Puerto Rico, February 21-26, 1997. Information comes from several major sources: U. S. Bureau of the Census; National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program; National Center for Health Statistics; National Institute on Aging (NIA)/NCI SEER Study on Comorbidity and Cancer in the Elderly; and NCI cancer prevalence estimates. Data on the aging population demonstrate an unprecedented expansion of the segment of the population aged > or =65 years. By 2030, 1 in 5 Americans will be aged > or =65 years. Because cancer incidence and mortality rates are highest in persons aged > or =65 years, expansion of this age group takes on great importance for medical professionals who provide treatment to older aged cancer patients. In addition, older aged cancer patients are likely to have preexisting conditions at diagnosis, creating a special clinical challenge. There is an urgent need to better understand the influence of aging on the early detection, diagnosis, and treatment of cancer. Clinicians who treat older persons (geriatricians, oncologists, and other health professionals) can benefit from the integration of the knowledge and approaches of each others' fields. The foundation for this multidisciplinary effort is linked with the education and training of future clinicians.


Journal ArticleDOI
15 Jan 1997-Cancer
TL;DR: The goal of this study was to characterize the clinicopathologic features of follicular dendritic cell sarcoma, a very uncommon neoplasm.
Abstract: BACKGROUND The goal of this study was to characterize the clinicopathologic features of follicular dendritic cell sarcoma, a very uncommon neoplasm. METHODS The 17 cases were collected from the consultation and surgical pathology files of the authors, including 8 previously reported cases. The histologic and immunohistochemical features and outcome were analyzed. RESULTS The patients had a median age of 40 years, with a slight female predominance. Seven patients presented with enlarged lymph nodes, and ten presented with tumor in extranodal sites. Two cases were associated with hyaline-vascular Castleman's disease. The tumors had an average greatest dimension of 6.7 cm. The most common histologic feature was a storiform or fascicular array of spindle, ovoid, or polygonal cells with oval nuclei, delicate nuclear membrane, vesicular or granular chromatin, distinct nucleoli, indistinct cell borders, and frequently fibrillary cytoplasm. There were often scattered multinucleated forms. The tumor cells sometimes formed sheets, circular whorls, follicle-like structures, trabeculae, or pseudovascular spaces. There was a sprinkling of small lymphocytes, with or without cuffing around blood vessels. The neoplastic cells were immunoreactive for CD21 (17 of 17 cases), CD35 (17 of 17 cases), desmoplakin (10 of 17 cases), epithelial membrane antigen (14 of 16 cases), S-100 protein (6 of 17 cases), and CD68 (2 of 17 cases), but not cytokeratin. Ultrastructural studies showed villous processes connected by desmosomes. Only one harbored the Epstein-Barr virus. Among 13 patients with a median follow-up of 3 years, local recurrence occurred in 6, metastasis in 6, and 3 died of disease. CONCLUSIONS Follicular dendritic cell sarcoma exhibits distinctive histologic features that permit its presumptive recognition, but a firm diagnosis requires confirmation with special studies. Because it has a significant recurrent and metastatic potential (the latter risk having been previously underestimated), it should be viewed as an intermediate grade malignancy. An intraabdominal location is associated with a particularly aggressive clinical course. Cancer 1997; 79:294-313. © 1997 American Cancer Society.

Journal ArticleDOI
15 Apr 1997-Cancer
TL;DR: Hepatocellular carcinoma occurs in patients with hepatitis C virus‐RNA positive chronic liver disease and it is important to prevent HCC with drug administration.
Abstract: BACKGROUND Hepatocellular carcinoma (HCC) occurs in patients with hepatitis C virus-RNA positive chronic liver disease. It is important to prevent HCC with drug administration. METHODS A retrospective study was undertaken to evaluate the long term preventive effect of Stronger Neo-Minophagen C (SNMC) on HCC development. SNMC is a Japanese medicine that is commonly administered to patients with chronic hepatitis C to improve the serum alanine aminotransferase (ALT) level. Of 453 patients diagnosed with chronic hepatitis C retrospectively in the study hospital between January 1979 and April 1984, 84 patients (Group A) had been treated with SNMC; SNMC was given at a dose of 100 mL daily for 8 weeks, then 2-7 times a week for 2-16 years (median, 10.1 years). Another group of 109 patients (Group B) could not be treated with SNMC or interferon for a long period of time (median, 9.2 years) and were given other herbal medicine (such as vitamin K). The patients were retrospectively monitored, and the cumulative incidence of HCC and risk factors for HCC were examined. RESULTS The 10th-year rates of cumulative HCC incidence for Groups A and B were 7% and 12%, respectively, and the 15th-year rates were 12% and 25%. By Cox regression analysis, the relative risk of HCC incidence in patients not treated with SNMC (Group B) was 2.49 compared with that of patients treated with SNMC (Group A). CONCLUSIONS In this study, long term administration of SNMC in the treatment of chronic hepatitis C was effective in preventing liver carcinogenesis. Cancer 1997; 79:1494-500. © 1997 American Cancer Society.

Journal ArticleDOI
01 Oct 1997-Cancer
TL;DR: The role of occult lymph node micrometastases and their relevance to disease recurrence was evaluated in a literature search of the entire MEDLINE data base as mentioned in this paper, with the cutoff point ranging from 0.2-2.0 mm.
Abstract: BACKGROUND The presence or absence of regional lymph node metastases has been one of the most important determining factors in recommending adjuvant chemotherapy for patients with breast carcinoma. However, because of the 15-20% failure rate at 5 years for lymph node negative patients, other tumor-related prognostic factors have gained greater significance in this decision-making process. Many investigators have reported finding micrometastases that were not detected by routine sectioning of the lymph nodes but were identified by multiple sectioning and additional staining. This review attempts to evaluate the role of occult lymph node micrometastases and their relevance to disease recurrence. METHODS A literature search of the entire MEDLINE data base was conducted. All relevant articles were reviewed for the criteria they used to define micrometastases. The frequency of detection of micrometastases by various methodologies and the prognostic significance of such deposits were examined. RESULTS Tumor deposits involving the lymph nodes were found to be arbitrarily categorized as either micrometastases or macrometastases, with the cutoff point ranging from 0.2-2.0 mm. The detection rate of such deposits by conventional techniques was inadequate. Serial sectioning and immunohistochemistry appeared to increase the detection rate by 9-33%. A definite survival disadvantage was noted for patients with such occult metastases. CONCLUSIONS Current routine histologic examination of regional lymph nodes underestimates breast carcinoma metastases. Serial sectioning and immunohistochemistry increase the yield but are too labor-intensive and expensive for routine use. However, the introduction of the sentinel lymph node biopsy in lieu of axillary lymph node dissection in cases of breast carcinoma holds promise for making these methods practical and cost-effective. Cancer 1997; 80:1188-97. © 1997 American Cancer Society.

Journal ArticleDOI
15 Sep 1997-Cancer
TL;DR: The aim of this study was to determine the biologic significance of Glut1 and Glut3 overexpression in Stage I NSCLC.
Abstract: BACKGROUND Increased expression of Glut1 and Glut3 has been reported in many human cancers, including nonsmall cell lung carcinoma (NSCLC). The aim of this study was to determine the biologic significance of Glut1 and Glut3 overexpression in Stage I NSCLC. METHODS Using immunohistochemistry and polyclonal anti-Glut1 and anti-Glut3 antibodies, the authors immunostained sections of formalin fixed, paraffin embedded tissues from 289 Stage I NSCLCs. The Kaplan-Meier survival method, the log rank test, and Fisher's exact test were used for statistical analysis. RESULTS Of the 289 cases, 49 (17%) were negative for both Glut1 and Glut3, 239 (83%) were Glut1 positive, 61 (21%) were Glut3 positive, 179 (62%) were positive for Glut1 but negative for Glut3, 1 (0.3%) was positive for Glut3 but negative for Glut1, and 60 (21%) were positive for both Glut1 and Glut3. Only 1 of 50 Glut1 negative tumors (2%) was positive for Glut3, whereas 60 of 239 Glut1 positive tumors (25%) were positive for Glut3 (P < 0.0001). Glut1 or Glut3 were detected more often in poorly differentiated and undifferentiated tumors (P <0.0001 and P = 0.0008, respectively). Overexpression of Glut1 and/or Glut3 was associated with poorer survival (P = 0.0133), especially in patients with well-differentiated and moderately differentiated tumors (P = 0.0017). CONCLUSIONS In Stage I NSCLC, Glut3 overexpression likely occurs after Glut1 overexpression. The appearance of Glut1 positive clones is associated with aggressive biologic behavior, which is worsened by the emergence of Glut3 positive clones. Glut1 and Glut3 are significant of poor prognosis indicators in cases of NSCLC. Cancer 1997; 80:1046-51. © 1997 American Cancer Society.

Journal ArticleDOI
01 Feb 1997-Cancer
TL;DR: In this article, the frequency of human papillomavirus (HPV) DNA in squamous cell carcinoma (SCC) at different sites of the esophagus, head and neck and compared the clinical behavior of HPV positive and negative tumors.
Abstract: BACKGROUND Certain strains of human papillomavirus (HPV) have been shown to be etiologically related to the development of uterine cervical and other genital cancers, but their role in the development of malignancies at other sites is less well established. Previous studies have shown HPV DNA in tumors of the head and neck, but its prevalence has varied depending on the detection methods and the types of tumor and/or tissue examined. This study was undertaken to estimate the frequency of HPV DNA in squamous cell carcinoma (SCC) at different sites of the esophagus, head and neck and to compare the clinical behavior of HPV positive and negative tumors. METHODS DNA was extracted from frozen tissue of 167 SCCs of the esophagus, head and neck. The DNA was screened for HPV sequences by polymerase chain reaction with two sets of consensus primers, one to a conserved region in the L1 gene (MY09/MY11) and the other to a conserved region in the E1 open reading frame (IU/IWDO). The products were run on agarose gels, detected by ethidium bromide staining, and then the gels were subjected to Southern blot analysis and hybridized with probes specific to HPV 6, 16, and 18. All tumors found to be HPV positive with the consensus primers were amplified with type specific primers, and in selected cases the presence of HPV DNA was confirmed by restriction enzyme digestion of the tumor DNA with conventional Southern blot analysis. RESULTS Overall, HPV sequences were found in 25 of 167 tumors (15%), but HPV was detected most frequently in tumors in Waldeyer's tonsillar ring. In that area, 9 of 15 (60%) were HPV positive. No HPV DNA was detected in 11 esophageal SCCs, 7 tumors of the pharynx/hypopharynx, or 6 pyriform sinus carcinomas. HPV DNA was detected in the following tumor sites: 1 of 28 (3.6%) in the larynx, 1 of 10 (10%) in the oral cavity, 5 of 39 (12.8%) in the tongue, 2 of 15 (13.5%) in the floor of the mouth, 3 of 21 (14.3%) supraglottic, and 1 of 7 (14.3%) in the lip. A high incidence of HPV DNA was also found in metastatic tumors located in cervical lymph nodes for which no primary site was clinically identified (3 of 8, 37.5%). With respect to age, gender, and tobacco and alcohol consumption, analysis of clinical data obtained by retrospective review showed no difference between patients with HPV DNA in their tumors and those in which no HPV was detected. However, HPV positive patients had larger tumors (P = 0.09) and a higher incidence of lymph node metastasis (P = 0.003). In spite of the higher stage of disease at presentation in HPV positive patients, there was no significant difference in 3-year survival rates between HPV positive patients and HPV negative patients (43.1% vs. 48.8%, respectively). Median follow-up was 27 months. CONCLUSIONS In the head and neck, HPV-associated SCC had site specificity with the viral DNA frequently found in tumors in Waldeyer's tonsillar ring. Patients with HPV positive tumors presented with a higher stage of disease than patients with HPV negative tumors, but there was no significant difference in the 3-year survival rates between these two groups of patients. Cancer 1997; 79:595-604. © 1997 American Cancer Society.

Journal ArticleDOI
01 Jul 1997-Cancer
TL;DR: The clinical significance of increased expression of one of the angiogenic factors, vascular endothelial growth factor (VEGF), in early stage ovarian carcinoma is examined in this study.
Abstract: BACKGROUND Tumor angiogenesis is essential for solid tumor growth. Yet, the importance of any particular factor in neoplastic proliferation is poorly defined. This study examines the clinical significance of increased expression of one of the angiogenic factors, vascular endothelial growth factor (VEGF), in early stage ovarian carcinoma. METHODS Tumor specimens from 68 patients with International Federation of Gynecology and Obstetrics Stage I and II ovarian carcinoma were evaluated for VEGF expression. Antisense and corresponding sense (control) RNA probes were transcribed from the pCR™II construct (Invitrogen, San Diego, CA), which contained human VEGF cDNA. The antisense probe was designed to include a highly conserved region of the VEGF coding sequence and thus detect all known variants. After in situ hybridization, sections were assessed for overexpression of VEGF. RESULTS Twenty-nine of the tumor samples overexpressed VEGF, whereas 39 specimens did not. In patients whose tumors demonstrated elevated VEGF expression, 25% were without evidence of disease recurrence at last follow-up. In contrast, 75% of the patients whose tumors did not overexpress VEGF were without evidence of disease at last follow-up (P 108 months for the VEGF negative group (P 120 months for the VEGF negative group (P 0.05). Assignment to a high risk group, as defined by the Gynecologic Oncology Group of the National Cancer Institute, was somewhat predictive of a shorter relapse free interval (P = 0.056). In a multivariate analysis, however, only elevated VEGF expression was associated with poorer survival. CONCLUSIONS In this analysis, patients with early stage ovarian carcinoma with increased VEGF expression had a poorer prognosis. Further study of VEGF may ultimately lead to identification of patients with high risk lesions whose tumor biology portends a worse prognosis and who therefore may benefit from aggressive adjuvant therapy. Cancer 1997; 80:98-106. © 1997 American Cancer Society.

Journal ArticleDOI
15 Feb 1997-Cancer
TL;DR: This study compares the prediction accuracy of the TNM staging system with that of artificial neural network statistical models.
Abstract: BACKGROUND The TNM staging system originated as a response to the need for an accurate, consistent, universal cancer outcome prediction system. Since the TNM staging system was introduced in the 1950s, new prognostic factors have been identified and new methods for integrating prognostic factors have been developed. This study compares the prediction accuracy of the TNM staging system with that of artificial neural network statistical models. METHODS For 5-year survival of patients with breast or colorectal carcinoma, the authors compared the TNM staging system's predictive accuracy with that of artificial neural networks (ANN). The area under the receiver operating characteristic curve, as applied to an independent validation data set, was the measure of accuracy. RESULTS For the American College of Surgeons' Patient Care Evaluation (PCE) data set, using only the TNM variables (tumor size, number of positive regional lymph nodes, and distant metastasis), the artificial neural network's predictions of the 5-year survival of patients with breast carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.720; ANN, 0.770; P < 0.001). For the National Cancer Institute's Surveillance, Epidemiology, and End Results breast carcinoma data set, using only the TNM variables, the artificial neural network's predictions of 10-year survival were significantly more accurate than those of the TNM staging system (TNM, 0.692; ANN, 0.730; P < 0.01). For the PCE colorectal data set, using only the TNM variables, the artificial neural network's predictions of the 5-year survival of patients with colorectal carcinoma were significantly more accurate than those of the TNM staging system (TNM, 0.737; ANN, 0.815; P < 0.001). Adding commonly collected demographic and anatomic variables to the TNM variables further increased the accuracy of the artificial neural network's predictions of breast carcinoma survival (0.784) and colorectal carcinoma survival (0.869). CONCLUSIONS Artificial neural networks are significantly more accurate than the TNM staging system when both use the TNM prognostic factors alone. New prognostic factors can be added to artificial neural networks to increase prognostic accuracy further. These results are robust across different data sets and cancer sites. Cancer 1997; 79:857-62. © 1997 American Cancer Society.

Journal ArticleDOI
01 Jun 1997-Cancer
TL;DR: The development of malignant and benign tumors in patients with neurofibromatosis type 1 (NF1) was investigated in a long term follow‐up study of 70 adult NF1 patients living in Göteborg, Sweden, on January 1, 1978.
Abstract: BACKGROUND The development of malignant and benign tumors in patients with neurofibromatosis type 1 (NF1) was investigated in a long term follow-up study of 70 adult NF1 patients living in Goteborg, Sweden, on January 1, 1978. Their mean age at that time was 44 years (range, 20-81 years). The 70 NF1 patients had previously been investigated in a population-based study. METHODS The first part of this study involved a cancer registry study. The authors compared the number of tumors in the 70 NF1 patients reported to the Swedish Cancer Registry during the period 1978-1989 with the number of tumors expected in the general population by matching the incidence rates of the two populations specific to age, time of follow-up, and gender. The 95% confidence interval for the risk quotient between the risk to the patients and the risk to the general population was estimated. The second part of the study was a clinical pathologic follow-up study. All living patients were offered a clinical reexamination in 1990. All hospital records for all the NF1 patients were reviewed, and death certificates were also reviewed when available. RESULTS Malignant tumors were reported to the Cancer Registry four times as often in the NF1 patient group as in the general population (95% confidence interval, 2.1-7.6) during the follow-up period 1978-1989. Before 1978, 5 of 70 patients (7%) had 6 malignant tumors; these patients were not included in the Cancer Registry study. Using all available clinical data on the 70 NF1 patients from their birth up to 1990, the authors found that 17 of 70 patients (24%) had developed a total of 19 malignant tumors, namely, 5 sarcomas (in 7% of patients), 13 carcinomas (in 16%), and 1 malignant melanoma (in 1%). Four pheochromocytomas (in 6% of patients), 2 adenomas, and 1 C-cell hyperplasia were diagnosed. Five gastrointestinal stromal tumors (in 7% of patients) were also diagnosed. CONCLUSIONS Malignant tumors were reported to the Swedish Cancer Registry significantly more often in the NF1 patients than was expected in the general population matched for age, gender, and time of follow-up. The development of tumors is part of the NF1 disease process, and this deserves attention both in the clinical setting and in family counseling dealing with complications of NF1 in adulthood. Cancer 1997; 79:2125-31. © 1997 American Cancer Society.

Journal ArticleDOI
15 Feb 1997-Cancer
TL;DR: Pituitary carcinomas are rare adenohypophysial neoplasms, the definition, diagnosis, therapy, and prognosis of which are controversial.
Abstract: BACKGROUND. Pituitary carcinomas are rare adenohypophysial neoplasms, the definition, diagnosis, therapy, and prognosis of which are controversial. METHODS. Pituitary carcinomas were defined as primary adenohypophysial neoplasms with documented craniospinal and/or systemic metastases. The authors report a clinicopathologic study of 15 examples examined by light microscopy, immunohistochemistry, and image analysis. Both proliferative activity and p53 tumor suppressor gene expression were studied. RESULTS. The study group consisted of 15 patients, including 8 males and 7 females ranging in age from 34-71 years (mean, 56 years). Of these patients, seven had adrenocorticotropic hormone (ACTH)-producing tumors (four in the context of Nelson's syndrome), seven had prolactin-producing tumors, and one had a non-functioning tumor. No evidence of diabetes insipidus was seen in any case. Fourteen tumors were initially considered macroadenomas. Of the ten cases for whom tumor extent was known, all had invasive tumors. The interval from the initial diagnosis of adenoma to that of carcinoma ranged from 0.3 to 18.0 years (mean, 6.6 years; median, 5.0 years); the longest mean interval (15.3 years) occurred for patients with Nelson's syndrome. The latency was twice as long for ACTH-producing tumors as for prolactin (PRL) cell tumors (9.5 vs. 4.7 years). All carcinomas showed a greater tendency toward systemic metastasis than craniospinal metastasis ; the rate of systemic metastasis was 71% for PRL cell tumors and 57% for ACTH-producing tumors. Thirteen percent of tumors showed both patterns of metastasis. Fully 50% of primary tumors and the majority of metastases showed nuclear pleomorphism and/or hyperchromasia. The mean mitotic, MIB-I, and proliferating cell nuclear antigen indices for primary tumors and metastases were as follows: 2/10 high-power field (hpf), 2.6% and 11%, respectively; 6/10 hpf, 7.8% and 16%, respectively. Staining for p53 protein was noted in 57% of primary tumors and 88% of metastatic tumors; a relative increase in p53 expression in metastases was noted in 83%. All but one of the primary and metastatic tumors were aneuploid. The most common treatments were radiation therapy and, for PRL cell carcinomas, dopamine agonist administration. Both treatments provided only palliation. Eighty percent of the patients died of metastatic disease 7 days to 8 years after the diagnosis of carcinoma; of these, 66% died within I year. At last follow-up, 20% of patients were alive with metastases 9-18 months after diagnosis. CONCLUSIONS. Nearly all pituitary carcinomas present as functioning, microscopically atypical or mitotically active, invasive macroadenomas. By definition, after an interval related to their immunotype, all metastasize. The tumors show a greater tendency toward systemic metastasis than craniospinal metastasis and are associated with poor prognosis. Radiation and dopamine agonist therapy generally provide only palliation. Proliferation indices and p53 expression tend to be higher in metastases than in primary tumors. The current definition of pituitary carcinoma requires the demonstration of metastasis; however, high mitotic and MIB-1 label-ing indices as well as p53 immunoreactivity suggest the diagnosis and appear to be of prognostic significance. A redefinition of aggressive pituitary tumors is proposed-one that facilitates the recognition of tumors prone to metastasis.

Journal ArticleDOI
01 May 1997-Cancer
TL;DR: In a pilot study, the authors evaluated the feasibility and effects of aerobic training in the rehabilitation of cancer patients after completing high dose chemotherapy.
Abstract: BACKGROUND Fatigue and loss of physical performance are frequent problems of cancer patients. In a pilot study, the authors evaluated the feasibility and effects of aerobic training in the rehabilitation of cancer patients after completing high dose chemotherapy. METHODS Sixteen patients participated in a specially designed rehabilitation program for 6 weeks. The patients entered the program, which consisted of walking on a treadmill, shortly after completing treatment. Sixteen patients who did not train served as controls. Physical performance (maximum speed on the treadmill test), cardiac function, and hemoglobin concentration were compared at the time of discharge from the hospital and 7 weeks later. At the second examination, fatigue and limitations in daily activities due to impaired endurance were assessed during personal interviews. RESULTS At the time of discharge from the hospital, maximum physical performance (training group: 6.2 ± 1.1 km/hour; controls: 6.2 ± 1.3 km/hour) and hemoglobin concentration (training group: 10.1 ± 1.4 g/dL; controls: 10.1 ± 1.2 g/dL) were similar for both groups. After 7 weeks, improvement in maximum physical performance (training group: 8.3 ± 1.6 km/hour; controls 7.5 ± 1.3 km/hour) and hemoglobin concentration (training group: 13 ± 1 g/dL controls: 12 ± 1.4 g/dL) were significantly higher for the training group (P < 0.05). By the second examination, no patient in the training group but 4 controls (25%) reported fatigue and limitations in daily activities due to low physical performance. CONCLUSIONS Aerobic exercise improves the physical performance of cancer patients recovering from high dose chemotherapy. To reduce fatigue, this group of patients should be counseled to increase physical activity rather than rest after treatment. Cancer 1997; 79:1717-22. © 1997 American Cancer Society.

Journal ArticleDOI
01 Feb 1997-Cancer
TL;DR: In this paper, the effects of current methods of diagnosis and treatment on the course of the disease were assessed, and the authors concluded that the detection of metastasis to the thyroid gland often indicates poor prognosis, aggressive surgical and medical therapy may be effective in a small percentage of patients.
Abstract: Background The incidence of metastasis to the thyroid gland in autopsy series varies from 1.25% to 24%. Metastasis to the thyroid gland is usually considered a terminal event, and the effectiveness of conventional treatment has been questioned. The authors assessed the effects of current methods of diagnosis and treatment on the course of the disease. Methods Forty-three patients with metastasis to the thyroid gland were studied retrospectively. Primary tumor origin was identified in all but two cases. Metastasis to the thyroid gland was confirmed by fine-needle aspiration cytology or histology. Data were analyzed for the frequency and types of malignant lesions, the clinical course of disease, and the prognosis after thyroid involvement. Results The kidney was the most common primary tumor site (33%), followed by lung (16%), breast (16%), esophagus (9%), and uterus (7%). The time from diagnosis of the primary tumor to metastasis to the thyroid gland was considerable for renal cell adenocarcinoma (mean, 106 months) and for adenocarcinomas of the breast (mean, 131 months) and uterus (mean, 132 months). In 12 patients, this interval was more than 120 months. Fine-needle aspiration cytology detected metastatic malignancy in 29 of 30 patients. Treatment involved surgery alone, surgery with adjuvant therapy, or nonsurgical methods. Two patients with uterine adenocarcinoma and one with breast adenocarcinoma had disease regression with no evidence of tumor recurrence. Conclusions In any patient with a previous history of malignancy, no matter how remote that history is, a new thyroid mass should be considered recurrent malignancy until proved otherwise. Although detection of metastasis to the thyroid gland often indicates poor prognosis, aggressive surgical and medical therapy may be effective in a small percentage of patients.

Journal ArticleDOI
01 Jul 1997-Cancer
TL;DR: Pleuropulmonary blastoma is a unique dysontogenetic neoplasm of childhood that appears as a pulmonary and/or pleural‐based mass and is characterized histologically by a primitive, variably mixed blastematous and sarcomatous appearance.
Abstract: BACKGROUND. I'leuropulmonary blastoma (PPB) is a unique dysontogenetic neoplasm of childhood that appears as a pulmonary and/or pleural-based mass and is characterized histologically by a primitive, variably mixed blastematous and sarcomatous appearance. METHODS. Histologic material from all cases was reviewed and the tumors subclassified as type I (purely cystic), type II (cystic and solid), or type HI (purely solid). Data regarding presenting symptoms, family history, operative findings, pathologic subtypes, therapeutic interventions, and outcome were correlated with survival by standard statistical methods. RESULTS. The series was comprised of 24 males and 26 females. Respiratory difficulty with or without fever was the most common clinical symptom reported. lyst formation in the affected lung was identified radiographically in 19 children (38%) at or before the definitive pathologic diagnosis. The ages at presentation of the 7 type 1, 24 type 11, and 19 type III PPBs were significantly different: 10, 34, and 44 months, respectively (P< 0.001). Local recurrence developed in I of 7 type I PPBs (14%) and in 18 of 43 type 11 and III PPBs (46%); distant metastasis occurred in 13 patients, chiefly to the brain/spinal cord or bone, and was observed only in those with type II or type III PPB. Patients with pleural or mediastinal involvement fared significantly worse than those without such involvement. Five-year survival was 83% for type I and 42% for types II and III. Survival differences on the basis of pathologic subtype did not reach statistical significance. CONCLUSIONS. PPB is an aggressive, intrathoracic neoplasm of early childhood with an unfavorable outcome. Although survival differences among patients with different histologic subtypes of disease did not reach statistical significance, the apparently better outcome for patients with purely cystic type I tumors may be borne out in a large series. These observations support the premise that type I and III PPB are bridged morphologically by type 11 PPB with its combined cystic and solid features. The PPB should be regarded as the pulmonary dysontogenetic analogue to Wilms' tumor in the kidney, neuroblastoma in the adrenal gland, and hepatoblastoma in the liver. Molecular genetic investigations, especially in constitutional PPB, should be revealing. In view of the poor outcomes for patients with types II and III, new and aggressive therapies must be developed.

Journal ArticleDOI
15 Oct 1997-Cancer
TL;DR: In this paper, the authors conducted a retrospective review of 14 patients with characteristics similar to those in the literature in terms of outcome, and the 5-year survival rate for these patients was 14%.
Abstract: BACKGROUND. Fortunately, primary malignant mucosal melanoma of the head and neck is a rare entity. A paucity of data elucidating the predictive factors as well as the unpredictable and aggressive biologic behavior of mucosal melanoma compound the vexing clinical situation. This review summarizes what the literature reveals about the epidemiology, patient survival, patterns of local recurrence, and local and distant metastasis of the disease. Over 1000 patients with this disease have been reported. Survivals at 5 and 10 years is 17% and 5%, respectively. Approximately 19% of patients present with lymph node metastasis and another 16% develop lymph node metastases after treatment, whereas 10% present with distant metastasis. Local metastasis does not affect survival; this is in sharp contrast with skin melanoma. Over 50% of patients experience local treatment failure, and salvage treatment is effective in only 25% of these cases. Local failure is the harbinger of distant metastases. Patients with nasal mucosal melanoma have a 31% 5-year survival rate, whereas sinus melanoma patients fare poorly, with a 0% rate of 5-year survival. METHODS. The authors conducted a retrospective review of 14 patients with characteristics similar to those in the literature in terms of outcome. RESULTS. The 5-year survival rate for these patients was 14%. Whole-body positron emission tomography was performed on 3 patients to detect metastatic disease. The patterns of local recurrence, distant metastasis, and survival for these patients were compared with the same data for patients described in the literature. CONCLUSIONS. Surgery appears to have the greatest efficacy in the management of mucosal melanoma, although radiation therapy may play an increasingly important role in the future.

Journal ArticleDOI
01 May 1997-Cancer
TL;DR: The purpose of this study was to review the study institution's experience with EPSCCA with specific emphasis on the epidemiology and response to treatment of these uncommon neoplasms.
Abstract: BACKGROUND Extrapulmonary small cell carcinoma (EPSCCA) is often an underrecognized clinicopathologic entity, distinct from small cell lung carcinoma. The purpose of this study was to review the study institution's experience with EPSCCA with specific emphasis on the epidemiology and response to treatment of these uncommon neoplasms. METHODS Using the tumor registry database of the study institution, the authors retrieved and reviewed the records of all patients with EPSCCA treated between 1974 and 1994. Study eligibility required that the patients had a normal chest radiograph, computed tomography scan of the chest, sputum cytology, and/or negative bronchoscopy. Patients with well differentiated neuroendocrine carcinomas and Merkel cell carcinomas of the skin were excluded. RESULTS Primary sites of EPSCCA in the current series were: gastrointestinal system in 29 patients, ear, nose, and throat in 14, genitourinary system in 12, internal genitalia in 10, upper respiratory system in 5, unknown primary-lymph nodes in 5, unknown primary-other in 2, the thymus in 3, and the peritoneum in 1. After the initial evaluation and confirmation of histologic diagnosis, 10 of 81 patients had been lost to follow-up. Of the remaining 71 patients, 54 had limited disease. Forty of the 54 patients underwent surgical treatment of their malignancy; 10 patients (25%) remained alive and disease free at least 3 years after surgery, whereas 30 patients (75%) relapsed with a median disease free survival of 6 months. Six patients of 54 with limited disease were treated with chemotherapy and radiation. Five of these 6 (83%) relapsed at a median time of 11.5 months. Another 8 of the total of 54 patients received only radiation therapy and all had disease recurrence at a median time of 5 months. In the group of patients with extensive or recurrent disease, platinum-based chemotherapy was employed in 22 patients. There was a 72% response rate with a median duration of 8.5 months. Seven patients had doxorubicin-based chemotherapy. There was a 57% response rate with a median duration of 4.5 months. In the current study group of patients, the 3-year disease free and overall survival rates were 26% and 38%, respectively, whereas the 5-year disease free and overall survival rates were each 13%. CONCLUSIONS EPSCCA is usually a fatal disease, with a 13% 5-year survival rate. In a small percentage of patients, surgery can be curative if the tumor is small and confined to the organ of origin. Because of the poor overall outcome, one needs to consider the possible use of adjuvant chemotherapy in appropriate circumstances if surgery is to be employed. In most patients with limited disease, the combination of chemotherapy and radiation as the primary treatment can be as effective as surgery. EPSCCA is responsive to commonly employed regimens for small cell lung carcinoma; however, the responses are short-lived. The extent of disease at diagnosis represents the most sensitive predictor of survival. Cancer 1997; 79:1729-36. © 1997 American Cancer Society.

Journal ArticleDOI
01 Dec 1997-Cancer
TL;DR: Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects.
Abstract: BACKGROUND Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects METHODS The authors report on a randomized, controlled trial of mammographic screening for breast carcinoma that was conducted among 51,611 women (21,650 women who were invited to a screening [the study group] and 29,961 women in a control group) ages 39–59 years in Gothenburg, Sweden Among women in the study group, the screening interval was 18 months The screening phase of the trial took place in 1982–1991, and follow-up for breast carcinoma mortality continued until December 31, 1996 Mortality from breast carcinoma was analyzed using a Poisson regression model Overall and age specific effects of invitation to mammography screening on breast carcinoma mortality were calculated Three mortality effects were estimated: the effect on deaths from breast tumors diagnosed during the screening phase of the trial, as assessed by an independent Endpoint Committee (the EPC evaluation model); the effect on deaths from breast carcinoma diagnosed during the screening phase of the trial, as determined by data from the National Cancer Registry and the National Cause of Death Register (the SCB evaluation model); and the effect on deaths from all breast carcinomas diagnosed up to December 31, 1996, as determined by the National Cancer Registry and the National Cause of Death Register (the SCB follow-up model) RESULTS A nonsignificant, 21% reduction in the rate of mortality from breast carcinoma with invitation to screening was observed using the EPC evaluation model (relative risk [RR], 079; 95% confidence interval [95% CI], 058–108; P = 014); and a borderline significant, 23% rate reduction was observed using the SCB follow-up model (RR, 077; 95% CI, 060–100; P = 005) Age specific analyses yielded greater mortality rate reductions for the groups of women ages 39–44 years, 45–49 years, and 55–59 years, but there was no mortality rate reduction in the group of women ages 50–54 years The effects of invitation to mammographic screening on the incidence of lymph node-positive disease closely paralleled the effects of invitation on breast carcinoma mortality The effect on breast carcinoma mortality was consistent with the effect on all-cause mortality, suggesting no bias in classification of cause of death Breast carcinoma incidence in the study group was almost identical to the incidence in the control group after trial by screening had ended in the control group (RR, 098; 95% CI, 088–109; P = 07) CONCLUSIONS The current results support the commonly observed 20–30% reduction in breast carcinoma mortality with invitation to screening The impression that screening is less effective in women younger than 50 years may be an oversimplification Age specific effects should be a target for further research Cancer 2003;10:2387–96 © 2003 American Cancer Society DOI 101002/cncr11361

Journal ArticleDOI
01 Oct 1997-Cancer
TL;DR: Despite significant advances in understanding the biology of renal cell carcinoma (RCC) during the past decade, metastatic disease remains nearly incurable and a major medical challenge.
Abstract: BACKGROUND Despite significant advances in understanding the biology of renal cell carcinoma (RCC) during the past decade, metastatic disease remains nearly incurable and a major medical challenge. Because RCC is known to be immunogenic, immunotherapeutic agents such as recombinant human interleukin-2 (rIL-2) and interferon-α (IFN-α) have represented encouraging treatment modalities. METHODS A review of the natural history of and therapeutic approaches to RCC was examined. Studies involving rIL-2 alone and in combination with other adjuvant therapies were critically evaluated. RESULTS Overall response rates for metastatic RCC patients treated with rIL-2 were similar (i.e., in the range of 15-20%), regardless of whether rIL-2 was administered as monotherapy or in combination with IFN-α. Recombinant IL-2 monotherapy response rates were similar to those of IFN-α, but with an increased frequency of complete responses and enhanced response duration. Subcutaneous administration generally resulted in lower toxicity than intravenous administration. The roles of chemotherapy or adoptive immunotherapy in combination with rIL-2 and IFN-α therapy remain unclear and require further study. The importance of patient performance status as a predictor of response and survival in rIL-2 therapy was demonstrated. CONCLUSIONS The use of rIL-2 with or without IFN-α may represent the most useful therapeutic approach currently available for patients with good performance status. In patients with borderline performance status or severe comorbid disease, therapeutic approaches depend on patient factors and outcome expectation and may involve cytokine therapy. However, regardless of performance status, palliative measures and/or observation are important choices, because the majority of patients with metastatic RCC are incurable. Cancer 1997; 80:1198-220. © 1997 American Cancer Society.

Journal ArticleDOI
15 Oct 1997-Cancer
TL;DR: The mode of action of BPs originally was ascribed to their ability to adsorb strongly to hydroxyapatite crystals, and to inhibit their growth and dissolution, but it has gradually become clear that this is insufficient to account for all their effects.
Abstract: Michael J. Rogers, Ph.D. B Donald J. Watts, Ph.D. isphosphonates (BPs) were first studied over 30 years ago as stable analogues of a naturally occurring inorganic pyrophosphate (PPi), R. Graham G. Russell, M.D., Ph.D. which were shown to be able to inhibit the precipitation of calcium phosphate in vitro and biologic calcification in vivo. A key step oc1 Department of Human Metabolism and Clinical curred when it was shown that they also inhibited bone resorption Biochemistry, University of Sheffield Medical induced by a wide variety of agents and had profound effects on School, Sheffield, United Kingdom. calcium metabolism in vivo. 2 Department of Molecular Biology and BiotechThe first clinical uses of BPs followed soon after in the late 1960s nology, University of Sheffield, Sheffield, United and included their use as agents for bone scanning, based on their Kingdom. ability to adsorb to bone mineral, for which they remain outstandingly useful. Concurrently they were shown to be strikingly effective in clinical disorders associated with increased bone resorption, initially in Paget’s disease of bone, then in hypercalcemia of malignancy, myeloma, and bone metastases, and much later in osteoporosis. As a result, several BPs (e.g., etidronate, clodronate, pamidronate, alendronate, and tiludronate) now are licensed as drugs for various indications, and more should follow (risedronate, ibandronate, zoledronate, etc.). Because of the current emphasis on osteoporosis, their value in patients with Paget’s disease and in those with malignancy runs the risk of being undervalued. The mode of action of BPs originally was ascribed to their ability to adsorb strongly to hydroxyapatite crystals, and to inhibit their growth and dissolution, but it has gradually become clear that this is insufficient to account for all their effects. The ability to make BPs with minimal inhibitory effects on bone mineralization but increased relative potency on bone resorption was achieved many years ago. Remarkable progress has been made in increasing their potency as inhibitors of bone resorption by factors of 100–10,000 fold. One key feature appears to be the insertion of a nitrogen atom at critical positions in the side chain. These may be in alkyl side chains, (e.g., butyl-NH2) as in alendronate, or in the highly potent -N substituted derivatives of aminohydroxypropylidene bisphosphonate (APD) (pamidronate) (e.g., dimethyl APD, or methylpentenyl APD [ibandronate]). Comparable high potencies are obtained with heterocyclic ring Presented at the Skeletal Complications of Macompounds containing nitrogen (e.g., with imidazole, pyridinyl [e.g., lignancy Symposium, Bethesda, Maryland, April as in risedronate] or picolyl groups). These compounds are remark19–20, 1997. ably potent, and are able to suppress bone resorption in experimental animals at doses of õ 1 mg per day. Address for reprints: Graham Russell, Department of Human Metabolism and Clinical BioA simple hypothesis for the effects of BPs on bone resorption is chemistry, University of Sheffield Medical that the compounds are selectively concentrated in bone, where they School, Beech Hill Road, Sheffield, S10, 2RX, interfere with the action of osteoclasts by as yet poorly defined mechaUnited Kingdom. nisms. It is likely that BPs are internalized by osteoclasts and interfere Received June 3, 1997; accepted June 16, 1997. with specific biochemical processes. Thus BPs interfere with osteo-

Journal ArticleDOI
15 Aug 1997-Cancer
TL;DR: Primary germ cell tumors of the mediastinum are unusual neoplasms with histopathologic features that are similar to those of germ cell tumor in the gonads.
Abstract: BACKGROUND Primary seminomas of the mediastinum are unusual neoplasms that are morphologically indistinguishable from their gonadal counterparts but may have different biologic behavior because they arise at this particular location. METHODS The clinical and pathologic features in 120 cases of primary mediastinal seminoma were reviewed, and the immunohistochemical staining patterns in 50 of these tumors were also analyzed. RESULTS The patients were all men between the ages of 14 and 79 years (mean age, 46.5 years). Their clinical symptoms included cough, chest pain, and dyspnea. In some patients, the lesions were asymptomatic and discovered incidentally on routine chest radiographs. None of the patients had a previous history of testicular neoplasm or tumor elsewhere. Macroscopically, the tumors were described as soft and tan, with a slightly lobulated cut surface, and measured up to 16 cm in greatest dimension. Histologically, the morphologic features were similar to those of tumors occurring in the gonads, namely, a neoplastic proliferation of round-to-polygonal cells with indistinct cell borders, clear-to-lightly-eosinophilic cytoplasm with round-to-oval nuclei and prominent nucleoli, associated with a prominent inflammatory background composed mainly of mature lymphocytes. Necrosis, hemorrhage, multinucleated giant cells, granulomatous reaction, and remnants of thymic tissue were observed in a variable number of cases; mitoses were rare. Immunohistochemical studies in 50 cases showed cytoplasmic staining with placental alkaline phosphatase in 80% of the tumors, focal dotlike positivity for CAM 5.2 low-molecular-weight keratins in 75%, focal cytoplasmic staining for wide-spectrum keratin in 70%, focal positive reaction with vimentin in 70%, and focal positivity with HCG in singly scattered cells in 5%. Immunostains for carcinoembryonic antigen, epithelial membrane antigen, and α-fetoprotein were negative in all the cases studied. Fifty patients were Stage I, 3 patients were Stage II, and 12 patients were Stage III. Clinical follow-up information was obtained for 65 cases (54%). Forty-nine patients were alive and disease free after a period ranging from 1 to 19 years (mean follow-up, 10 years). Sixteen patients died within the same period and were found to have metastases to distant organs. Of the 16 patients who died, 6 showed extension of the tumor outside of the mediastinal compartment at the time of initial diagnosis (Stage III lesions). Aside from clinical staging, the authors' findings also suggest that patients >37 years have worse outcomes than younger individuals. The authors were unable to find any correlation between histopathologic features and clinical behavior in any of these cases. CONCLUSIONS Clinical and pathologic staging of mediastinal seminomas are important parameters that can be useful in determining the clinical outcomes of patients with these tumors. Tumor invasion into adjacent organs represents a marker of increased morbidity and mortality. The authors' findings suggest that patients with mediastinal seminomas may have a very good prognosis when the diagnosis is made early; patients with more advanced lesions may require more aggressive therapy for improved local control and prevention of distant metastases. Cancer 1997; 80:691-8. © 1997 American Cancer Society.