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Mitotic checkpoint protein hsMAD2 as a marker predicting liver metastasis of human gastric cancers.

hsMAD2, the human homologue of mitotic arrest deficient 2 (MAD2), is a key component of the mitotic checkpoint system. Recently, mutations and decreased expression of mitotic checkpoint genes including hsMAD2 have been reported in cancer cell lines with defective mitotic checkpoint. However, the genetic alterations in the genomic hsMAD2 gene have not been determined in gastric cancers. Moreover, the biological implications of the overexpressed hsMAD2 in primary cancers are unknown. In this study, we analyzed 32 primary gastric cancers with polymerase chain reaction (PCR) amplification of all exons, including flanking intronic sequences, of the genomic hsMAD2 gene followed by direct DNA sequencing. We also measured the hsMAD2 protein levels in cancer and normal tissues by semi-quantitative immunoblotting. No mutations were found in the coding sequences, although three single nucleotide polymorphisms (SNPs) were identified in the noncoding sequences in 13 of 32 patients. These SNPs were not associated with either hsMAD2 expression or disease progression. The semi-quantitative western blot analysis showed hsMAD2 was significantly overexpressed in gastric cancer tissues compared with corresponding normal tissues (P < 0.001). The calculated ratio of the hsMAD2 protein in cancer tissue (C) to that in corresponding normal tissue (N) (C / N ratio) was significantly higher in patients with well differentiated adenocarcinoma (P = 0.0274) or with synchronous liver metastasis (P = 0.0025). A C / N ratio greater than 3 was observed more frequently in patients with synchronous liver metastasis. Therefore, C / N ratio > 3 may be clinically important as a predictive indicator for metachronous liver metastasis of gastric cancers.

Adenocarcinoma↗

[Observations on cancer metastasis from an unknown primary location].

Following a short introduction in which the criteria used to classify patients suffering from cancer metastasis from an occult primary location are defined, the paper reports two cases of this type: an omental metastasis occluding the upper colon and an inguinal lymph node metastasis. Referring to the international literature, the Authors then analyse the reasons for the inability to recognise the neoplasm, its incidence, patients survival, the most appropriate diagnostic course and possible treatment of these cases. In conclusion, over and above the definition of a truly autonomous nosological status of metastasis of unknown origin, it is important to follow a correct diagnostic procedure in order to establish the most appropriate form of therapy.

Adenocarcinoma↗

Chronic pancreatitis and extrapancreatic cancer: a retrospective study among 181 patients with chronic pancreatitis.

The relationship between chronic pancreatitis (CP) and extrapancreatic cancer has been debated in the recent years. In prospective studies, it has been found that pancreatic cancer develops in 0-5% of patients with chronic pancreatitis. Many papers describe an increased relative risk for developing extrapancreatic cancer in patients suffering from chronic pancreatitis. In this study including 181 patients with CP, we found 14 patients with extrapancreatic cancer (three of these had two different types of cancer). No patient had pancreatic cancer. It was found that the respiratory airways and upper gastrointestinal tract were the dominating locations (five and four cases, respectively), but also genital and hemolymphopoietic cancers were represented (four and two cases, respectively). Two patients had metastatic cancer with unknown primary tumor. The patients with cancer tended to be older than those without cancer. The patients with CP had a 2.43 times greater risk of developing cancer than the general Danish population (age and sex standardized comparison). The relatively large number of cancers in the upper gastrointestinal tract and respiratory airways suggest that tobacco and alcohol may be responsible, as these organs have the highest exposure to these compounds, which are well known carcinogens.

Adult↗

Expression of human milk fat globulin proteins in cells of haemopoietic origin.

Lineage-specific gene expression has been used for the identification of metastasis of cancers with unknown primary site or of disseminated cancer cells in haemopoietic compartments such as bone marrow or in lymph nodes. For the muc1, cytokeratin-19 and the CEA genes, the transcription in haemopoietic cells has been shown recently. Here, the expression of the mammary epithelium related antigens BA46 (lactadherin) and BA70 in lymphoid and myeloid cell lines, and in clinical specimens is analysed. By Northern-hybridization with specific oligonucleotides an ubiquitous transcription of both genes, independent from the provenance of cells or the chromosomal gender was found. Both mRNA molecules were amplified by rtPCR from the samples and the specificity could be confirmed by sequence analysis. Peptide-specific antibodies were raised in rabbits and used for Western-blot analysis and for immunocytochemical studies. Both antibodies reacted with total cell lysates from myeloid and lymphatic cells. In immunocytochemistry antibody P717 (anti-lactadherin) had a significant strong staining of the myeloid cell lines K562 and HL60 suggesting a participation of lactadherin in leukocyte-function. Using antibody P718, strong stains were seen in myeloid line K562 and lymphoid line ST486. In conclusion, our findings expand the results that the concept of lineage-specific gene expression is no longer valid at the molecular level.

Amino Acid Sequence↗

A case with widespread cutaneous metastases of unknown primary origin: grave prognostic finding in cancer.

We present a 52-year-old man with widespread cutaneous metastases (CMs) of unknown primary origin. Although we performed many of the investigations, we could not find out a primary origin of malignancy. There are no practical algorithms to identify the primary of cutaneous metastatic tumors of unknown origin. An algorithm in cancer patients with CMs seems to be needed to manipulate such cases. We believe that more reports related with this issue must be published to form an algorithm in such cases.

Biomarkers, Tumor↗

[Hepatic metastasis of unknown primary site].

In this retrospective study, 91 patients (30%) out of a series of 304 with metastatic cancer of unknown primary site were found to have liver metastases. The liver was the only metastatic site in 28 (31%) cases and was associated with other sites in 63 (69%) cases. Median age was 62 yr in 61 male patients and 59 yr in 30 female patients. Thirty patients were submitted to an extensive investigation in search of the primary tumor, including systematic endoscopies: no primary cancer was found in these patients. In 61 other patients, only symptom-oriented investigations were performed and the primary cancer was found in 11 cases. The histologic type was adenocarcinoma in 71 (78%) cases, undifferentiated in 11 (12%) cases, epidermoid in 5 (6%) cases and determined by cytology alone in 4 cases. The median survival was 4 months in patients with metastases in the liver only, and 5 months in the other patients. This difference was not significant, so prognostic factors such as the Karnofsky index, weight loss, CEA and LDH levels were evaluated in the entire group; these factors do not have significant prognostic value. By contrast, when patients were able to receive chemotherapy, median survival was better (4 months) than without (median survival: 1 month; P = 0.005). In addition, in the case of objective response to chemotherapy, the median survival was 9 months versus 3.5 months for patients without objective response (P = 0.001). Seventy-three out of 91 patients (80%) were treated with chemotherapy regimen; 65 patients were evaluable: the objective response rate was 11 +/- 7% (7/65). Different regimens were used. With a non-toxic combination of fluorouracil, vinblastine and cyclophosphamide, 3 partial responses greater than or equal to 50% out of 43 patients (7 +/- 8%) were obtained. No significant advantage was observed when adriamycin was added to FU (4/13): 31 +/- 25%. Second- or third line chemotherapy regimen due to progression of the disease after the first-line combination provided only one objective response out of 36 patients. According to this retrospective study we recommend that overinvestigation be avoided in patients, with liver metastases of unknown primary site and that these patients be treated with non-toxic drug combinations.

Adenocarcinoma↗

Role of whole body positron emission tomography/computed tomography scan with 18F-fluorodeoxyglucose in patients with biopsy proven tumor metastases from unknown primary site.

AIM: The aim of this study was to evaluate the role of whole body PET/CT scan with (18)F-fluorodeoxyglucose (FDG) in the detection of the primary tumor in patients with metastatic cancer from unknown primary origin (CUP syndrome). METHODS: Sixty-eight consecutive patients, with CUP syndrome (39 lymph nodes, 29 visceral biopsy proven tumor metastases), underwent a whole-body FDG-PET/CT study. All enrolled patients were unsuccessfully studied, within the previous month, with physical examination, laboratory tests and conventional diagnostic procedures. All the pathological findings identified at PET/CT scan and suspected for primaries, were further investigated. After PET study, the minimum follow-up period for the inclusion in the studied population was 3 months. RESULTS: The primary tumor site was correctly identified by FDG-PET/CT in 24 patients (24/68, 35.3%): lung (n=9), rino/oro-pharynx (n=6), pancreas (n=5), colon (n=2), uterus (n=2). In 5 cases, FDG-PET scan did not identify a primary pathological focus, which was subsequently detected by other diagnostic methods within 3 months. In 39 patients (39/68, 57.4%), the primary tumor site was not localized. However, in 9 of them, FDG-PET/CT scan identified further unexpected metastases, modifying the stage of disease. Overall, the following oncological treatment was influenced by the PET scan, in a total of 33 patients (33/68, 48.5%). CONCLUSIONS: Our data strongly support the diagnostic contribution of whole body FDG-PET/CT scan in the evaluation of patients with CUP syndrome and suggest its use in an early phase of the diagnostic iter to optimize patient management.

Adult↗

The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma.

BACKGROUND: Patients who present with unknown primary carcinomas represent 10% to 15% of the patients with cancer who present to medical centers. Despite data in the literature indicating minimal success in determining the location of primary carcinomas, these patients continue to be evaluated exhaustively. Additionally, identification of the location of primary carcinomas does not often affect treatment. Clinical treatment and prognosis are only affected if a reevaluation of the pathologic findings yields a potentially curative diagnosis of an undifferentiated lymphoma, germ cell tumor, or a hormonally sensitive carcinoma. METHODS: Tumor registry files from January 1, 1990, through December 31, 1992, were retrospectively retrieved to identify adult patients who presented with metastasis of an unknown primary site at the H. Lee Moffitt Cancer Center and Research Institute, a 162-bed tertiary care cancer center specialty hospital affiliated with the University of South Florida College of Medicine, Tampa. Medical records were reviewed for age, sex, histologic findings of previous malignant growth, types and duration of symptoms, and mode of presentation. Fifty-six of the 199 patients were included in the study; 31 were men (55.4%) and 25 were women (44.6%), with ages ranging from 33 to 83 years. Diagnostic evaluations were reviewed and included data from procedures conducted at both the H. Lee Moffitt Cancer Center and at outside facilities. Diagnostic studies performed included barium swallow; intravenous pyelogram; mammogram; abdominal ultrasound; chest x-ray film; bone scan; magnetic resonance imaging; computed tomography of the head, chest, abdomen, and pelvis; laparotomy; bronchoscopy; gastroscopy; and colonoscopy. Information for the diagnostic test procedures was taken from the point of initial patient contact until the determination of metastatic disease. RESULTS: The primary cancer site was found in four (7.1%) of the 56 cases in the study and could not be classified as curable by systemic means. The average cost of diagnosis was $17,973, with 19.6% of the patients surviving for more than 1 year. The mean survival period was 8.1 months. A total of 410 tests were performed with only four tests correctly identifying the location of the primary tumor. CONCLUSIONS: Once a potentially curable malignancy has been excluded, there is little justification to support extensive diagnostic evaluation of the patient. Substantial costs are incurred and survival is often not significantly affected. It was estimated that 1.2 million new cancer cases would have occurred during 1994, with approximately 10% of these patients presenting with cancer of unknown primary origin. Based on cost assessments, investigation of these patients would exceed $1.5 billion. This clinical scenario is one where attention to outcome, clinical management, and expense should be carefully considered.

Adult↗

[Positron-emission tomography in oncology].

This review analyses clinical results, new trends and recommendations of the leading medical centers concerning application of positron-emission tomography (PET) with F-18 fluorodeoxyglucose (F18 FDG) in cancer patients. This method of radionuclide visualization has been widely introduced for the last decade in diagnosis of cancer of unknown primary location, or CUP-syndrome, bronchogenic cancer of the lungs, cancer of the head and neck, malignant lymphoma and melanoma, colorectal and neuroendocrine cancer. Efficacy of this procedure, physiological grounds, performance are considered. Potentialities of F18 FDG PET are demonstrated in tumor screening, detection of metastases, recurrences after surgical, radiation or drug antitumor treatment or monitoring. In combination with CT, MRT, USI and other techniques, F18 FDG PET raises accuracy of the diagnosis of pathological changes at any stage of cancer with resulting improvement in further therapeutic and follow-up efficacy.

Colorectal Neoplasms↗

Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial.

PURPOSE: Resistance to topoisomerase (TOP) 1 and 2 inhibitors is a potentially important reason for treatment failure, and may be related, in part, to a down-regulation of the specific TOP target. Investigators in our laboratories previously noted such a down-regulation of the target, along with a reciprocal up-regulation of the alternate TOP. Therefore, sequencing TOP inhibitors may provide a means for overcoming resistance to the TOP I and II inhibitors. Furthermore, point mutations in TOP I, which confer resistance to TOP I inhibitors, were associated with collateral sensitivity to cisplatin. EXPERIMENTAL DESIGN: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m(2)/day) on days 1 to 3 with etoposide (70-80 mg/m(2)/day) and cisplatin (20-25 mg/m(2)/day) on days 8 to 10. The timing of the drug sequence was based on the prior Phase I pharmacokinetic and pharmacodynamic studies of camptothecin and etoposide, and the level of the TOP targets in peripheral blood monocytes. RESULTS: Fifteen patients (7 males and 8 females) received 40 courses of therapy across three dose levels. The median age was 56 (range, 39-77), and the median performance status was 1 (range, 0-2). The diagnoses included: non-small cell lung cancer (7), head and neck cancer (2), cancer of unknown primary (2), and 1 each of ovarian cancer, prostate cancer, gastric cancer, and renal cancer. Level 1 (topotecan 1.0 mg/m(2)/day; etoposide 80 mg/m(2)/day; and cisplatin 25 mg/m(2)/day) produced severe and prolonged febrile neutropenia in the first patient treated, and the subsequent patients were then entered onto a reduced dose level (cohort 2: topotecan 0.75 mg/m(2)/day; etoposide 70 mg/m(2)/day; and cisplatin 20 mg/m(2)/day). Three of 6 patients on cohort 2 experienced grade IV neutropenia >5 days, and a decision was then made to add filgrastim at 5 micro g/kg rather than additionally reduce the dosages (cohort 3). Eight patients were then treated on cohort 3, and 1 of the 8 patients experienced a grade 4 neutropenia. Thus, cohort level three was considered the recommended dose for Phase II studies. Twelve of the 15 patients had disease assessable for response to therapy. Seven achieved stable disease for >/==" BORDER="0">2 months, whereas 5 showed continued progression of their disease. CONCLUSIONS: These data show that sequencing TOP 1 and 2 inhibitors is feasible, and topotecan 0.75 mg/m(2)/day days 1-3; etoposide 70 mg/m(2)/day days 8-10; and cisplatin 20 mg/m(2)/day days 8-10 with filgrastim at 5 micro g/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

Adult↗

[Analysis of the p53 gene status of lymph node metastasis in the head and neck region in occult primary cancer].

BACKGROUND: Lymph node metastasis in the head and neck region with occult primary cancer are a fairly rare tumor entity in head and neck cancer. Tumor biological parameters as well as mechanism and cause for the development of this so called "cancer of unknown primary" (CUP) are not well investigated in head and neck cancer. Mutations of the p53 tumor suppressor gene are the most prevalent genetic alteration of human malignancies and show an incidence of up to 50% in head and neck cancer. For a further tumor biological definition of CUP the p53 status was determined. METHODS: Twenty-three archival formalin fixed paraffined CUP of an occult squamous cell carcinoma of the head and neck region were examined. In all cases a primary cancer was never diagnosed. The DNA extracted from the tumor material was amplified with specific primers for exon 4-9 of the p53 gene and subsequently sequenced. RESULTS: None of the 23 CUP cases showed a mutation or polymorphism in exon 4-9 of the p53 gene. CONCLUSIONS: The total absence of p53 mutations in the so called mutational "hot spots" shows a significant difference to the frequency of primary tumors of the head and neck region. May be this tumor biological characterisation helps to further elucidate the growth behaviour of CUP in the head and neck region and the reason for their development.

Antisense Elements (Genetics)↗

[Pituitary metastases. 3 cases].

OBJECTIVE: Review cases with hyothalamo-hypophyseal metastases which raise complex therapeutic situations. PATIENTS AND METHODS: Files of patients hospitalized from 1992 to 1996 at the Cochin Hospital Endocrinology unit were compared with data reported in the literature. RESULTS: We had patients with pituitary metastases from breast cancer and 69 cases have been reported in the literature: 72 patients, 57% men and 43% women, mean age 57.2 +/- 12.3 years. The primary tumor was identified in 58.3% of the cases. The primary cancer was unknown and revealed by the pituitary metastasis in 41.7% of the cases. The primary tumor was a breast cancer in 31.9% of the cases, and lung cancer in 30.5%. The main clinical signs were vision disorders (40.3%) and diabetes insipisus (29.1%). The principal differential diagnosis was hypophyseal adenoma. Short term prognosis was not good. DISCUSSION: These data are in agreement with the older literature excepting the high prevalence of primary cancers revealed by pituitary metastasis, probably a result of progress in hypophyseal exploration techniques. CONCLUSION: The prevalence of pituitary metastasis will continue to increase with longer survival in cancer patients. Metastasis should thus be entertained as a possibility in patients with a hypothalamo-hypophyseal tumor, particularly after the age of 59, in order to hasten diagnosis and provide early treatment.

Aged↗

Management of the unknown primary in patients with metastatic cancer of the head and neck.

The evaluation of the patient with metastatic cervical lymph node squamous cell carcinoma and an unknown primary tumor frequently involves the use of guided biopsies as a diagnostic tool. This study was performed to assess the effectiveness of these biopsies. Using a retrospective chart review, we identified 25 patients who had undergone a total of 100 guided biopsies to evaluate an unknown primary malignancy of the head and neck. We found that 99 of the 100 biopsies were negative for malignancy. Although guided biopsies were obviously not helpful in these cases, we believe this might be attributable to the fact that the method of performing them is inconsistent among surgeons. Therefore, we present an algorithm for the management of the unknown primary head and neck malignancy, including recommendations regarding the use of guided biopsies.

Adult↗

A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients.

Preliminary data would suggest that the pineal hormone, melatonin (MLT), may enhance tamoxifen (TMX) anti-tumour efficacy. Both MLT and TMX have been used as single agents in the palliative treatment of metastatic neoplasms, other than the classical hormone-dependent tumours, without, however, any clear efficacy. On this basis, a phase II study with TMX plus MLT has been performed in untreatable metastatic solid tumour patients. The study included 25 metastatic solid tumour patients other than breast cancer and prostate cancer (six unknown primary tumour; four melanoma; four uterine cervix carcinoma; five pancreatic cancer; three hepatocarcinoma; two ovarian cancer; one non-small-cell lung cancer), for whom no other effective standard therapy was available, because of poor clinical conditions, no response to previous chemotherapies and/or chemotherapy-resistant tumours. Both drugs were given orally every day until disease progression (TMX, 20 mg day-1 at noon; MLT, 20 mg day-1 in the evening). Three patients had a partial response (PR) (12%; 95% confidence limits 2-24%) (one cervix carcinoma; one melanoma; one unknown primary tumour). A stable disease (SD) was achieved in 13 other patients, whereas the remaining nine patients progressed. Performance status (PS) improved in 9/25 patients, whose median score increased from 50% to 70%. Finally, a survival longer than 1 year was observed in 7/25 (28%) patients. This phase II study would suggest that the neuroendocrine combination with TMX plus MLT may have some benefit in untreatable metastatic solid tumour patients, either in controlling cancer cell proliferation or improving the PS.

Adult↗

Cancer in neck nodes with unknown primary site: role of mucosal radiotherapy.

Sixty-nine patients with metastatic squamous cell carcinoma in neck nodes with an unknown primary lesion were treated with curative intent between October 1964 and December 1986. Sixty-five patients received radiotherapy to the neck and at least part of the mucosa of the head and neck, whereas 4 patients received treatment to the neck only. Mucosal doses were approximately 5,000 cGy-6,000 cGy at 170 cGy-180 cGy per fraction. Eight patients (12%) subsequently developed mucosal site failures, a figure that did not differ significantly from the incidence of a second metachronous head and neck cancer following definitive irradiation in a series of 393 patients with lesions of the supraglottic larynx, pharyngeal wall, pyriform sinus, or tonsillar area. This suggests that radiotherapy was highly effective in preventing the appearance of cancer at the unknown primary site from which the neck metastasis arose. Absolute and cause-specific 5-year survival rates were 48% and 66%, respectively.

Adult↗

Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study.

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.

Adult↗