A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity.

Dendritic cells, the most potent 'professional' antigen-presenting cells, hold promise for improving the immunotherapy of cancer. In three different well-characterized tumour models, naive mice injected with bone marrow-derived dendritic cells prepulsed with tumour-associated peptides previously characterized as being recognized by class I major histocompatibility complex-restricted cytotoxic T lymphocytes, developed a specific T-lymphocyte response and were protected against a subsequent lethal tumour challenge. Moreover, in the C3 sarcoma and the 3LL lung carcinoma murine models, treatment of animals bearing established macroscopic tumours (up to 1 cm2 in size) with tumour peptide-pulsed dendritic cells resulted in sustained tumour regression and tumour-free status in more than 80% of cases. These results support the clinical use of tumour peptide-pulsed dendritic cells as components in developing effective cancer vaccines and therapies.

Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity.

Cytotoxic T lymphocytes (CTLs) are a critical component of the immune response to tumors. Tumor-derived peptide antigens targeted by CTLs are being defined for several human tumors and are potential immunogens for the induction of specific antitumor immunity. Dendritic cells (DC) are potent antigen-presenting cells (APCs) capable of priming CTL responses in vivo. Here we show that major histocompatibility complex class I-presented peptide antigen pulsed onto dendritic APCs induces protective immunity to lethal challenge by a tumor transfected with the antigen gene. The immunity is antigen specific, requiring expression of the antigen gene by the tumor target, and is eliminated by in vivo depletion of CD8+ T cells. Furthermore, mice that have rejected the transfected tumor are protected from subsequent challenge with the untransfected parent tumor. These results suggest that immunization strategies using antigen-pulsed DC may be useful for inducing tumor-specific immune responses.

Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines.

Antigen presentation by host dendritic cells (DC) is critical for the initiation of adaptive immune responses. We have previously demonstrated in immunogenic murine tumor models that bone marrow (BM)-derived DC pulsed ex vivo with synthetic tumor-associated peptides, naturally expressed by tumor cells, serve as effective antitumor vaccines, protecting animals against an otherwise lethal tumor challenge (Mayordomo, J.I., T. Zorina, W.J. Storkus, C. Celluzzi, L.D. Falo, C.J. Melief, T. Ildstad, W.M. Kast, A.B. DeLeo, and M.T. Lotze. 1995. Nature Med. 1:1297-1302). However, T cell-defined epitopes have not been identified for most human cancers. To explore the utility of this approach in the treatment of tumors expressing as yet uncharacterized epitopes, syngeneic granulocyte/macrophage colony-stimulating factor-stimulated and BM-derived DC, pulsed with unfractionated acid-eluted tumor peptides (Storkus, W.J., H.J. Zeh III, R.D. Salter, and M.T. Lotze. 1993. J. Immunother. 14:94-103) were used to treat mice bearing spontaneous, established tumors. The adoptive transfer of 5 x 10(5) tumor peptide-pulsed DC dramatically suppressed the growth of weakly immunogenic tumors in day 4 to day 8 established MCA205 (H-2b) and TS/A (H-2d) tumor models, when applied in three biweekly intravenous injections. Using the immunogenic C3 (H-2b) tumor model in B6 mice, tumor peptide-pulsed DC therapy resulted in the erradication of established d14 tumors and long-term survival in 100% of treated animals. The DC-driven antitumor immune response was primarily cell mediated since the transfer of spleen cells, but not sera, from immunized mice efficiently protected sublethally irradiated naive mice against a subsequent tumor challenge. Furthermore, depletion of either CD4+ or CD8+ T cells from tumor-bearing mice before therapy totally suppressed the therapeutic efficacy of DC pulsed with tumor-derived peptides. Costimulation of the host cell-mediated antitumor immunity was critical since inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of peptide-pulsed DC in vivo. The analysis of the cytokine pattern in the draining lymph nodes and spleens of tumor-bearing mice immunized with DC pulsed with tumor-eluted peptides revealed a marked upregulation of interleukin (IL) 4 and interferon (IFN) gamma production, as compared with mice immunized with DC alone or DC pulsed with irrelevant peptides. DC-induced antitumor effects were completely blocked by coadministration of neutralizing monoclonal antibody directed against T helper cell 1-associated cytokines (such as IL-12, tumor necrosis factor alpha, IFN-gamma), and eventually, but not initially, blocked by anti-mIL-4 mAb. Based on these results, we believe that DC pulsed with acid-eluted peptides derived from autologous tumors represents a novel approach to the treatment of established, weakly immunogenic tumors, and serves as a basis for designing clinical trials in cancer patients.

Therapy of murine tumors with p53 wild-type and mutant sequence peptide-based vaccines.

The BALB/c Meth A sarcoma carries a p53 missense mutation at codon 234, which occurs in a peptide, termed 234CM, capable of being presented to cytotoxic T lymphocytes (CTL) by H-2Kd molecules (Noguchi, Y., E.C. Richards, Y.-T. Chen, and L.J. Old. 1994. Proc. Natl. Acad. Sci. USA. 91:3171-3175). Immunization of BALB/c mice with bone marrow-derived dendritic cells (DC), generated in the presence of granulocyte macrophage colony-stimulating factor and interleukin 4, and prepulsed with the Meth A p53 mutant peptide, induced CTL that specifically recognized peptide-pulsed P815 cells, as well as Meth A cells naturally expressing this epitope. Immunization with this vaccine also protected naive mice from a subsequent tumor challenge, and it inhibited tumor growth in mice bearing day 7 subcutaneous Meth A tumors. We additionally determined that immunization of BALB/c mice with DC pulsed with the p53 peptide containing the wild-type residue at position 234, 234CW, induced peptide-specific CTL that reacted against several methylcholanthrene-induced BALB/c sarcomas, including CMS4 sarcoma, and rejection of CMS4 sarcoma in vaccination and therapy (day 7) protocols. These results support the efficacy of DC-based, p53-derived peptide vaccines for the immunotherapy of cancer. The translational potential of this strategy is enhanced by previous reports showing that DC can readily be generated from human peripheral blood lymphocytes.

Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial).

BACKGROUND: On the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. PATIENTS AND METHODS: Seventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m(2), i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m(2) b.i.d., days 1-14 every 21 days. RESULTS: Overall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population. Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3-4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand-foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. CONCLUSION: Combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.

Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial.

BACKGROUND: Trastuzumab (Herceptin(R)) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. PATIENTS AND METHODS: HERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. RESULTS: The overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54-0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1-2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26-1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). CONCLUSIONS: Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors.

BACKGROUND: Several randomized trials have tested the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in relieving chemotherapy-induced bone marrow suppression. However, the use of CSFs in the treatment of neutropenic fever remains virtually unexplored. PURPOSE: This study evaluated the benefits of adding CSF therapy to the standard antibiotic treatments given to cancer patients for chemotherapy-induced neutropenic fever. The usefulness of CSFs was quantified in terms of reducing the following: (a) the duration of neutropenia, (b) the length of hospitalization, and (c) the overall cost of the treatment. METHODS: A randomized trial was conducted to test whether the administration of either G-CSF or GM-CSF improved the outcome of standard antibiotic therapy (ceftazidime plus amikacin) in nonleukemic cancer patients with fever (> 38 degrees C) and grade IV neutropenia (absolute neutrophil count [ANC] < 500/mm3) induced by standard-dose chemotherapy. Of 121 patients who entered the trial, 39 received G-CSF (5 micrograms/kg body weight per day), 39 received GM-CSF (5 micrograms/kg body weight per day), and 43 received a placebo beginning just after the first dose of antibiotics. Treatments were continued for at least 5 days (7 days with clinically or microbiologically documented infections) or until 2 days after fever subsided and ANCs rose above 1000/mm3. RESULTS: The median duration of grade IV neutropenia (ANC of < 500/mm3) was 2 days in both CSF arms and 3 days in the placebo arm (P < .001). The median duration of neutropenia with an ANC of less than 1000/mm3 was also significantly shorter in patients receiving G-CSF or GM-CSF (P < .001). The median duration of fever was similar in the three arms. The median hospital stay was 5 days (range, 5-14 days) in the G-CSF arm, 5 days (range, 5-10 days) in the GM-CSF arm, and 7 days (range, 5-34 days) in the placebo arm (P < .001). The median time on CSF was 4 days in both treatment arms. The mean cost of overall treatment was reduced by $1300-$1400 in the CSF arms compared with the placebo arm (P = .11 for G-CSF versus placebo; P = .06 for GM-CSF versus placebo; P = .7 for G-CSF versus GM-CSF). CONCLUSIONS: Adding G-CSF or GM-CSF therapy to antibiotic treatment shortens the duration of neutropenia and the duration of hospitalization in patients with neutropenic fever. A statistically nonsignificant trend toward lower cost was observed in the CSF arms as compared with the placebo arm. IMPLICATIONS: The benefits of CSFs to cancer patients with chemotherapy-induced neutropenic fever merit further evaluation in large randomized trials.

Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia. METHODS: A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count <100/mm(3)), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status of 3-4 (Eastern Cooperative Oncology Group scale), or prior inpatient status. Eligible patients were randomly assigned to receive the antibiotics ceftazidime and amikacin, with or without G-CSF (5 microg/kg per day). The primary study end point was the duration of hospitalization. All P values were two-sided. RESULTS: Patients randomly assigned to receive G-CSF had a significantly shorter duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and hospital stay (median, 5 days versus 7 days; P = 0.015) than patients in the control arm. The incidence of serious medical complications not present at the initial clinical evaluation was 10% in the G-CSF group and 17% in the control group (P = 0.12), including five deaths in each study arm. The median cost of hospital stay and the median overall cost per patient admission were reduced by 17% (P = 0.01) and by 11% (P = 0.07), respectively, in the G-CSF arm compared with the control arm. CONCLUSIONS: Adding G-CSF to antibiotic therapy shortens the duration of neutropenia, reduces the duration of antibiotic therapy and hospitalization, and decreases hospital costs in patients with high-risk febrile neutropenia.

Biweekly gemcitabine plus vinorelbine in first-line metastatic breast cancer: efficacy and correlation with HER2 extracellular domain.

Purpose. To assess the toxicity and efficacy of biweekly gemcitabine plus vinorelbine in first-line advanced breast cancer, and to establish whether circulating HER2 ECD levels correlate with the efficacy of the combination. Patients and methods. 52 patients were treated with gemcitabine 2500 mg/m(2) plus vinorelbine 30 mg/m(2), both on day 1 of 14-day cycles, for a maximum of 10 cycles. Baseline serum levels of HER2 ECD were assessed with an ELISA. Results. All patients were evaluable for toxicity, and 50 for efficacy. Overall toxicity was moderate. Grade 3 neutropenia occurred in 35% of patients and grade 4 in 19%. Other grade 3 toxicities were observed in less than 6%. There was one episode of febrile neutropenia, and one death after cycle three. Overall response rate was 52% (95% CI: 38% to 66%), with 2 patients achieving a CR (4%). Response rate did not correlate with HER2 ECD, with 50% of HER2 ECD positive patients responding, vs 48.5% of the HER2 ECD negative. Median overall survival was 24.6 months. Conclusion. Gemcitabine plus vinorelbine, given as an every-two-week schedule, is an active regimen in advanced breast carcinoma. This combination can be an option when anthracyclines and taxanes are not preferred. HER2 ECD has no predictive value in this non-taxane combination.

Identification of Meth A sarcoma-derived class I major histocompatibility complex-associated peptides recognized by a specific CD8+ cytotoxic T lymphocyte.

The finding that class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) recognize peptide antigens (epitopes) bound to class I MHC molecules has accelerated efforts to identify CTL-defined tumor peptides for the development of peptide-based cancer immunotherapy. The Meth A sarcoma is probably one of the best studied of all murine tumors. It is extremely lethal unless protective immunity is induced. We recently reported the characterization of a cloned H-2Kd-restricted, CD8+ anti-Meth A CTL line (CTLMA-9C; Frassanito et al., Cancer Res., 54: 4424-4429, 1994). The cytotoxic reactivity of this CTL was shown to be restricted to Meth A sarcoma, and the results of the analysis of the immunogenicity of the CTL-resistant variant of Meth A, designated Meth A4R, indicate that the CTL-defined epitope is functional in tumor rejection. Here we have isolated class I MHC-associated peptides from Meth A sarcoma by mild acid treatment and resolved them into sixty fractions by reverse phase-HPLC. These fractions were then tested for their ability to sensitize the DBA/2 mastocytoma P815 to cytolysis by the anti-Meth A CTL. A single fraction, fraction 27, has been repeatedly identified as containing the CTL-defined epitope. Peptides eluted from the CTL-resistant variant, Meth A4R, failed to sensitize P815 to cytolysis by the anti-Meth A CTL, while fraction 27 derived from Meth A sensitized Meth A4R to lysis by the CTL. These findings confirm the peptide nature of the epitope recognized by CTL on the surface of Meth A. Our future efforts will focus on the identification and sequence analysis of the tumor peptides and the development of a tumor peptide-based vaccine model for immunotherapy.

[Surveillance of commensal flora evolution and infections in neutropenic cancer patients submitted to chemoprophylaxis]. / Vigilancia de la evolución de la flora comensal y de las infecciones en pacientes oncológicos con neutropenia sometidos a quimioprofilaxis.

The evolution of the flora and its resistance to different antimicrobials in neutropenic patients submitted to high-dose chemotherapy with autologous blood stem-cell transplantation, and the relation of these findings to the etiology of the infections the patients developed was studied in order to evaluate the suitability of the chemoprophylaxis and the empirical antibiotic therapy used. Forty-one patients were analyzed in a period of 28 months. The chemoprophylaxis used was levofloxacin, fluconazole and acyclovir. The empirical sequential treatment was an initial administration of cefepime, followed by teicoplanin and amikacin. Cultures were done of nasal and pharyngeal smears, Hickman catheter and stools, 1 day before chemoprophylaxis started and then on days 5 and 9. In the case of fever, three sets of blood cultures and urine cultures were done and samples from areas related to the clinical condition were analyzed. Levofloxacin induced the selection of resistant strains or species in the flora and in the infectious agents. Fluconazole also selected resistant species in the flora. Seventeen infections were documented in eleven patients, produced by Gram-positive bacteria in thirteen cases (81.25%) and by Gram-negative bacteria in three (18.75%). The coagulase negative staphylococci and Enterococcus faecalis were the most frequent agents of infection. We identified on nine occasions the same microorganism in the flora and in the pathological product; this suggests its endogenous origin and supports the use of prospective cultures of the flora, monitoring the sensibility of the microorganisms isolated to the antimicrobials used in chemoprophylaxis and empirical treatment.

Reversible peripheral neuropathy induced by a single administration of high-dose paclitaxel.

Peripheral neuropathy (PN) is the main side effect with cycles of paclitaxel at standard doses (175 mg/m2 for 21 days). Administration of a single high-dose paclitaxel (HDP) is a novel approach for the treatment of cancer. We have prospectively measured neurotoxicity induced by HDP during a phase I trial. Nineteen patients were treated with escalating doses of paclitaxel by 24-hour infusion. In our study, PN induced by HDP was moderate, reversible, and not dose limiting. Severe PN was seen in patients who had received previous neurotoxic chemotherapy, and caution on the administration of HDP in this setting is warranted.

Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer.

The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m(2)/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m(2)) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m(2)) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m(2)) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4-6.6 months) and median survival was 11 months (95% CI: 7.9-14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m(2) i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m(2) p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m(2) and UFT 300 mg/m(2).

IL-12-engineered dendritic cells serve as effective tumor vaccine adjuvants in vivo.

The recent identification of tumor-associated antigens (TAA) and TAA-derived peptides presented by MHC molecules to T cells has provided the tools to design and test clinical vaccines for treating human malignancies, such as melanoma. While the most effective adjuvant for use in vaccine formulation remains unclear, autologous dendritic cells (DC) appear to be good candidate adjuvants. We have previously shown that syngeneic bone marrow-derived DC when pulsed ex vivo with relevant TAA-derived peptides can effectively vaccinate mice against a subsequent challenge with tumor or can effectively treat animals bearing established tumors. In this report, we have engineered murine interleukin-12 (mIL-12), a potent stimulator of cell-mediated immunity, into murine DC using retroviral-mediated or plasmid-based transfection procedures. Transfectants produced up to 25 ng rIL-12/10(6) cells/48 hours. These engineered cells are capable of promoting enhanced anti-tumor, antigen-specific CTL responses compared to nontransduced DC.

Leiomyosarcoma of the soft tissues in a patient with nevoid basal-cell carcinoma syndrome.

A 57-year-old man was admitted with complaints of progressive anorexia, weight loss and right flank pain. He had been treated for basal-cell carcinoma of the skin 19 years before. On physical examination, eight moles in the face, back and left thigh were found along with palmar pits. In addition, a painful induration in his right thigh was evident. Biopsy proved that six moles were basal-cell carcinomas and the thigh mass a high-grade leiomyosarcoma. Computed tomographs revealed multiple metastases in the lungs and the liver. The patient was treated with epirubicin, with partial response, and subsequently with ifosfamide. He died 17 months after diagnosis. Whereas the world literature records several cases of soft tissue tumors in patients with nevoid basal-cell carcinoma syndrome, this is the first report of a simultaneous occurrence of leiomyosarcoma and nevoid basal-cell carcinoma syndrome.

Neoplasms of unknown primary site: a clinicopathological study of autopsied patients.

BACKGROUND: Malignant neoplasms of an unknown primary site (NUPS) remain a diagnostic and therapeutic challenge in clinical practice. With this in mind, we have reviewed all autopsies performed in patients with NUPS in a single institution. PATIENTS AND METHODS: By reviewing 1656 autopsies performed on adults in our institution (1974-1990), 43 cases of NUPS were found. (NUPS was defined as histologically proven malignant tumor for which a primary site could not be found after anamnesis, complete physical examination, chest X-ray and routine chemistries.) RESULTS: There were 24 men (56%) and 19 women. Mean age was 62 years (76% of patients were aged 40-75). Clinical presentation included general deterioration (73%), digestive symptoms (58%), liver enlargement (58%) abdominal pain (56%), respiratory symptoms (45%), ascites (26%) and node enlargement (16%). Abnormalities in analysis and image tests were frequent but nonspecific. Median time from admission to death was 42 days (range, 4-135). Pathologic diagnoses at autopsy were: 23 adenocarcinomas (53%), arising from pancreas (6), biliary tree (6), lung (3), prostate (2), stomach (1), kidney (1) and unknown (4); 3 squamous carcinomas (5%) (1 renal pelvis, 1 biliary tree, 1 stomach); 5 undifferentiated carcinomas (1 lung, 4 unknown); and 12 miscellaneous tumors (including 3 lymphomas, 3 neuroendocrine tumors, 3 hepatocarcinomas, 2 mesotheliomas and 1 melanoma). There was a tendency towards a metastatic pattern different from that expected from the primary tumor. Image tests were of little usefulness in the search for the primary tumor. CONCLUSIONS: 1) Adenocarcinomas were the most frequent tumor presenting as NUPS, especially from the pancreas and biliary tree. 2) In this series, at least 11% of patients were amenable to standard systemic therapies (3 lymphomas and 2 prostatic adenocarcinomas) if a correct pathologic diagnosis could have been established when alive. 3) Presenting symptoms and metastatic pattern differed from those expected for the primary neoplasm eventually found. 4) Image tests were often misleading as regards the primary site, although they were useful to quantify the dissemination of the tumor.