Liver metastases from breast cancer: the role of surgical treatment.

BACKGROUND/AIMS: To evaluate short- and long-term outcomes in the surgical treatment of liver metastases from breast cancer METHODOLOGY: Between 1984 and 1999 we observed 26 patients with secondary liver localization (25 metachronous) from breast cancer. The median disease-free interval was 70 months (4-136). Median age at the time of liver surgery was 56 years (36-76). The 18 patients included: 1 patient at stage 1, 10 at IIA, 6 stage II B and 1 patient at stage IV. Seven patients were found to have axillary lymph nodes metastases. Fifteen patients had infiltrating ductal carcinoma, 2 a lobular carcinoma and 1 patient a mixed-component carcinoma. The grading was G3 in 10 and G2 in 8 patients. Regarding the recettorial status, 5 patients were ER+ PR-, 8 patients were ER+PR-, 4 patients were ER-PR-. In 9 cases the patients underwent adjuvant chemotherapy (5 of them following postoperative radiotherapy) and in 14 cases Tamoxifen was used. Surgery was conservative in 13 cases and demolitive in 5 cases. RESULTS: The follow-up (3-70 months) was completed in 15 patients out of 18 observed cases. Nine patients died; six patients are still living, 4 of them "disease-free", 2 having advanced metastatic disease, in treatment. There was neither long-term or perioperative major morbidity nor mortality in our group. The overall 5-year-survival was 25% in patients whose liver metastases developed within 3 years after breast surgery compared with 40% in those ones with metastatic disease diagnosed more than 3 years after. CONCLUSIONS: Surgery of liver metastases from breast cancer can be performed with low morbidity and mortality in selected patients.

[Papillary carcinoma of the thyroid arising on thyroglossal duct cysts: report of a case and review of the literature]. / Carcinoma papillare della tiroide insorto su cisti del dotto tireoglosso: a proposito di un caso e revisione della letteratura.

Thyroglossal duct cysts are the most common congenital disorder of the neck. One percent of cases may degenerate and give rise to a cancer, mainly arising in the pericystic thyroid tissue. Some 250 cases have been reported in the literature to date. We report here on a 39-year-old man with a midline mass in the neck measuring 4 cm max. The patient was examined preoperatively by ultrasonography of the neck and assay of thyroid hormones, which yielded a diagnosis of a thyroglossal duct cyst. On the basis of these findings, the patient underwent surgery to remove the mass and, after an extempore histopathological examination, was submitted to total thyroidectomy owing to the presence of papillary carcinoma of the thyroid arising on the thyroglossal duct cyst with multiple foci in the context of the thyroid gland. Most thyroid cancers at the time of surgery are confined to the thyroid gland, infiltrating the adjacent structures in approximately 20% of cases and the local-regional lymph nodes in 8 to 11.5%. Thyroid papillary adenocarcinoma is multifocal in 21% of cases. The multifocal nature of the cancer makes total thyroidectomy mandatory at the same time as surgery is performed to remove the cyst.

Ifosfamide, cisplatin and etoposide combination in locally advanced inoperable non-small-cell lung cancer: a phase II study.

From March 1993 to February 1997, 43 eligible patients with inoperable stage IIIA (ten patients) and stage IIIB (33 patients), histologically confirmed NSCLC received 3 courses of the ICE combination (ifosfamide 1.5 g m(-2) and mesna 750 mg m(-2) two times a day, cisplatin 25 mg m(-2) and etoposide 100 mg m(-2), all administered intravenously (i.v.) on days 1-3 every 3 weeks) with G-CSF support. After three cycles, patients were submitted to radical surgery or received two additional courses of the ICE regimen and/or curative radiotherapy. Grade 3-4 neutropenia occurred in 21% of 114 evaluable courses, but was of short duration, leading to neutropenic fever in 5% of the courses. Severe thrombocytopenia and anaemia were observed in 13% and 3% of the courses respectively. Non-haematological toxicity was generally mild with only two episodes of reversible renal impairment. The overall response rate after three chemotherapy courses was 69% (28 partial responses, one complete response). Ten patients (8/10 patients in stage IIIA, 2/33 patients in stage IIIB) underwent radical surgery. Median TTP for patients not undergoing surgery (n = 33) was 8 months (range 3-34+); median DFS for patients rendered NED by surgery (n = 10) was 26 months (range 1-54+). Median OS for the entire group was 12.5 months (range 2-57+). The ICE regimen is active in locally advanced NSCLC with acceptable toxicity and warrants further exploration as induction chemotherapy in larger series.

Resistance of ribosomal protein mRNA translation to protein synthesis shutoff induced by poliovirus.

Poliovirus infection induces an overall inhibition of host protein synthesis, although some mRNAs continue to be translated, suggesting different translation requirements for cellular mRNAs. It is known that ribosomal protein mRNAs are translationally regulated and that the phosphorylation of ribosomal protein S6 is involved in the regulation. Here, we report that the translation of ribosomal protein mRNAs resists poliovirus infection and correlates with an increase in p70(s6k) activity and phosphorylation of ribosomal protein S6.

Small nucleolar RNAs and nucleolar proteins in Xenopus anucleolate embryos.

We investigated the presence and localization, in the cells of anucleolate mutant embryos of Xenopus laevis, of three representative small nucleolar RNAs (snoRNAs), U3, U15 and U17, and of two nucleolar proteins, nucleolin and fibrillarin. The levels of the three snoRNAs in the anucleolate mutant are the same as in normal embryos, in contrast to 5S RNA and ribosomal proteins. In situ hybridization showed that, in the absence of fully organized nucleoli, the three RNAs are diffusely distributed in the nucleus and partly associated with a number of small structures. Nucleolin and fibrillarin are also present in the anucleolate embryos as in normal embryos, although there is less nucleolin mRNA in the former. The two nucleolar proteins were localized by immunofluorescence microscopy. Fibrillarin, similar to its associated U3 and U15 snoRNAs, is diffusely distributed in the anucleolate nucleus and is partly associated with small structures, probably prenucleolar bodies and pseudonucleoli. Nucleolin also appears diffusely distributed in the nucleus with some spots of higher concentration, but with a different pattern with respect to fibrillarin.

Role of surgery in the treatment of recurrent esophageal cancer.

Neoplastic recurrence is the most common cause of death after surgery for esophageal cancer. The Authors review the therapeutic options evaluating in terms of palliation of dysphagia and complication and mortality rates. Prognostic factors and mechanisms determining the recurrence are also reviewed. A strategy for a rational approach in the management of recurrent esophageal cancer emerges from both the literature and their own experience. Notwithstanding the small life span of these patients, the treatment of esophageal obstruction is mandatory. The therapeutic options that be considered are: palliative resection, surgical bypass, laser therapy, intubation, radiotherapy. The site of obstruction, the presence of metastasis, the general status can lead to the optimal choice. In terms of palliation of dysphagia the surgical approach seems to obtain the best results, even if high complication and mortality rates have been reported. Bypass is the second surgical choice when applicable. The other non-surgical modalities have been administered in large series of patients with good results. Combination therapies can obtain better results.

Accelerated chemotherapy with high-dose epirubicin and cyclophosphamide plus r-met-HUG-CSF in locally advanced and metastatic breast cancer.

BACKGROUND: This study evaluated the toxicity of high-dose epirubicin and cyclophosphamide plus r-met-HUG-CSF (G-CSF) given every 2 weeks and compared the dose-intensity achieved with this schedule with that obtained in a previous study we conducted in which the same regimen was given every 3 weeks without G-SCF (EC 21). The secondary objective was to explore the activity of this regimen. PATIENTS AND METHODS: Between December 1991 and March 1994, 41 patients (pts), 19 with locally advanced breast cancer (LABC) and 22 with metastatic breast cancer (MBC), were given high-dose epirubicin (Hd-Epi) (120 mg/m2) and cyclophosphamide (CTX) (600 mg/m2) on day 1 every 14 days (EC 14) plus granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/d s.c. on days 2-12). A total of 8 cycles in LABC pts (4 pre- and post-surgery), and 6-8 cycles in MCB pts were administered. The results were compared with those obtained in the previous study. RESULTS: The incidence of WHO grade 3-4 neutropenia was significantly reduced in the EC 14 + G-CSF regimen (25.2% vs. 46.8% in 214 and 250 evaluable cycles, respectively, p<0.0001), as well as the incidence of neutropenic fever (7% vs. 3%, p=0.05). Grade 3-4 anemia (36.6% vs. 8% pts, p=0.001) and grade 3-4 thrombocytopenia (17.1% vs. 0 pts, p=0.002), were significantly more frequent in EC 14 + G-CSF. No significant differences in the other side effects were found. A total of 17 of 207 of the cycles (8.2%) were delayed in the EC 14 + G-CSF vs. 58/271 (21.4%) in the EC 21 (p<0.0001). The main reasons for these treatment delays were neutropenia (1% vs. 15%), anemia (3% vs. 0) and thrombocytopenia (1% vs. 0). As a result of treatment acceleration and differences in dose delays, the patients on EC 14 + G-CSF received a higher dose-intensity (Epi 58.51 mg/m2/wk vs. 36.8 mg/m2/wk; CTX 292.52 mg/m2/wk vs. 182.9 mg/m2/wk). A complete response at surgery was obtained in 9/19 (47.4%) LABC pts. An objective CR was obtained in 11/22 MBC pts (50%) and a partial response in 8/22 (36.4%), yielding an overall response rate of 86.4%. CONCLUSIONS: Hd-Epi + CTX is very active against both LABC and MBC. The administration of G-CSF allows dose intensification of both drugs (a 59.5% increase of the actual dose intensity) with acceptable clinical tolerance (a lower incidence of neutropenia but a higher incidence of anemia and thrombocytopenia). Only a specifically designed phase III trial will lead to definitive conclusions regarding the greater antitumor activity of accelerated CSF-including regimens as compared to standard chemotherapy for advanced breast cancer.

Different forms of U15 snoRNA are encoded in the introns of the ribosomal protein S1 gene of Xenopus laevis.

Recent cloning and sequencing of one of the two Xenopus gene copies (S1b) coding for the ribosomal protein S1 has revealed that its introns III, V and VI carry a region of about 150 nt that shares an identity of 60%. We show here the presence in Xenopus oocytes and cultured cells of a 143-147 nt long RNA species encoded by these three repeated sequences on the same strand as the S1 mRNA and by at least one repeat present in the S1 a copy of the r-protein gene. We identify these RNAs as forms of the small nucleolar RNA U15 (U15 snoRNA) because of their sequence homology with an already described human U15 RNA encoded in the first intron of the human r-protein S3 gene, which is homologous to Xenopus S1. Comparison of the various Xenopus and human U15 RNA forms shows a very high conservation in some regions, but considerable divergence in others. In particular the most conserved sequences include two box C and two box D motifs, typical of most snoRNAs interacting with the nucleolar protein fibrillarin. Adjacent to the two D boxes there are two sequences, 9 and 10 nt in length, which are perfectly complementary to an evolutionary conserved sequence of the 28S rRNA. Modeling the possible secondary structure of Xenopus and human U15 RNAs reveals that, in spite of the noticeable sequence diversity, a high structural conservation in some cases may be maintained by compensatory mutations. We show also that the different Xenopus U15 RNA forms are expressed at comparable levels, localized in the nucleoli and produced by processing of the intronic sequences, as recently described for other snoRNAs.

Intracellular immunization with cytosolic recombinant antibodies.

We report the application of a strategy to inactivate cellular proteins in vertebrate cells based on the intracellular expression of immunoglobulin genes. We have selected, in this instance, the p21 protein, encoded by the ras proto-oncogene, as a target protein. The variable regions of the neutralizing anti-p21ras monoclonal antibody Y13-259 were cloned in vectors for the expression of either the whole antibody molecule or its single-chain Fv fragment (ScFv) derivative. In order to target the recombinant antibodies to the cytosol, their hydrophobic leader sequence for secretion was mutated or deleted. When these proteins are expressed in the cytosol of Xenopus laevis oocytes they colocalize with the endogenous p21ras protein in the cytoplasmic face of the oocyte plasma membrane, and they markedly inhibit the H1 kinase activity induced by insulin. Moreover, cytosolic anti-p21ras ScFv fragments block the ensuing meiotic maturation. Thus the intracellular expression of both whole antibodies and antibody domains can be used to block a biological function.

U17XS8, a small nucleolar RNA with a 12 nt complementarity to 18S rRNA and coded by a sequence repeated in the six introns of Xenopus laevis ribosomal protein S8 gene.

U17XS8 RNA is a 220 nt small RNA coded by a sequence repeated in each of the six introns of the gene for ribosomal protein S8 of Xenopus laevis. It is mainly localized in the nucleolus, as shown by in situ hybridization, and it is assembled in a ribonucleoprotein particle (RNP) sedimenting at about 12S, slightly faster than U3 RNP, and with a density of 1.45 g/ml. DNA and RNA microinjections in Xenopus oocytes have shown that U17XS8 RNA is not the product of an independent transcription unit, but is produced by processing of intron sequences of r-protein S8 transcript, as has been recently shown for other small nucleolar RNAs encoded in the introns of other genes. Its accumulation during Xenopus development, oogenesis and embryogenesis, increases in parallel to that of r-protein S8 mRNA. Another interesting feature is the presence in the U17XS8 RNA of a 12 nt sequence complementary to 18S rRNA. The results presented suggest a possible role of this RNA in some step(s) of ribosome assembling in the nucleolus. Some relevant differences between Xenopus U17XS8 RNA and the corresponding human U17 RNA, recently described, have been observed.

Structure and expression of the nerve growth factor gene in Xenopus oocytes and embryos.

A large part of the coding portion of the Xenopus nerve growth factor (NGF) gene has been identified and cloned by the use of a chicken cDNA probe and its sequence has been determined. Comparison of the derived amino acid sequence of mature Xenopus NGF with that of other species showed a high conservation, whereas comparison of the prepropeptide showed large divergent regions alternated with short conserved regions. Expression of the NGF gene was examined during development of oocytes and embryos. Surprisingly, NGF mRNA was found in the oocyte; it is present in small previtellogenic as well as in fully grown oocytes. NGF mRNA, passed to the embryo at fertilization, is degraded before the gastrula stage and starts accumulating again around the stage of the neurula. The association of NGF mRNA with polysomes is indicative of NGF synthesis during oogenesis. In fact, by using antibodies against mouse NGF it was possible to reveal NGF molecules present as precursors. These molecules accumulate during oogenesis and are maintained in the embryos up to the blastula stage; a very faint band corresponding to a smaller size peptide is sometimes detected. A maternal role for the NGF can be proposed, although a possible activity of NGF in the oocyte cannot be ruled out.

Experimental changes in the amount of maternally stored ribosomes affect the translation efficiency of ribosomal protein mRNA in Xenopus embryo.

The amount of maternal free ribosomes in developing Xenopus embryos has been experimentally modified; an increase was obtained by microinjection of purified ribosomes into fertilized eggs, and a decrease was induced by treatment with a drug which reduces the amount of free ribosomes. The effect of this manipulation on the partition of the ribosomal protein mRNA (rp-mRNA) was analyzed during embryo development; it was observed that when ribosomes available for translation are in excess, polysome loading with rp-mRNA decreases. Conversely, when ribosomes are scarce, polysome loading of rp-mRNA increases. These experiments, which artificially stress events observed in the course of development, indicate that there is a relationship between the availability of ribosomes in the cells and the utilization of rp-mRNA for synthesis of ribosomal proteins, as already suggested by previous observations on r-protein synthesis during embryogenesis.

Combinations of monoclonal antibodies can distinguish primary lung tumors from metastatic lung tumors sampled by fine needle aspiration biopsy.

Transthoracic fine needle aspiration (FNA) biopsies performed under computed tomography (CT) scan (CT-FNA) have greatly improved the cytodiagnosis of lung tumors. However, the distinction between a primary lesion and a metastatic lesion still may be difficult on the basis of morphologic criteria. To evaluate whether a selected panel of monoclonal antibodies (MoAb) to tumor-associated antigens (TAA) can improve the diagnostic potential of FNA, we have immunocytochemically analyzed 122 pulmonary CT-FNA. Whereas conventional cytology was capable of recognizing only the neoplastic nature of the lesions, the immunocytochemical diagnosis could identify the primary or metastatic nature of the pulmonary masses in 92.5% of the cases. The immunocytochemical findings were confirmed by clinical-histopathologic data. The current results demonstrate that the use of immunocytochemical methods can significantly improve the diagnostic accuracy of conventional cytology of lung masses.

Ribosomal protein, histone and calmodulin mRNAs are differently regulated at the translational level during oogenesis of Xenopus laevis.

The localization of r-protein mRNA in subcellular compartments has been analysed. It was observed that the mRNA for a representative r-protein (L1) is diffuse in the cytoplasm, as shown by in situ hybridization experiments and that the distribution of rp-mRNA between polysomes and light mRNPs changes during oogenesis. In early oogenesis this mRNA is found mostly in subpolysomal fractions, whereas at the beginning of vitellogenesis (stage II) it becomes associated with polysomes where it remains in a constant amount at later stages. Histone and calmodulin mRNA, on the contrary, are mostly associated with non-polysomal fast-sedimenting particles throughout oogenesis. This suggests that the partition of different classes of mRNA between polysomes, light mRNP and heavy particles depends on their nature and might be determined by different requirements for these mRNAs during oogenesis.

Peritoneovenous shunt and neoplastic ascites: a 5-year experience report.

The cases of 42 patients with malignant ascites treated with a peritoneal venous shunt over a 5-year period are reviewed to establish the incidence of surgical and postsurgical complications. Although the yield of malignant cells found in the peripheral blood was increased after shunting, no new hematogenous metastases were observed after the operation. No evidence of disseminated intravascular coagulation was observed after shunt placement. While the shunt effectively relieved the discomfort due to abdominal distention and respiratory impairment, no restoration of cutaneous hypersensitivity was observed in the nine patients who were anergic prior to surgery. The median survival of patients with breast and gynecological cancer, after surgery, was significantly longer than the survival of patients with primary gastrointestinal neoplasma. In conclusion, peritoneal venous shunt appears to be an effective and safe method to improve the quality of life of patients with malignant ascites.

A proposed TNM classification for malignant primary liver tumours.

On the basis of 211 hepatic resections and reresections, a study was made to evaluate the possibility of compiling a checklist for primary liver tumours according to the TNM classification. This would aid the surgeon in planning therapy and provide a useful guide for prognosis and late results.

Our experience with resection of primary and secondary liver tumours.

The authors retrospectively analyse the results achieved in recent years by surgical treatment of 103 malignant primary or secondary liver cancers: (Three patients have been operated on twice at different times for recurrence.) 23 hepatic resections were performed for benign lesions. The operative mortality is very low, the incidence of postoperative complications is minimal, and the survival up to 8 years is rather satisfactory. In all cases we used Ton That Tung's surgical technique, that is, "finger fracture with intraparenchymal ligature of the vasculobiliary pedicles."

Ribosomal-protein synthesis is not autogenously regulated at the translational level in Xenopus laevis.

Whether ribosomal-protein synthesis in Xenopus laevis is autogenously controlled at the translational level as is known to occur in prokaryotes has been studied. For this purpose ribosomal (r) proteins were prepared from X. laevis ribosomal subunits and group fractionated by ion-exchange chromatography. They were then added to an in vitro translation system directed by an oocyte mRNA fraction which contains template activity for r proteins. The synthesized radioactive products were analyzed by 2D gel electrophoresis and compared with controls. Similarly in vivo experiments were performed by microinjection of the fractionated proteins into the cytoplasm of Xenopus oocytes followed by incubation with [35S]methionine for different times. In all the experiments no evident effect of r proteins on the translation of their own mRNA was observed.