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Background: Although leucovorin (LV) + 5-fluorouracil (5-FU) is considered the treatment of choice for advanced colorectal cancer in most countries, the optimal schedule of this combination has not yet been established. Low-dose LV appears to be as active as high-dose LV in the daily-times-five regimen, but no randomized study of the levorotatory stereoisomer (6S-LV) given at two different dose levels has been published., Patients and Methods: Between November 1991 and June 1994, 422 patients (all with measurable disease previously untreated with chemotherapy) were randomized to 6S-LV (100 mg/sqm/i.v.) + 5-FU (370 mg sqm/15 min i.v. infusion), both administered for 5 days every 28 days (arm A), or to 6S-LV (10 mg/sqm/i.v./5-FU (doses as above), also given for 5 days every 28 days (arm B). The primary endpoint of the study was the comparison of response rates (WHO criteria): the secondary endpoint was the assessment of survival and tolerability. No evaluation of the quality of life or the symptomatic effect of treatment was planned., Results: The response rate was 9.3% in arm A (95% CI: 5.4-13.1), with 2 CR and 18 PR, and 10.7% in arm B (95% CI: 6.5-14.9), with 3 CR + 19 PR, without any significant difference (P = 0.78). The median time to progression was eight months in both groups and overall survival was 11 months, with no difference between treatments. Toxicity mainly consisted of gastrointestinal side effects (mucositis and diarrhoea), which were rarely severe (grade 3-4: 5%-10% of patients) and similar in the two groups., Conclusions: In this large-scale multicentre trial, the low and high doses of 6S-LV appeared to be equivalent in terms of the biochemical modulation of 5-FU in advanced colorectal cancer although, for several reasons (including the timing and the strict criteria of response evaluation, the high number of patients with unfavourable prognostic factors, the multi-institutional nature of the study, the dose and modality of 5-FU administration), the response rate was lower than that reported in some of the other published studies. Given the considerable difference in economic cost between the two dosages, the use of high-dose 6S-LV in the daily-times-five regimen is not recommended in clinical practice.

The antigens encoded by the major histocompatibility complex (MHC) are cell surface glycoproteins that play a fundamental role in the regulation of the immune response. Anomalous MHC expression in tumor cells has been viewed as an important feature to escape tumor recognition by immune cells. Low or absent MHC class I expression as well as ectopic MHC class II expression have been often observed to correlate with high grade malignancy and metastatic potential in a variety of human cancers. To date, very little investigation of MHC (HLA in man) class I and class II expression in human pancreatic cancer has been reported. We investigated this aspect on frozen sections of 8 pancreatic adenocarcinomas and 18 established in vitro cell lines. HLA class I was expressed in all but two cancers whereas de novo HLA class II expression was detected in 3 of 8 cancers. Interestingly, a hierarchy in the expression of the various subsets of HLA class II was found with HLA- DR > -DP > -DQ. Results on cell lines strongly resembled the ones obtained in cancer tissues. However, a peculiar feature was observed in certain cell lines. HLA class II antigens were expressed in only a few cell lines and in some of them a mixed population of positive and negative cells was found. Sorting and cloning of the two populations confirmed the existence of tumor cell clones with stable and distinct HLA class II phenotype. Taken together, these results indicate the cellular heterogeneity of pancreatic cancer cells with regard to the qualitative and quantitative expression of major histocompatibility complex genes, and may provide new insights for a better understanding of the tumorhost relationships in this extremely severe form of neoplasia.

HMB-45 is an anti-melanoma monoclonal antibody widely used in diagnostic pathology owing to its great specificity in identifying poorly differentiated melanomas. In this study, by a series of sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) immunoblots with the enhanced chemiluminescent (ECL) detection method on the HU-214 melanoma cell line, we identified the antigen of HMB-45 in a protein or proteins of 30-35 kDa. Although this result is in discrepancy with the previous literature which identified the antigen as a protein of 7 or 10 kDa, a family of proteins of 25-70 kDa of as a protein of 100 kDa (gp100), the present data indicate that the antigen signal we found might be specific. Furthermore, immunoblots on neuraminidase-treated cell lysates show, in agreement with already published data, that the antigen might be a sialated glycoprotein with the sialic acid involved in the epitope. Immunoblots on partially purified melanosomes confirmed the presence of the antigen in these organelles.

We report at unique, previously unreported pancreatic tumor occurring in a 60-year-old woman who was preoperative diagnosed on cytoaspiration as having clear cell carcinoma. The resected tumor consisted of a population of large epithelioid cells with clear or eosinophilic, granular cytoplasm, rich in glycogen, with nuclear pleomorphism and no mitotic activity. In spite of the epithelioid appearance, the tumor cells were negative for epithelial (CAM 5.2, KL1, AE1-AE3), endocrine (neuron-specific enolase [NSE], chromogranin A), and acinar (lipase, amylase) markers and positive for actin and melanogenesis-related marker HMB 45. Ultrastructurally, the neoplastic cells showed membrane-bound granules; no evidence of either epithelial or melanocytic differentiation was present. These morphophenotypic features have never been reported in a pancreatic tumor and overlap those of clear cell "sugar" tumor of the lung. The same morphophenotypic features are observed in a family of lesions characterized by the presence of the perivascular epithelioid cell that also includes lymphangiomyomatosis and angiomyolipoma. The present case may be considered a novel member of this family of lesions. We propose this new entity be named clear cell "sugar" tumor of the pancreas.

The biochemical modulation of 5-fluorouracil (5-FU) by means of methotrexate (MTX) and 6-S leucovorin (LV) seems mainly directed at two different intracellular targets, supporting the hypothesis of possible non-cross resistance between these two methods of 5-FU potentiation. Thirty-one patients, all previously treated with 5-FU and LV for advanced colorectal cancer (ACC), were treated with MTX = 200 mg/m2 iv day 1 and 5-FU 600 mg/m2 day 2 with 6-S LV 10 mg/m2 po q 6 h X 6 starting 24 h after MTX, repeated every 2 weeks. Of 30 evaluable patients, 2 Partial Remissions (PR) were achieved (Response Rate = 6.6%; 95% Confidence Interval 0%-14%). Eight patients had disease stabilization (SD). The overall median survival was 5 months (range 1-11). No WHO grade III-IV toxicities were reported. Despite the good tolerability, this combination of MTX, 5-FU and LV rescue has minimal activity in ACC after the failure of 5FU+LV-based chemotherapy.

Background: Over the last few years, estrogen receptor (ER) determination by immunohistochemistry (ER-ICA) has been extensively used, but it still remains to be established whether this method can replace the standard biochemical technique using dextran-coated charcoal (ERDCC)., Patients and Methods: ER were determined by both the dextran-coated charcoal (DCC) method and immunohistochemistry (ICA) in 699 patients with primary breast cancer; other parameters (age, pathological T-pT- and nodal status -pN-, progesterone receptors by DCC, proliferative index by ICA) were also recorded. The 'best' cut-off for ERICA was evaluated by means of Receiver Operating Characteristics (R.O.C.) analysis; logistic regression analysis was used to find adequate 'weights' for stain intensity., Results and Conclusions: A significant correlation was found between the two methods (p < 0.001). R.O.C. analysis revealed that the 'best' cut-off for the ERICA score was 45% (sensitivity 0.810, specificity 0.804). Logistic regression analysis showed that an ERICA score which also considers staining intensity does not add any useful information concerning ER content in breast cancers.

There is abundant psychophysical evidence in humans suggesting the existence of parallel pathways subserving different aspects of vision. However, there is little direct proof of the neural structures underlying the two pathways. We present direct anatomical evidence that in the normal human optic tract fibres are segregated according to size. Large axons, likely to correspond to the magnocellular pathway of non-human primates, take a more ventral and superficial course than the smaller axons belonging to the parvocellular pathway. This anatomical segregation not only reinforces the hypothesis of parallel pathways but, more importantly, offers a unique opportunity for studying the psychophysical effects of selective damage to one or the other fibre contingent.

We report a comparative study of 3 clear cell tumors of the lung (CCTL) and 3 angiomyolipomas (AML) of the kidney. Morphological analysis shows that the cells of CCTL are identical to the perivascular epithelioid component of AML. Phenotypically they both consistently expressed melanoma-associated antigens recognized by Moabs HMB45 and HMSA-1, while they were negative for HMSA-5. A minority of cells also expressed S-100 protein, vimentin and actin. In addition, one case of CCTL showed mature adipose tissue entrapped in the proliferation, thus suggesting an intermediate form between CCTL and AML. Based on morphological and phenotypical similarities, it is suggested that CCTL and AML belong to the same family of lesions, characterized by the presence of a peculiar muscle cell, expressing different melanoma-associated antigens.

A preoperative diagnosis of renal angiomyolipoma (AML) is of great importance for a correct management of these patients with this tumor. In fact when the lesion is small and asymptomatic a conservative approach may be considered. We have evaluated the radiographic and fine needle aspiration cytology (FNAB) findings in 8 cases of AML. In 3 cases both radiology and cytology were suggestive of carcinoma and thus the patients underwent surgery. In one case both techniques suggested AML but surgery was performed because the lesion was large and symptomatic. In 4 cases where both radiology and cytology suggested AML no surgery was performed. Follow-up data are consistent with the benign nature of the lesions. The immunocytochemical analysis of the FNAB with a panel of antibodies including keratin, vimentin, actin and HMB-45 was indicative of AML in 7 of 8 cases, including 2 of the 3 cases misdiagnosed as carcinomas. The presence of HMB-45-positive perivascular epithelioid cells in the FNABs was the most significant finding. It is concluded that immunocytochemical analysis of FNAB with this monoclonal antibody panel can increase the accuracy of preoperative diagnosis of AML, and allow consideration of a conservative approach in selected cases.

A rare case of single, pedunculated, ball-like rhabdomyoma of the pulmonary valve, causing moderate right ventricular outflow obstruction in an infant with tuberous sclerosis, is presented. The diagnostic and surgical implications are discussed.

Eleven tumors of the ampulla of Vater (5 stage IV and 2 stage II adenocarcinomas, 1 stage II papillary carcinoma, 1 neuroendocrine carcinoma, and 2 adenomas, one with foci of carcinoma) were examined for Ki-ras and p53 gene mutations by single-strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction-amplified DNA fragments. Ki-ras mutations were found in one adenocarcinoma and in the adenoma with foci of carcinoma, both involving mainly the intraduodenal bile duct component of the ampulla. Seven cases showed p53 gene mutations: four advanced-stage adenocarcinomas, the papillary carcinoma, the neuroendocrine carcinoma, and the adenoma with foci of carcinoma. Nuclear accumulation of p53 protein was immunohistochemically detected in the morphologically high-grade areas of the five cancers harboring a p53 gene missense point mutation. The adenomas, the two frame shift-mutated cancers, and the adenomatous and low-grade cancer areas of mutated carcinomas were immunohistochemically negative. Our data suggest that in ampullary neoplasia 1) p53 mutations are common abnormalities associated with the transformation of adenomas and low-grade cancers into morphologically high-grade carcinomas, and 2) Ki-ras mutations are relatively less frequent and might be restricted to tumors originating from the bile duct component of the ampulla.

We describe the microscopic, histochemical, immunohistochemical, and ultrastructural features of hundreds of neuroendocrine tumorlets occurring within a pulmonary lobe severely scarred by intralobar sequestration in a nonsmoking 49-year-old white man. To our knowledge, there have thus far been no descriptions or detailed analyses of neuroendocrine tumorlets arising within a pulmonary sequestration. The neuroendocrine tumorlets appeared in the form of minute aggregates--mostly microscopic, up to a maximum of 0.3 cm in greatest diameter--of small round and short spindle-shaped cells. They were organized in compact nests of fascicles and were supplied with round or elongated euchromatic nuclei and scant weakly eosinophilic cytoplasm. The neuroendocrine tumorlets were clustered around diseased bronchioles or embedded in a fibrotic pulmonary parenchyma with a distinctive infiltrative appearance. Sometimes they lay near an artery channel without an identifiable bronchiole or herniated into distal airways. Most of the neuroendocrine tumorlets were strongly argyrophilic on Grimelius staining. Immunohistochemically, there was reactivity for markers of epithelial and neuroendocrine differentiation together with evidence of orthotopic production of calcitonin, serotonin, and gastrin-releasing peptide and ectopic production of vasoactive intestinal peptide. Ultrastructurally, most of the neuroendocrine cells showed 100- to 120-nm dense-core membrane-bound secretory granules; mucus secretory cells were also present. We prefer the term neuroendocrine tumorlets over the generally used term carcinoid tumorlets, because the nature of these lesions is undefined and the relationship with neuroendocrine pulmonary neoplasms is not yet established.

A series of 36 human thymomas have been immunohistochemically analyzed using a panel of antibodies recognizing B-cell markers including CD20. Most thymomas exhibiting the cortical pattern, according to the criteria of Marino and Muller-Hermelink, were characterized by areas of medullary differentiation containing variable numbers of CD20+ B lymphocytes, thus mimicking the medulla of normal thymus. On the other hand, B cells were absent or rare in thymomas recognized as mixed using the same morphological criteria. Surprisingly, we observed in most mixed thymomas variable numbers of CD20+ spindle cells, characterized by long slender processes. Using double-marker analysis we could demonstrate the epithelial nature of these cells (expression of keratin and lack of lymphoid and B-cell-related markers). The immunoreactivity of thymoma epithelial cells with L26, an antibody widely used in the characterization of B-cell lymphomas, can represent a drawback of practical relevance in the differential diagnosis of mediastinal tumors.

Caring for a patient implies performing technical interventions and caring for the whole person, recognising his/her personal life, habits, family, wills. The working experience of an intensive care unit of Bellinzona is described: the theoretical framework that led the health team to start this new approach to intensive care patients and its translation in everyday practice. Verbal and non verbal communication skills (with the patient and the team) are pivotal in this approach; relatives are considered partners in the care of the patient and an essential element of the caring environment. Nurses identified meaningful data (soft data) related to living experience of the patient, to the interaction with the healing environment, his/her patterns of communication, and their use in the intensive care unit is described.

We report and immunohistochemically document the first (to the best of our knowledge) case of malignancy in which an intraductal carcinoma resembling apocrine breast cancer arose within a papillary hidradenoma of the vulva. Papillary hidradenoma is generally thought to originate from apocrine sweat glands, but a derivation from milk line remnants of the vulva should also be considered. Immunoreactivities for low- and high-molecular-weight cytokeratins, alpha-smooth-muscle-specific actin, carcinoembryonic antigen, S100 protein, and gross cytic disease fluid protein 15, an antigen of apocrine differentiation, show features that resemble those of an intraductal apocrine breast cancer. Positivity for gross cystic disease fluid protein 15 as well as the presence of estrogen and progesterone receptors suggest that tumor cells are controlled by ovarian steroid hormones. To our knowledge, no cases of malignancy arising from a papillary hidradenoma have been proved to date. Therefore, we also discuss previously reported cases of putative cancers that have developed in papillary hidradenomas. In the case presented herein, a local excision with a narrow rim of surrounding tissue was performed, and the patient was alive and well, without signs of recurrence, after 2 years of follow-up.

HMB-45 (melanocytic cell-specific monoclonal antibody) immunoreactivity was investigated in 10 cases of angiomyolipoma (AML) (1 with massive regional lymph node involvement) of the kidney and detected in all of them. No HMB-45 immunoreactivity was found in other tumors of the region which can occasionally be confused with AML, such as renal cell carcinoma, Wilms' tumor, and retroperitoneal sarcoma (leiomyosarcoma and liposarcoma). These findings indicate that HMB-45 is not a melanocyte-restricted marker and suggest that its expression might be useful in distinguishing AML from other tumors of the kidney and retroperitoneum.

HMB45 is a melanoma-specific monoclonal antibody that has found widespread use in diagnostic pathology. Recent reports, however, have suggested that this antibody may cross-react with a small number of carcinomas and other epithelial cells. The authors tested the hypothesis that these latter reports represent examples of false-positive immunostaining by comparing the immunostaining on breast, salivary gland, and lung tumors with the following: (1) a commercial ascites preparation of this monoclonal antibody; (2) a protein A-purified antibody preparation derived from ascites fluid; and (3) supernatant fluid obtained from the hybridoma cell line. The authors found that all examples of nonmelanoma immunostaining in the carcinomas tested were eliminated with the nonascites fluid preparations, whereas strong immunostaining of melanomas was retained. The authors conclude that contaminated commercial ascites fluid preparations of HMB45 may account for most, if not all, of the reports of nonmelanoma immunostaining with HMB45.

Nine cases of peripheral giant cell granuloma of the oral cavity have been immunohistochemically analyzed to assess the nature of the giant cells. Giant cells were unreactive when tested with antibodies recognizing myelomonocytic and macrophage markers (lysozyme, MAC 387, HAM 56) but showed strong immunoreactivity with MB1, an antibody reactive with osteoclasts. It is concluded that giant cells characterizing giant cell granuloma exhibit a phenotype distinct from other giant cells found in sites of chronic inflammation and may be true osteoclasts.

Over the last ten years the Italian National Research Council (C.N.R.) has launched an educational program aimed at favoring the delivery of the most up to date care for cancer patients in community hospitals. Among various tumors for which this effort was undertaken, management guidelines for colorectal cancer were developed in 1978 by a multidisciplinary team of national experts and reported in booklets distributed nationwide under the aegis of the Colorectal Cancer Task Force. In 1988, the C.N.R. funded an evaluation to learn whether: a) the guidelines were widely diffused in the target physician populations; b) their content was accepted by those who received them and, c) practice patterns were consistent with the recommendations in the guidelines. Overall results indicate only a limited effect. Despite clear evidence of a positive self-selection in the physicians' survey, guidelines were familiar to only 47% of responders. Although acceptance of at least some specific recommendations was good among doctors aware of the guidelines (greater than or equal to 60% responders), this finding loses relevance since a not negligible proportion of those not aware of them had the same convictions. Finally, analysis of practice patterns showed serious deficiencies (mostly in terms of thoroughness of operative staging) even in centers where more widespread knowledge of the guidelines should have led to better quality of care. The paper also discusses the comparability of our findings to results of a similar evaluation carried out in the U.S.A. Our results underscore the importance of analyzing the process of diffusion in any assessment of interventions based on knowledge dissemination.

Attacks of laryngeal edema in patients with hereditary angioedema (HAE) have been successfully treated with the infusion of C1-inhibitor (C1-INH) concentrate. No side effects were observed.

HMB-45 (melanocytic cell-specific monoclonal antibody) immunoreactivity has been detected by the immunoperoxidase technique in the cytoplasm of 2 of 100 breast carcinomas. In addition, normal breast lobules and ducts were occasionally found to have positive results in 6 of 100 cases. These findings indicate the need to exercise caution in the interpretation of HMB-45 immunoreactivity for immunohistochemical characterization of neoplasms.

The purpose of this study was to report the results of different treatments in 20 patients with hereditary angioedema. Effectiveness of tranexamic acid in preventing swellings was evaluated in 15 patients: in all but 3 subjects tranexamic acid was effective without serious side effects. 15 severe attacks of edema were managed with intravenous infusions of either kallikrein inhibitor (8 cases) or concentrate of C1 esterase inhibitor (7 cases). In only 1 case was the kallikrein inhibitor unsuccessful. C 1 esterase inhibitor concentrate proved highly effective in the treatment of acute attacks (the result was lacking in one patient because of too low dosage of the drug). No side effects were observed with both treatments, but improvement was more rapidly achieved with infusion of C1 esterase inhibitor. The serum levels of C4 and C1 esterase inhibitor and the activity of C 1 esterase inhibitor before and after long-term prophylaxis and acute attacks treatment were investigated.

Prophylactic treatment with antifibrinolytic agents, epsilon-aminocaproic and tranexamic acid, reduces the incidence and severity of attacks in patients with hereditary angioedema. Long-term effectiveness or risk of antifibrinolytic agents has not been established. Sixteen patients needing continuous prophylaxis because of frequency and severity of attacks were treated with tranexamic acid. In four patients this treatment was ineffective and the drug was withdrawn after 2 months. A remission or reduction in the frequency or severity of attacks was observed in 12 patients treated for a period ranging from 8 to 34 months. Hepatic tests and blood fibrinolytic activity were not influenced by long-term oral treatment with tranexamic acid.

Serum C1 esterase inhibitor was determined in 138 members of 18 italian families with hereditary angioedema by immunochemical and enzymatic assays. On the basis of quantitative and functional findings, the type A of hereditary angioedema was diagnosed in 44 subjects, and the type B in 15. Some technical devices concerning serum sample handling were identified. The influence of heparin, EDTA, and citrate on C1 esterase inhibitor activity of normal plasma was also investigated.

From 1978 to 1982 at the Oncology Unit of the Rho Hospital, we followed 96 women who had been operated for breast cancer. In 22 cases (23%) the first signs of recurrence were changes in the following: physical examination (9), symptoms (7), ESR (3), bone scan (2), alkaline phosphatase (1), chest X-ray (1). An adequate follow-up schedule is based on the following: a) limited examinations causing little disturbance to the patient, easily feasible, sensitive, specific, and of limited cost; b) lead-intervals of various tests set according to the risk of relapse; c) critical periodic review of the series, with constant updating of information in the literature.