p-carborane-bridged bipyridine ligands for energy transfer between two iridium centers.

Two iridium(III) complexes displaying for one a high HOMO-LUMO gap and for the other a weaker gap were linked in a controlled and logical manner to closo-p-carborane spacers. The bridging ligand is composed of 5-ethynyl-2,2'-bipyridine units, and the peripherical Ir-ligands are orthometalated 2',4'-difluoro-2-phenylpyridine (dfppy) (λ(abs) at 400 nm for the "Ir(dfppy)2(bpy')") for the energy donor fragment and dibenzo[a,c]phenazine (dbpz) (λ(abs) at 525 nm for "Ir(dbpz)2(bpy')") for the energy acceptor fragment.Redox, spectroscopic, and photophysical properties for models and the donor-carborane-acceptor complex were determined. Efficient energy transfer from the "Ir(dfppy)2(bpy')" moiety to the "Ir(dbpz)2(bpy')" fragment is occurring with a rate constant of 3.3 × 10(8) s(-1) despite weak electronic coupling through the inert p-carborane spacer. From flash photolysis experiments it is shown that, by excitation of the donor, a low lying triplet state localized on the acceptor bridging ligand side is formed which decays by conversion to the (3)MLCT of the acceptor fragment which phosphoresces at 644 nm.

Photoinduced electron/energy transfer across molecular bridges in binuclear metal complexes.

Molecular bridges that efficiently move charge between remote donor and acceptor sites can be thought of as molecular wires. Insight into the properties of molecular wires can be obtained by studying photoinduced electron transfer in covalently linked donor--bridge--acceptor systems. This article summarizes some of the recent progress in the study of such systems involving transition metal complexes as donor and acceptor units. Specific classes of molecular bridges are considered, namely, polyphenylene, and polyquinoxaline bridges. Basic questions are discussed, such as the transfer mechanisms, the associated distance and bridge structure dependence, and the interplay between energy and electron transfer.

MIB-1 proliferative activity in invasive breast cancer measured by image analysis.

AIMS: To determine cell proliferation in infiltrating breast carcinomas. METHODS: Using the MIB-1 monoclonal antibody, the proliferation index was measured in paraffin wax sections of 871 breast cancers. The MIB-1 proliferation index was compared with other markers of disease progression: size, lymph node status, histotype, oestrogen and progesterone receptor status, expression of p53 and Neu, and DNA ploidy. All parameters were measured using image analysis. In 347 tumours, the MIB-1 and Ki-67 proliferation indexes were compared. Follow up data were available for 170 cases (median 66.5 months). RESULTS: Of the tumours, 314 (36%) had a high proliferation index. The MIB-1 proliferation index was correlated directly with size, nodal status, overexpression of p53 and Neu, and the DNA index; and inversely with oestrogen and progesterone receptor status. The correlation between MIB-1 and Ki-67 proliferation indexes was statistically significant. In patients with pT1 tumours, a low proliferation index correlated with a longer relapse-free interval and overall survival; node negative patients with a low proliferation index had a longer overall survival. CONCLUSIONS: The MIB-1 proliferation index is a reliable, practical and useful method of measuring proliferative activity and is an important predictor of clinical behaviour.

Aminoglutethimide in advanced breast cancer: plasma levels and clinical results after low and high doses.

Drug plasma levels, metabolism data and clinical results were evaluated after the daily administration of either 500 or 1,000 mg aminoglutethimide (AG, Orimeten, Ciba-Geigy) plus hydrocortisone acetate (20 mg b. i. d.). A total of 34 patients with advanced breast cancer entered the study: 17 were given 1,000 mg/day and 17 received 500 mg/day for at least 3 months. A novel HPLC method was developed to determine the levels of AG and its known metabolites [N-acetyl-AG (NAG), formyl-AG, nitroglutethimide, hydroxy-AG] in the biological samples. AG plasma concentration was significantly higher during the 1,000-mg/day regimen. NAG was the only metabolite observed in plasma, always occurring at concentrations lower than those of the parent drug. The ratios between NAG and AG levels distinguish two statistically different groups of patients. Irrespective of the dose, a partial response was observed in 44% of the patients; no change in 32% of cases; and progressive disease had an incidence of 24%. The probability of response was not dependent on the drug AUC or on the NAG/AG ratio and did not significantly depend on previous hormone treatment. Neither the plasmatic level of the AG or metabolite concentrations nor the NAG/AG ratio seemed to affect the incidence of side effects.

Depressive symptoms and quality of life in home-care-assisted cancer patients.

To examine the prevalence of depressive symptoms and its relationship with quality-of-life domains in home-care cancer patients at an advanced stage of illness, 86 patients were given psychological tests for depression (Hospital Anxiety Depression Scale) (HAD) and quality of life (EORTC-QLQ-C30) 1 week after admission to the home-care program. Using a proper cut-off score on the HAD-Depression subscale, depressive symptoms were reported by 45% of the patients. The quality of life of depressed patients was more affected than non-depressed patients in the social, emotional, cognitive, and physical domains. Significant correlations were found between depression scores and impairment in most quality-of-life areas. These findings support the importance of depression and quality-of-life evaluation in patients with advanced cancer who are followed in a home-care setting. This evaluation is needed to provide patients, their families, and caregivers with appropriate psychosocial interventions.

Biological indices predictive of survival in 519 Italian terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The knowledge of prognostic factors capable of subdividing cancer patients into groups having homogenous survival times is useful even in very advanced stages of illness. This prospective multicenter study assessed these prognostic factors in 530 terminal patients with solid tumors who were undergoing only palliative care. Thirteen hematological and urinary parameters were assessed on admission and every 28 days thereafter. In 519 assessable patients with a median survival of 32 days, six biological parameters demonstrated a statistically significant predictive prognosis. A poor prognosis was predicted by high total white blood count (WBC) (P < 0.0001), high neutrophil percentage (P < 0.0001), low lymphocyte percentage (P < 0.0001), low serum albumin level (P = 0.0015), low pseudocholinesterase level (P < 0.0001), and high proteinuria (P = 0.0064). Multiple regression analysis showed that only WBC, lymphocyte percentage and pseudocholinesterase level were independent predictors of survival. The individualization of biological parameters having an independent prognostic capacity is a useful step in the attempt to identify subsets of patients with a homogeneous prognosis. The biological factors needed are easily detected by means of a simple blood test and do not require invasive operations on patients who are already debilitated.

A new palliative prognostic score: a first step for the staging of terminally ill cancer patients. Italian Multicenter and Study Group on Palliative Care.

In recent years, extensive research has been performed to identify prognostic factors that predict survival in terminally ill cancer patients. This study describes the construction of a simple prognostic score based on factors identified in a prospective multicenter study of 519 patients with a median survival of 32 days. An exponential multiple regression model was adopted to evaluate the joint effect of some clinico-biological variables on survival. From an initial model containing 36 variables, a final parsimonious model was obtained by means of a backward selection procedure. The Palliative Prognostic Score (PaP Score) is based on the final model and includes the following variables: Clinical Prediction of Survival (CPS), Karnofsky Performance Status (KPS), anorexia, dyspnea, total white blood count (WBC) and lymphocyte percentage. A numerical score was given to each variable, based on the relative weight of the independent prognostic significance shown by each single category in the multivariate analysis. The sum of the single scores gives the overall PaP Score for each patient and was used to subdivide the study population into three groups, each with a different probability of survival at 30 days: (1) group A: probability of survival at 30 days > 70%, with patient score < or = 5.5; (2) group B: probability of survival at 30 days 30-70%, with patient score 5.6-11.0; and (3) group C: probability of survival at 30 days < 30%, with patient score > 11.0. Using this method, 178/519 (34.3%) patients were classified in risk group A, 205 (39.5%) patients were in risk group B, and 136 (26.2%) patients were in risk group C. The patients classified in the three risk groups had a very different survival experience (logrank = 294.8, P < 0.001), with a median survival of 64 days for group A, 32 days for group B, and 11 days for group C. The PaP Score based on simple clinical and biohumoral variables proved to be statistically significant in a multivariate analysis. The score is valid in this population (training set). An independent validation on another patient series (testing set) is required and is the object of a companion paper.

Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The aim of this work was to validate a previously constructed prognostic score for terminally ill cancer patients in order to determine its value in clinical practice. The Palliative Prognostic Score (PaP Score) was tested on a population of 451 evaluable patients consecutively entered in the hospice programs of 14 Italian Palliative Care Centers. The score subdivided patients into three specific risk classes based on the following six predictive factors of death: dyspnea, anorexia, Karnofsky Performance Status (KPS), Clinical Prediction of Survival (CPS), total white blood count (WBC), and lymphocyte percentage. The performance of the PaP Score index in the training and testing sets was evaluated by comparing mortality rates in the 3 prognostic risk categories. The score was able to subdivide the validation-independent case series into three risk groups. Median survival was 76 days in group A (with a 86.6% probability of 30-day survival), 32 days in group B (with a 51.6% probability of 30-day survival), and 14 days in group C (with a 16.9% probability of 30-day survival). Survival medians were remarkably similar to those of the training set (64 days in group A, 32 days in group B, and 11 days in group C). In the complex process of staging terminally ill patients, the PaP Score is a simple instrument which permits a more accurate quantification of expected survival. It has been validated on an independent case series and is thus suitable for use in clinical practice.

Immunometric assays of ras and c-erbB-2/neu overexpression in breast cancer: a pilot study.

The expression of the ras and c-erbB2 oncoproteins (p21 and p185, respectively), together with estrogen receptor (ER) and progesterone receptor (PgR) determination, has been retrospectively analyzed in 68 primary breast carcinomas and in 19 normal breast tissue samples. The aims of this study were: a) to explore the association between ras and c-erbB2 expression; b) to evaluate the relationship between ras and c-erbB2 expression and both steroid receptor status and the classical clinical and pathological parameters; and c) to compare two different methods for p185 determination. p185 and p21 were measured by enzyme immunoassay (EIA); p185 was also determined by Western blotting (WB); ER and PgR were assayed by radioligand binding assay. The highest value of p185 in benign breast lesions was used as the threshold to distinguish between positive and negative samples. With this threshold the c-erbB2 oncoprotein was overexpressed in 41.2% (with EIA) and in 50% (with WB) of cancer samples. The concordance rate between the two methods was 79.4. No significant association was found between p21 and p185 levels either in cancer or in normal breast tissue samples. Increasing levels of tumor p21 were associated with a shorter time to recurrence and overall survival. Increasing levels of p185 were associated with a significantly shorter time to recurrence (p185 EIA: p = 0.04, p185 WB: p = 0.029) and overall survival (p185 EIA: p = 0.04, p185 WB: p = 0.029).

Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemotherapy.

Nausea and vomiting induced by chemotherapy are a major cause of distress to patients and reduce compliance with potentially beneficial treatment. Itasetron hydrochloride is a new 5-hydroxytryptamine3 (5-HT3) antagonist with potent antiemetic properties. It is more potent than ondansetron in animal models and in early clinical studies it demonstrates a long half-life and does not undergo hepatic biotransformation before elimination. The aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given intravenously (i.v.) to patients due to receive high-dose cisplatin chemotherapy (50-120 mg/m2) for the first time. Thirty-nine patients were enrolled in the trial and received a single i.v. infusion of itasetron hydrochloride at a dose of 17-280 microg/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2). Antiemetic protection was demonstrated by doses in the range of 35-280 microg/kg. The 17 microg/kg dose was not effective. Treatment failure (>5 emetic episodes/24 hours) was reported in only six (16%) of the 38 evaluable patients over all treatment groups. Adverse events were generally mild or moderate and of a similar type and incidence to those of current 5-HT3 antagonists. Physicians' and patients' assessments of efficacy and tolerability of itasetron hydrochloride were similar, the majority rating the treatment as 'good' or 'very good'. In conclusion, itasetron hydrochloride is effective in the dose range 35-280 microg/kg in preventing cisplatin-induced emesis. Taken together with results from a larger dose-finding study, a dose corresponding to 35 microg/kg (equivalent to 2.5 mg itasetron, calculated as free base) has been pursued in Phase III studies with the i.v. formulation.

Immunoscintigraphy in malignant melanoma: a five-year clinical experience.

Immunoscintigraphy (IS) with 99Tcm-labelled anti-melanoma monoclonal antibody F(ab')2 fragments was performed in 135 melanoma patients, 64 males and 71 females, aged 19-82 years (mean 52.3 years) between December 1987 and December 1991. The first group of IS was performed in 50 patients before surgery to assess optimal management: seven true positive and one true negative were obtained in ocular and visceral melanomas, while in cutaneous MM sensitivity, specificity and accuracy in assessing lymph node involvement were, respectively, 61.5, 93.3 and 83.7%. The second group of 128 IS is relative to 85 patients in follow-up: excluding 13 cases with known metastatic disease and 12 inconclusive tests, sensitivity, specificity and accuracy were, respectively, 83.3, 98.8 and 96.1%. Immunoscintigraphy is free of side effects even after repeated administrations and is a useful adjunct to standard diagnostic techniques as a basis for treatment decisions.

Effects of two different hydrocortisone doses on human peripheral blood lymphocyte nucleologram.

The effect of 200 and 500 mg of hydrocortisone hemisuccinate given i.v. on the circulating lymphocyte nucleologram was studied in 12 healthy volunteers. Transient lymphopenia was observed in all treated subjects, with the nadir at 3 to 9 h after drug administration. An evaluation of the lymphocyte nucleologram, at this time, showed a statistically significant decrease in mono- and binucleolated lymphocytes. By 24-36 h, the number of total lymphocytes and the nucleologram had returned to baseline values. No differences were revealed among the two groups of subjects. The role of lymphocyte redistribution and of lymphocytolysis to explain the lymphocytopenia and the behaviour of lymphocyte nucleologram is discussed.

Clinical usefulness of estrogen receptor immunocytochemistry in human breast cancer.

We assessed the reliability of the immunocytochemical assay of estrogen receptor (ER-ICA) as a marker of clinical outcome. Relapse-free interval (RFI) and overall survival (OS) according to ER-ICA status were retrospectively evaluated on a series of 210 patients who had undergone surgery for primary breast cancer between January 1985 and December 1988. ER assay by the dextran-coated charcoal method (DCC) was also performed in 189 tumors. A significant positive correlation was found between the DCC and ER-ICA assays, with an overall agreement of 79%. ER-ICA status showed a prognostic predictive power with respect to OS and RFI in the whole series of patients and in the subset of node-positive patients. It was also a marker of outcome with respect to OS in the subsets of node-negative patients and patients with tumors < or = 2 cm in diameter. Moreover, the predictive value of the ER-ICA assay was higher than that of the DCC assay in the present study. These findings emphasize the clinical usefulness of the ER-ICA assay as a measure for prognosis.

[Effect of antiblastic polychemotherapy (CMF) on the number of circulating monocytes in patients with breast cancer]. / Effetto della polichemioterapia antiblastica (CMF) sul numero dei monociti circolanti in pazienti affette da cancro della mammella.

The behaviour of the number of circulating monocytes has been studied in 34 patients suffering from breast cancer and subjected to antiblastic polychemotherapy in accordance with the CMF pattern. In 25 patients the absolute number of monocytes fell after treatment, while in 9 it rose. The percentage of monocytopenic patients rose from 29% to 50% of the total series. The pathogenetic mechanisms of this behaviour are discussed and it is emphasized that antiblastic treatment with cytostatic drugs can be included among the causes of monocytopenia.

[Therapy and follow-up of breast cancer. Experiences in 11 years of observation]. / Terapia e follow-up del carcinoma mammario. Esperienze di 11 anni di osservazioni.

Out of 1260 biopsies performed on neoplasias of the breast in 11 years' surgical practice, 463 (36,7%) malignant tumours were encountered. The surgical strategy in the latter cases was based on two basic parameters: a) the histological report on the intraoperative biopsy; b) the clinical stage (TNM). After surgery oncological treatment followed the now universal standard practice: --T1, T2, T3, N+, M0 and T4 independent of N or M: multiple chemotherapy for 6-12 months then periodic check ups as in N- cases. --M1: multiple chemotherapy, hormone and radiation treatment combined in various ways. The results obtained in terms of trouble free periods and survival are in line with reports in the literature including those describing a larger number of cases.

Immunoscintigraphic localization in a benign thyroid neoplasm of a monoclonal antibody directed against melanoma.

In a prospective study for evaluation of the use of a monoclonal antibody directed against melanoma in the staging of patients affected by malignant melanoma, we report monoclonal antibody uptake in a follicular thyroid adenoma. Computed tomography, ultrasonography, and pertechnetate scintigraphy did not provide a certain diagnosis. Only pathologic examination of the surgical specimen was conclusive.

Photoinduced electron transfer in ruthenium(II)/Tin(IV) multiporphyrin arrays.

The photophysical behavior of a series of heterometallic arrays made of a central Sn(IV) porphyrin connected, respectively, to two (SnRu(2)), four (SnRu(4)), or six (SnRu(6)) ruthenium porphyrin units has been studied in dichloromethane. Two different motifs connect the ruthenium porphyrin units to central tin porphyrin core, axial coordination via ditopic bridging ligands and/or coordination to peripheral pyridyl groups of the central porphyrin ring. A remarkable number of electron transfer processes (photoinduced charge separation and recombination processes) have been time-resolved using a combination of emission spectroscopy and fast (nanosecond) and ultrafast (femtosecond) absorption techniques. In these systems both types of molecular components can be selectively populated by light absorption. In all the arrays, the local excited states of these units (the tin porphyrin singlet excited state and the ruthenium porphyrin triplet state) are quenched by electron transfer leading to a charge-separated state where the ruthenium porphyrin unit is oxidized and the tin porphyrin unit is reduced. For each array, the two forward electron transfer processes, as well as the charge recombination process leading back to the ground state, have been kinetically resolved. The rate constants obey standard free-energy correlations with the forward processes lying in the normal free-energy regime and the back reactions in the Marcus inverted region. The comparison between the trimeric (SnRu(2)) and pentameric (SnRu(4)) arrays shows that all the electron transfer processes are faster in the latter than in the former system. This can be rationalized in terms of differences in electronic factors (due to the different connecting motifs) and driving force. In less polar solvents, such as toluene, the energy of the charge-separated states is substantially lifted, leading to a switch (from electron transfer to triplet energy transfer) in the deactivation mechanism of the excited ruthenium triplet.

Photoinduced processes in self-assembled porphyrin/perylene bisimide metallosupramolecular boxes.

Two new supramolecular boxes, (ZnMC)(2)(rPBI)(2) and (ZnMC)(2)(gPBI)(2), have been obtained by axial coordination of N,N'-dipyridyl-functionalized perylene bisimide (PBI) dyes to the zinc ion centers of two 2+2 porphyrin metallacycles (ZnMC = [trans,cis,cis-RuCl(2)(CO)(2)(Zn·4'-cis-DPyP)](2)). The two molecular boxes involve PBI pillars with different substituents at the bay area: the "red" PBI (rPBI = N,N'-di(4-pyridyl)-1,6,7,12-tetra(4-tert-butylphenoxy)perylene-3,4:9,10-tetracarboxylic acid bisimide) containing tert-butylphenoxy substituents and the "green" PBI (gPBI = N,N'-di(4-pyridyl)-1,7-bis(pyrrolidin-1-yl)perylene-3,4:9,10-tetracarboxylic acid bisimide) bearing pyrrolidinyl substituents. Due to the rigidity of the modules and the simultaneous formation of four pyridine-zinc bonds, these discrete adducts self-assemble quantitatively and are remarkably stable in dichloromethane solution. The photophysical behavior of the new supramolecular boxes has been studied in dichloromethane by emission spectroscopy and ultrafast absorption techniques. A different photophysical behavior is observed for the two systems. In (ZnMC)(2)(rPBI)(2), efficient electron transfer quenching of both perylene bisimide and zinc porphyrin chromophores is observed, leading to a charge separated state, PBI(-)-Zn(+), in which a perylene bisimide unit is reduced and zinc porphyrin is oxidized. In the deactivation of the perylene bisimide localized excited state, an intermediate zwitterionic charge transfer state of type PBI(-)-PBI(+) seems to play a relevant role. In (ZnMC)(2)(gPBI)(2), singlet energy transfer from the Zn porphyrin chromophores to the perylene bisimide units occurs with an efficiency of 0.7. This lower than unity value is due to a competing electron transfer quenching, leading to the charge separated state PBI(-)-Zn(+). The distinct photophysical behavior of these two supramolecular boxes is interpreted in terms of energy changes occurring upon replacement of the "red" rPBI by "green" gPBI.