Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer.

BACKGROUND: A phase I/II study was performed to determine the safety and activity of a capecitabine plus oxaliplatin and irinotecan (COI) regimen using capecitabine concurrently with oxaliplatin and irinotecan in previously untreated patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients received irinotecan on day 1, oxaliplatin (85 mg/m(2)) on day 2 and capecitabine (1000 mg/m(2) orally twice daily) on days 2-6 of a biweekly schedule. Three dose levels ranging from 150 to 180 mg/m(2) were explored for irinotecan in sequential cohorts of three to six patients. Once the recommended dose was determined, a total of 28 eligible patients were planned at this dose level. RESULTS: Thirty-eight patients received a median of six cycles. The recommended phase II dose of irinotecan was 180 mg/m(2). Toxicity was manageable: the most common severe toxicities were diarrhoea (24%) and nausea (16%). Of 27 assessable patients treated at the recommended dose, 17 achieved a partial response (overall response rate (ORR) 63%; 95% confidece interval (CI), 44 to 78%), with eight patients undergoing liver metastasectomy. Estimated progression-free survival and overall median survival were 8.5 and 23.5 months, respectively. CONCLUSIONS: Biweekly COI is feasible and active. Tolerability and ease of administration make the regimen well suited for downsizing hepatic colorectal metastases before curative surgery.

Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study.

This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, irinotecan 240 mg m(-2) day 1; q21) or TEGAFOX (UFT 250 mg m(-2) day days 1-14, LV 90 mg day days 1-14, oxaliplatin 120 mg m(-2) day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3-4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1-55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6-51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12-23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies.

[Determinants of depression in 111 Italian patients with systemic sclerosis]. / Determinanti della depressione in 111 pazienti italiani con sclerosi sistemica.

BACKGROUND: A high prevalence of depressive symptoms has been described in systemic sclerosis (SSc), but no clear association with organ involvement or objective indices of disease severity has been depicted. To date, no effort has been made to determine the prevalence of depressive symptoms in Italian patients with SSc or to clarify their cause. METHODS: One-hundred-eleven SSc patients were asked to fill in the Beck Depression Inventory (BDI) questionnaire, the scleroderma Health Assessment Questionnaire (sHAQ) and two additional questions assessing the patient's familiar support and the social consequences of the patient's change in physical appearnace. RESULTS: Thirty-seven subjects (33.4%) presented mild to severe depressive symptoms (BDI >/=17). On univariate analysis the diffuse cutaneous form of the disease (p=0.019), higher pulmonary systolic pressures on echocardiogram (p=0.016), lower FVC percentage of predicted values (p=0.022), higher sHAQ values (p<0.001) or higher VAS values for pain (p=0.007), lung involvement (p=0.02), Raynaud's phenomenon severity (p=0.002), ulcers severity (p=0.006) or disease severity (p<0.001), were associated with the presence of pathologic depressive symptoms. On multivariate analysis only the VAS for disease severity relevant to BDI scores (p=0.016). Social behaviour changes due to SSc-related physical involvement were reported in 14 patients (38%) with depressive symptoms (p=0,006) and were more likely to be observed in younger patients (p=0.001) with a more severe Raynauds's phenomenon (p=0.013). CONCLUSIONS: Mild to severe depressive symptoms are common in SSc patients especially in those with a worse perception of disease severity, these patients should be carefully monitored and a psychological assistance counselled whenever necessary.

Capecitabine chemoradiation for rectal cancer after curative surgery.

This study reports the tolerability and feasibility of capecitabine, an oral fluoropyrimidine, chemoradiation as postoperative treatment. Stage II-III rectal cancer patients received 2 cycles of bolus 5-FU (425 mg/m2) and leucovorin (LV) (20 mg/m2) on days 1-5 q3w followed by oral capecitabine (800 mg/m2 bid) continuously during pelvic radiotherapy (total 50.4 Gy). Two additional cycles of 5-FU/LV were finally administered. Forty-one radically resected patients (median age: 61 years) were enrolled. All patients were evaluable for safety. Grade 3 adverse events included: proctitis (n = 3, 7%), diarrhea (n = 5, 12%), and leukopenia (n = 1, 2%). The overall rate of grade 3 diarrhea and leukopenia was 15% (95% confidence interval, 5-29%). Capecitabine chemoradiation in the adjuvant setting is well tolerated and is convenient to administer. These results support the use and further study of capecitabine chemoradiation in radically resected rectal cancer patients.

Pathological features as predictors of recurrence after radical resection of gastric cancer.

BACKGROUND: The aim of this study was to investigate the pattern and timing of recurrence and to determine associated risk factors after radical resection of gastric cancer including D2 dissection. METHODS: A total of 274 patients who had undergone radical resection of gastric cancer with nodal involvement or T3-4 tumour were randomized to receive chemotherapy or no further treatment (control group). Locoregional recurrence and distant metastasis were analysed in a competing risks framework, by estimating the crude cumulative incidence in each group. Multiple regression models were used to investigate the influence of treatment and pathological features on the risk of recurrence. RESULTS: Overall, the 7 year rate of locoregional relapse was 15.8 per cent and that of distant recurrence was 34.5 per cent. There was a significant association between pathological node (pN) stage and distant relapse (P < 0.001), and between pathological tumour (pT) stage and locoregional recurrence (P = 0.024). Chemotherapy had no significant effect on either locoregional or distant recurrence. CONCLUSION: The rate of locoregional recurrence after radical surgery for gastric cancer was lower than that in studies based on more conservative surgery. The pT stage was related to the rate of locoregional recurrence whereas pN stage had an impact on distant recurrence.

Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours.

OBJECTIVES: Neuroendocrine tumours (NETs) are heterogeneous neoplasms for which there is no standard treatment. We have previously proposed an effective polychemotherapy (5-fluorouracil, dacarbazine and epirubicin), which only produced objective responses of brief duration. The present study aimed to assess in a multidisciplinary manner the efficacy of the same regimen at intensified doses in patients with advanced NETs. PATIENTS AND METHODS: Eighty-two consecutive patients entered the study, of whom 21 had inoperable, locally advanced disease and 61 had metastatic disease. Seventy-two patients were evaluated for objective, biochemical and subjective responses. Response rate, time to progression (TTP) and overall survival (OS) were evaluated based on histotype. RESULTS: An objective response was observed in 20 patients (intention-to-treat and standard analysis 24.4% and 27.8%, respectively). Complete biochemical and subjective responses were obtained in 25.1% and 38.9% of the cases. The median duration of treatment was 4 months and the objective responses had a median duration of 38 months. After a 60-month follow-up the median TTP and OS were 21 and 38 months, respectively. CONCLUSIONS: Our polychemotherapy regimen is effective, with long duration, and is well tolerated both for gastroenteropancreatic and lung NETs, as well as for tumours with a more aggressive clinical behaviour. The new WHO endocrine tumour histotyping, examining also the tumour biology, may give additional information for selecting patients to chemotherapy.

Capecitabine: indications and future perspectives in the treatment of metastatic colorectal and breast cancer.

Fluoropyrimidines remain the most important drugs in the treatment of breast and colorectal carcinoma, but response rates and survival time have been disappointing. Optimal administration is by continuous intravenous infusion, which makes it cumbersome to use and compromises patient independence. Recently, a number of new agents, including fluorouracil prodrugs and selective dihydropyrimidine dehydrogenase inhibitors, have been studied, with promising results. Capecitabine is the first in a new class of fluoropyrimidines. It is an oral, tumor-activated anticancer drug whose activity mimics that of continuously infused 5-fluorouracil. Capecitabine circumvents dihydropyrimidine dehydrogenase catabolism and appears to be at least as active against metastatic colorectal and breast cancer as conventionally administered intravenous 5-fluorouracil, with significantly less toxicity, an improved quality of life, and lesser cost. Capecitabine may ultimately provide enhanced antitumor activity to fluorouracil-containing regimes for advanced colorectal and breast cancer.

Is videopupillography useful in the diagnosis of Alzheimer's disease?

Patients with Alzheimer's disease (AD) reportedly exhibit greater pupillary dilation than healthy subjects in response to tropicamide. By means of videopupillography, we have found that the average basal pupillary diameter was greater in AD patients than in normal controls and that there is an inverse relationship between the average pupillary diameter and the maximal dilation obtained following tropicamide application in both groups. Pupillary response to tropicamide and videopupillography do not distinguish between Alzheimer's patients and controls.

Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits.

The relevance of low folate levels as determinants of cognitive deficits and the usefulness of folate supplementation in the treatment of cognitive deficits was reviewed from the literature. Over 40 papers and book chapters published in English, French, German, Italian and Spanish were examined. This represents those papers published in the international literature in the last 10 years which were identified by various key words including folate, cognition and aging (or ageing). Among these papers, only 13 articles specifically addressed issues relevant to the criteria adopted for this review. The remaining papers were principally concerned with depression and or with other pathologies of the aged associated with folate deficiency. Although the specific role of low folate levels in the physiopathology of dementia is still under debate, a growing consensus is emerging in the literature where low folate as well as cobalamin levels in aged patients with cognitive deficits are being considered as a sign of functional problems in the absorption and utilization of vitamins, and not merely as a sign of bad eating habits. In studies where folate compounds were evaluated for treatment effects, the results of a majority of investigations indicated that folate treatment was effective in lessening cognitive deficits. Treatment efficacy, however, has not yet been sufficiently demonstrated by these results because there were no controlled studies and the methodology was heterogeneous for the evaluation of cognitive characteristics. An ad hoc double-blind, controlled versus placebo pilot study was undertaken to evaluate the efficacy of folic acid in 30 aged patients with abnormal cognitive decline and folate level below 3 ng/ml to better understand the value of this type of intervention. Our results from this preliminary study demonstrated that patients treated with folic acid for 60 days showed a significant improvement on both memory and attention efficiency when compared with a placebo group. The intensity of memory improvement was positively correlated with initial severity of folate deficiency. On the contrary, the severity of initial cognitive decline was unrelated to the degree of folate deficiency.

Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection.

BACKGROUND: Genital infection with certain strains of human papillomavirus (HPV) is associated with a high risk of malignant transformation, and HPV-associated cervical intraepithelial neoplasia (CIN) can become invasive cancer. Host factors are critical in regulating tumor growth, and cytokines that modulate immunologic control may be of particular importance. The type 1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are immunostimulatory and are thus capable of limiting tumor growth. The type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are immunoinhibitory and are thus capable of stimulating tumor growth. PURPOSE: We analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) in women with CIN associated with localized or extensively spread HPV infection. METHODS: Thirty women diagnosed with CIN and 10 age- and sex-matched healthy control subjects were enrolled in the study conducted at Istituto Nazionale Tumori, Milan, Italy. The following parameters were analyzed: 1) HPV infection of the cervix and other sites of the lower genital tract by colposcopic, cytologic, and histologic examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in response to stimulation with soluble antigen (influenza [FLU] antigen) or to cell-associated human leukocyte antigen (HLA) alloantigen; and 4) in vitro production of the type 1 cytokines IL-2 and IFN gamma and of the type 2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation. Statistical significance was determined by nonparametric tests (two-sided). RESULTS: High-grade CIN associated with HPV infection was detected in all case patients, and HPV type 16 or 18 infection was detected in cervical tissue of 21 (70%) of 30 case patients. HPV infection that had spread to other sites of the lower genital tract, thus resulting in more extensive disease, was detected in 16 (53%) of the 30 individuals with CIN, whereas HPV infection was limited to the portio in 14 (47%). IL-2 production by PBMCs in response to stimulation with soluble antigen or HLA alloantigen was reduced in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. In contrast, IL-4 and IL-10 production in response to mitogen stimulation was elevated in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. The highest production of IL-4 and IL-10 was detected in patients with HPV infection that had extended beyond the genital tract. CONCLUSIONS: CIN is characterized by different immunologic profiles, in which HPV infection is or is not confined to the portio. Production of cytokines that mainly enhance potentially protective cell-mediated immunity is defective in the women in whom extended HPV infection was observed. A pronounced shift from type 1 to type 2 cytokine production is associated with more extensive HPV infection. IMPLICATIONS: These data reinforce the need for detailed analyses of immune dysregulation in CIN patients. They also suggest the potential usefulness of the cytokine assays for determining prognosis or deciding whether cytokine-based therapy is indicated.

Hypernatremic dehydration in the elderly on admission to hospital.

Dehydration is the most common cause of fluid and electrolyte disturbances in the elderly. This condition is related to the lack of increase in water intake in the presence of an increased fluid loss. The aim of this study was to evaluate the prevalence of hypernatremic dehydration in elderly patients admitted to the hospital. We retrospectively studied 2,894 subjects admitted to the acute ward of the Geriatric Section of the Department of Medical and Surgical Disciplines of the University of Torino from January 1990 to July 1995. Among them 84 (2.9%) patients, mean age 77.3 +/- 9.8 years, had serum sodium levels and blood urea nitrogen greater than 145 mEq/L and 25 mg/dL respectively with serum creatinine below 3 mg/dL. The prevalence of hypernatremic dehydration increases with age. Only 1.6% of the subjects under 65 years old are affected by this condition, against 5.3% of those over 85 years. The mortality rate observed during hospitalization is 29.8%. Mortality is positively related to serum sodium levels. We found mortality rates of 33.3% and 71.4% respectively in subjects with serum sodium levels from 151 to 153 mEq/L and in those with values over 154 mEq/L. Both serum sodium levels and age are independent risk factors for mortality (O.R. 1.31 and 1.07 respectively).

Type 1 cytokine production and low prevalence of viral isolation correlate with long-term nonprogression in HIV infection.

Cytokine production, prevalence of viral isolation, and surface marker expression of peripheral blood mononuclear cells (PBMCs) were analyzed in HIV+ individuals with different patterns of disease progression to establish correlations between these parameters. Thus, mitogen-stimulated in vitro production of interferon gamma (IFN-gamma) and interleukin 2 (IL-2) (type 1 cytokines), and of IL-4 and IL-10 (type 2 cytokines) as well as prevalence of viral isolation were evaluated in 26 HIV+ long-term nonprogressors (LTNPs), in 28 HIV+ patients with progressive HIV infection (PI), and in 24 HIV-seronegative controls (HCs). Surface expression of activation and nonactivation markers was also analyzed in a group of these donors. We report that (1) IL-2 and IFN-gamma production is reduced and IL-4 and IL-10 production is increased in PI patients compared to HCs and LTNPs; (2) prevalence of HIV isolation is lower in LTNPs compared to PI, and the primary viral isolates in LTNPs show a slow/low (S/L) phenotype; and (3) the elevated production of type 2 cytokines is paralleled by an increase in CD57+CD4+CD7- lymphocytes. Thus, whereas a high IL-2, high IFN-gamma/low IL-4, low IL-10 cytokine production pattern is present in HC and in LTNP HIV+, progression of HIV infection is associated with a low IL-2 low IFN-gamma/high IL-4, high IL-10 cytokine profile; increased prevalence of HIV isolation; and an augmented percentage of CD57+CD4+CD7- lymphocytes. These findings further confirm that a dominant type 1 cytokine profile together with reduced prevalence of virus isolation is associated with lack of progression in HIV infection.

Nutritional patterns in elderly patients with dementia of Alzheimer type.

Body weight and some nutritional serum parameters (albumin, urea nitrogen, creatinine, glycemia, hemoglobin, total cholesterol, triglycerides, potassium) were analyzed in 44 subjects aged over 60 in order to evaluate weight loss and its possible link with the progression of dementia. Patients were consecutively admitted to our Day Hospital with the complaint of psychogeriatric symptoms. They all were living at home, no one presented risk factors for malnutrition and their cognitive impairment did not exceed the 4th degree of GDS (Global Deterioration Scale). Subjects were divided into two groups on the basis of diagnosis at discharge: (i) Possible or probable dementia of Alzheimer type (30 subjects, mean age 72.1 +/- 5.9 years), (ii) Age-associated memory impairment (14 subjects, mean age 73.6 +/- 6.2 years). One year later, a second control of body weight and nutritional parameters was performed. Differences between these latter measures versus the initial values were not significant when analyzed in the total group of demented patients or in the subgroups with different degree of cognitive impairment and physical activity. A possible hypothesis to explain the absence of differences among groups is that the caregivers were very carefully looking after all the patients examined.

Determination of selected trace elements in patients affected by dementia.

The relationship between dementia and trace elements is widely debated. Neurotoxicity of aluminium is well recognized. The purpose of the study was to evaluate serum levels of a few trace elements and a few serum proteins in demented subjects. The study was carried out on 452 women, age range 73-88 years. Thirty one of them were affected by dementia of Alzheimer type in early or middle stages. The diagnosis had been performed by history, physical and instrumental examinations, as well as by psychometric tests. The following parameters were determined: iron, zinc, copper, serum albumin, transferrin, ceruloplasmin. Iron, copper and zinc are somewhat lower in demented subjects than in controls, but the differences are statistically not significant. The slightly diminished levels of serum albumin and transferrin in the study group may be related to a mild malnutrition. The reduction of the proteins binding trace elements, particularly of transferrin, could cause a higher bioavailability of neurotoxic trace elements such as aluminium.

Health and functional status in elderly patients living in nursing homes.

Socio-economic background, functional status, multiple pathology and medical conditions requiring care have been evaluated in 506 elderly subjects living in nursing homes in Turin (Italy). In the sample 78.8% are women, mean age 84.2 years, only 21.2% are men, mean age 76.3 years. Particularly in the oldest age classes women are more represented than men. Most subjects (94.3%) require help in at least one Activity of Daily Living (ADL). Part of the sample (21.2%) comes from home, 13.2% from acute wards, 9.1% from long term care wards, 6.3% from mental hospitals, 26.3% from residential homes. Education level is rather low. Before retirement, many men were workmen (38.3%), while many women were housewives (46.6%). Multiple pathology is very common: 23.7% of patients suffer from 4 pathologies, more than 5 diseases are present in 18.8%, while only 4.7% of subjects have less than two pathologies. Half of the sample (52.6%) is affected by dementia, 37.6% by cardiovascular diseases, 29.1% by chronic obstructive lung disease and 25.5% by stroke. Bone fractures are present in 22.1% of the subjects. Severe impairments in strength and/or motility in at least two limbs affect 43.7% of patients, double incontinence 49.2%, severe disturbances in speech and communication 35.4%. The prevalence of care needs is higher in women compared with men. More females than males need aid in walking, help in eating, diapers, pressure sores prevention and bedposts.

Restorative effect of total parenteral nutrition on natural killer cell activity in malnourished cancer patients.

Decreased natural killer cell activity (NKCA) is associated with malnutrition in both cancer and non-cancer patients. We have studied the effect of total parenteral nutrition (TPN) on NKCA in 9 malnourished cancer patients, candidates for surgery. TPN was administered for a median of 10 days (range 7-11), providing 1.5-fold the estimated resting energy expenditure, with 30% as fat. Calorie:nitrogen ratio was 150:1. Basal human recombinant interferon-alpha 2a (rIFN-alpha 2a) and human recombinant IL-2 rIL-2) activated NKCA were measured, as were the main nutritional parameters, prior to and after TPN. NKCA increased in all patients and reached the normal range in 5, 3 and 4 subjects, respectively, for basal, rIFN-alpha 2a and rIL-2 activated NKCA. As regards nutritional assessment, body weight and IgM levels significantly increased from 47.7 to 50.1 kg and from 174 to 237 mg/dl, respectively. This study demonstrates that a 10-day TPN course increases and sometimes restores normal NKCA. Such effect was constant and preceded nutritional changes.

Production of type-1 and type-2 cytokines by peripheral blood mononuclear cells of psoriatic patients.

We investigated the function of peripheral blood mononuclear cells (PBMC) in 16 patients with active psoriasis, in 15 patients with static psoriasis and in 27 healthy volunteers, by examining in vitro proliferation and antigen- and mitogen-stimulated production of interleukin-2 (IL-2) and IL-4. Plasma levels of the neuropeptide substance P were also determined. Defective alloantigen (ALLO)- and phytohaemagglutinin (PHA)-stimulated IL-2 production was detected in 42% and in 45% of psoriatic patients, respectively. The number of defective IL-2 responders was higher in static (60%) than in active (25%) psoriasis. The reduction of IL-2 responses in the former group was associated with an increase of IL-4 production. Thus PBMC of 66% of patients with static psoriasis but none of the patients with active psoriasis produced elevated amounts of PHA-stimulated IL-4. Variations of plasma substance P levels followed the same pattern of IL-4, being higher in static than in active psoriasis. These observations suggest a co-ordinated action of IL-4 and substance P as modulators of the clinical course of psoriasis. Our data show a possible correlation between the clinical evolution of psoriasis and the production of type-1 and type-2 cytokines, suggesting that the former may have a prominent role in the activation of psoriasis, while the latter may play a protective role.