A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas.

BACKGROUND: A phase I open-label dose-escalation study was conducted to define the safety, tolerability, and pharmacokinetics (PK) of PankoMab-GEX, a glyco-optimised humanised IgG1, with high affinity to a novel tumour-specific glycopeptide epitope of MUC1 (TA-MUC1) with excellent preclinical anti-tumour activity. PATIENTS AND METHODS: Seventy-four patients with advanced TA-MUC1-positive carcinomas received PankoMab-GEX intravenously every 3 (Q3W), 2 (Q2W), or 1 (QW) week in doses of 1-2200 mg in a three-plus-three dose-escalation design until disease progression (NCT01222624). RESULTS: No maximum tolerated dose was reached. Adverse events were mainly mild-to-moderate infusion-related reactions (IRRs) by the first infusion in 45% of patients. Only one dose-limiting toxicity, a grade III IRR, was observed. PankoMab-GEX exhibited linear PK over all doses. Mean terminal half-life was 189 ± 66 h (Q3W), without dose dependency. A target trough level ≥50 µg/mL was reached after one infusion with doses ≥1700 mg Q3W in 80% of patients. Clinical benefit in 60 evaluable patients included one complete response in a patient with ovarian cancer treated 483 d and confirmed disease stabilisation in 19 patients lasting a median (range) of 23 (10-109) weeks. All but two of the patients with clinical benefit had received a compounded total dose ≥700 mg over a 3-week period, including 8 of 12 (67%) patients with ovarian cancer. CONCLUSION: PankoMab-GEX is safe, well tolerated, and showed promising anti-tumour activity in advanced disease. A phase IIb study is ongoing evaluating the efficacy of PankoMab-GEX as a maintenance therapy in advanced ovarian cancer.

A correlational study between signature, writing abilities and decision-making capacity among people with initial cognitive impairment.

BACKGROUND: Some clinical conditions, including dementia, compromise cognitive functions involved in decision-making processes, with repercussions on the ability to subscribe a will. Because of the increasing number of aged people with cognitive impairment there is an acute and growing need for decision-making capacity evidence-based assessment. AIMS: Our study investigates the relationship between writing abilities and cognitive integrity to see if it is possible to make inferences on decision-making capacity through handwriting analysis. We also investigated the relationship between signature ability and cognitive integrity. METHODS: Thirty-six participants with diagnosis of MCI and 38 participants with diagnosis of initial dementia were recruited. For each subject we collected two samples of signature-an actual and a previous one-and an extract of spontaneous writing. Furthermore, we administered a neuropsychological battery to investigate cognitive functions involved in decision-making. RESULTS: We found significant correlations between spontaneous writing indexes and neuropsychological test results. Nonetheless, the index of signature deterioration does not correlate with the level of cognitive decline. DISCUSSION: Our results suggest that a careful analysis of spontaneous writing can be useful to make inferences on decision-making capacity, whereas great caution should be taken in attributing validity to handwritten signature of subjects with MCI or dementia. CONCLUSIONS: The analysis of spontaneous writing can be a reliable aid in cases of retrospective evaluation of cognitive integrity. On the other side, the ability to sign is not an index of cognitive integrity.

Disease progression pattern in metastatic breast cancer patients treated with anti-HER2 therapies

Purpose. Over the last decade a dramatic improvement in the treatment and prognosis of human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC) has been achieved. This study aimed to describe pattern, timing of metastases, and time to progression (TTP) of MBC patients (pts) treated with multiple lines of therapy with trastuzumab and/or lapatinib. Methods. Clinical-pathologic features, treatment-lines and metastatic sites were collected from the institutional database; TTP was evaluated for each treatment-line. A meta-analysis of treatment-line estimates was performed; Q test and I 2-index were used to detect and estimate heterogeneity. Cox’s proportional hazards model and Fine and Gray’s proportional subhazards model in a competing risks setting were used to detect differences in hazard rate and to estimate relative risks. Results. 112 pts were analyzed. The median number of treatment-lines administered was 6 (range 1–17) and 524 (86 %) disease progression events were observed (median follow up 4.2 years). Distribution of metastases at baseline remained consistent across all lines. Having a given site affected by metastasis was a major risk factor of progression in that site. Hormone-receptor-positive pts resulted more likely to progress on bone (HR = 1.88). Elderly pts were less likely to progress on CNS (HR = 0.73). Median TTP resulted superior to 5 months up to the 6th line of treatment, reaching a plateau at the 9th treatment-line. Conclusions. These data suggest that risk factors for progression in HER2 positive MBC do not significantly differ between various distributions of metastases, and that MBC pts benefit from anti-HER2 therapy even in late treatment-lines (AU)

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Disease progression pattern in metastatic breast cancer patients treated with anti-HER2 therapies.

PURPOSE: Over the last decade a dramatic improvement in the treatment and prognosis of human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC) has been achieved. This study aimed to describe pattern, timing of metastases, and time to progression (TTP) of MBC patients (pts) treated with multiple lines of therapy with trastuzumab and/or lapatinib. METHODS: Clinical-pathologic features, treatment-lines and metastatic sites were collected from the institutional database; TTP was evaluated for each treatment-line. A meta-analysis of treatment-line estimates was performed; Q test and I (2)-index were used to detect and estimate heterogeneity. Cox's proportional hazards model and Fine and Gray's proportional subhazards model in a competing risks setting were used to detect differences in hazard rate and to estimate relative risks. RESULTS: 112 pts were analyzed. The median number of treatment-lines administered was 6 (range 1-17) and 524 (86 %) disease progression events were observed (median follow up 4.2 years). Distribution of metastases at baseline remained consistent across all lines. Having a given site affected by metastasis was a major risk factor of progression in that site. Hormone-receptor-positive pts resulted more likely to progress on bone (HR = 1.88). Elderly pts were less likely to progress on CNS (HR = 0.73). Median TTP resulted superior to 5 months up to the 6th line of treatment, reaching a plateau at the 9th treatment-line. CONCLUSIONS: These data suggest that risk factors for progression in HER2 positive MBC do not significantly differ between various distributions of metastases, and that MBC pts benefit from anti-HER2 therapy even in late treatment-lines.

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.

BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Association of partial AZFc region deletions with spermatogenic impairment and male infertility.

BACKGROUND: Complete deletions of the AZFc region in distal Yq are the most frequent molecular genetic cause of severe male infertility. They are caused by intrachromosomal homologous recombination between amplicons--large, nearly identical repeats--and are found in 5-10% of cases of azoospermia and severe oligozoospermia. Homologous recombination may also generate different partial deletions of AZFc, but their contribution to spermatogenic impairment has not been confirmed. METHODS: In this study we analysed the prevalence and characteristics of different partial AZFc deletions and their association with spermatogenic failure. We studied 337 infertile men with different spermatogenic impairment and 263 normozoospermic fertile men using AZFc specific sequence tagged site markers and DAZ specific single nucleotide variants. RESULTS: We identified 18 cases of partial AZFc deletions in the infertile group (5.3%) and one case in the control group (0.4%). Seventeen deletions had the "gr/gr" pattern, one the "b2/b3" pattern, and one represented a novel deletion with breakpoints in b3 and b4 amplicons. Partial AZFc deletions were associated with different spermatogenic phenotypes ranging from complete azoospermia to only moderate oligozoospermia. CONCLUSIONS: Together with published data, our analysis of DAZ gene copy suggested that the contribution of the different deletions to male infertility varies: only partial AZFc deletions removing DAZ1/DAZ2 seem to be associated with spermatogenic impairment, whereas those removing DAZ3/DAZ4 may have no or little effect on fertility. These data show that, beside complete AZFc deletions, specific partial deletions represent a risk factor for male infertility, even if with different effect on spermatogenesis.

Characterization of HSFY, a novel AZFb gene on the Y chromosome with a possible role in human spermatogenesis.

HSFY (heat shock transcription factor, Y chromosome) has been mapped in the AZFb region of the Y chromosome, whose deletion results in severe male infertility. HSFY belongs to the heat shock factor family that has been shown to be implicated in spermatogenesis both in animals and humans. We report the characterization of the genomic structure, the number of copies on the Y chromosome and the expression of the gene. By comparison of data obtained from expression analysis and from GenBank cDNA sequences, seven exons were identified. Alternative splicing generates three different transcripts and proteins, each containing an HSF domain typical of HSF proteins. Two identical and functional full-length copies of HSFY map in palindrome P4 of AZFb, whereas four similar sequences mapping in two clusters in palindrome P1 of AZFc and P3 seem to represent pseudogenes. Sequences similar to few HSFY exons are also located in the short arm of chromosomes Y, X and 22. Expression analysis revealed that the three HSFY transcripts are differentially expressed, transcript 1 being present in many tissues including testis and ejaculated sperm, and transcripts 2 and 3 being testis-specific. These data suggest that HSFY could have an important role in human spermatogenesis.

[Dientamoeba fragilis: is it really fragile? Approach to specimen handling and rapid microscopic diagnosis]. / Dientamoeba fragilis: è realmente fragile? Approccio al trattamento del campione e diagnosi rapida al microscopio.

Dientamoeba fragilis is a pathogenic protozoan parasite with a world-wide distribution. Interestingly, a resistant cyst stage has not been demonstrated and it is still an unsolved problem how this parasite can survive successfully outside the human host. D. fragilis was found in 2% of approximately 2500 individuals unselected who submitted stools for parasitological examination during 2001 in Padua (Italy). The goal of this study was to detect the protozoan stages and the duration of persistence of this protozoa in faeces stored in different environmental conditions. The trophozoites of D. fragilis were detected up to 60 days after the collection of the faeces stored at 4 degrees C and Giemsa stained. The laboratory detection rate of the organism is greatly enhanced by use of preservative to fix stool specimens immediately after passage. Alternatively, a microscopic observation of the collected stool has to be performed immediately after passage followed by examination of permanently-stained smears. Demonstration of the charateristic "golf-club" and "acanthopodia-like" structures in unstained fixed faecal material by direct microscopy (400x) are suitable for a rapid identification of D. fragilis.

[Alteration of spermatogenesis and Y chromosome microdelations. Analysis of the DAZ gene family]. / Alterazioni della spermatogenesi e microdelezioni del cromosoma Y. Analisi della famiglia genica DAZ.

The Y chromosome has a fundamental role in sex determination and regulation of spermatogenesis. Three regions (designated as AZFa, b, and c) on the long arm of this chromosome exist, deletions of which result in severe damage to spermatogenesis with azoospermia or severe oligozoospermia. Recent progresses in molecular biology and extraordinary development of assisted reproduction techniques contributed to the research on this chromosome and the genes involved in spermatogenesis. About 10-15% of subjects affected by azoospermia or severe oligozoospermia carry a deletion in one or more AZF regions, 60% of which involves AZFc. The genes responsible for the testicular phenotype observed in these subjects are DBY and USP9Y for AZFa, RBMY1 for AZFb, and DAZ for AZFc. In this article, the current knowledge on biology and genetics of the Y chromosome are reported with particular interest to deletions found in infertile subjects. Furthermore, the more recent advances on DAZ gene and its role in spermatogenesis and male infertility are discussed.

Hemispheric specialization in quantification processes.

Three experiments were carried out to study hemispheric specialization for subitizing (the rapid enumeration of small patterns) and counting (the serial quantification process based on some formal principles). The experiments consist of numerosity identification of dot patterns presented in one visual field, with a tachistoscopic technique, or eye movements monitored through glasses, and comparison between centrally presented dot patterns and lateralized tachistoscopically presented digits. Our experiments show left visual field advantage in the identification and comparison tasks in the subitizing range, whereas right visual field advantage has been found in the comparison task for the counting range.

Remembering spatial locations: effects of material and intelligence.

The aim of the present work was to test some of the criteria for automaticity of spatial-location coding claimed by Hasher and Zacks, particularly individual differences (as intelligence invariance) and effortful encoding strategies. Two groups of subjects, 15 with mental retardation (Down Syndrome, mean chronological age, 20.9 yr.; mean mental age, 11.6 yr.) and 15 normal children (mean age, 11.5 yr.), were administered four kinds of stimuli (pictures, concrete words, nonsense pictures, and abstract words) at one location on a card. Subsequently, subjects were presented the items on the card's centre and were required to place the items in their original locations. Analysis indicated that those with Down Syndrome scored lower than normal children on the four tasks and that stimuli were better or worse remembered according to their characteristics, e.g., their imaginability. Results do not support some of the conditions claimed to be necessary criteria for automaticity in the recall of spatial locations as stated by Hasher and Zacks.