Systemic treatment in advanced phyllodes tumor of the breast: a multi-institutional European retrospective case-series analyses.

BACKGROUND: We aimed at investigating outcome of systemic treatments in advanced breast PT. METHODS: All cases of advanced breast PT treated with systemic treatments from 1999 to 2019, in one of the referral sarcoma centers involved in the study, were retrospectively reviewed. RESULTS: 56 female patients were identified. Median age was 52 (range of 25-76) years. Patients received a median number of 2 systemic treatments (range of 1-4). Best responses according to RECIST were 1 (3.7%) CR, 11 (40.7%) PR, 6 (22.2%) SD, 9 (33.3%) PD with anthracyclines plus ifosfamide (AI); 2 (16.7%) PR, 4 (33.3%) SD, 6 (50.0%) PD with anthracycline alone; 3 (18.8%) PR, 4 (25.0%) SD, 9 (56.3%) PD with high-dose ifosfamide given as a continuous infusion (HD-IFX); 3 (20.0%) SD, 12 (80.0%) PD with a gemcitabine-based regimen (with 2 patients not evaluable); 1 (8.3%) PR, 2 (16.7%) SD, 9 (75.0%) PD with trabectedin (with 1 patient not evaluable); 1 (16.7%) PR, 1 (16.7%) SD, 4 (66.7%) PD with tyrosine-kinase inhibitors (TKI). The median PFS were 5.7 (IQR 2.5-9.1) months with AI; 3.2 (IQR 2.2-5.0) months with anthracycline alone; 3.4 (IQR 1.4-6.7) months with HD-IFX; 2.1 (IQR 1.4-5.2) months with gemcitabine-based chemotherapy; 1.8 (IQR 0.7-6.6) months with trabectedin; 3.4 (IQR 3.1-3.8) months with TKI. With a median follow-up of 35.3 (IQR 17.6-66.9) months, OS from the start of first-line systemic treatment was 15.2 (IQR 7.6-39.6) months. CONCLUSION: In this series of advanced PT (to our knowledge, the largest reported so far), AI was associated with a high rate of responses, however, with a median PFS of 5.7 months. Other systemic treatments were poorly active.

Predictive markers in elderly patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors: an array-based pharmacogenetic study.

So far, no reliable predictive clinicopathological markers of response to aromatase inhibitors (AIs) have been identified, and little is known regarding the role played by host genetics. To identify constitutive predictive markers, an array-based association study was performed in a cohort of 55 elderly hormone-dependent breast cancer (BC) patients treated with third-generation AIs. The array used in this study interrogates variants in 225 drug metabolism and disposition genes with documented functional significance. Six variants emerged as associated with response to AIs: three located in ABCG1, UGT2A1, SLCO3A1 with a good response, two in SLCO3A1 and one in ABCC4 with a poor response. Variants in the AI target CYP19A1 resulted associated with a favourable response only as haplotype; haplotypes with increased response association were also detected for ABCG1 and SLCO3A1. These results highlight the relevance of host genetics in the response to AIs and represent a first step toward precision medicine for elderly BC patients.

Observational study on adjuvant trastuzumab in HER2-positive early breast cancer patients.

AIM: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates. PATIENTS & METHODS: Data on a group of HER2-positive patients collected from 13 oncology centers of northeast Italy were analyzed. RESULTS: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not-relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients. CONCLUSION: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2-positive early-stage breast cancer patients.

TRAbectedin in adVanced rEtroperitoneal well differentiated/dedifferentiated Liposarcoma and Leiomyosarcoma (TRAVELL): results of a phase II study from the Italian Sarcoma Group.

BACKGROUND: This is a multicentre, single-arm, phase II study aimed at further exploring the activity of trabectedin as second-/further-line treatment in retroperitoneal leiomyosarcoma (LMS) and well-differentiated/dedifferentiated liposarcoma (LPS). MATERIALS AND METHODS: The primary endpoint was the growth modulation index (GMI) defined as the ratio between PFS under trabectedin (PFS) and during previous chemotherapy treatment: time to progression (TTP-1). Secondary endpoints were objective response rate (ORR) and PFS. As per protocol, patients were considered responders if the GMI was >1.33, non-responders if <0.75 and neither if 0.76-1.32. RESULTS: Overall 91 patients were assessable for the primary endpoint (32 patients with LMS and 59 patients with LPS): the median number of cycles received was 6.0 (Q1-Q3 3.0-12.0), and the main reason for treatment discontinuation was disease progression in 72% of patients. The median PFS was 6.0 months, while the median TTP1 was 7.5 months (8.1 and 6.4 months for LMS and LPS, respectively). Thirty-three patients [52%, 95% confidence interval (CI) 36% to 58%, P = 0.674, odds of response 1.1] had a GMI >1.33 (LMS 46%, 95% CI 26% to 67%, odds of response 0.85; LPS 56%, 95% CI 40% to 72%, odds of response 1.3). Overall, in LPS we observed 15/47 patients with a GMI <0.5 and 15/47 patients with a GMI >2. Among LMS patients, 9/26 had a GMI <0.5 and 10/26 had a GMI >2. Overall, ORR (complete response + partial response) was 16% (24% for LMS and 12% for LPS). CONCLUSIONS: While the primary endpoint of the study was not met, we noticed a subgroup of patients with a markedly discrepant TTP with trabectedin in comparison to previous therapy (GMI <0.5 or >2, the latter including some patients with a long TTP with trabectedin). A mismatch between PFS and overall survival was observed, possibly due to the natural history of the two different histologies and the availability of further lines in LMS.

Low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, outcome of advanced disease: retrospective study from the Ultra-Rare Sarcoma Working Group.

BACKGROUND: To present findings from a retrospective study conducted by the Ultra-Rare Sarcoma Working Group on metastatic low-grade fibromyxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), and hybrid (H)-LGFMS/SEF across 28 global centres. METHODS: Patients treated at participating institutions from January 2000 to September 2022 were retrospectively selected. Diagnosis was confirmed by expert pathologists. Primary endpoint was progression-free survival (PFS-1) from metastasis detection to first progression or death. PFS-2 was calculated from therapy initiation. RESULTS: A total of 101 patients were identified (32 LGFMS, 50 SEF, 19 H-LGFMS/SEF). Median (m) follow-up was 62.1 months. mPFS-1 was 28.7, 11.8, and 20.3 months for LGFMS, SEF, and H-LGFMS/SEF, respectively. mOS was 145.8, 41.9, and 113.5 months, respectively. Treatments included anthracycline-based chemotherapy, gemcitabine-based chemotherapy (G), pazopanib, trabectedin, others. mPFS-2 was: 20.1, 5.5, and 3.5 months in H-LGFMS/SEF, SEF, and LGFMS, respectively, with anthracyclines; 19.5, 7.7, and 6.9 months in LGFMS, SEF, and H-LGFMS/SEF, respectively, with pazopanib; 12.0, 9.7, and 3.1 months in H-LGFMS/SEF, LGFMS, and SEF, respectively. Occasional responses occurred with ifosfamide/oral cyclophosphamide, and prolonged stable disease with immune checkpoint inhibitors. CONCLUSIONS: In this series, the largest available, metastatic LGFMS, SEF, and H-LGFMS/SEF showed different courses. Systemic agents have modest efficacy, informing future trials of novel agents for these tumours.

Safety and activity of sunitinib in elderly patients (≥ 70 years) with metastatic renal cell carcinoma: a multicenter study.

BACKGROUND: Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). RESULTS: Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. CONCLUSIONS: Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

West Nile virus transmission through organ transplantation in north-eastern Italy: a case report and implications for pre-procurement screening.

PURPOSE: West Nile virus (WNV) transmission through organ transplantation occurs rarely and screening of organ donors for WNV infection remains controversial. This report describes the case of WNV encephalitis in a kidney recipient and the case of asymptomatic WNV infection in the organ donor, both observed at Treviso Hospital, northeastern Italy. After briefly reviewing the literature, we discuss the implications for WNV screening. METHODS: We reviewed medical, laboratory and epidemiological records at our hospital, and the literature concerning cases of organ-transmitted WNV infections and WNV screening of organ donors in Italy and worldwide. RESULTS: The kidney recipient was the first confirmed case of WNV infection notified in northeastern Italy in 2011, and the first case of WNV infection in a cluster of four transplant recipients who acquired the infection from a common organ donor. The organ donor, whose WNV infection was only retrospectively diagnosed by IgM detection, represents the index case of a WNV outbreak in the Treviso Province. Screening of her blood prior to organ recovery did not show detectable levels of WNV nucleic acid with the use of quantitative real-time polymerase chain reaction. CONCLUSIONS: This report emphasizes that transplant-acquired WNV neuroinvasive disease can be particularly severe. We suggest that pre-procurement screening of organ donors by testing blood with both WNV IgM capture ELISA and a sensitive nucleic acid testing should be adopted during the transmission season in the present Italian epidemiological setting.

Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study.

BACKGROUND: Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). PATIENTS AND METHODS: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons. RESULTS: Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). CONCLUSIONS: Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

Clinical prognostic factors in advanced epithelioid haemangioendothelioma: a retrospective case series analysis within the Italian Rare Cancers Network.

BACKGROUND: This multicentric, retrospective study conducted within the Italian Rare Cancer Network describes clinical features and explores their possible prognostic relevance in patients with advanced epithelioid haemangioendothelioma (EHE) started on surveillance. PATIENTS AND METHODS: We collected data on adult patients with molecularly confirmed, advanced EHE consecutively referred at five sarcoma reference centres between January 2010 and June 2018, with no evidence of progressive disease (PD) and started on surveillance. Overall survival (OS) and progression-free survival (PFS) univariable and multivariable Cox analyses were performed. In the latter, due to the low number of cases and events, penalized likelihood was applied, and variable selection was performed using a random forest model. RESULTS: Sixty-seven patients were included. With a median follow-up of 50.2 months, 51 (76%) patients developed PD and 16 (24%) remained stable. PD at treatment start did not meet RECIST version 1.1 in 15/51 (29%) patients. The 3-year PFS and OS were 25.4% and 71.1%, respectively, in the whole population. Tumour-related pain (TRP) was the most common baseline symptom (32.8%), followed by temperature (20.9%), fatigue (17.9%), and weight loss (16.4%). Baseline TRP (P = 0.0002), development of TRP during follow-up (P = 0.005), baseline temperature (P = 0.002), and development of fatigue during follow-up (P = 0.007) were associated with a significantly worst PFS. An association between baseline TRP (P < 0.0001), development of TRP during follow-up (P = 0.0009), evidence of baseline serosal effusion (P = 0.121), and OS was recorded. CONCLUSION: Because of the poor outcome observed in EHE patients presenting with serosal effusion, TRP, temperature, or serosal effusion, upfront treatment in this subgroup could be considered.

PTCH1 gene haplotype association with basal cell carcinoma after transplantation.

BACKGROUND: Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals. OBJECTIVES: To search for novel common polymorphisms in the proximal 5' regulatory region upstream of PTCH1 gene exon 1B, and to investigate the possible association of PTCH1 polymorphisms and haplotypes with BCC risk after organ transplantation. METHODS: Three PTCH1 single nucleotide polymorphisms (rs2297086, rs2066836 and rs357564) were analysed by restriction fragment length polymorphism analysis in 161 northern Italian OTRs (56 BCC cases and 105 controls). Two regions of the PTCH1 gene promoter were screened by heteroduplex analysis in 30 cases and 30 controls. RESULTS: Single locus analysis showed no significant association. Haplotype T(1686)-T(3944) appeared to confer a significantly higher risk for BCC development (odds ratio 2.98, 95% confidence interval 2.55-3.48; P = 0.001). Two novel rare polymorphisms were identified at positions 176 and 179 of the 5'UTR. Two novel alleles of the -4 (CGG)(n) microsatellite were identified. No association of this microsatellite with BCC was observed. CONCLUSIONS: Haplotypes containing T(1686)-T(3944) alleles were shown to be associated with an increased BCC risk in our study population. These data appear to be of great interest for further investigations in a larger group of transplant individuals. Our results do not support the hypothesis that common polymorphisms in the proximal 5' regulatory region of the PTCH1 gene could represent an important risk factor for BCC after organ transplantation.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Medical treatment of malignancy-associated hypercalcemia.

Malignancy-associated hypercalcemia (MAH) is the commonest cause of hypercalcemia in hospitalized patients. Its incidence is 15 cases per 100,000 person-year. Such complication develops in almost 10% of patients with advanced cancer representing, ultimately, the most frequent cause of death in several patients with cancer. Parathyroid hormone related protein (PTHrP), which has strong homology to parathyroid hormone, is the commonest hormonal mediator of MAH. Overall, about 80% of patients with MAH have increased PTHrP serum levels. Bisphosphonates are synthetic analogues of pyrophosphate, and represent the principal support of treatment. Several bisphosphonates have shown to decrease serum calcium levels by inhibiting PTH-dependent osteoclast activation. They are potent and effective inhibitors of osteoclast-mediated bone resorption, and have shown antiangiogenic properties in some experimental models. At present, pamidronate, zoledronate and ibandronate should be considered the drugs of choice in the treatment of MAH. Old agents such as mithramycin, calcitonine, and gallium nitrate have practically been abandoned due to their limited activity and huge side effects, especially for the kidney. A new experimental approach to MAH involves the blockade of receptor activator of nuclear factor-kappa B ligand, usually abbreviated as RANKL. RANKL is a key element in the differentiation, function, and survival of osteoclasts, which plays an essential role in removing Ca(++) from the bone in response to PTH stimulation. This review provides information about the actual medical treatment of MAH.

Cardiac toxicity: old and new issues in anti-cancer drugs.

Although rare, cardiotoxicity is a significant complication of cancer treatment. The incidence and severity of cardiovascular side effects are dependent on the type of drugs used, dose and schedule employed, and age of patients, as well as the presence of coexisting cardiac diseases and previous mediastinal irradiation. Classically, anthracyclines are among one of the most active agents in oncology, but their use is often hampered by their cumulative dose-limiting cardiotoxicity. In the past decade, combination therapy with new drugs such as taxanes or anti- EGFR, and Her-2 therapy as a single agent have also resulted in unexpected cardiotoxicity. Cardiac damage can be secondary to an alteration of cardiac rhythm, changes in blood pressure and ischaemia, and can also alter the ability of the heart to contract and/or relax. The clinical spectrum of these toxicities can range from subclinical abnormalities to being catastrophic, life-threatening and sometimes fatal. Knowledge of this toxicity can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient. In this work we present an exhaustive review of the cardiovascular side effects associated to new anticancer drugs, from new formulations of anthracyclines to tyrosine kinase inhibitors and monoclonal antibodies.

Modulation by cADPr of Ca2+ mobilization and oxidative response in dimethylsulfoxide- or retinoic acid-differentiated HL-60 cells.

In human phagocytic cells, reactive oxygen species (ROS) generation in response to N-formyl-L-Methionyl-L-Leucyl-L-Phenylalanine (fMLF) is largely dependent on cytosolic free calcium concentration ([Ca2+]i). Cyclic ADP-ribose (cADPr) is able to regulate Ca2+ release from intracellular stores through the ryanodine receptor but its potential role in biological responses has so far not been determined. In this study, we examined whether extracellular and intracellular cADPr is required in fMLF-induced [Ca2+]i rise and consequently in the oxidative response in human neutrophil-like HL-60 cells differentiated with dimethylsulfoxide or all-trans-retinoic acid (ATRA). We establish that extracellular cADPr cannot elicit [Ca2+]i elevation. Furthermore, we demonstrate that 8-Br-cADPr, a functional antagonist of cADPr, inhibits Ca2+ entry into HL-60 cells differentiated with ATRA and stimulated with fMLF (95+/-4 and 148+/-5 nM respectively, n=3). Finally, we show that this partial inhibition of Ca2+ mobilization is unrelated to ROS production (10.0+/-0.3 vs. 9.6+/-0.5 A.U., n=3). In conclusion, we showed that cADPr can control fMLF-induced Ca2+ influx but is unable to regulate a Ca2+-dependent biological response, i.e. H2O2 production.

Isolated limb perfusion for the management limb threatening soft tissue sarcomas: The role of histological type on clinical outcomes.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) is an effective neoadjuvant treatment to avoid amputation in patients with locally advanced extremity soft tissue sarcomas (STS). We aimed to investigate whether STS histological type plays a role in predicting clinical outcomes. METHODS: This study reports a retrospective analysis of 125 patients with limb threatening STS (liposarcoma, n = 41; malignant peripheral nerve sheath tumor, n = 20; leiomyosarcoma, n = 20; miscellany, n = 44), who underwent HILP from 1990 through 2015 at our institution. The following endpoints were evaluated: tumor response (assessed by radiological imaging and histology), limb sparing rate, local progression-free survival (LPFS) and overall survival (OS). RESULTS: On average, overall (complete + partial) tumor response was significantly greater in patients affected with liposarcoma as compared to those with other histotypes (radiological response rate: 38/41, 92.7% vs 66/84, 78.6%, P-value: 0.048; mean histological necrosis: 83.6% vs 52.9%, P < 0.0001). Limb sparing rate was also higher among patients with liposarcoma as compared to other histotypes (39/41, 95.1% vs 62/84, 73.8%, P-value: 0.005). As regards survival, LPFS was similar across tumor types, whereas OS resulted significantly worse in patients with limb leiomyosarcoma (log-rank P-value: 0.009). CONCLUSIONS: HILP is a very effective treatment modality for limb threatening STS. In our series, liposarcoma appears to be the histological type most sensitive to HILP in terms of tumor response and thus limb sparing, which might help clinicians in the patient selection process.

How to measure the bogoliubov quasiparticle amplitudes in a trapped condensate

We propose an experiment, based on two consecutive Bragg pulses, to measure the momentum distribution of quasiparticle excitations in a trapped Bose gas at low temperature. With the first pulse one generates a bunch of excitations carrying momentum q, whose Doppler line is measured by the second pulse. We show that this experiment can provide direct access to the amplitudes u(q) and v(q) characterizing the Bogoliubov transformations from particles to quasiparticles. We simulate the behavior of the nonuniform gas by numerically solving the time dependent Gross-Pitaevskii equation.

Attitudes and knowledge about transplantation in dialyzed patients requesting a cadaveric kidney graft.

AIM: Eighty-two patients answered a multiple choice questionnaire aimed at identifying their presumed and actual knowledge regarding transplantation, given immediately before evaluation by our transplant team for inclusion on our kidney transplant waiting list. SUBJECTS, METHODS AND RESULTS: A total of 78% stated that they had no or incomplete knowledge of transplantation and 22% were very well informed. The mean score for technical knowledge of transplantation (duration, requirement for removal of native kidneys, possibility of obtaining a second transplant, duration of immunosuppressive therapy and duration of the risk of rejection) was 3.1 +/- 0.15 SEM (maximal possible score 5), that for risk knowledge (risks of infections, unpleasant side effects, hypertension, diabetes mellitus, viral infections and cancer) was 1.4 +/- 0.15 (maximal possible score 6). A total of 23% knew that the spouse could donate a kidney, 74% stated that only a blood relative could and 3% that living donation was impossible. CONCLUSIONS: There is scarce knowledge about transplantation, especially with regard to the risks and living donation.

Beta 2-microglobulin removal by synthetic dialysis membranes. Mechanisms and kinetics of the molecule.

Beta 2-microglobulin (beta 2-m) accumulation represents a possible complication of long term dialysis. It is therefore important to evaluate the capacity of removal of this molecule from the patient by different dialysis membranes. The present study is aimed at evaluating the mechanisms involved in beta 2-m removal by three different synthetic membranes: a) highly asymmetric hydrophobic polysulfone (Biosulfane, NMC), b) moderately asymmetric and hydrophobic polysulfone (PS600, Fresenius), c) Polyacylonitrile (AN69HF, Hospal). The adsorption capacity and sieving coefficients of the three membranes for native and labeled beta 2-m were studied in vitro utilizing human blood. The amount adsorbed by the membrane was measured by the elution of the molecule obtained with a detergent solution. Clearances, total removal and membrane adsorption were studied in six patients treated in a randomized sequence with the three membranes. For this purpose, plasma and dialysate measurements as well as total collection of spent dialysate and beta 2-m elution from the used dialyzers were carried out. Ex novo generation of beta 2-m did not take place during in vitro circulation. The molecule was removed by the studied membranes both by filtration and adsorption. The Biosulfane membrane removed beta 2-m mostly by adsorption while the PS600 membrane removed beta 2-m almost entirely by filtration. Intermediate behaviour was shown by AN69 membrane. Similar quantities of beta 2-m were removed from the patients with the three membranes. Total removal could only be precisely measured by adding the quantity of beta 2-m eluted from the membrane to the amount recovered in the spent dialysate. Out of total removal, adsorption was more than 90% with Biosulfane, while only 5% with the PS600. These findings contribute to the understanding of the discrepancy found between the clearance measured from the plasma side and that measured from the dialysate side. In conclusion, clearance and sieving measurements for beta 2-m cannot be correctly performed unless the capacity of adsorption of the membrane is taken into account.

Targeted approaches to triple-negative breast cancer: current practice and future directions.

Triple-negative breast cancer (TNBC), that is breast cancer which stains negatively at immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), comprises a particularly aggressive subtype of breast cancer, with high rate of early local and distant relapse. TNBC have demonstrated sensitivity to cytotoxic treatment regimens, but in the absence of HER2, ER and PR there is no benefit from hormonal therapy or trastuzumab. The lack of known specific molecular targets has promoted abundant research in order to find possible "vulnerabilities" in TNBC and the evaluation of novel biomarkers overcoming the traditional approach based on hormonal receptors and HER2-targeted therapy is one of the priorities in breast cancer research. Drugs under investigation can be broadly subdivided into four groups: (1) Agents that create DNA damage (i.e. cisplatin, cyclophosphamide); (2) Agents that inhibit poly (ADP-ribose) polymerase (PARP); (3) Tyrosin-kinase inhibitors and monoclonal antibodies; (4) Agents that inhibit downstream signals. Several preclinical and early phase clinical trials for the treatment or management of patients with triple-negative breast tumors are underway. Nonetheless, so far the major issue to deal with when trying to provide evidence for TNBC is the small numbers of the sample in the clinical studies and the retrospective nature of most of them. Future large studies could help in defining optimal treatment strategies for TNBC, both in the advanced setting as well as in the (neo) adjuvant setting.