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We provide the optimal measurement strategy for a class of noisy channels that reduce to the identity channel for a specific value of a parameter (spreading channels). We provide an example that is physically relevant: the estimation of the absolute value of the displacement in the presence of phase randomizing noise. Surprisingly, this noise does not affect the effectiveness of the optimal measurement. We show that, for small displacement, a squeezed vacuum probe field is optimal among strategies with same average energy. A squeezer followed by photodetection is the optimal detection strategy that attains the quantum Fisher information, whereas the customarily used homodyne detection becomes useless in the limit of small displacements, due to the same effect that gives Rayleigh's curse in optical superresolution. There is a quantum advantage: a squeezed or a Fock state with $N$ average photons allow to asymptotically estimate the parameter with a $\sqrt{N}$ better precision than classical states with same energy., Comment: 4+4 pages, 4 figures

We study the energy exchange between two bosonic systems that interact via bilinear transformations in the mode operators. The first mode is considered as the thermodynamic system, while the second is regarded as the bath. This work finds its roots in a very recent formulation of quantum thermodynamics [1] which allows to consider baths that are not described by the usual Boltzmann-Gibbs canonical form. Baths can possess quantum properties, such as squeezing or coherence, and can be initially correlated with the system, even through entanglement. We focus mainly on the case of Gaussian states, by quantifying the relation between their defining parameters, namely the mean values of the quadratures and the covariance matrix, and relevant thermodynamical quantities such as the heat exchanged and the work performed during the interaction process. We fully solve the case of initially uncorrelated Gaussian states and provide the most general form of the first law of thermodynamics in this case. We also discuss the case of initially correlated states by considering a number of relevant examples, studying how correlations can assist some phenomena, e.g. work extraction or anomalous heat flows. Finally, we present an information-theoretic approach based on the Renyi entropy of order two for clarifying more generally the role of correlations on heat exchanges., 25 pages, 2 figures. Improved version with new references

// Francesco Lodola 1, 11, * , Umberto Laforenza 2, * , Fabio Cattaneo 3, * , Federico Alessandro Ruffinatti 4 , Valentina Poletto 5 , Margherita Massa 6 , Richard Tancredi 7 , Estella Zuccolo 1 , Dlzar Ali Khdar 1 , Alberto Riccardi 7, 8 , Marco Biggiogera 9 , Vittorio Rosti 5, ** , Germano Guerra 10, ** and Francesco Moccia 1 ** 1 Laboratory of General Physiology, Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Pavia 27100, Italy 2 Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy 3 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy 4 Department of Life Sciences and Systems Biology, Turin 10123, Italy 5 Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, Foundation IRCCS Policlinico San Matteo, Pavia 27100, Italy 6 Laboratory of Immunology Transplantation, Foundation IRCCS Policlinico San Matteo, Pavia 27100, Italy 7 Medical Oncology Unit, Foundation IRCCS Salvatore Maugeri, Pavia 27100, Italy 8 Department of Internal Medicine, University of Pavia, Pavia 27100, Italy 9 Laboratory of Cell Biology and Neurobiology, Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Pavia 27100, Italy 10 Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso 86100, Italy 11 Current address: Italian Institute of Technology, Center for Nano Science and Technology, Milano 20133, Italy * These authors should be considered as co-first authors ** These authors share the Senior Authorship of the manuscript and should be regarded as co-last authors Correspondence to: Francesco Moccia, email: francesco.moccia@unipv.it Germano Guerra, email: germano.guerra@unipv.it Keywords: VEGF, breast cancer, endothelial colony forming cells, intracellular Ca 2+ oscillations, angiogenesis Received: June 01, 2017 Accepted: July 12, 2017 Published: August 14, 2017 ABSTRACT Endothelial colony forming cells (ECFCs) represent a population of truly endothelial precursors that promote the angiogenic switch in solid tumors, such as breast cancer (BC). The intracellular Ca 2+ toolkit, which drives the pro-angiogenic response to VEGF, is remodelled in tumor-associated ECFCs such that they are seemingly insensitive to this growth factor. This feature could underlie the relative failure of anti-VEGF therapies in cancer patients. Herein, we investigated whether and how VEGF uses Ca 2+ signalling to control angiogenesis in BC-derived ECFCs (BC-ECFCs). Although VEGFR-2 was normally expressed, VEGF failed to induce proliferation and in vitro tubulogenesis in BC-ECFCs. Likewise, VEGF did not trigger robust Ca 2+ oscillations in these cells. Similar to normal cells, VEGF-induced intracellular Ca 2+ oscillations were triggered by inositol-1,4,5-trisphosphate-dependent Ca 2+ release from the endoplasmic reticulum (ER) and maintained by store-operated Ca 2+ entry (SOCE). However, InsP 3 -dependent Ca 2+ release was significantly lower in BC-ECFCs due to the down-regulation of ER Ca 2+ levels, while there was no remarkable difference in the amplitude, pharmacological profile and molecular composition of SOCE. Thus, the attenuation of the pro-angiogenic Ca 2+ response to VEGF was seemingly due to the reduction in ER Ca 2+ concentration, which prevents VEGF from triggering robust intracellular Ca 2+ oscillations. However, the pharmacological inhibition of SOCE prevented BC-ECFC proliferation and in vitro tubulogenesis. These findings demonstrate for the first time that BC-ECFCs are insensitive to VEGF, which might explain at cellular and molecular levels the failure of anti-VEGF therapies in BC patients, and hint at SOCE as a novel molecular target for this disease.

Background Neovascularisation supports the metastatic switch in many aggressive solid cancers. Tumour neovessels are mostly lined by endothelial cells sprouting from nearby capillaries, but they could also be contributed by circulating endothelial progenitor cells (EPCs). However, scant information is available about tumour-derived EPCs. Methods We carried out the first thorough, unbiased comparison of phenotype, function and genotype of normal versus tumour-derived endothelial colony forming cells (ECFCs), a truly endothelial EPC subtype. We used healthy donors–derived ECFCs (N-ECFCs) as control for breast cancer (BC)– and renal cell carcinoma (RCC)–derived ECFCs. Results We found that both BC- and RCC-ECFCs belong to the endothelial lineage. Normal and tumour-derived ECFCs did not differ in terms of proliferative and tubulogenic rates. However, RCC-ECFCs were more resistant to rapamycin-induced apoptosis, whereas BC-ECFCs were more sensitive as compared with N-ECFCs. Gene expression profiling revealed 382 differentially expressed genes (DEGs; 192 upregulated and 150 downregulated) and 71 DEGs (33 upregulated, 38 downregulated) when comparing, respectively, BC- and RCC-ECFCs with N-ECFCs. Nonetheless, BC- and RCC-derived ECFCs shared 35 DEGs, 10 of which were validated by qRT-PCR; such 35 DEGs are organised in a gene network centred on FOS. Conclusion These results provide the first clear-cut evidence that BC- and RCC-derived ECFCs exhibit an altered gene expression profile as compared with N-ECFCs; yet, they share a common gene signature that could highlight novel and more specific targets to suppress tumour vascularisation.

BACKGROUND: The acromion clavicular joint dislocations are common injuries of the shoulder. The severity is dependent upon the degree of ligamentous injury. Surgical treatment is typically performed in higher grade acromioclavicular separation with several static and dynamic operative procedures with or without primary ligament replacement. METHODS: 47 patients with acute Rockwood type III, IV, and V injuries were treated surgically with LARS reconstruction. The success of technique was evaluated by radiographic outcomes for each patient at every follow-up visit (one, three, 12 months), while to assess pain reduction and clinical evaluation Visual Analogue scale score (VAS) and Constant-Murley score (CMA) was performed, respectively. An One Way Analysis of Variance (Kruskal-Wallis test), a multiple comparison Turket test, or a t-test (Mann-Whitney Rank Sum Test) were used when required. RESULTS: Follow-up radiographs revealed maintenance of anatomical reduction in 41 patients, and no bone erosions has been identified. In short-term joint functional recovery has been observed. Indeed, after 12 months pain on the VAS-scale in all groups decreased significantly (P < 0.05), and the CMS revealed a significant overall improvement (P < 0.05). CONCLUSION: These data demonstrate that the use of the LARS allows to provide stability to the joint and especially to ensure its natural elasticity, relieving pain and improving joint function already one month post-surgery.

The aim of this study was to demonstrate the correlation between human epidermal growth factor receptor 2 (HER2) overexpression and some poor prognosis factors in patients affected by ductal carcinoma in situ (DCIS). We evaluated 48 cases of DCIS, divided into two groups according to HER2 amplification status. Nuclear grade and "cancerization of lobules" were determined within primary DCIS and Ki67, estrogen receptor (ER), PR, and HER2 expression was established using immunohistochemistry. The histopathological variables in HER2-positive and in HER2-negative patients were compared to determine the recurrence risk. We also considered the median age at the time of surgery according to HER2 status. There were 11 recurrences (23%), 6 DCIS (55%), and 5 invasive cancer (45%). In an 8-year-long median follow-up, we hypothesized high risk of recurrence in HER2-positive DCIS. Patients with HER2-positive DCIS were younger than HER2-negative ones (p = 0.002). HER2-positive DCIS was also related to histopathological predictors of recurrence such as high nuclear grade (p < 0.001), high Ki67 expression (p = 0.003), low ER and PgR levels (p < 0.001), and the presence of "cancerization of lobules" (p < 0.049). Our trial suggests that HER2 amplification in primary DCIS is identified more frequently in younger patients and hypothesizes high risk of recurrence in HER2-positive DCIS related to histopathological predictors of overall relapse as high nuclear grade, high Ki67 expression, low ER and PgR levels, and the presence of "cancerization of lobules." In HER2-positive DCIS, other variables of recurrence risk are compared to HER2-negative lesions, without statistical significance. Our results show that HER2 testing might suggest clinicians the optimal treatment of patients with DCIS.

We address the problem of optimising entanglement witnesses when a limited fixed set of local measurements can be performed on a bipartite system, thus providing a procedure, feasible also for experiments, to detect entangled states using only the statistics of these local measurements. We completely characterize the class of entanglement witnesses of the form $W = P ^{\Gamma}$, where $\Gamma$ denotes partial transposition, that can be constructed from the measurements of the bipartite operators $\sigma_{x}\otimes\sigma_{x},$ $\sigma_{y}\otimes\sigma_{y}$ and $\sigma_{z}\otimes\sigma_{z}$ in the case of two-qubit systems. In particular, we consider all possible extremal decomposable witnesses within the considered class that can be defined from this set of measurements. Finally, we discuss possible extensions to higher dimension bipartite systems when the set of available measurements is characterized by the generalized Gell-Mann matrices. We provide several examples of entanglement witnesses, both decomposable and indecomposable, that can be constructed with these limited resources., Comment: 7 pages

We consider uncertainty relations that give lower bounds to the sum of variances. Finding such lower bounds is typically complicated, and efficient procedures are known only for a handful of cases. In this paper we present procedures based on finding the ground state of appropriate Hamiltonian operators, which can make use of the many known techniques developed to this aim. To demonstrate the simplicity of the method we analyze multiple instances, both previously known and novel, that involve two or more observables, both bounded and unbounded., 14 pages, 3 figures

We investigate quantum steering for multipartite systems by using entropic uncertainty relations. We introduce entropic steering inequalities whose violation certifies the presence of different classes of multipartite steering. These inequalities witness both steerable states and genuine multipartite steerable states. Furthermore, we study their detection power for several classes of states of a three-qubit system., Comment: 3 figures

This paper describes the current status of the design, implementation, and test of a data acquisition (DAQ) system for the prototypes of the front-end electronics of the Antiproton Annihilation at Darmstadt ($\mathrm{\bar{P}ANDA}$) Micro Vertex Detector (MVD). The features of this DAQ, called Juelich Digital Readout System (JDRS), are driven by the requirements imposed by the physics program of the experiment, such as continuous data collection without external triggering. Flexibility and modularity are thus key points for this system, which is meant to operate during a test beam, as well as in a laboratory environment. The implementation of the system is based on an off-theshelf field-programmable gate array (FPGA) board. So far, two different application-specific integrated circuits (ASICs) have been successfully connected to the JDRS. Tests to establish the performance of the JDRS in terms of processing speed and reliability have been carried out and are still ongoing.

Endothelial colony forming cells (ECFCs) represent a population of truly endothelial precursors that promote the angiogenic switch in solid tumors, such as breast cancer (BC). The intracellular Ca2+ toolkit, which drives the pro-angiogenic response to VEGF, is remodelled in tumor-associated ECFCs such that they are seemingly insensitive to this growth factor. This feature could underlie the relative failure of anti-VEGF therapies in cancer patients. Herein, we investigated whether and how VEGF uses Ca2+ signalling to control angiogenesis in BC-derived ECFCs (BC-ECFCs). Although VEGFR-2 was normally expressed, VEGF failed to induce proliferation and in vitro tubulogenesis in BC-ECFCs. Likewise, VEGF did not trigger robust Ca2+ oscillations in these cells. Similar to normal cells, VEGF-induced intracellular Ca2+ oscillations were triggered by inositol-1,4,5-trisphosphate-dependent Ca2+ release from the endoplasmic reticulum (ER) and maintained by store-operated Ca2+ entry (SOCE). However, InsP3-dependent Ca2+ release was significantly lower in BC-ECFCs due to the down-regulation of ER Ca2+ levels, while there was no remarkable difference in the amplitude, pharmacological profile and molecular composition of SOCE. Thus, the attenuation of the pro-angiogenic Ca2+ response to VEGF was seemingly due to the reduction in ER Ca2+ concentration, which prevents VEGF from triggering robust intracellular Ca2+ oscillations. However, the pharmacological inhibition of SOCE prevented BC-ECFC proliferation and in vitro tubulogenesis. These findings demonstrate for the first time that BC-ECFCs are insensitive to VEGF, which might explain at cellular and molecular levels the failure of anti-VEGF therapies in BC patients, and hint at SOCE as a novel molecular target for this disease.

In the present work, we study tripartite quantum steering of quantum correlations arising from two local dichotomic measurements on each side in the two types of partially device-independent scenarios: $1$-sided device-independent scenario where one of the parties performs untrusted measurements while the other two parties perform trusted measurements and $2$-sided device-independent scenario where one of the parties performs trusted measurements while the other two parties perform untrusted measurements. We demonstrate that tripartite steering in the $2$-sided device-independent scenario is weaker than tripartite steering in the $1$-sided device-independent scenario by using two families of quantum correlations. That is these two families of quantum correlations in the $2$-sided device-independent framework detect tripartite entanglement through tripartite steering for a larger region than that in the $1$-sided device-independent framework. It is shown that tripartite steering in the $2$-sided device-independent scenario implies the presence of genuine tripartite entanglement of $2\times 2 \times 2$ quantum system, even if the correlation does not exhibit genuine nonlocality or genuine steering., 14 pages, 4 figures, accepted for publication in Physical Review A

We consider two (natural) families of observables ${O}_{k}$ for systems with dimension $d=3,4,5$: the spin observables ${S}_{x},\phantom{\rule{0.16em}{0ex}}{S}_{y}$, and ${S}_{z}$, and the observables that have mutually unbiased bases as eigenstates. We derive tight entropic uncertainty relations for these families, in the form ${\ensuremath{\sum}}_{k}H({O}_{k})\ensuremath{\ge}{\ensuremath{\alpha}}_{d}$, where $H({O}_{k})$ is the Shannon entropy of the measurement outcomes of ${O}_{k}$ and ${\ensuremath{\alpha}}_{d}$ is a constant. We show that most of our bounds are stronger than previously known ones. We also give the form of the states that attain these inequalities.

Background The purpose of this study was to assess the activity and safety of the combination of vinorelbine (VNR) and capecitabine (CAP) as first-line treatment in HER2–negative (HER – ) metastatic breast cancer (MBC). Patients and Methods Patients (42) enrolled in trial A received intravenous (i.v.) VNR 25 mg/m2 on days 1 and 8 of a 21-day cycle combined with CAP 1000 mg/m2 twice daily for 14 consecutive days followed by 1 week of rest. Trial B (46 patients) followed trial A when the oral formulation of VNR became available at our institution. Patients received oral VNR (60 mg/m 2 on days 1-8) combined with the same CAP schedule as in trial A. Results The response rate (RR) in trial A was 73.2% (95% confidence interval [CI], 56.4-82.8), including 12.2% complete responses (CRs). Clinical benefit was achieved in 78% of patients (95% CI, 63.2-87.9). In trial B, overall RR was 76% (95% CI, 62.0-86.0), with 13% CRs and clinical benefit of 80.4% (95% CI, 66.8-89.3). In trial A, median progression-free survival (PFS) was 8.2 months (range, 6-14+ months) and median overall survival (OS) was 32.4 months (range, 17-36+ months). In trial B, median PFS and OS were 8.8 months (range, 8-21+ months) and 34.3 months (14-39+ months), respectively. Treatment-related toxicity was manageable. Quality of life assessment showed a statistically significant difference regarding body image ( p = .001), sexual functioning ( p = .02), and future perspectives ( p = .03) in women receiving chemotherapy fully by the oral route. Conclusion This joint analysis shows that both tested schedules can produce high objective RRs with encouraging PFS, manageable toxicity profile, and suggested benefit on some aspects of quality of life for the fully oral combination.

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.

46 adult patients with non-lymphoblastic acute leukaemia (AnLL) had pretreatment proliferative activity of bone marrow (BM) blasts determined simultaneously with propidium iodide DNA flow cytofluorometry (as the percentage of cells with DNA content intermediate between the diploid and the tetraploid values, 2n-4n cell %) and in vitro tritiated thymidine cytoautoradiography (as the labelling index, LI). They were then treated with the same chemotherapy regimen, including 2-3 courses of sequential vincristine, arabinosylcytosine and adriamycin, for response induction, and monthly courses of different cytostatics for maintenance. Median 2n-4n cell % was 9.9 and median LI was 5.9. A close linear relationship (r = 0.913, p less than 0.001) between the two parameters was found. Patients having a 2n-4n cell % greater than 15.6 responded more often to chemotherapy than patients having a lower percentage (p less than 0.05) but also experienced a shorter duration of first response (p less than 0.05). Overall survival was longer in patients with 2n-4n cell % greater than 15.6 (p less than 0.02). Multiple regression analysis indicates that 2n-4n cell % is a statistically significant (p less than 0.05) independent factor correlating with duration of response in adult AnLL.

Pegfilgrastim is a covalent conjugate of filgrastim and polyethylene glycol that has proved to be effective in supporting myelopoiesis during chemotherapy. Since very limited information is available on the biological effects of pegfilgrastim on neutrophils exposed to chemotherapy, we analyzed the following parameters in neutrophils of patients undergoing dose-dense chemotherapy for breast cancer: apoptosis, by a TUNEL technique; actin polymerization, using FITC-labeled phalloidin, and alkaline phosphatase activity by cytochemistry. Peripheral blood buffy coat smears were obtained before starting treatment and immediately before each chemotherapy course. After pegfilgrastim stimulation we observed the following: (1) stability of the absolute neutrophil count for the whole duration of treatment and no infectious events; (2) a reduction in the neutrophil constitutive apoptosis rate in comparison with that observed in control patients treated with standard chemotherapy courses with no growth factor support; (3) persistent abnormalities of actin assembly in neutrophils, indicative of changes in cytoskeletal organization, and (4) a significant increase in the activity of leukocyte alkaline phosphatase, a sensitive marker of the later stages of neutrophil maturation. In conclusion, these results suggest that pegfilgrastim improves the neutrophil functions in patients exposed to chemotherapy by inhibition of constitutive apoptosis, thereby prolonging the survival of these cells.

Aims and Background Sequential docetaxel and gemcitabine following initial docetaxel plus epirubicin or vinorelbine association could be worthwhile as first-line treatment of metastatic breast cancer. Methods Fifty-eight patients entered a phase II study that included two sequential phases. In the first phase, 36 and 22 patients previously unexposed or exposed to adjuvant anthracyclines received the association of docetaxel (75 mg/m2, day 1) with epirubicin (75 mg/m2, day 1) or vinorelbine (20 mg/m2, days 1 and 5), respectively, every 21 days for 4 courses. In the second phase, patients who had a response (R) or stable disease (SD) received docetaxel (35 mg/m2) and gemcitabine (800 mg/m2) on days 1, 8 and 15 every 28 days for 4 courses. Results In the first phase, grade ≥ III neutropenia occurred in 51% and 37% of patients during docetaxel-epirubicin and docetaxel-vinorelbine, respectively. In the second phase, it occurred in the 27% and 15% of patients initially treated with docetaxel-epirubicin and docetaxel-vinorelbine, respectively. On an intention to treat basis, the complete (CR) + partial response (PR) rate to the first phase was 71%, and 22% of patients had SD, without a significant difference between the docetaxel-epirubicin and docetaxel-vinorelbine arms. After the second phase, the CR + PR rate was 65%, and 14% of patients had SD. Median time to progression and survival were 12.1 and 22.0 months, respectively, without a significant difference between patients initially treated with docetaxel-epirubicin and docetaxel-vinorelbine. Conclusions Following an initial docetaxel-based treatment, weekly docetaxel and gemcitabile maintains high percentages of R and SD, with improved toxicity. Survival was similar in patients previously untreated and treated with adjuvant anthracyclines.

Preclinical data indicate there is strong synergism of action against Ewing sarcoma in sequential treatment with trabectedin followed by irinotecan and it appears to be related to a selective blockade of the transcription factor EWS–FLI1. This combination was evaluated in Ewing sarcoma patient who was progressing with standard therapies. Trabectedin was given as a 24-h iv infusion on day 1 at the dose of 1 mg/sqm, and irinotecan 75 mg/sqm on day 2 and then on days 2 and 4, every 3 weeks from the seventh course. The therapy was well tolerated with transient hematological toxicity and transaminitis and induced stabilization of the disease lasting for 11 courses, with clinical improvement and marked reduction of the need for opioids. However, shortly before the 12th course, sudden death occurred, possibly due to cerebral stroke, presumably not related to the drug treatment. The encouraging clinical benefit observed with the combination and its good tolerability deserves further investigation in Ewing sarcoma.

e21509 Background: End-of-life palliative chemotherapy does not improve quality of life nor does it prolong survival of terminal cancer patients. On the contrary, it is related not only to increased health costs, but also to severe therapy related side effects and to patient and caregiver distress. The first point of the ASCO’s Top Five List, released in 2012, tried to address the issue of chemotherapy overuse near the end of life. We tried to determine the aggressiveness of end of life care at our Institute by evaluating the number of patients who received end-of-life chemotherapy. We also aimed to verify whether the recent ASCO recommendations were followed or not. Methods: Electronic medical records were examined to identify patients who received at least one cycle of palliative chemotherapy and who died either in the Oncology or in the Palliative Care unit of the ICS Maugeri hospital between January 2014 and December 2015. Results: 181 patients were included in the study. 22% (40 patients) of these received chemotherapy in the last 4 weeks, and 6% (10 patients) in the last 2 weeks of life. 45% (18) of patients who were actively treated in the last month of life began a new chemotherapeutic regimen within the same period of time. Recently diagnosed patients were more likely to be treated aggressively in their last weeks of life (chi-square test, p value = 0.007). 12% of patients (7 patients) who started a new chemotherapeutic regimen within 90 days of death had already received 3 or more previous regimens. Futhermore, 16% of them (19 patients) had an ECOG PS of 3 or 4 at the beginning of the last regimen. The median survival since the beginning of the last chemotherapeutic regimen was 63 days for patients with a PS of 1 or 2 and 32 days for patients with a PS of 3 or 4 (Logrank test, p = 0.005). Conclusions: Almost 1 patient out of 4 receives end-of-life chemotherapy at our institute. About 30% of our patients began a new chemotherapeutic regimen even though they were in compromised clinical conditions or did not respond to 3 or more previous regimens. Our data highlight a relevant abuse of active anticancer treatments; efforts should be done to reduce these figures and to focus on supportive care near the end of life.

Purpose: Several trials have suggested that intrahepatic chemotherapy increases the likelihood of response in advanced colon cancer patients, but has no significant impact on survival due to the development of extrahepatic metastases. We report our experience of combined hepatic intraarterial and systemic chemotherapy in advanced colorectal cancer patients. Methods: A group of 35 patients received intrahepatic FUDR (0.3 mg/kg per day for 14 days by continuous infusion), followed, after 1 week's rest, by systemic 5-FU and L-leucovorin (370 and 100 mg/m2 per day, respectively, both for 5 consecutive days). After another week off therapy, the combined intrahepatic and systemic regimen was repeated and cycles continued until disease progression. Results: Of 32 assessable patients, 17 (53.1%) had an objective response, while 8 (25%) had disease stabilization. Median time to progression (TTP) was 32 weeks (range 8–104 weeks), while the median overall survival was only 39 weeks (range 9–109 weeks). Incomplete liver perfusion was the only variable that showed a significant correlation with a poorer survival (P=0.046, log-rank test). Conclusions: Our results are in agreement with previous data suggesting a relative efficacy of such a treatment approach for advanced colon cancer patients. More thorough investigations are warranted, especially as an adjuvant treatment for selected high-risk patients.

The occurrence of thrombotic thrombocytopenic purpura (TTP) in cancer patients receiving chemotherapy has been well established; although this entity is rare, its clinical importance seems to be growing. We describe 3 cases of TTP developing in cancer patients receiving different chemotherapeutic regimens. Using a sensitive high-performance liquid chromatographic method, we evaluated the stable nitric oxide end products, nitrite and nitrate, in the plasma of these patients. Nitric oxide is one of the key components involved in maintaining the normal nonthrombogenicity of the vascular endothelium. In our 3 patients, we found increased nitrate titers that were substantially higher than those observed in patients with de novo TTP. The observed increased release of nitrate could be interpreted as the consequence of massive disruption of endothelial integrity, with consequent passive nitric oxide release in vivo, or an adaptive mechanism of the endothelium to compensate for diffuse microvascular occlusion. The 2 mechanisms may both be involved, but the normal titers of nitric oxide end products in de novo TTP suggest that the former mechanism is more important, at least in cancer chemotherapy-related TTP.

The outcome of patients with metastatic breast cancer (MBC) has clearly improved over the past decades and the proportion of women living with their disease for several years is increasing. However, the usefulness of multiple lines of treatment is still debated and under evaluation. The available data from both randomized trials and large retrospective series are reviewed and discussed in order to analyze management practices, with emphasis on potential prognostic and predictive factors for clinical outcome. At present, evidence-based medicine provides some support for the use of second-line and to a lesser degree and in selected cases, third-line chemotherapy in human epidermal growth factor receptor 2 (HER2) negative MBC. Beyond third-line treatment, messages from recently reported retrospective studies also suggest a clear potential gain for women receiving further therapies after disease progression, since each line can contribute to a longer survival. In HER2-positive disease, the data from observational and retrospective studies support a clinical benefit from the use of trastuzumab beyond disease progression and emerging evidences from randomized controlled trials are leading to the introduction of newer HER2-targeted therapies in multiple lines. The question ‘How many lines of treatment should we give patients?’ clearly needs further research through prospective, high-quality clinical trials, aiming for a better definition of factors with prognostic and predictive role. In the meantime, the ‘optimal’ treatment strategy should probably be to use as many therapeutic options as possible, either in sequence or combination, to keep the best efficacy/toxicity balance, considering MBC as a chronic disease.

Thermal ablative techniques have gained increasing popularity as safe and effective options for patients with unresectable solid malignancies. Microwave ablation has emerged as a relatively new technique with the promise of larger and faster ablation areas without some of the limitations of radiofrequency thermal ablation. Herein, we report our preliminary results on the feasibility and efficacy of thermal ablation for hepatocellular carcinoma (HCC) with a new 2.45-MHz microwave generator.Under ultrasound guidance 194 HCCs in 144 patients were treated through a percutaneous approach. The median diameter of lesions was 2.7 cm (range=2.0-11.0 cm); 68 lesions had a diameter greater than 30 mm. We used a microwave generator (AMICA-GEM, Apparatus for MICrowave Ablation) connected to a 14- or 16-gauge coaxial antenna endowed with a miniaturized sleeve choke to reduce back heating effects and increase the sphericity of the ablated area. Contrast-enhanced computed tomography scan was carried out one month after treatment, and then every three months to assess efficacy.Complete ablation was achieved in 94.3% of the lesions after a mean of 1.03 percutaneous sessions. For small HCCs (diameter3 cm) complete necrosis was obtained in 100%. Local tumor progressions were found in 10 treated lesions (5.1%) a median of 19.5 months after ablation. Minor complications occurred in 5.1% procedures. No deaths, or other major complications occurred.In our experience, the new device for microwave ablation proved to provide an effective and safe percutaneous ablative method, capable of producing large areas of necrosis.

The purpose of this study was the pharmacokinetic (PK) profile assessment in the serum of patients affected by hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) with drug-eluting beads.This study included 20 patients, 12 treated with DC Bead® and 8 with HepaSphere Microsphere®, preloaded with epirubicin. No patient randomization was used for the inclusion in one group or in the other. Peripheral blood samples were obtained from all patients after the treatment, until 24 hours past the procedure.The pharmacokinetic study showed low peak serum epirubicin concentrations with greater drug exposure for the DC Bead® group (p0.05). The highest drug concentration after microsphere injection was observed at 5 minutes in all 20 patients. In the time interval between 1 and 24 hours after TACE, persisting levels of epirubicin were detected in peripheral blood samples.A persistent and sustained drug elution for both types of microparticles was found.

Myelosuppression is a common dose-limiting toxicity of chemotherapy (CT). Hematopoietic growth factors such as granulocyte (G) or granulocyte-macrophage (GM) colony-stimulating factor (CSF) and erythropoietin (EPO) have improved the management of CT-induced neutropenia and anemia, respectively, but no totally satisfactory solution to treatment-related thrombocytopenia has entered clinical practice [9]. Although thrombocytopenia associated with conventional doses of CT rarely requires treatment, it is still a major cause of morbidity and mortality in cancer patients undergoing high-dose (HD) CT. Platelet (PLT) transfusions, which need to be given frequently after autologous circulating progenitor cell (CPC) transplantation, are expensive and associated with the risk of alloimmunization or infectious disease transmission. Interleukin (IL)-11 acts synergistically with IL-3, thrombopoietin, or stem cell factor to stimulate various stages of human megakaryocytopoiesis [3, 8, 11]. Cur

Sorafenib is the only therapy approved for advanced hepatocellular carcinoma no longer eligible for transcatheter arterial chemoembolization. Hepatic intra-arterial chemotherapy has been shown to be an effective and safe therapy for advanced hepatocellular carcinoma. Cetuximab has been administered intravenously to patients with advanced hepatocellular carcinoma, showing encouraging results in terms of its safety and toxicity profile.Our purpose was to evaluate the safety and feasibility of hepatic arterial chemotherapy with cetuximab, cisplatin and 5-fluoruracil for patients with advanced hepatocellular carcinoma, not responsive or not eligible for sorafenib therapy.From January 2010 to January 2011, 12 patients received a 2-day course of chemotherapy consisting of repeated daily hepatic arterial administration of 20 mg of cisplatin as 2-h infusion, 5-fluorouracil at 500 mg/m(2) as 5-h infusion and cetuximab 500 mg/m(2) as 12-h infusion. Cycles were repeated every 14 days.After a mean of four months of therapy, computed tomography revealed five partial responses, five cases of stable disease and two of progressive disease. The toxicity profile was favourable, with no G4 gastrointestinal, hematologic or skin side-effects, or severe deterioration of liver function.Hepatic intra-arterial chemotherapy with cetuximab is a safe and feasible treatment for advanced hepatocellular carcinoma, with promising results in patients with initial poor prognosis.

This study was aimed at determining: (a) the degree of mobilization of peripheral blood hematopoietic progenitors (PBSC) induced by a single course of standard-dose chemotherapy (CT) followed by G-CSF and the feasibility and safety of the administration of multiple courses of intensified CT with repeated PBSC reinfusions; (b) the relationship between the number of mononuclear cells (MC) in S-phase of the cell cycle (as evaluated by DNA flow cytometry, FCM), the CRT-GM and the CD34(+) cells in the leukapheresis product. Six patients with metastatic breast cancer received a course of standard FEC (5-FU 600 mg/m(2), epirubicin 75 mg/m(2), cyclophosphamide, CTX, 600 mg/m(2), day 1) followed by G-CSF (5 mu g/kg twice a day, from day 3 until leukapheresis), which served as both initial treatment for their disease as well as the PBSC mobilization technique. Collected PBSC were fractionated and reinfused, without G-CSF, following each of further 5 subsequent intensified FEC (HD-FEC: 5-FU 750 mg/m(2), epirubicin 100 mg/m(2), CTX 1,000 mg/m(2)) courses planned at 21-day intervals. The individual hematopoietic reconstitution curves showed superimposable profiles for all patients, and the leukaphereses were performed between days 7 and 10 after the first CT course. A median of 18.8x10(9) (10.4-35.6) MC, 9.3 (2.6-23.3) CD34(+) cells x 10(6)/kg body weight and 9.8 (1.6-27.3) CFU-GM x 10(4)/kg body weight were collected from each patient (with 1 or 2 phereses). All patients received the planned 5 courses of HD-FEC followed by PBSC reinfusion, without experiencing haematological cumulative toxicity >WHO grade 3 for WBC and >grade 2 for PLT. No >grade 3 non-hematological toxicity was recorded. There were no treatment-related delays in CT administration so that the delivered average relative dose-intensity (ARDI) was 1.65. A good correlation was seen between the percentage of MC in S-phase and the number of CFU-GM (R(2)=0.566, p

Objectives. The clinical, laboratory and radiologic features at diagnosis of 684 newly diagnosed patients with monoclonal gammopathy were revised in order to underline the differences between monoclonal gammopathies of undetermined significance (MGUS) and stage I multiple myeloma (MM). Design. Patients were screened for inclusion in a prospective controlled protocol for treatment of MM. Those having serum or urine monoclonal component (MC) were diagnosed as MM when they demonstrated osteolysis and/or bone marrow plasma cells (BMPC) > 20%; patients not fulfilling these criteria were considered MGUS. Setting. Patients were recruited from 24 general or university hospitals from the departments of internal medicine, haematology and medical oncology. Subjects. Seven-hundred-and-fifty were enrolled between January 1986 and March 1990; 684 (343 MGUS and 341 MM) were able to be evaluated for this study and 78 were stage I MM. Interventions. Complete clinical, radiologic and laboratory work-up was carried out at the referral centres. Main outcome measures. The main outcome expected was the confirmation that BMPC > 20% could reliably differentiate stage I MM from MGUS. Results. At a median follow-up of 36 months (minimum follow-up: 18 months), MGUS had a lower progression rate to overt MM, longer overall survival and different causes of death than stage I MM. Further differences concerned erythrocyte sedimentation rate (28 vs. 47, P < 0.001), per cent reduction of normal immunoglobulin (86 vs. 60%, P < 0.001), serum MC (1.6 vs. 2.2 g dl−1, P < 0.001) and thymidine kinase level (3.3 vs. 4.5 mU ml−1, P < 0.05). Conclusions. The study suggests that 20% BMPC can be taken as a safe cut-off point at which to differentiate MGUS from early MM and outlines a few simple parameters which can be of diagnostic aid.

Information on the kinetics of bone marrow (BM) myeloid precursors (BMMP) is required for integrating cancer chemotherapy with granulocyte-macrophage colony-stimulating factor (rhGM-CSF), with the aim of reducing neutropenia. Using bivariate flow-cytometric analysis of the in vivo incorporation of bromode-oxyuridine (BUDR) vs DNA content we have studied the kinetics of BMMP in 21 patients with SCLC during the first of six chemotherapy courses (etoposide, epirubicin, and cis-platinum, days 1-3, every 21 days), given alone (eight patients) or followed by rhGM-CSF (10 micrograms/kg/day s.c., days 4-14) as BM rescue (eight patients) or both preceded (days -17 to -7, as BM priming) and followed by rhGM-CSF (five patients). At 11-14 days after the start of these therapies there was an increase in the baseline proliferative activity of proliferating BMMP and a shortening in the time needed by the metamyelocyte to mature and to leave the marrow. Both effects were greater and were maintained to a significantly greater degree a week later in patients who received chemotherapy plus rhGM-CSF rescue than in those who received chemotherapy alone or rhGM-CSF priming alone. At day 11-14 the pretreatment median cell production rate of pBMMP was increased by 340%, 150%, and 183% and the maturation time was reduced by 80%, 45%, and 57%, respectively, in the three groups. A week later, the corresponding figures were 206%, 111%, and 157% and 50%, 18%, and 45%. Hence, an identical rhGM-CSF schedule is more effective in increasing the neutrophil production by BMMP when given following chemotherapy as BM rescue than before it as BM priming. In both the rescue and the priming schedule, the increase in proliferative activity of BMMP just at the end of rhGM-CSF stimulation was linked to both an increase in the labeling index and a reduction in duration of S-phase (TS), while a week later it was linked solely to reduction in TS. This could actually reduce one of the two kinetic targets of subsequently administered cytostatics, i.e., a high LI and a long time spent in S phase. From this study, accurate kinetic data can be obtained with the in vivo BUDR technique that are useful in scheduling rhGM-CSF.

Image-guided transcatheter hepatic chemoembolization (TACE) is accepted worldwide as an effective treatment for patients with unresectable hepatocellular carcinoma (HCC) and for adequate preservation of liver function. Although considered relatively safe, TACE has been associated with several complications. The aim of this study was to determine the prevalence of the complications associated with TACE therapy and to correlate it with certain risk factors, either well-known or not yet evaluated.A total of 330 chemoembolization procedures performed in 170 patients (117 males and 53 females) over a period of 64 months were retrospectively analysed. Among the patients, 123 had hepatocellular carcinoma, 10 had intrahepatic cholangiocarcinoma and 37 had hepatic metastases. The variables considered were: tumour histotype, bilioenteric anastomosis, previous or combined treatment with radiofrequency thermal ablation, antibiotic prophylaxis, chemotherapeutic agents, use of new drug-eluting microspheres, comorbidities such as diabetes, patient age and the presence of vascular anatomical variations.A total of 30 complications occurred in 27 procedures. The total complication rate per procedure was 9.1% and approximately 75% of patients had postembolization syndrome. The difference in the prevalence of complications was statistically significant in the group of diabetic patients (13.3%) compared to the remaining patients (6.3%) (p = 0.002) and in patients with biliary stents (25%) compared to those without stents (7.75%) (p = 0.027).These data show that diabetes mellitus and the presence of bilioenteric anastomosis are risk factors for developing complications after TACE. The use of new drug-eluting microspheres did not increase the risk of complications.

In many cell systems, resistance to cytotoxic drugs is acquired by the amplification and/or overexpression of the multidrug resistance (mdr) gene, which codes for the glycoprotein, p170 (P-glycoprotein). Moreover, in a variety of malignant tumours there is increasing evidence of the relationship between the DNA ploidy pattern of patients and their prognosis. In this study we aimed to evaluate these two potential indicators of constitutive drug resistance in human colorectal tumours. We employed a method to quantify simultaneously, on a per cell basis, mdr gene expression (using the C219 monoclonal antibody for P-glycoprotein) and nuclear DNA content with high-resolution bivariate flow cytometry. The study was performed on a human colon-carcinoma-derived cell line (LoVo) and its doxorubicin-resistant variant (LoVo/Dx) and on tumour samples and adjacent normal mucosa from 35 untreated patients with colon cancer. The P-glycoprotein was found in both LoVo and LoVo/Dx cells with levels slightly lower in the parental than in the resistant subline (P, NS). A multi-drug-resistant specific probe for mRNA expression and Western blot assay confirmed the specificity of p170 expression. All of the colon cancer with unimodal diploid DNA distribution and all the normal colonic mucosa samples showed P-glycoprotein expression, without a statistically significant difference in median values between tumours and normal samples. Tumours with bimodal DNA distribution showed median values of P-glycoprotein expression of their hyperdiploid cell clones significantly higher than those of their diploid clones and of the tumours with unimodal DNA distribution (P less than 0.005). Our results show the feasibility of bivariate flow-cytometric analysis of P-glycoprotein expression and DNA content on clinical material and support the hypothesis that the MDR phenotype and DNA ploidy together may influence the biological behaviour of colon cancer in vivo.

The expression of the p170 multidrug resistance protein by bone marrow plasma cells (BMPC) was assessed at clinical presentation in 53 patients with multiple myeloma (MM) using the C219 monoclonal antibody. Twenty-two of the 53 (41 per cent) patients had variable aliquots (1–60 per cent, median = 6 per cent) of p170 + BMPC by immunocytochemistry. Five of 10 patients studied using bivariate flow cytometry had both diploid and hyperdiploid (DNA index ranged from 1·2 to 1·5) BMPC with hyperdiploid clones having significantly greater p170 expression than diploid ones. Of the 37 patients evaluated for a response, 20 (54 per cent) had responded to induction chemotherapy. The presence of p170+ BMPC was a negative indicator for achieving response. The response rate was 75 per cent for p170- and 25 per cent for p170 + cases (p< 0·01), with no difference on the basis of treatment schedule (melphalan and prednisone, 24 patients; peptichemio, vincristine and prednisone, 13 patients). No difference in response and survival duration was found between p170+ and p170- patients. In six of nine patients studied both at diagnosis and following induction chemotherapy the p170+ BMPC% increased irrespective of the type of treatment or outcome.

Intrahepatic cholangiocarcinoma (ICC) is a rare life-threatening disease, whose only treatment with potential for cure is surgical resection. However, only 27% of patients at most are suitable for surgery when first diagnosed. For patients with unresectable disease, therapeutic options are chemotherapy or chemoradiation. We evaluated the feasibilty and safety of oxaliplatin-eluting microspheres transarterial chemoembolization (OEM-TACE) associated with chemotherapy (ChT) in patients affected by unresectable ICC. Between December 2005 and May 2008 we treated nine patients (six female and three male) with unresectable ICC. All patients had undergone OEM-TACE associated with chemotherapy with oxaliplatin and gemcitabine. A retrospective comparison was carried out with a historical group of 11 patients treated with ChT only, estimating the prevalence of adverse effects and the median survival of the two groups. A total of 30 TACEs were performed during the observational time (ranging from one to seven procedures per patient). OEM-TACEs were followed by few adverse effects (AEs), without G4 AEs, according to CTACAE 3.0. According to RECIST criteria, 44% (4/9) of patients achieved partial responses and 56% (5/9) stabililization of disease. Overall survival analysis in the two groups showed a significantly increased survival in patients treated with ChT and OEM-TACE, with respect to those treated with ChT (30 vs. 12.7 months; p = 0.004). In conclusion, in our experience OEM-TACE associated with ChT in the treatment of advanced unresectable ICC is a safe and feasible treatment causing no major adverse events. Although RECIST criteria can underestimate the rate of responses in patients treated with locoregional therapies, we achieved very encouraging results. A randomized multicentric trial is warranted to assess the actual superiority of OEM-TACE associated with ChT compared to conventional chemotherapy.

EUE cells adapted to grow for long times in a hypertonic medium have a longer cell cycle than those growing in isotonic medium. To elucidate whether this lengthening involves specific cycle phases to differing extents, the expression of two cycle-related protein, PCNA and statin, was studied by dual parameter flow cytometry of indirect immunofluorescence protein labelling and DNA content. In isotonic medium, most cells, in all the cycle phases, were PCNA positive; in contrast, PCNA negative cells and statin positive cells were very few in number and only fell in the G0/l range of DNA contents. In hypertonic medium, the frequency of PCNA positive cells was lower, and that of statin positive cells higher, than in isotonic medium, particularly in the Go/1 range of DNA contents: this suggests that a G0 block occurs under long-term hypertonic stress. Consistently, dual parameter flow cytometric measurement of BrdUrd immunofluorescence labelling and DNA content showed that fewer cells entered S phase in hypertonic medium and their progression through the S phase was slower; evidence was also found for the occurrence of a G2 block. These kinetics changes were fully reversible in isotonic medium, thus indicating the adaptive nature of the EUE response to hypertonicity.

The authors investigated the relationship between flow cytometric DNA index (DI, defined as the ratio of the DNA content of malignant cells to that of normal cells) and other prognostic factors (grade and stage, anatomical site, age and sex) with the survival of 115 patients with colorectal cancer. Multiple biopsy specimens from 62 patients were taken during colonoscopy before surgery. Additional samples from 53 patients were obtained from paraffin-embedded material. All patients were treated with surgery only. Fresh-frozen material gave higher incidence of DNA aneuploidy than paraffin-embedded material (79% versus 41%). The patients with DNA diploid tumors (DI = 1) had a better overall survival than those with DNA aneuploid tumors (DI = 1). Among DNA aneuploid tumors, those with DI greater than 1.2 (excluding DI = 2) were worse than those with DI = 1.2 (excluding DI = 1) and DI = 2. Cox's regression analysis showed that pathologic stage was more important for prognosis than DNA index, whereas age, sex, histologic grade, and anatomic site were removed from the analysis as not relevant for prognosis. Relative risk of death (RR), in reference to patients with DI = 1 and Stages A + B (RR = 1), were RR = 1.8 for patients with carcinomas with Stage C. RR = 2.7 for patients with carcinomas with DNA near-diploid and DNA tetraploid tumors. RR = 3.5 for those with DI greater than 1.2 (excluding DI = 2), and RR = 8.0 for those with Stage D. These data indicate that flow cytometrically evaluated DI values have a relevant independent power for predicting the clinical outcome of colorectal cancer patients.

Bivariate flow cytometric analysis of the cell proliferation-associated nuclear protein, identified as the “proliferating cell nuclear antigen” (PCNA)/cyclin and of nuclear DNA content, was performed in quiescent and mitogen-stimulated human peripheral blood lymphocytes, in EUE (human embryonic epithelium) cells, before and after a long-term exposure to a hypertonic (HT) medium, in 4 human leukemic cell lines and in fresh bone marrow (BM) cells from 10 patients with untreated acute non-lymphoblastic leukemia (ANLL). The PCNA/cyclin was detected using both an autoantibody extracted from sera of systemic lupus erythematosus patients and the recently produced mouse monoclonal antibody (MoAb) IgG, named 19F4. The distribution of cells in the different phases of the cycle and the percentage of S-phase cells were obtained in duplicate samples, by DNA flow cytometry (FCM) and by dual parameter FCM of DNA content and bromodeoxyuridine (BUDR) incorporation. In all cell types, the non-specific cytoplasmic background fluorescence was significantly lower with the MoAb compared to that obtained with the polyclonal Ab. The percentage of PCNA-positive cells (both with the autoantibody and the 19F4 MoAb) was always higher than that of S-phase cells by DNA FCM and of BUDR-labeled cells. The pattern of PCNA-expression in both normal proliferating cells and acute leukemia cells, showed that most G0/G1 cells did not express significant amounts of PCNA; an increase in PCNA immunofluorescence was found in late G1 cells, and further increases were observed in S- and G2-M phase cells. PCNA/cyclin, as revealed both with autoantibodies and with the 19F4 MoAb, is associated with all actively or potentially dividing (i.e. G1, S and G2-M) cells thus identifying the proliferative cellular compartment. Combined with the use of multiparameter FCM techniques, the PCNA immunolocalization offers a useful tool to study cell kinetics in normal and leukemic human cell populations.

From October 1983 to December 1988, 84 consecutive adult patients with acute non-lymphoblastic leukaemia (ANLL; median age = 51 yr) were uniformly treated to induce remission (CR) with intravenous vincristine and cytarabine sequentially followed by daunomycin and infusion cytarabine. From October 1983 to December 1985 consolidation was non-intensive (2 courses with the same drugs used for induction) (protocol ANLL83: 27 patients, median age = 45). From January 1986 to December 1988 consolidation was intensive (4 courses of vincristine and cytarabine sequentially followed by etoposide plus thioguanine or amsacrine) (protocol ANLL86: 57 patients, median age = 57). Excluding early deaths, the CR rate was 71.6%. Median CR, responsive patient survival and overall survival were 11.1, 15.3 and 8.5 mo, respectively. For protocol ANLL83 and ANLL86, median CR was 8.7 and 13.2 mo (P less than 0.05) and median survival was 13.1 and 16.9 mo (P less than 0.05) for responders and 8.0 and 9.2 mo (P not significant) for all patients. Intensive consolidation including drugs not previously used for induction seems to prolong CR duration and responder survival in adult ANLL.

Data on the long-term treatment of myeloma bone disease with bisphosphonates are scanty. In a prospective pilot trial we evaluated the effect of long-term parenteral administration of dichloromethylene bisphosphonate (Clodronate), in addition to standard chemotherapy, in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2-8) of Clodronate: 300 mg/day i.v. for seven days followed by 100 mg/day i.m. for 10 days, administered at a mean interval of 4 months (range 3-6). The median follow-up was 24 months (range 8-36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits; these effects were maintained throughout the follow-up. In three hypercalcemic episodes serum calcium became normal after 2-5 days of treatment with Clodronate. No toxic or side effects were noticed. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients (p less than 0.001) in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures (p less than 0.001). Supportive Clodronate therapy contributes significantly in controlling the progression of myeloma bone disease.

Hepatocellular carcinoma is one of the most common malignancies in the world, with the liver being the second most frequently involved organ in metastatic disease. Although the gold standard treatment for malignant liver disease is surgical resection, only few patients can undergo such an intervention. This explains the current great interest in various loco-regional therapies, of which radiofrequency thermal ablation (RFA) is the most common. To date, only a few studies have evaluated the complications associated with this treatment. The aim of this study was to determine the rate of complications, divided into major and minor, in patients treated with RFA. A total of 373 hepatic lesions in 250 patients were treated with 292 sessions of percutaneous ultrasound-guided RFA. According to our data, ten patients (4%) had major, complications, twelve patients (4.8%) had minor complications, no deaths occurred. Around 30% of patients had a body temperature increase of up to 38 'C. All complications, except one, were treated with nonsurgical therapies. One patient with massive hemoperitoneum required surgery. In conclusion, percutaneous RFA is a loco-regional therapy associated with a low incidence of side-effects and a negligible risk of death.

The medical treatment of non-small-cell lung cancer (NSCLC) has progressively changed since the introduction of “targeted therapy”. The development of one of these molecular drug categories, e. g., the epidermal growth factor receptor (EGFR) tyrosine-kinase (TK) selective inhibitors, such as the orally active gefitinib and erlotinib, offers an interesting new opportunity. The clinical response rates obtained with their employment in unselected patient populations only account for approximately 10%. Because of this, over the last two years numerous studies have been performed in order to identify the patient subsets that could better benefit from these agents. Not only patient characteristics and clinical-pathological features, such as never-smoking status, female gender, East Asian origin, adenocarcinoma histology, bronchioloalveolar subtype, but also molecular findings, such as somatic mutations in the EGFR gene, emerge as potentially useful prognostic and predictive factors in advanced NSCLC. Further, specifically designed clinical trials are still needed to completely clarify these and other open issues that are reviewed in this paper, in order to clarify all the interesting findings available in the clinical practice.

Patients with advanced cancer are known to have dysfunctions of the immune system. Dendritic cells (DCs) are potent antigen-presenting cells that play a crucial role in antitumor immune response. At least two peripheral blood DC subsets have been described: myeloid-derived CD11c+CD123- DCs (DC1) and lymphoid-derived CD11c-CD123+ DCs (DC2). Upon interaction with T cells, DC2 seemed to support the generation of a Th2 response, while DC1 predominantly prime a Th1 response. Our study was aimed at investigating the number of circulating DCs, and their subsets and functions in 32 patients with advanced breast cancer that achieved an objective response after a standard-dose sequential chemotherapy (CT), compared to 40 healthy controls. Circulating DC subsets and intracellular cytokine production in CD4+ and CD8+ subsets were analyzed using a tri-color flow cytometry assay. DC subsets were identified in peripheral blood, calculating their percentage gated as lin- HLA-DR+ and using BDCA-1, BDCA-2 and BDCA-3 specific markers, as DC1 and DC2 according to expression of CD11c and CD123, respectively. Intracellular cytokines were evaluated in CD4+(Th1 and Th2) and CD8+ (Tc1 and Tc2) T lymphocytes. The mean percentage of BDCA-1+BDCA-2+BDCA-3 was similar to that of DC1+DC2 (p=ns). The mean percentage of DCs and DC1/DC2 ratio were slightly decreased before CT in cancer patients compared with healthy controls (p=ns). After CT, the percent-age of DC1 further decreased (p=0.02). The production of IFN-gamma (Th1 and Tc1) significantly decreased (p0.03) while that of IL-4 (Th2 and Tc2) increased (p=0.04), thus confirming a shift toward a Th2 CD4 and Tc2 CD8 phenotype and the predominance of type 2 DCs. Our results could help clarify the mechanisms of the immune response or immune status of patients with advanced breast cancer that undergo cytotoxic CT and contribute to improve the selection of potential candidates for active immunotherapy trials.

Using a commercial ELISA assay, we evaluated circulating VEGF and bFGF levels in 203 consecutive patients with solid tumors, and sought a correlation between them and with the grade of anemia. Serum VEGF values were within the normal range in 128 patients (63.05%), with a mean value of 675.04 pg/ml (median, 571.00; range, 0-2796.54). The analysis of VEGF values per tumor group did not provide any statistically significant difference. Regarding bFGF, 143 patients (70.44%) had measurable, and thus abnormal, bFGF values. Overall, mean bFGF serum value was 57.14 pg/ml (median, 8.30; range, 0-4334.71), with the highest bFGF levels found in breast carcinoma patients. As expected, a large number of our patients was fairly anemic, mean hemoglobin level being 11.47 g/dl (median, 11.30; range, 7.1-19.20), the lowest titers being observed in prostate carcinoma patients. No statistically significant correlation was found between serum VEGF and hemoglobin values (r=0.004) but a significant negative correlation was seen between serum bFGF and hemoglobin (r=-0.22, p