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The object of this work was to determine the influence of trimming hooves on claw growth and claw reduction of Mediterranean Italian Buffalo cows. Data from Mediterranean Italian Buffalo cows of two commercial dairy herds in the province of Salerno were used in this study. Buffalo cows were divided into three groups according to the presence of absence of abnormal claw growth and trimming claws. For two groups of animals, five hoof measurements (the height of the heel, the length and width of the sole, the length of the foot wall and the perpendicular distance between the coronary band and the sole) were collected each four months. Whereas, hooves were trimmed to the third group of buffaloes and claw measurements were taken before and after the trimming procedure. Hoof growth and its reduction was monitored for one year by collecting each four months the same measurements as the other two groups of animals. The results showed significant differences in hoof growth between animals with hoof problems and animals without hoof problems or with trimmed hooves. [ABSTRACT FROM AUTHOR]

The main purpose of this work was to identify the correct functional conformation of hooves of Italian Mediterranean buffalo cows through the identification of buffaloes that showed no defects in perpendicularly foot placed, or claw malformations. To achieve this goal two groups of animals in two commercial herds located in the Piana del Sele (Salerno) were monitored for a year. Every four months five claw measurements were collected for each animal in each group (height of the heel, length and width of the sole, length of the wall and the perpendicular distance between the coronary band and the sole). The work has provided index for the detection of ideal claws in Italian Mediterranean Buffalo cows. [ABSTRACT FROM AUTHOR]

Background: High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen.Methods: Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.Results: Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b.Conclusions: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present. [ABSTRACT FROM AUTHOR]

Background: Paediatric acute B-cell lymphoblastic leukaemia is the most common cancer of the paediatric age. Although the advancement of scientific and technological knowledge has ensured a huge step forward in the management of this disease, there are 15%-20% cases of recurrence leading to serious complications for the patient and sometimes even death. It is therefore necessary to identify new and increasingly personalised biomarkers capable of predicting the degree of risk of B-ALL in order to allow the correct management of paediatric leukaemia patients., Methods: Starting from our previously published results, we validate the expression level of LINC00958 in a cohort of 33 B-ALL and 9 T-ALL childhood patients, using in-silico public datasets as support. Expression levels of LINC00958 in B-ALL patients stratified by risk (high risk vs. standard/medium risk) and who relapsed 3 years after the first leukaemia diagnosis were also evaluated., Results: We identified the lncRNA LINC00958 as a biomarker of B-ALL, capable of discriminating B-ALL from T-ALL and healthy subjects. Furthermore, we associated LINC00958 expression levels with the disease risk classification (high risk and standard risk). Finally, we show that LINC00958 can be used as a predictor of relapses in patients who are usually stratified as standard risk and thus not always targeted for marrow transplantation., Conclusions: Our results open the way to new diagnostic perspectives that can be directly used in clinical practice for a better management of B-ALL paediatric patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Altieri, Buono, Lanzilli, Mirabelli, Cianflone, Beneduce, De Matteo, Parasole, Salvatore and Smaldone.)

Research Question: How do clinical rectovaginal examination and transvaginal ultrasound examination perform in the diagnosis of parametrial infiltration in patients with endometriosis?, Design: This was a multicentre prospective observational study. Patients with suspected deep endometriosis at clinical examination and/or at ultrasound evaluation and scheduled for surgery were included. Following multicentre multidisciplinary meetings, consensus was obtained on terms and methodology to define the parametrium at pelvic anatomy, ultrasound and surgery. Sensitivity, specificity, accuracy, and positive and negative likelihood ratios were calculated for clinical and ultrasound examinations with respect to surgery., Results: In total, 195 women were selected for the present study and 164 were included in the analysis. Ultrasound examination had good to high specificity (>80%) for all parameters, except the left lateral parametrium (78.8%). The sensitivity of ultrasound examination was good to high for fixity of the right and left ovaries, uterosacral ligaments, retrocervix and rectovaginal space; and low for the anterior and lateral parametria, vagina, bladder and bowel. Clinical examination had good to high specificity for fixity of the left ovary, anterior parametrium, right uterosacral ligament, retrocervix and vagina; and low specificity for fixity of the right ovary, lateral parametrium, left uterosacral ligament and rectovaginal space. The sensitivity of clinical examination was good for the uterosacral ligaments and rectovaginal space, and low for the remaining parameters., Conclusion: Ultrasound examination provided good specificity for all the parameters, but sensitivity was low for the anterior and lateral parametria. Clinical examination provided good specificity for the anterior and posterior parametria, but sensitivity was low for the anterior and lateral parametria. Further prospective studies are needed to validate this methodology and confirm the results., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

(1) Background: Preeclampsia (PE) usually presents with hypertension and proteinuria, related to poor placentation. Reduced maternal-fetal immunological tolerance is a possible trigger of inadequate placentation. Aberrant antigen expression of HLA-DR has been observed in the syncytiotrophoblast of PE patients. In this study, we analyzed plasma levels of Human Leukocyte Antigen (HLA)-DR+ syncytiotrophoblast-derived extracellular vesicles (STEVs) during the three trimesters of pregnancy in relation to PE onset. (2) Methods: Pregnant women underwent venous blood sampling during the three trimesters. STEVs were collected from plasma via ultracentrifugation (120,000 g) and characterized by Western blot, nanotracking analysis and flow cytometry for the expression of Placental Alkaline Phosphatase (PLAP), a placental-derived marker, and HLA-DR. (3) Results: Out of 107 women recruited, 10 developed PE. STEVs were detected in all three trimesters of pregnancy with a zenith in the second trimester. A significant difference was found between the non-PE and PE groups in terms of plasma levels of HLA-DR+ STEVs during all three trimesters of pregnancy. (4) Conclusions: More research is needed to investigate HLA-DR+ as a potential early marker of PE.

Acute leukemia is the most common pediatric cancer. In most cases, this disease results from the malignant transformation of either the B-cell (B-ALL) or, less frequently, T-cell progenitors (T-ALL). Recently, a marked overexpression of KCTD15, a member of the emerging class of the potassium (K) channel tetramerization domain-containing proteins (KCTDs) has been detected in both patients and continuous cell lines as in vitro model systems. Because there is growing evidence of the key, yet diversified, roles played by KCTDs in cancers, we here report an exhaustive analysis of their expression profiles in both B-ALL and T-ALL patients. Although for most KCTDs, no significant alterations were found in these pathological states, for some members of the family, significant up- and down-regulations were detected in comparison with the values found in healthy subjects in the transcriptome analysis. Among these, particularly relevant is the upregulation of the closely related KCTD1 and KCTD15 in T-ALL patients. Interestingly, KCTD1 is barely expressed in both unaffected controls and B-ALL patients. Therefore, not only does this analysis represent the first study in which the dysregulation of all KCTDs is simultaneously evaluated in specific pathological contexts, but it also provides a promising T-ALL biomarker that could be suitable for clinical applications.

Background: Long non-coding RNAs are RNAs longer than 200 bps that do not encode any proteins and are able to alter gene expression by acting on different steps of regulation, including DNA methylation and chromatin structure. They represent a class of biomarkers of crescent interest in the hematologic and oncologic fields. Recent studies showed that the expression levels of specific lncRNAs correlate with the prognosis of paediatric patients with Acute Lymphoblastic Leukaemia., Methods: We used NGS approaches to analyse the transcriptome of 9 childhood B-ALL patients and 6 childhood T-ALL patients, in comparison with B and T healthy lymphocytes from cord blood. We validate our findings both ex vivo, in a different cohort of 10 B-ALL and 10 T-ALL patients, and in silico using public datasets., Results: We characterised the lncRNA landscape for B-ALL, T-ALL, healthy B, and T cell progenitors. From the characterised signature, we selected candidate lncRNAs able to discriminate not only B-ALL and T-ALL from healthy subjects but also between the two types of leukaemia, and subsequently validated their potential as a diagnostic tool in an additional cohort of paediatric patients. We confirmed our finding with open access transcriptomic data, comparing ALL lncRNAs with AML lncRNA landscape as well. Finally, expression correlation analyses of T-ALL selected lncRNA biomarkers suggested a possible role in lymphocyte activation and the β-catenin signalling pathway for AC247036.1 and involvement in hedgehog signalling for HHIP-AS1., Conclusions: Our work identified a lncRNA signature discriminating paediatric B-ALL and T-ALL from healthy subjects, between them and from AML. This study provides the keystone to future clinical studies determining the theragnostic value of the characterised long non coding transcriptome panorama in a clinical setting for childhood patient management., (© 2022. The Author(s).)

Background: Surgical exploration remains the gold standard for evaluating the extension of disease and predicting resectability. A laparoscopy-based scoring model was developed by Fagotti and colleagues in 2006 and updated in 2015, based on the intraoperative presence or absence of some specific cancer features. The model proved an overall accuracy rate of 77% to 100% and is considered the reference test for assessing resectability in our institution., Objective: The primary aim of the study was to analyze the agreement between preoperative ultrasound examination and laparoscopic findings in assessing the extension of intraabdominal disease using 6 parameters described by Fagotti's score., Study Design: This was a prospective single-center observational study. Between January 2019 and June 2020, consecutive patients with clinical or radiological suspicion of ovarian or peritoneal cancer were assessed with preoperative ultrasound examination and assigned a score based on the 6 Fagotti score parameters (great omentum, liver surface, lesser omentum/stomach/spleen, parietal peritoneum, diaphragms, bowel disease). Presence of mesenteral retraction of the small bowel and miliary carcinomatosis on the serosa were also evaluated. Each parameter was correlated with laparoscopic findings. Concordance was calculated between ultrasound and laparoscopic parameters using Cohen's kappa., Results: Cohen's kappa ranged from 0.70 to 0.90 for carcinomatosis on the small or large bowel, supracolic omentum, liver surface, and diaphragms. Cohen's kappa test was lower for carcinomatosis on the parietal peritoneum (k=0.63) and on the lesser omentum or lesser curvature of the stomach or spleen (k=0.54). The agreement between ultrasound and surgical predictive index value (score) was k=0.74. For the evaluation of mesenteral retraction and miliary carcinomatosis, the agreement was low (k=0.57 and k=0.36, respectively)., Conclusion: The results of ultrasound and laparoscopy in the assessment of intraabdominal tumor spread were in substantial agreement for almost all the parameters. Ultrasound examination can play a useful role in the preoperative management of patients with ovarian cancer when used in dedicated referral centers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate the functional outcomes of nerve-sparing surgery for deep infiltrating endometriosis (DIE) with or without posterolateral parametrectomy., Methods: A multicenter, observational, retrospective, cohort study was performed including all symptomatic women who underwent nerve-sparing laparoscopic excision of DIE and preoperative and postoperative assessment of functional outcomes through validated questionnaires between April 2019 and March 2020. Women with posterolateral parametrial DIE (P-group) and women with no parametrial involvement (NP-group) were compared in terms of preoperative and postoperative functional outcomes related to pelvic organs assessed through validated questionnaires (KESS and GIQLI for bowel function, BFLUTS for urinary function, and FSFI for sexual function); pain symptoms at 3-month follow up assessed through an 11-point visual analogue scale (VAS) for dyschezia, dysmenorrhea, dyspareunia and chronic pelvic pain; surgical outcomes; and rate of urinary voiding dysfunction at 3-month follow up., Results: One-hundred patients were included: 69 in the P-group and 31 in the NP-group. Preoperative and postoperative values of questionnaires, pain symptoms, and postoperative complication rates were comparable between the two groups, except for postoperative dyspareunia and sexual dysfunction, which were statistically higher in the P-group. Only patients in the P-group experienced urinary voiding dysfunction, but no statistical significance was reached (P = 0.173)., Conclusion: Posterolateral parametrectomy for DIE appears to be associated with a higher risk of postoperative dyspareunia and sexual dysfunction., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80-85%. However, 15-20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0-21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission ( n = 13) or reducing MRD levels ( n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5-59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

Like other KCTD proteins, KCTD15 is involved in important albeit distinct biological processes as cancer, neural crest formation, and obesity. Here, we characterized the role of KCTD15 in different physiological/pathological states to gain insights into its diversified function(s). The silencing of KCTD15 in MLL-rearranged leukemia models induced attenuation of the NF-κB pathway associated with a downregulation of pIKK-β and pIKB-α. Conversely, the activation of peripheral blood T cells upon PMA/ionomycin stimulation remarkably upregulated KCTD15 and, simultaneously, pIKK-β and pIKB-α. Moreover, a significant upregulation of KCTD15 was also observed in CD34 hematopoietic stem/progenitor cells where the NF-κB pathway is physiologically activated. The association between KCTD15 upregulation and increased NF-κB signaling was confirmed by luciferase assay as well as KCTD15 and IKK-β proximity ligation and immunoprecipitation experiments. The observed upregulation of IKK-β by KCTD15 provides a novel and intriguing interpretative key for understanding the protein function in a wide class of physiological/pathological conditions ranging from neuronal development to cancer and obesity/diabetes., (© 2021. The Author(s).)

Background: Long non-coding RNAs (lncRNAs) represent a diverse class of RNAs involved in the regulation of various physiological and pathological cellular processes, including transcription, intracellular trafficking, and chromosome remodeling. LncRNAs deregulation was linked to the development and progression of various cancer types, such as acute leukemias. In this context, lncRNAs were also evaluated as a novel class of biomarkers for cancer diagnosis and prognosis. Here, we analyzed TEX41 in childhood B cell acute lymphoid leukemia (B-ALL)., Methods: Total RNA was extracted from pediatric B-ALL patients (at diagnosis and after induction of therapy) and from healthy subjects. Total RNA was also extracted from different leukemia cell line models. The expression level of TEX41 was evaluated by q-RT-PCR. Also, the dataset deposited by St. Jude Children's Research Hospital was consulted. Furthermore, the silencing of TEX41 in RS4;11 cell line was obtained by 2'-Deoxy, 2'Fluroarabino Nucleic Acids (2'F-ANAs) Oligonucleotides, and the effect on cell proliferation was evaluated. Cell cycle progression and its regulators were analyzed by flow cytometry and immunoblotting., Results: We exploited the St Jude Cloud database and found that TEX41 is a lncRNA primarily expressed in the case of B-ALL (n = 79) while its expression levels are low/absent for T-cell ALL (n = 25) and acute myeloid leukemia (n = 38). The association of TEX41 with B-ALL was confirmed by real-time PCR assays. TEX41 disclosed increased expression levels in bone marrow from patients with B-ALL at diagnosis, while its expression levels became low or absent when retested in Bone Marrow cells of the same patient after 1 month of induction therapy. Also, silencing experiments performed on RS4;11 cells showed that TEX41 downregulation impaired in vitro leukemic cell growth determining their arrest in the G2-M phase and the deregulation of cell cycle proteins., Conclusions: Our findings highlight that TEX41 is an upregulated lncRNA in the case of B-ALL and this feature makes it a novel potential biomarker for the diagnosis of this leukemia subtype in pediatric patients. Finally, TEX41 expression seems to be critical for leukemic proliferation, indeed, silencing experiments targeting TEX41 mRNA in the RS4;11 cell line hampered in vitro cell growth and cell cycle progression, by inducing G2-M arrest as confirmed propidium iodide staining and by the upregulation of p53 and p21 proteins.

Background: A radical surgical approach represents the mainstay treatment for gynecological malignancy, and preoperative staging of ovarian cancer is crucial. Ultrasound evaluation is widely recognized as the gold standard technique for the characterization of ovarian masses due to a high sensitivity for malignancy. In addition, its accuracy in defining intra-abdominal ovarian cancer spread has been previously proposed., Primary Objective: To analyze the agreement between preoperative ultrasound examination and laparoscopic findings in assessing the extension of intra-abdominal disease using six parameters as described by Fagotti's score., Study Hypothesis: When performed by expert examiners, ultrasound can be an accurate technique to assess tumor spread in ovarian cancer and therefore to predict surgical resectability., Trial Design: This is a single-center prospective observational study. Patients with clinical and/or radiological suspicion of advanced ovarian or peritoneal cancer will be assessed with preoperative ultrasound and assigned a score based on the six Fagotti's laparoscopic score parameters. Each parameter will then be correlated with laparoscopic findings., Major Inclusion/exclusion Criteria: Eligible patients include women 18-75 years of age with clinical and/or imaging suggestive of advanced ovarian or peritoneal cancer, and an ECOG performance status 0-3., Primary Endpoints: Sensitivity and specificity of ultrasound in detecting carcinomatosis, using the parameters of Fagotti's score as a reference standard. Agreement between preoperative ultrasound examination and laparoscopic findings in assessing the extension of intra-abdominal disease as described in Fagotti's score., Sample Size: 240 patients., Estimate Dates for Completing Accrual and Presenting Results: The accrual started in January 2019. Enrollment should be completed approximately by October 2020 and the results will be analyzed by December 2020., Trial Registration: The study received the Ethical Committee approval on July 19 2018 (Protocol 28967/18 ID:2172)., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Long non-coding RNAs (lncRNAs) are emerging as key gene regulators in the pathogenesis and development of various cancers including B lymphoblastic leukaemia (B-ALL). In this pilot study, we used RNA-Seq transcriptomic data for identifying novel lncRNA-mRNA cooperative pairs involved in childhood B-ALL pathogenesis. We conceived a bioinformatic pipeline based on unsupervised PCA feature extraction approach and stringent statistical criteria to extract potential childhood B-ALL lncRNA signatures. We then constructed a co-expression network of the aberrantly expressed lncRNAs (30) and protein-coding genes (754). We cross-validated our in-silico findings on an independent dataset and assessed the expression levels of the most differentially expressed lncRNAs and their co-expressed mRNAs through ex vivo experiments. Using the guilt-by-association approach, we predicted lncRNA functions based on their perfectly co-expressed mRNAs (Spearman's correlation) that resulted closely disease-associated. We shed light on 24 key lncRNAs and their co-expressed mRNAs which may play an important role in B-ALL pathogenesis. Our results may be of clinical utility for diagnostic and/or prognostic purposes in paediatric B-ALL management.

Leukemic cells originate from the malignant transformation of undifferentiated myeloid/lymphoid hematopoietic progenitors normally residing in bone marrow. As the precise molecular mechanisms underlying this heterogeneous disease are yet to be disclosed, the identification and the validation of novel actors in leukemia is of extreme importance. Here, we show that KCTD15, a member of the emerging class of KCTD ((K)potassium Channel Tetramerization Domain containing) proteins, is strongly upregulated in patients affected by B-cell type acute lymphoblastic leukemia (B-ALL) and in continuous cell lines (RS4;11, REH, TOM-1, SEM) derived from this form of childhood leukemia. Interestingly, KCTD15 downregulation induces apoptosis and cell death suggesting that it has a role in cellular homeostasis and proliferation. In addition, stimulation of normal lymphocytes with the pokeweed mitogen leads to increased KCTD15 levels in a fashion comparable to those observed in proliferating leukemic cells. In this way, the role of KCTD15 is likely not confined to the B-ALL pathological state and extends to activation and proliferation of normal lymphocytes. Collectively, data here presented indicate that KCTD15 is an important and hitherto unidentified player in childhood lymphoid leukemia, and its study could open a new scenario for the identification of altered and still unknown molecular pathways in leukemia.

Chemotherapy-induced nausea and vomiting (CINV) is a distressing treatment side-effect that could negatively affect children's quality of life (QoL). Different scoring systems for CINV were applied and different antiemetic drugs were used; however, few studies have been performed in children undergoing chemotherapy with Aprepitant. Herein, we report a pediatric experience on efficacy and safety of Aprepitant as part of triple antiemetic prophylaxis, in a cohort of thirty-two children and adolescents with Hodgkin Lymphoma (HL), treated with moderate/highly emetogenic chemotherapy (MEC/HEC) regimens in a single Hemato-Oncology Institution. The triple therapy was compared to standard antiemetic therapy in a cohort of twenty-three HL patients (control group). Aprepitant therapy was associated to a significant decrease of chemotherapy-induced vomiting (p = 0.0001), while no impact on the reduction of nausea was observed; these observations were also confirmed by multivariate analysis (p = 0.0040). Aprepitant was well tolerated and the most commonly reported adverse events were neutropenia and hypertransaminasemia. No significant differences on the toxicity were observed between the two compared groups. Our experience on Aprepitant efficacy and safety, associated with feasibility of orally administration, suggests a possible widespread use of the drug to prevent pediatric CINV., Competing Interests: The authors have declared that no competing interests exist.

Purpose: It is well known that hepatocellular carcinoma (HCC) is an arginine auxotroph due to argininosuccinate synthetase I deficiency. This study's purpose was to evaluate the effects of pegylated arginine deiminase (ADI) in terms of toxicity, tumor response, alpha-fetoprotein (AFP) levels, and serum arginine levels., Patients and Methods: Eighty patients were randomly assigned to receive either 80 IU/m(2) or 160 IU/m(2) of ADI weekly for up to 6 months. Adverse events, serum arginine, AFP levels, and antibody production against ADI were measured on a regular basis. In addition, disease response and time to progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) and survival rates were evaluated., Results: Four patients were excluded from the survival analysis because they developed exclusion criteria after randomization, but before first treatment. The number of patients in the two cohorts were similar (n = 37 in the low-dose cohort, n = 39 in the high-dose cohort). Mean (+/-SE) survival for all subjects was 15.8 months (474 days +/- 39 days) from time of diagnosis of unresectable disease. Arginine levels remained below baseline for 50 days while antibodies against ADI reached a plateau at approximately the same time. There were no deaths attributed to ADI treatment. Only two patients were withdrawn for immunogenic-related adverse events. Grade 2, 3, or 4 toxicities were recorded in 92, 19, and 0 patients, respectively., Conclusion: Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.

Hepatitis C virus (HCV) is one of the major risk factors for chronic hepatitis, which may progress to cirrhosis and hepatocellular carcinoma, as well as for type II mixed cryoglobulinemia (MC), which may further evolve into an overt B-cell non-Hodgkin's lymphoma (NHL). It has been previously shown that B-cell receptor (BCR) repertoire, expressed by clonal B-cells involved in type II MC as well as in HCV-associated NHL, is constrained to a limited number of variable heavy (VH)- and light (VL)-chain genes. Among these, the VK3-20 light chain idiotype has been selected as a possible target for passive as well as active immunization strategy. In the present study, we describe the results of a multiparametric analysis of the innate and early adaptive immune response after ex vivo stimulation of human immune cells with the VK3-20 protein. This objective has been pursued by implementing high-throughput technologies such as multiparameter flow cytometry and multiplex analysis of cytokines and chemokines.

Purpose: Capecitabine is an oral chemotherapeutic agent, already used in breast and colon cancer. Previous data showed encouraging results in the treatment of recurrent ovarian cancer. The aim of this study was to describe activity and toxicity of capecitabine in patients with platinum resistant or refractory ovarian cancer., Methods: Patients were eligible if they had cytologically or histologically proven epithelial ovarian cancer, refractory or resistant to prior platinum-containing chemotherapy. Capecitabine was administered at the dose of 1,250 mg/m(2) twice daily on days 1-14 of a 21-day cycle for a maximum of six cycles. The primary end point of the study was activity in terms of objective response rate in according to RECIST criteria. A two-stage minimax design for phase II studies was used: at least four objective responses had to be reached among 32 evaluable patients to define the treatment active., Results: Between March 2006 and October 2007, 36 patients were enrolled. All patients had ovarian cancer and 83.3% had previously received two or three lines of chemotherapy. Thirty-two patients were evaluable for response and included in the activity analysis. The objective response rate was 3.1% [95% exact confidence interval (CI): 0.08-16.22%], lower than the threshold required to define the treatment as active. The median progression free survival was 68 days (95% CI: 65-120). Haematological toxicity was not frequent. Nausea and fatigue were common, but never severe, and they were observed in 13 (37.1%) and 12 (34.2%) patients, respectively. Diarrhoea occurred in 11 patients (31.5%) and it was of grade 3 in 8.6% of cases. Grade 1-2 stomatitis was observed in seven patients (20%). Cardiovascular toxicity was reported in two cases, including a death for pulmonary embolism., Conclusions: Capecitabine is not active in platinum resistant non mucinous ovarian cancer, producing a response rate lower than that required by study design. Further trials are not warranted in these patients.

Background: The arginine-degrading enzyme, arginine deiminase conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw), reduces extracellular arginine, has minimal toxicity, decreases tumor burden and improves liver function in patients with chronic hepatitis C virus infection (HCV) and inoperable hepatocellular carcinoma (HCC). Reduced extracellular arginine inhibits viral replication through unknown mechanisms. It is hypothesized that ADI-SS PEG 20,000 mw reduces HCV viral titers through nitric oxide (NO)-dependent effects., Methods: The effects of ADI-SS PEG 20,000 mw (dose, 160 IU/m2; three cycles of four once-weekly i.m. injections) on HCV titers, serum NO and plasma arginine, were evaluated using archived plasma from patients with HCC and HCV and in vitro cell model measurements of HCV replication., Results: ADI-SS PEG 20,000 mw selectively inhibited HCV replication in vitro (IC50 = 0.027 IU/mL). Fifteen HCC/HCV patients completed treatment. The HCV titers were reduced by up to 99% in five out of 10 (50%) HCV-serotype 1b patients (P = 0.0093). These patients also experienced significant improvements in liver function (P = 0.0091). There were concomitant reductions of plasma arginine and serum NO levels. The HCV titer was not reduced in HCV-type 2c patients., Conclusion: Reduction of extracellular arginine by ADI-SS PEG 20,000 mw in HCC patients reduces HCV viral titers and improves liver function, possibly through suppression of NO.