Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study.

BACKGROUND: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. PATIENTS AND METHODS: In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. RESULTS: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. CONCLUSION: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.

Human pancreatic tumors grown in mice release tissue factor-positive microvesicles that increase venous clot size.

Essentials Tumor-bearing mice have larger venous clots than controls. Human tissue factor is present in clots in tumor-bearing mice. Inhibition of human tissue factor reduces clot size in tumor-bearing mice. This new mouse model may be useful to study mechanisms of cancer-associated thrombosis. SUMMARY: Background Pancreatic cancer patients have a high rate of venous thromboembolism. Human pancreatic tumors and cell lines express high levels of tissue factor (TF), and release TF-positive microvesicles (TF+ MVs). In pancreatic cancer patients, tumor-derived TF+ MVs are present in the blood, and increased levels are associated with venous thromboembolism and decreased survival. Previous studies have shown that mice with orthotopic human or murine pancreatic tumors have circulating tumor-derived TF+ MVs, an activated clotting system, and increased incidence and mean clot weight in an inferior vena cava stenosis model. These results suggest that TF+ MVs contribute to thrombosis. However, the specific role of tumor-derived TF+ MVs in venous thrombosis in mice has not been determined. Objectives To test the hypothesis that tumor-derived TF+ MVs enhance thrombosis in mice. Methods We determined the contribution of TF+ MVs derived from human pancreatic tumors grown orthotopically in nude mice to venous clot formation by using an anti-human TF mAb. We used an inferior vena cava stasis model of venous thrombosis. Results Tumor-bearing mice had significantly larger clots than control mice. Clots from tumor-bearing mice contained human TF, suggesting the incorporation of tumor-derived MVs. Importantly, administration of an anti-human TF mAb reduced clot size in tumor-bearing mice but did not affect clot size in control mice. Conclusions Our results indicate that TF+ MVs released from orthotopic pancreatic tumors increase venous thrombosis in mice. This new model may be useful for evaluating the roles of different factors in cancer-associated thrombosis.

Capecitabine with/without mitomycin C: results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma.

PURPOSE: Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C. METHODS: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m(2) day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m(2) day 1 (ARM B) as second-line therapy. Cycles were repeated in both arms every 3 weeks. Tumor assessment was performed every 2 months. The primary endpoint was the probability of being progression free at 6 months (PFS-6) from treatment start. According to the Fleming design, the study aimed to enroll 26 pts per arm. An exploratory endpoint was to assess thymidylate synthase (TS) and thymidine phosphorylase (TP) expression, as biomarkers predictive for clinical outcomes of capecitabine treatment. RESULTS: Between October 2011 and 2013, 57 metastatic pts were enrolled: ARM A/B 28/29. Accordingly, 55 (26/29) pts were assessable for the primary endpoint: 2 (8%) ARM A and 3 (10%) ARM B pts were PFS-6. Main G3-4 toxicities were: hand-foot syndrome and transaminitis in 4/0%, and thrombocytopenia, diarrhea and fatigue in 0/3% of pts. No statistically significant correlation was found between TS or TP expression and pts' outcome. CONCLUSIONS: Since capecitabine yielded a disappointing outcome and the addition of mitomycin C did not improve the results, new therapeutic strategies need to be explored to improve survival in this disease setting.

Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. METHODS: This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). RESULTS: Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. CONCLUSION: RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.

Mechanism of leptin expression in breast cancer cells: role of hypoxia-inducible factor-1alpha.

We reported previously that the obesity hormone leptin is overexpressed in breast cancer biopsies. Here, we investigated molecular mechanisms involved in this process, focusing on conditions that are associated with obesity, that is, hyperinsulinemia and induction of hypoxia. By using quantitative real-time PCR, immunofluorescent detection of proteins and enzyme-linked immunosorbent assays, we found that treatment of MCF-7 breast cancer cells with high doses of insulin or the hypoxia-mimetic agent CoCl2, or culturing the cells under hypoxic conditions significantly increased the expression of leptin mRNA and protein. Notably, the greatest leptin mRNA and protein expression were observed under combined hyperinsulinemia and hypoxia or hypoxia-mimetic treatments. Luciferase reporter assays suggested that increased leptin synthesis could be related to the activation of the leptin gene promoter. DNA affinity precipitation and chromatin immunoprecipitation experiments revealed that insulin, CoCl2 and/or hypoxia treatments augmented nuclear accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) and increased its interaction with several upstream leptin regulatory sequences, especially with the proximal promoter containing four hypoxia-response elements and three GC-rich regions. By using reverse chromatin precipitation, we determined that loading of HIF-1alpha on the proximal leptin promoter concurred with the recruitment of p300, the major HIF coactivator, suggesting that the HIF/p300 complex is involved in leptin transcription. The importance of HIF-1alpha in insulin- and CoCl2-activated leptin mRNA and protein expression was confirmed using RNA interference.

Acrocephalosyndactyly, Apert type, in a newborn: Cerebral sonography.

We describe the clinical and cerebral ultrasonographic features of a rare case of type 1 acrocephalosyndactyly (Apert syndrome). The patient was a newborn male whose twin had died in utero. Most cases of Apert syndrome are sporadic, although autosomal dominant inheritance has also been reported. Diagnosis is based on physical examination together with imaging data. Since Apert syndrome can give rise to numerous CNS abnormalities, affected newborns should undergo echoencephalography for more complete characterization of their malformations.

Sonographic detection of rhabdomyosarcoma of the urinary bladder.

Rhabdomyosarcoma (RMS) is the most common malignant pelvic tumor in the young child, occurring typically in children aged 2-4 years. It arises from the prostate or the trigone of the bladder in boys, and from the vagina or uterus in girls. We report a case of bladder rhabdomyosarcoma and discuss the ultrasonographic images. The mass produced filling defect on the contrast cystogram and also was demonstrated with CT.

Hemimegalencephaly in hypomelanosis of Ito: early sonographic pattern and peculiar MR findings in a newborn.

Sonography is a reliable tool for the evaluation of the most severe congenital abnormalities of the brain; in the present case it provided an early demonstration of hemimegalencephaly in hypomelanosis of Ito in a newborn affected by body hemihypertrophy and skin lesions. Serial magnetic resonance (MR) examinations confirmed the asymmetry of the cerebral hemispheres, and documented the evolution of the hemispheric growth and the presence of unusual aspects.

Serum interleukin-10 levels in patients with advanced gastrointestinal malignancies.

BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. In this study, the authors investigated the prognostic significance of IL-10 levels in the sera of 58 patients with advanced gastric or colorectal carcinoma. METHODS: IL-10 serum levels were measured before chemotherapy, on completion of chemotherapy, and at follow-up by means of a commercially available enzyme-linked immunoadsorbent assay kit. The results then were analyzed in comparison with other prognostic variables and a model predicting overall survival (OS) and time to disease progression (TTP) was generated. RESULTS: Elevated levels of serum IL-10 were found in carcinoma patients compared with healthy controls (19.6 +/- 6.8 pg/mL vs. 9.2 +/- 1.5 pg/mL; P < 0.0001), with those patients with metastatic disease showing significantly higher levels than patients with undisseminated disease (21.9 +/- 6. 7 pg/mL vs. 15.5 +/- 3.6 pg/mL; P = 0.0003). Retrospective analysis of prechemotherapy IL-10 serum levels showed a significant difference between responders and nonresponders (15.8 +/- 2.5 pg/mL vs. 21.6 +/- 7.6 pg/mL; P < 0.0001). Moreover, a further significant increase in IL-10 serum levels was observed in nonresponders at the end of therapy (21.6 +/- 7.6 pg/mL prechemotherapy vs. 31.3 +/- 11.6 pg/mL postchemotherapy; P < 0.0001) whereas no significant differences were observed in responders. Using univariate analysis, both OS and TTP were shown to be affected by the median pathologic levels of IL-10; multivariate analysis related to OS and TTP identified performance status and IL-10 serum level as the relevant prognostic factors, respectively. Finally, stepwise regression analysis identified IL-10 serum level and metastases as the prognostic factors related to both OS and TTP. CONCLUSIONS: The results of the current study show that measurement of pretreatment serum levels of IL-10 is of independent prognostic utility in patients with advanced gastrointestinal carcinoma and may be useful for the detection of disease progression.

Amifostine: A selective cytoprotective agent of normal tissues from chemo-radiotherapy induced toxicity (Review).

Patients receiving systemic cancer chemotherapy must often have their dose intensity of therapeutic agents reduced, because a broad range of organs are adversely affected. Therefore, research and the development of agents protecting the normal tissues from the toxicity of antineoplastic therapy, without reducing the antitumour efficacy, are very important. Amifostine, a prodrug that forms an activated free thiol, when dephosphorylated by alkaline phosphatase, appears selective in its entry in non-malignant cells, and exerts a protective effect from toxicity induced by chemo- or radiotherapy on normal tissues, through free radical scavenging, hydrogen donation and inhibition of DNA damage. Studies in vitro and experimental models have confirmed the protective properties of amifostine in normal cells. In clinical trials pretreatment with amifostine reduced the frequency of cyclophosphamide induced neutropenia and nephro-, oto- and neurotoxicity of platinum compounds. In some cases the use of amifostine have also potentiated the effects of several drugs, such as alkylating agents and, in recent studies, taxanes. The main potentially dose-limiting adverse effect is hypotension, that is often asymptomatic. Amifostine is thus usefully employed in order to obtain a better quality of life in patients receiving oncologic treatments.

Imaging of neonatal hemangiomas, two cases.

Hemangiomas are the most common tumor of infancy. Most hemangiomas are harmless and follow a benign clinical course and undergo regression with time. Sometimes they can destroy vital organs and become life-threatening. We report two cases of neonatal hemangiomas which presented very different clinical aspects and course.

A pilot study of adjuvant chemotherapy with double modulation of 5-fluorouracil by methotrexate and leucovorin in gastric cancer patients.

BACKGROUND: Thirty-four patients with gastric cancer in stage II and III were enrolled, after curative resection, in a pilot study to assess the feasibility and the impact on relapse of a double modulation of 5-Fluorouracil (5FU) by Methotrexate (MTX) and 1-Leucovorin (LFA) as adjuvant chemotherapy. METHODS: The schedule was: MTX 500 mg/m2d. 1, LFA 250 mg/m2d.2, 5FU 600 mg/m2d.2. Cycles were repeated every two weeks for 16 times. Quality of life during treatment was evaluated with the EORTC QLQ-C30. RESULTS: At a median follow-up of 24 months, 21 (61%) patients treated with postoperative chemotherapy, were disease-free. Toxicity was primarily gastrointestinal, but its intensity was usually mild. The feasibility of treatment was also confirmed from the results of QLQ-C30 questionnaire. CONCLUSIONS: This study demonstrates that the schedule tested is feasible as postoperative treatment in curatively resected gastric cancer patients and prompts the initiation of a randomized trial with a no-treatment control arm.

Soluble interleukin-2 receptor and soluble CD8 antigen levels in serum from patients with solid tumors.

High levels of soluble lymphocyte antigens have been described in a large number of tumors and, particularly, in hematopoietic neoplasms. As previously reported, many antitumor immune responses are IL-2 dependent: clinical observations indicate that a worse survival in advanced tumor patients is related with a decrease of soluble IL-2 levels. A soluble form of CD8 has been described: as found in Hodgkin's disease and acute lymphoblastic leukemia, sCD8 levels have a prognostic value. To explain the significance of these soluble molecules in solid tumors, we a) determinated sIL-2R and sCD8 in 84 patients; b) correlated the expression of p55 chain of IL-2R and CD8 antigen on the cell-surface of peripheral lymphocytes to sIL-2R and sCD8 levels; c) analyzed endogenous IL-2R levels in patients with lung cancer. An increase of sIL-2R was found in 82% of cases, while high levels of sCD8 were observed in 32%; no correlation was observed between sIL-2R and the expression of p55 on the surface of peripheral lymphocytes: IL-2 levels in patients with NSCLC were significatively reduced, when compared to healthy controls, with an inverse relationship between endogenous IL-2 concentration and sIL-2R levels. Whatever may be the physiopathological mechanism of the increase of sIL-2 observed in solid tumors, this rise may contribute to the immunodepression correlated to neoplastic disease. Therefore, higher levels of sIL-2R/IL-2 ratio has a negative biologic prognostic significance. We think that determinating CD8 antigen in the serum can offer a more sensitive and specific measurement of activation of suppressor/cytotoxic T-lymphocytes.

Increased serum levels of tumor necrosis factor-alpha are correlated to soluble intercellular adhesion molecule-1 concentrations in non-small cell lung cancer patients.

Tumor necrosis factor (TNF)-alpha has been shown to induce shedding of ICAM-1. Experimental studies report that soluble intercellular adhesion molecule-1 (sICAM-1) may interfere with the host immunesurveillance system. Serum levels of TNF-alpha and sICAM-1 were determined by ELISA in 112 non-small cell lung cancer (NSCLC) patients. Serum concentration of TNF-alpha and sICAM-1 were related to tumor burden and progression; a significant correlation was observed between circulating levels of TNF-alpha and sICAM-1. Our study suggests that ICAM-1 could be a marker of TNF-alpha activity and that high levels of these molecules may have a prognostic value in lung cancer.

[A case of congenital hepatic hemangioendothelioma treated with prednisone: the echographic changes and Doppler study]. / Un caso di emangioendotelioma epatico congenito trattato con prednisone: modificazioni ecografiche e studio Doppler.

Imaging investigations and other findings observed in a term infant with a multicentric hepatic hemangioendothelioma, admitted to the Intensive Care Unit at the age of 13 days because of non specified feeding difficulties and dyspnoea, are presented. Physical examination revealed cardiac bruit and congestive heart failure with marked hepatomegaly; in addition there were multiple small skin hemangiomas. Echocardiography was negative, abdominal sonography showed multiple round lesions of mixed echogenicity in the liver, large vascular channels, a right hepatic artery and hepatic veins enlarged, a caliber of the aorta below the level of the superior mesenteric artery reduced. The infant was additionally investigated by whole-body scintigraphy with 99mTc-labeled red blood cells to determine the possibility of coexistence of other visceral hemangiomas and by MR, in which the tumor manifested as multiple well-circumscribed space-occupying nodules of high signal intensity on T2-weighted images with evidence of fast flow. The baby underwent furosemide and steroid therapy: serial two-dimensional US scans showed change in echogenicity, responding to therapy. Doppler sonography has proven to be also very useful in the monitoring therapy determining changes in flow pattern and velocity at the level of hepatic, cerebral and renal vessels: before therapy we observed a reduction of the diastolic flow until the zero line through the internal carotid artery and renal artery with an increase of the Resistance Index. It means that this important component can be compromised in the presence of a hepatic hemangioendothelioma.

Analysis of recovery time indexes in 5-fluorouracil-treated cancer patients.

Based on our previous experience in doxorubicin-treated patients, in whom we observed a significant increase of ventricular recovery time indexes, we analyzed these non- invasive parameters of myocardium electrical instability in forty-three 5-fluorouracil-treated patients, to test the hypothesis of a mechanoelectrical disarrangement occurring in 5-fluorouracil (5FU) cardiotoxicity. All patients enrolled were studied at the first presentation and following chemotherapy. The study showed the absence of any significant changes in recovery time indexes or in other electrocardiographic parameters. Our data suggest that 5FU does not interfere with electrical properties of myocardial fibers.

Serum levels of interleukin-6 as a prognostic factor in advanced non-small cell lung cancer.

Serum levels of interleukin-6 (IL-6) were evaluated in a group of advanced non-small cell lung cancer (NSCLC) patients using an enzyme-linked immunosorbent assay. The data were related to clinical status and to cisplatin-based chemotherapy response. The mean IL-6 concentrations were higher than the controls (p<0.0001); patients with metastatic tumor had higher levels than those with undisseminated disease (p<0.006). Tumor progression was associated with an increase of IL-6 levels. Patients who responded to chemotherapy had lower serum IL-6 levels compared with unresponsive patients (p<0.0001). These data suggest that NSCLC patients with high levels of IL-6 have a worse clinical outcome and may manifest resistance to cisplatin chemotherapy.

Circulating levels of soluble intercellular adhesion molecule-1 in non-small cell lung cancer patients.

Intercellular adhesion molecule-1 has been implicated in tumor progression and metastasis. Like soluble forms of other membrane receptors, a circulating form of intercellular adhesion molecule-1 (sICAM-1) has been identified in the serum of healthy subjects and it has been found in malignant diseases at increased levels. This study evaluated the serum concentration of sICAM-1 in 112 patients with non-small cell lung cancer (NSCLC). Soluble ICAM-1 levels were significantly higher in all patients when compared with the controls; serum concentration of sICAM-1 correlated with clinical stage and tumor progression. These results suggest that elevated levels of serum ICAM-1 could be of prognostic importance in patients with NSCLC.