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Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants.

Introduction: Transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) are established procedures for treating hepatocellular cancer and selected malignancies with liver metastasis. The aim of this study is to describe a monoinstitutional case series of local approaches in patients with liver metastases from rare head and neck cancers (HNCs).Methods: This is a retrospective series of adult patients with HNC treated with liver locoregional approaches (TACE or RFA) at our institution from 2007 to 2018. In case of chemoembolization, the preferred chemotherapeutic drug was doxorubicin. Response according to RECIST (Response Evaluation Criteria in Solid Tumors) was assessed with contrast-enhanced computed tomography scans.Results: Thirty-four patients were treated (20 men, median age 58 years) with TACE (27), transarterial embolization (2), or RFA (7). Primary tumours were salivary gland (21), thyroid (6), nasopharyngeal (5), and sinonasal cancers (2). Seventeen patients (50%) had a single metastatic liver nodule; 70% of the remaining 17 patients had at least three liver metastases. The median diameter of the metastatic liver mass undergoing treatment was 39 mm (range 11–100 mm). Median follow-up was 27.6 months. Response rate was 35% (3% complete, 32% partial response). Median progression-free survival and overall survival were 6.9 and 19.6 months, respectively. Treatment-related adverse events occurred in 59% of patients (21% grade ⩾ 3; no grade 5).Discussion: This retrospective case series demonstrates that locoregional radiologic approaches for rare HNCs with liver metastases are feasible. These procedures deserve further prospective studies before being considered safe and active in these malignancies where the availability of effective systemic treatments is lacking.

Introduction: Although many reports have analyzed the outcomes of central venous catheters (CVCs) in oncologic and oncohematologic patients, current guidelines do not routinely recommend a specific type of CVC over the other.Methods: We retrospectively evaluated the outcomes of 178 patients with CVCs referred to an Italian specialized cancer center between January 2016 and December 2018. The analysis compares midterm peripherally inserted central venous catheters (PICCs) with long-term centrally inserted catheters, including totally implanted ports and tunneled catheters with central insertion (tCVCs).Results: A total of 130 PICCs (73%) and 48 tCVCs (27%) were analyzed. The overall complication rate was significantly increased in the PICC cohort compared to the tCVC cohort (43.1% vs 25%, respectively; p= 0.037), leading to complication-related device removal in 30.8% of PICCs vs 12.5% of tCVCs (p= 0.013). No significant differences in terms of catheter-related thromboses (p= 0.676) or catheter-related infections (p= 0.140) were detected. Nonthrombotic obstructions were significantly higher in the PICC group compared to the tCVC cohort (p= 0.006). Overall complication-free survival was significantly longer for tCVCs compared to PICCs (hazard ratio [HR], 0.262; 95% confidence interval [CI], 0.128–0.536; p< 0.0001), as well as obstruction-free survival (HR, 0.082; 95% CI, 0.018–0.372; p< 0.0001). In multivariable analysis, the type of CVC was independently correlated with the occurrence of any complication (HR, 0.273; 95% CI, 0.135–0.553; p< 0.0001).Conclusions: This Italian real-world experience suggests that PICCs are associated with a higher risk of overall complications compared with tCVCs. Catheter choice in oncologic patients should be guided by treatment type and duration, risk–benefit assessment, patient preferences, and compliance.

In the presence of peritoneal disease, patients often should undergo biopsy of the peritoneum for acquiring a specific pathologic diagnosis. Ultrasound is ideal for guiding peritoneal biopsy, although in some situations, it can be technically challenging. The addition of a contrast agent can improve the visualization of lesions and adjacent organs, providing radiologists increased confidence. A contrast agent can identify perfused areas within the target lesion, improving diagnostic accuracy. We present 3 cases of contrast‐enhanced ultrasound–guided peritoneal biopsy. In all cases, we gained a specific diagnosis. No immediate or delayed complications occurred. Contrast‐enhanced ultrasound–guided biopsy proved to be a simple, safe, and accurate diagnostic method.

Background: The rapid spread of coronavirus disease (COVID-19) is affecting many countries. While healthcare systems need to cope with the need to treat a large number of people with different degrees of respiratory failure, actions to preserve aliquots of the healthcare system to guarantee treatment to patients are mandatory.Methods: In order to protect the Fondazione IRCCS–Istituto Nazionale dei Tumori di Milano from the spread of COVID-19, a number of to-hospital and within-hospital filters were applied. Among others, a triage process to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity in patients with cancer was developed consisting of high-resolution low-dose computed tomography (CT) scan followed by reverse transcription polymerase chain reaction (RT-PCR) detection of SARS-CoV-2 in nose–throat swabs whenever CT was suggestive of lung infection. To serve symptomatic patients who were already admitted to the hospital or in need of hospitalization while waiting for RT-PCR laboratory confirmation of infection, a COVID-19 surveillance zone was set up.Results: A total of 301 patients were screened between March 6 and April 3, 2020. Of these, 47 were hospitalized, 53 needed a differential diagnosis to continue with their cancer treatment, and 201 were about to undergo surgery. RT-PCR was positive in 13 of 40 hospitalized patients (32%), 14 of 52 day hospital patients (27%), and 6 of 201 surgical patients (3%).Conclusion: Applying filters to protect our comprehensive cancer center from COVID-19 spread contributed to guaranteeing cancer care during the COVID-19 crisis in Milan. A surveillance area and surgical triage allowed us to protect the hospital from as many as 33 patients infected with SARS-CoV-2.

Purpose: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients’ response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery.Methods: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation.Results: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score.Conclusions: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.

Lung cancer presenting as subsolid nodule (SSN) can show slow growth, hence treating SSN is controversial. Our aim was to determine the long-term outcome of subjects with unresected SSNs in lung cancer screening.

Purpose To evaluate the diagnostic yield and complication rate of 2 different biopsy techniques (fine-needle aspiration, FNA, and core-needle biopsy, CNB) in the diagnosis of pulmonary lesions in 2 distinct periods, 2010-2012 and 2013-2015.Methods We retrospectively analyzed the results of 691 CT-guided lung biopsies in 665 patients who were divided into 2 groups: cohort 1 (January 2010 to December 2012) was composed of 271 consecutive patients with 284 procedures either by FNA or CNB; cohort 2 (January 2013 to December 2015) was composed of 394 patients with 407 CNBs. Univariate and multivariate logistic regression modeling was used for selected outcomes including diagnostic yield, bleeding and pneumothorax.Results Cohort 1 comprised 165 men and 106 women (mean age 68.5 years) with 180 FNAs and 104 CNBs; cohort 2 comprised 229 men and 165 women (mean age 66.4 years) with 407 CNBs. The diagnostic yield increased in cohort 2 with respect to cohort 1. There was a slight increase in CT procedure complications (pneumothorax and bleeding) from cohort 1 to cohort 2. The overall risk of complications was greater for lesions <20 mm and for lesions at >20 mm distance from the pleura.Conclusions CT-guided CNB had a higher diagnostic yield than discretional use of either FNA or CNB; there was a slight but acceptable increase in complication rates.

The National Lung Screening Trial has achieved a 7% reduction in total mortality with low-dose computed tomography (LDCT) screening as compared with in the chest radiography arm. Other randomized trials are under way, comparing LDCT screening with no intervention. None of these studies was designed to investigate the impact of smoking habits on screening outcome. In the present study, we tested the effect of stopping smoking on the overall mortality of participants undergoing repeated LDCT screening for many years.

Small cell lung cancer (SCLC) constitutes a distinct component of symptomatic or advanced-stage lung cancers in clinical practice and in lung cancer screening trials. The purpose of this study was to describe the outcome of SCLC in lung cancer screening trials and compare the frequency of SCLC in our cohort with that in the major lung cancer screening trials.

The treatment of tumors of the testis represents an ideal model of care for cancer. Many different, intersecting strategies are available for managing germ-cell cancers, particularly in the early-stage disease. Which is ‘right’ remains a matter of debate, and requires balancing efficacy against late effects, bearing in mind the complexity of treatment strategies and the available expertise. The cornerstone of this model of success is linked to the quality and appropriateness of care.The current therapeutic strategy is very complex (Fig. 1). High-tech surgery, medical oncology and radiotherapy are involved at various levels of diagnostic techniques of the latest generation. The choice of therapy, alone or integrated, is often influenced by prognostic factors. In this article we will examine the important points and sometimes the subject of controversy in both diagnosis and treatment of these early-stage tumors (Clinical Stage I: disease confined to the testis; Clinical Stage IIA: retroperitoneal lymph nodes <2 cm).

Aims and background Neuroblastoma is the most common solid extracranial tumor in children. The median age of onset is 2 years, with more than 95% of patients younger than 10 years at diagnosis. As neuroblastoma is rare in adolescents and exceedingly rare in adults, few series are reported in the literature. In the present study, we analyzed the outcomes and clinical characteristics of a mono-institutional series.Methods We describe 27 consecutive patients over 12 years of age (range, 12–69) with previously untreated neuroblastoma treated at our Institution between 1982 and 2001.Results Overall survival at 5 and 10 years was 40% and 20%, respectively, and progression-free survival at 5 and 10 years was 18%. In the present series, there was a long interval between the onset of signs/symptoms and diagnosis, and between recurrence/progression and death. None had MYCN amplification.Conclusions The passive course of the disease in most of our patients did not reflect a more favorable outcome compared with younger patients, thus suggesting a possible genetically different subset of neuroblastoma in older patients. Free full text available at www.tumorionline.it

The aim of this study was to assess the feasibility of somatostatin receptor scintigraphy (SRS) for the detection of the site of unknown primary neuroendocrine neoplasms in patients in whom clinical examination and conventional radiological imaging had failed to do so. From 1996 to 2000, 36 patients were referred with gastro-entero-pancreatic (GEP) neuroendocrine tumours. In these patients, no clinical, radiological or endoscopic diagnostic modalities had been able to identify the primary tumour. Twenty-nine patients had liver metastases. Of the others, one had skin and one had lymph node metastases, three had diffuse metastatic involvement and two had carcinoid syndrome. SRS was carried out with both whole-body and single-photon emission tomography (SPET) acquisition, 24 and 48 h after the intravenous administration of 111In-pentetreotide. SRS findings were suggestive of the possible site of the primary lesion in 14 patients (39). Six patients underwent surgery on the basis of the SRS findings and, therefore, the final, i.e. pathological, diagnosis was reached. In two patients, the final diagnosis was obtained within 6 months of SRS by means of a follow-up computed tomography (CT) scan. In the remaining six patients, the final diagnosis was reached after at least 2 years of follow-up by means of clinical, radiological andor nuclear medicine findings. In all eight patients, the primary site identified during follow-up was consistent with the SRS findings. It can be concluded that SRS modified management in the six patients who had surgery. However, the most important finding was that SRS prompted surgical management in 17 of cases.

The development of more effective and convenient chemotherapy regimens for the treatment of gastric cancer that incorporate novel agents remains an exciting area of research. A phase II study was conducted to assess the response rate and toxicity profile of pemetrexed, a novel multitargeted antifolate, in previously untreated patients with measurable, advanced, or metastatic adenocarcinoma of the stomach or gastroesophageal junction. In this study, pemetrexed-induced toxicity at the starting dose of 500 mg/m2intravenously once every 21 days was considerable with each of the first six patients who experienced at least one episode of grade 3/4 toxicity. Two patients discontinued from study, and two patients died. All deaths were caused by drug-related toxicity. No responses were seen in this briefly treated group. These observations led to an amended study protocol designed to improve tolerability of pemetrexed with folic acid supplementation. Supplementation with folic acid 5 mg was given orally once daily for 2 days before pemetrexed on the day of treatment, and for 2 days following treatment. Tumor evaluation was performed after every two cycles of therapy. The trial was recently closed to accrual and preliminary clinical results are reported here. Thirty-two patients were enrolled and 30 patients were evaluable for efficacy. A total of 129 courses of pemetrexed were administered, and the median number of courses received per patient was four (range, one to eight courses). Two complete and five partial responses were observed, with four patients experiencing stable disease. In an intent-to-treat analysis, the overall response rate was 22%, and 23% for the evaluable patients. Median duration of response was 4.4 months (range, 3 to 11 months) and median time to treatment failure was 2.6 months (range, 0.5 to 12 months). Of the 32 patients treated, eight experienced grade 4 neutropenia and one had grade 4 thrombocytopenia. The most common nonhematologic toxicities were diarrhea, fatigue, mucositis, nausea and vomiting, skin rash, and reversible abnormalities in liver function. There was no case of nonhematologic grade 4 toxicity. Although the clinical experience with pemetrexed in advanced gastric cancer remains limited, the promising activity observed in this study indicates that combination studies are warranted. In addition, high-dose intermittent oral folic acid given in this study allowed administration of pemetrexed at the dose and schedule explored with a highly satisfactory safety profile and with no apparent compromise in efficacy. This article discusses how pemetrexed may be investigated in future clinical trials in gastric cancer. Semin Oncol 29 (suppl 18):63-68. Copyright 2002, Elsevier Science (USA). All rights reserved.

This study was designed to determine the feasibility, maximum tolerated dose, and toxicities of intraarterial administration of paclitaxel-albumin nanoparticles in patients with advanced head and neck and recurrent anal canal squamous cell carcinoma. Antitumor activity also was assessed. Forty-three patients (31 with advanced head and neck and 12 with recurrent anal canal squamous cell carcinoma) were treated intraarterially with ABI-007 every 4 weeks for 3 cycles. In total, 120 treatment cycles were completed, 86 in patients with head and neck carcinoma (median, 3 cycles; range, 1–4) and 34 in patients with anal canal carcinoma (median, 3 cycles; range, 1–4). ABI-007 was compared preliminarily with Taxol® for in vitro cytostatic activity. Increasing dose levels from 120 to 300 mg/m² were studied in 18 patients. Pharmacokinetic profiles after intraarterial administration were obtained in a restricted number of patients. The dose-limiting toxicity of ABI-007 was myelosuppression consisting of Grade 4 neutropenia in 3 patients. Nonhematologic toxicities included total alopecia (30 patients), gastrointestinal toxicity (3 patients, Grade 2), skin toxicity (5 patients, Grade 2), neurologic toxicity (4 patients, Grade 2) ocular toxicity (1 patient, Grade 2), flu-like syndrome (7 patients, Grade 2; 1 patient, Grade 3). In total, 120 transfemoral, percutaneous catheterization procedure–related complications occurred only during catheterization of the neck vessels in 3 patients (2 TIA, 1 hemiparesis) and resolved spontaneously. Intraarterial administration of ABI-007 by percutaneous catheterization does not require premedication, is easy and reproducible, and has acceptable toxicity. The maximum tolerated dose in a single administration was 270 mg/m². Most dose levels showed considerable antitumor activity (42 assessable patients with 80.9% complete response and partial response). The recommended Phase II dose is 230 mg/m² every 3 weeks. Cancer 2001;92:2592–602. © 2001 American Cancer Society.

Purpose:To evaluate the efficiency of a new high-capacity pump for systemic venous chemotherapy and to verify the quality of implantation by interventional radiology staff. Methods:A total of 47 infusion pumps with a 60-ml reservoir and variable flow rates (2, 6, 8, or 12 ml/24 hr) were implanted by radiologists in 46 patients with solid tumor metastases requiring treatment with a single, continuously infused cytostatic agent. The reservoir was refilled transcutaneously, usually once weekly. The flow accuracy of the pump was assessed from actual drug delivery recorded on 34 patients over a minimum observation period of 180 days. Results:No early complications occurred in any of the 47 implants in 46 patients. A total of 12 (25.53%) complications occurred between 3 and 24 months after implantation. Seven (14.90%) of these were due to the external design of the pump, while five (10.63%) were related to the central venous catheter. In the 34 patients available for pump evaluation (follow-up of at least 180 days), the system was used for a total of 14,191 days (range 180–911 days, mean 417.38 days), giving an overall complication rate of 0.84 per 1000 days of operation. The mean flow rate accuracy was 90.26%. Conclusion:The new implantable pump showed good flow rate accuracy and reliable operation. The pump-related complications were related to its external design and have now been corrected by appropriate modifications. From a radiologic and surgical viewpoint, the venous implantation procedure is identical to that of conventional vascular access devices and can be performed by radiologists familiar with these techniques. The current limitations lie in the high cost of the pump and, for certain drugs, the short time between refills.

Background and aims In the radiologic assessment of ovarian masses, the major difficulty consists in the late recognition and lack of parameters for a differential diagnosis between benign and malignant lesions, especially in the post-menopause when the incidence of cancer is higher. The use of a transvaginal probe and the color-Doppler examination have recently improved the study of the female pelvis. This study is aimed to verify the possibility of the color-Doppler imaging to differentiate between malignant and benign ovarian lesions during transvaginal echographies, on the basis of the qualitative and quantitative characteristics of the vascular pattern of the ovarian lesions.Results Twenty-six expansive ovarian lesions were studied: 8/26 showed no vascular signals and were considered benign as confirmed at histology. In the remaining lesions with some vascularization, the resistance index (RI) was evaluated: those with RI > 0.40 were considered benign, those with RI < 0.40 malignant. In 8/9 benign lesions and in 7/9 malignant neoplasms, the results of color-Doppler were coherent with histology. The results showed a sensibility of 87.5 % and a specificity of 88.8 % for the transvaginal examination.Conclusions The main advantages of the color-Doppler transvaginal examination are: the high frequency of visualization of the ovaries, even in postmenopausal patients; the definition of small lesions; the visualization of small parenchymal vessels, both physiologic and pathologic, and their quantitative analysis. The importance of the RI cutoff was critical for the differential diagnosis between benign and malignant lesions: we think that a cutoff of 0.50, instead of 0.40 proposed by other authors, would be far more appropriate.

Aims and background The aim of this work is to demonstrate the usefulness of carbon dioxide, used as contrast agent, in special indications in vascular interventional oncological procedures.Methods We studied 40 patients with digital subtraction angiography enhanced with CO2as a contrast agent. At the same time we utilized also, in all cases, jodinated contrast agent to evaluate the different opacification gradient, the different viscosity range and the different perfusion.Results The low viscosity of CO2allows demonstration of the presence of even minimal blood losses in gastrointestinal tumors and enhances arteriovenous shunts in hepatocellular carcinoma. Carbon dioxide can also be employed to assess the patency of small-sized catheters for chemotherapy infusion which do not allow easy injection of the traditional iodinated contrast agents characterized by high viscosity.Conclusion Carboangiographic study combined to digital subtraction angiography can clear some diagnostic problems and is further method to assess the outcome of angiographic interventional procedures in oncology.

Combination of the AKT inhibitor Perifosine (Æterna Zentaris GmbH, Germany) with the multikinase inhibitor Sorafenib (Nexavar, Bayer) induces gene expression profiling and signaling changes resulting in a synergistic cytotoxic activity against lymphoma cell lines. Based on this preclinical rationale, we performed a phase II study aimed at determining safety and activity of the Perifosine/Sorafenib combination therapy in relapsed/refractory lymphomas, and at evaluating predictive and prognostic biomarkers.Between July 2008 and November 2011, 40 patients (26 males and 14 females; median age, 42 years; range, 17–77 years) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 3), Waldenstrom macroglobulinemia (WM, n = 1), chronic lymphocytic leukemia (CLL, n = 8), and classical Hodgkin Lymphoma (cHL, n = 25) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this trial. Prior to study entry, patients received a median of 5 (range 2 – 11) lines of treatment with autologous stem cell transplant (SCT) performed in 27 (67%) and an additional allogeneic SCT in 17 (42%) patients. At study entry, 12 patients (30%) had relapsed and 28 (70%) refractory disease. Treatment plan included an initial 4-week treatment with Perifosine alone (50 mg BID, per os) to assess tolerability and tumor response. Subsequently, patients achieving less than partial remission (PR) were given the combination therapy, i.e., Perifosine (50 mg BID, per os) plus Sorafenib (400 mg BID, per os) until disease progression (PD) or clinical significant toxicity, whereas patients achieving more than PR went off-study and continued with Perifosine alone (50 mg BID, per os) until PD or clinical significant toxicity. Phosphorylation levels of ERK (pERK) and AKT (pAKT) were investigated by flow cytometry on peripheral blood lymphocytes (PBL) collected prior to therapy initiation and monthly thereafter. Tumor response was assessed according to the revised response criteria for malignant lymphoma of the International Working Group. The study was approved by the Institutional Review Board and Ethical Committee.Based on tumor response to the initial 4-week Perifosine therapy, 36 of 40 patients who achieved less than PR were subsequently administered with the combination therapy and are reported herein. In contrast, 4 CLL patients who achieved more than PR with Perifosine alone went off-study and continued with single agent therapy. Median duration of combination therapy was 4 months (range, 2 – 18). The most common drug-related toxicities were grade 1–2 anemia (17%), thrombocytopenia (9%), diarrhea (25%) and joint pain (22%). Hand-foot skin reaction was of grade 2 in 25% and of grade 3 in 14% of patients. Grade 4 neutropenia was observed in one patient. Definitive treatment discontinuation was required in 2 patients experiencing grade 3 pneumonitis. Best response to combination therapy included 8 (22%) PR, 15 (42%) stable disease (SD) and 13 (36%) PD. Median time to achieve PR was 4 months (range, 1–8) and median duration of response (DoR) was 4 months (range, 1 – 12). Patients achieving PR included 7 cHL and 1 CLL patients, resulting in an overall response rate (ORR) of 28% in the cHL subgroup. After a median follow-up of 14 months (range, 2 – 45), the median overall survival (OS) and progression free survival (PFS) for all study patients were 16 and 5 months, respectively; for responding cHL patients median OS was not reached and median PFS was 12 months. A significant correlation between pERK and pAKT reduction during the first two months of therapy and clinical response was demonstrated by logistic regression model. The reduction of pERK and pAKT values (i.e., the difference between baseline values vs 60-day values) was related to a highly significant probability to observe a clinical response (P = 0.003 and P = 0.005 for pERK and pAKT, respectively).Combination therapy with Perifosine and Sorafenib is well tolerated by heavily pretreated lymphoma patients. Promising activity in term of clinical response is observed in relapsed/refractory cHL patients, suggesting this subgroup could represent the target population for future studies. Early reduction of pERK and pAKT during the first two months of therapy has a significant predictive value of clinical response and needs to be confirmed in a larger cohort of patients.No relevant conflicts of interest to declare.

Abstract 3679

The AKT inhibitor Perifosine (Æterna Zentaris GmBH, Germany) has been shown in phase II studies to induce partial responses in a variety of solid tumors. Sorafenib (Nexavar, Bayer) is an oral multikinase inhibitor exerting in vitro and in vivo antiproliferative, antiangiogenic, and proapoptotic effects in a variety of hematological and nonhematological tumors. Our preclinical data demonstrating that the combination of Perifosine and Sorafenib induces gene expression profiling and signaling changes associated with a synergistic cytotoxic activity against lymphoma cell lines in vitro and in vivo, established the rationale for this ongoing phase II study aimed to determine safety and activity of Perifosine/Sorafenib combination therapy in relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).Between July 2008 and July 2010, 26 out of 36 planned patients (18 males and 8 females; median age, 42 years; range, 19–73 years) with relapsed/refractory diffuse large B cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 3), Waldenstrom macroglobulinemia (WM, n = 1), chronic lymphocytic leukemia (CLL, n = 4), and HL (n = 15) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this trial. Prior to study entry, patients received a median of 5 (range 2 – 11) lines of treatment with autologous SCT performed in 19 (73%) and an additional allogeneic SCT in 10 (38%) patients. At study entry, 7 patients had relapsed and 19 refractory lymphoma. Perifosine (50 mg BID, per os) was initially administered as single agent for 4 weeks to assess tolerability and tumor response. Patients achieving less than partial remission (PR) were given the combination therapy, i.e., Perifosine (50 mg BID, per os) plus Sorafenib (400 mg BID, per os) until disease progression or clinical significant toxicity. Patients achieving ≥PR went off-study and continued with Perifosine (50 mg BID, per os) alone until disease progression or clinical significant toxicity. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. NCI CTCAE v3.0 was used for toxicity assessment. The study was approved by the Institutional Ethical Committee.After a 4-week treatment with Perifosine alone, 22 out of 26 patients achieved

Abstract 2861

NHL patients with refractory disease or relapsing after autologous or allogeneic stem cell transplant (SCT) have very poor prognosis with currently available salvage chemotherapy. Sorafenib (Nexavar, BAY43-9006, Bayer) is an oral multikinase inhibitor approved by FDA for the treatment of renal cell carcinoma and hepatocellular carcinoma. Sorafenib exerts a broad range of antiproliferative, antiangiogenic, and proapoptotic effects against a variety of nonhematological tumors through the inhibition of the RAF/MEK/ERK pathway, the receptor tyrosine kinases c-kit, Flt3, RET, as well as the proangiogenic vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptor-β (PDGFR-β). Several lines of evidence suggest that Sorafenib might have a significant clinical impact in the treatment of malignant lymphomas by overcoming the cytoprotective effects of Bcl-XL, ERK, and Mcl-1 and eventually targeting additional signalling pathways relevant to lymphomagenesis. Our preclinical data demonstrating a marked cytotoxic activity of Sorafenib against NHL cell lines in vitro and in vivo in xenograft models, established the rationale for this currently ongoing phase II study aimed to determine safety and activity of Sorafenib in relapsed/refractory NHL.Between March 2008 and May 2009, 21 patients (16 males and 5 females; median age, 65 years; range, 29-74 years) with relapsed/refractory diffuse large B cell lymphoma (DLBCL, n = 11), follicular lymphoma (FL, n =4), mantle cell lymphoma (MCL, n =2), lymphoplasmacitoid lymphoma (LPL, n =1), chronic lymphocytic leukemia (CLL, n =2), and peripheral T-cell lymphoma (PTCL, n =1) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this phase II trial. Prior to study entry, patients received a median of 4 (range 2 - 7) lines of treatment, including autologous SCT in 15 (71%) and an additional allogeneic SCT in 5 (24%) cases. At study entry, 7 (33%) patients had relapsed and 14 (67%) refractory disease. Eligibility criteria included absence of any available treatment options of proven efficacy, at least one target lesion ≥2 cm, ECOG performance status of 0-1, and adequate bone marrow, liver and renal functions. Sorafenib (400 mg BID, per os) was administered continuously until disease progression or appearance of clinical significant toxicity probably related to study drug. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. NCI CTCAE v3.0 was used for toxicity assessment.To date, 21 patients received a median of 3 months (range, 1 – 11) of Sorafenib therapy. All patients are evaluable for toxicity and response, and 1 patient is still on therapy. Overall, therapy was well tolerated without significant adverse events. The most common drug-related non-hematological toxicities were grade 1-2 mucositis (14%), diarrhea (24%), hand-foot syndrome (24%), anorexia (29%), and fatigue (29%). Grade 3-4 hand-foot syndrome occurred in 19% of patients. Hematological toxicities included grade 1-2 neutropenia (10%) and thrombocytopenia (24%). Grade 3-4 neutropenia and thrombocytopenia were observed in 14%, and 24% of patients, respectively. Best response to Sorafenib included 1 (5%) complete remission (CR) occurring in the patient with LPL, and 1 (5%) partial remission (PR) in a patient with cutaneous DLBCL, for an overall response rate (ORR) of 10%. In both patients, response duration was 6 months. In addition, 9 (42%) patients achieved stable disease (SD) for a median of 3 months (range, 2 – 10), with 3 (14%) patients achieving SD for ≥6 months, while 10 (48%) patients progressed. Upon Sorafenib treatment, an extensive necrosis involving the central area of the tumor associated with a nearly complete disappearance of tumor vascularization was documented by computed tomography and contrast-enhanced ultrasound in two DLBCL and one FL patients bearing latero-cervical or abdominal lymphoid masses.Sorafenib as a single agent was well tolerated. Despite limited clinical activity (10% ORR), disease stabilization was experienced by 42% of patients. The potent antiangiogenic activity of Sorafenib in NHL patients bearing highly vascularized lymphoid masses suggests that further research should focus on combinations of Sorafenib with molecularly targeted agents eventually exerting antivascular activities.Off Label Use: The multikinase inhibitor Sorafenib has been used in a phase II trial in patients with relapsed/refractory NHL.

Abstract 1658

Introduction:HL patients with refractory disease or relapsing after autologous stem cell transplantation (SCT) have very poor prognosis with currently available salvage chemotherapy. ITF2357 (Italfarmaco S.p.A., Milano, Italy) is an orally bioavailable hydroxamate inhibitor of class I and II histone deacetylases (HDACs) with preclinical and clinical activity as single agent in hematopoietic cancers. Our preclinical data demonstrating a synergistic activity of ITF2357 with the alkylating agent Meclorethamine in HL cell lines, established the rationale for this currently ongoing phase II study aimed to determine activity and safety of the sequential ITF2357 and Meclorethamine treatment.

Introduction: HL patients with refractory disease or relapsing after autologous stem cell transplantation (SCT) have very poor prognosis with currently available salvage chemotherapy. ITF2357 (Italfarmaco S.p.A., Milano, Italy) is an orally bioavailable hydroxamate inhibitor of class I and II histone deacetylases (HDACs) with preclinical and clinical activity as single agent in hematopoietic cancers. Our preclinical data demonstrating a synergistic activity of ITF2357 with the alkylating agent Meclorethamine in HL cell lines, established the rationale for this currently ongoing phase II study aimed to determine activity and safety of the sequential ITF2357 and Meclorethamine treatment. Methods: Patients with relapsed/refractory HL who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled. Eligibility criteria included prior treatment with autologous and/or allogeneic SCT, prior treatment with single agent Meclorethamine, at least one target lesion ≥2 cm, ECOG performance status of 0–1, and platelet ≥75,000/μL. ITF2357 (50 mg QID, per os, days 1–3) followed by Meclorethamine (6 mg/sqm, intravenously, day 4) was dosed in 3-week cycles until disease progression or appearance of clinical significant toxicity, but for a maximum of 12 cycles. Tumor responses were determined after cycles 2, 6, 9 and 12 by computed tomography (CT) and positron emission tomography (PET) scan. Serum levels of thymus- and activation-regulated chemokine (TARC) were assessed by ELISA prior to each cycle of therapy. Results: To date, 19 patients have been enrolled (16 males and 3 females; median age, 33 years; range, 21–61 years), including 8 patients enrolled in a preliminary compassionate use trial, and 11 patients of a planned 23 enrolled in this ongoing phase II trial. Prior to study entry, patients received a median of 5 (range 2–7) lines of treatment with autologous SCT performed in 15 (79%) and an additional allogeneic SCT in 5 (26%) patients. At study entry, 6 patients had relapsed and 13 refractory HL. Seventeen of 19 patients received a median of 3 cycles (range, 1–10) of ITF2357/Meclorethamine and are evaluable for response by CT and PET scans. Best response to therapy included 2 (12%) complete remissions (CR) and 3 (18%) partial remissions (PR), for an overall response rate (ORR) of 30%. In addition, 5 (29%) patients had stable disease (SD) with 4 (23%) patients achieving SD for ≥4 months, while 7 (41%) patients progressed. After the first cycle of therapy, serum TARC levels were decreased by 70±16% (mean±SEM, P ≤0.05) in 5 patients who achieved major clinical responses (PR+CR), and by 16±14% (P = ns) in patients who achieved SD. Overall, therapy was well tolerated without significant adverse events, and no patient required dose reductions for management of toxicities. The most common drug-related non-hematological toxicities were grade 1–2 nausea (12/17) and fatigue (14/17). Four patients experienced infections [pneumonia (n = 1), oral herpes simplex (n = 2), oral candidiasis (n = 1)]. No prolongation of QT/QTc interval has been detected over 70 therapy cycles. Hematological toxicities included grade 1–2 anemia (13/17), neutropenia (7/17), and thrombocytopenia (12/17). Grade 3–4 neutropenia and thrombocytopenia were observed in 7 and 8 patients, respectively. RBC and platelet transfusions were required by 4 and 5 patients, respectively. Conclusions: Preliminary results from this ongoing trial suggest that ITF2357, in combination with Meclorethamine, demonstrates significant anti-tumor activity in heavily pretreated relapsed/refractory HL and is well tolerated. Preliminary data also suggest that early decrease in serum TARC levels may predict response to therapy.