A Novel Assay in Whole Blood Demonstrates Restoration of Mitochondrial Activity in Phagocytes After Successful HSCT in Hyperinflamed X-Linked Chronic Granulomatous Disease.

X-linked chronic granulomatous disease is a rare disease caused by mutations in the CYBB gene. While more extensive knowledge is available on genetics, pathogenesis, and possible therapeutic options, mitochondrial activity and its implications on patient monitoring are still not well-characterized. We have developed a novel protocol to study mitochondrial activity on whole blood of XCGD patients before and after transplantation, as well as on XCGD carriers. Here we present results of these analyses and of the restoration of mitochondrial activity in hyperinflamed X-linked Chronic Granulomatous Disease after hematopoietic stem cell transplantation. Moreover, we show a strong direct correlation between mitochondrial activity, chimerism, and DHR monitored before and after transplantation and in XCGD carriers. In conclusion, based on these findings, we suggest testing this new ready-to-use marker to better characterize patients before and after treatment and to investigate disease expression in carriers.

Perioperative and oncologic outcomes of open radical nephrectomy and inferior vena cava thrombectomy with liver mobilization and Pringle maneuver for Mayo III level tumor thrombus: single institution experience.

BACKGROUND: Scarce data are available regarding the technique and outcomes for patients with RCC and Mayo III caval thrombi. The aim of this study was to report surgical and oncological outcomes of RCC patients with Mayo III thrombi treated with radical nephrectomy and thrombectomy after liver mobilization (LM) and Pringle maneuver (PM). METHODS: Retrospective analysis of surgical technique, outcomes and cancer control in 19 patients undergoing LM and PM in a single tertiary care institution were analyzed. RESULTS: Overall, 78% of the patients had performance status ECOG 1 and 58% had a Comorbidity Index >2. Median surgical time was 305 minutes (IQR 264-440). Intraoperative complications were reported for 39% of patients and postoperative complications for 58% (only grade 1 and 2). Intensive Care Unit support was necessary in 16% of the cases. Median length of hospital stay was 9 days (IQR: 7-11). Thirty- and 90-day mortality were 5% and 15%. Two-year overall survival and cancer-specific survival were 60% and 62%, respectively. CONCLUSIONS: We reported surgical techniques, intra- and perioperative complications and follow-up in the largest cohort of RCC patients requiring LM and PM.

Necrosis volume and Choi criteria predict the response to endoscopic ultrasonography-guided HybridTherm ablation of locally advanced pancreatic cancer.

Background and study aims Endoscopic ultrasound (EUS)-guided ablation of pancreatic ductal adenocarcinoma (PDAC) with HybridTherm-Probe (EUS-HTP) is feasible and safe, but the radiological response and ideal tool to measure it have not been investigated yet. The aims of this study were to: 1) assess the radiological response to EUS-HTP evaluating the vital tumor volume reduction rate, Response Evaluation Criteria in Solid Tumors (RECIST1.1) and Choi criteria; 2) determine the prognostic predictive yield of these criteria. Patients and methods A retrospective analysis was performed of patients with locally advanced PDAC after primary treatment or unfit for chemotherapy prospectively treated by EUS-HTP. Computed tomography scan was performed 1 month after EUS-HTP to evaluate: 1) vital tumor volume reduction rate (VTVRR) by measuring necrosis and tumor volumes through a computer-aided detection system; and 2) RECIST1.1 and Choi criteria. Results EUS-HTP was feasible in 22 of 31 patients (71 %), with no severe adverse events. Median post-HTP survival was 7 months (1 - 35). Compared to pre-HTP tumor volume, a significant 1-month VTVRR (mean 21.4 %) was observed after EUS-HTP ( P  = 0.005). We identified through ROC analysis a VTVRR > 11.46 % as the best cut-off to determine post-HTP 6-month survival outcome (AUC = 0.733; sensitivity = 70.0 %, specificity = 83.3 %). This cut-off was significantly associated with longer overall survival (HR = 0.372; P  = 0.039). According to RECIST1.1 and Choi criteria, good responders to EUS-HTP were 60 % and 46.7 %, respectively. Good responders according to Choi, but not to RECIST1.1, had longer survival (HR = 0.407; P  = 0.04). Conclusions EUS-HTP induces a significant 1-month VTVRR. This effect is assessed accurately by evaluation of necrosis and tumor volumes. Use of VTVRR and Choi criteria, but not RECIST 1.1 criteria, might identify patients who could benefit clinically from EUS-HTP.

Leakage Risk Stratification After Laparoscopic Sleeve Gastrectomy (LSG): Is There a Role for Routine Postoperative CT Scan?

PURPOSE: Leakage of the gastric remnant after laparoscopic sleeve gastrectomy (LSG) represents an unpredictable, dreadful occurrence. Our aim was to assess whether routine postoperative CT scan is an effective tool for early prediction of leakage after LSG. MATERIALS AND METHODS: From a prospectively acquired database, all consecutive patients who underwent LSG between January 2015 and December 2018 were identified; within this database, all patients who were evaluated with at least one contrast-enhanced CT scan within 48 h from surgery were enrolled in this retrospective study. The selected CT findings included twisting of the gastric remnant, perigastric air bubbles, and hematoma; the antral segment proximal from the pylorus to the first staple firing was also analyzed in terms of distance (StP, stapler to pylorus distance) and linearity (LI, linearity index). RESULTS: After exclusions, 250 patients were included; 10 patients suffered from gastric leakage. Patients with perigastric hematoma and/or twisting of the distal part of the gastric remnant on routine postoperative CT scan were found to be more likely to develop leakage after LSG (p = 0.005 and p < 0.001, respectively). The mean StP was 45 ± 19.1 mm; the mean LI was 1.54 ± 0.4. Patients with subsequent development of leakage had significantly lower StP (26.7 ± 12.5 mm vs. 45.9 ± 18.9 mm; p = 0.001) and LI values (1.16 ± 0.11 vs. 1.55 ± 0.39; p = 0.002). CONCLUSION: Routine postoperative CT scan after LSG permits early stratification of leakage risk, thus providing an actual aid for patients' management.

Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.

BACKGROUND: Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. METHODS: This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 and oral capecitabine 1250 mg/m2 on days 1-28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. FINDINGS: Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. INTERPRETATION: Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. FUNDING: Celgene.

A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma.

BACKGROUND: The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). METHOD: Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. RESULTS: Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. CONCLUSIONS: In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. TRIAL REGISTRATION: NCT01730222.

First Occurrence of Plasmablastic Lymphoma in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Disease Patient and Review of the Literature.

Adenosine deaminase-deficient severe combined immunodeficiency disease (ADA-SCID) is a primary immune deficiency characterized by mutations in the ADA gene resulting in accumulation of toxic compounds affecting multiple districts. Hematopoietic stem cell transplantation (HSCT) from a matched donor and hematopoietic stem cell gene therapy are the preferred options for definitive treatment. Enzyme replacement therapy (ERT) is used to manage the disease in the short term, while a decreased efficacy is reported in the medium-long term. To date, eight cases of lymphomas have been described in ADA-SCID patients. Here we report the first case of plasmablastic lymphoma occurring in a young adult with ADA-SCID on long-term ERT, which turned out to be Epstein-Barr virus associated. The patient previously received infusions of genetically modified T cells. A cumulative analysis of the eight published cases of lymphoma from 1992 to date, and the case here described, reveals a high mortality (89%). The most common form is diffuse large B-cell lymphoma, which predominantly occurs in extra nodal sites. Seven cases occurred in patients on ERT and two after haploidentical HSCT. The significant incidence of immunodeficiency-associated lymphoproliferative disorders and poor survival of patients developing this complication highlight the priority in finding a prompt curative treatment for ADA-SCID.

Pre-treatment MDCT-based texture analysis for therapy response prediction in gastric cancer: Comparison with tumour regression grade at final histology.

PURPOSE: An accurate prediction of tumour response to therapy is fundamental in oncology, so as to prompt personalised treatment options if needed. The aim of this study was to investigate the ability of preoperative texture analysis from multi-detector computed tomography (MDCT) in the prediction of the response rate to neo-adjuvant therapy in patients with gastric cancer. MATERIAL AND METHODS: Thirty-four patients with biopsy-proven gastric cancer were examined by MDCT before neo-adjuvant therapy, and treated with radical surgery after treatment completion. Tumour regression grade (TRG) at final histology was also assessed. Image features from texture analysis were quantified, with and without filters for fine to coarse textures. Patients with TRG 1-3 were considered responders while TRG 4-5 as non- responders. The response rate to neo-adjuvant therapy was assessed both at univariate and multivariate analysis. RESULTS: Fourteen parameters were significantly different between the two subgroups at univariate analysis; in particular, entropy and compactness (higher in responders) and uniformity (lower in responders). According to our model, the following parameters could identify non-responders at multivariate analysis: entropy (≤6.86 with a logarithm of Odds Ratio - Log OR -: 4.11; p=0.003); range (>158.72; Log OR: 3.67; p=0.010) and root mean square (≤3.71; Log OR: 4.57; p=0.005). Entropy and three-dimensional volume were not significantly correlated (r=0.06; p=0.735). CONCLUSION: Pre-treatment texture analysis can potentially provide important information regarding the response rate to neo-adjuvant therapy for gastric cancer, improving risk stratification.

Gastric cancer: texture analysis from multidetector computed tomography as a potential preoperative prognostic biomarker.

OBJECTIVES: To investigate the association between preoperative texture analysis from multidetector computed tomography (MDCT) and overall survival in patients with gastric cancer. METHODS: Institutional review board approval and informed consent were obtained. Fifty-six patients with biopsy-proved gastric cancer were examined by MDCT and treated with surgery. Image features from texture analysis were quantified, with and without filters for fine to coarse textures. The association with survival time was assessed using Kaplan-Meier and Cox analysis. RESULTS: The following parameters were significantly associated with a negative prognosis, according to different thresholds: energy [no filter] - Logarithm of relative risk (Log RR): 3.25; p = 0.046; entropy [no filter] (Log RR: 5.96; p = 0.002); entropy [filter 1.5] (Log RR: 3.54; p = 0.027); maximum Hounsfield unit value [filter 1.5] (Log RR: 3.44; p = 0.027); skewness [filter 2] (Log RR: 5.83; p = 0.004); root mean square [filter 1] (Log RR: - 2.66; p = 0.024) and mean absolute deviation [filter 2] (Log RR: - 4.22; p = 0.007). CONCLUSIONS: Texture analysis could increase the performance of a multivariate prognostic model for risk stratification in gastric cancer. Further evaluations are warranted to clarify the clinical role of texture analysis from MDCT. KEY POINTS: • Textural analysis from computed tomography can be applied in gastric cancer. • Preoperative non-invasive texture features are related to prognosis in gastric cancer. • Texture analysis could help to evaluate the aggressiveness of this tumour.

Prospective comparison of MR with diffusion-weighted imaging, endoscopic ultrasound, MDCT and positron emission tomography-CT in the pre-operative staging of oesophageal cancer: results from a pilot study.

OBJECTIVE: To compare the diagnostic performance of MR and diffusion-weighted imaging (DWI), multidetector CT, endoscopic ultrasonography (EUS) and 18F-FDG (fluorine-18 fludeoxyglucose) positron emission tomography CT (PET-CT) in the pre-operative locoregional staging of oesophageal cancer. METHODS: 18 patients with oesophageal or Siewert I tumour (9 directly treated with surgery and 9 addressed to chemo-/radiotherapy before) underwent 1.5-T MR and DWI, 64-channel multidetector CT, EUS and PET-CT before (n = 18) and also after neoadjuvant treatment (n = 9). All images were analysed and staged blindly by dedicated operators (seventh TNM edition). Two radiologists calculated independently the apparent diffusion coefficient from the first scan. Results were compared with histopathological findings. After the population had been divided according to local invasion (T1-T2 vs T3-T4) and nodal involvement (N0 vs N+), sensitivity, specificity, accuracy, positive- and negative-predictive values were calculated and compared. Quantitative measurements from DWI and PET-CT were also analysed. RESULTS: For T staging, EUS showed the best sensitivity (100%), whereas MR showed the highest specificity (92%) and accuracy (83%). For N staging, MR and EUS showed the highest sensitivity (100%), but none of the techniques showed adequate results for specificity. Overall, MR showed the highest accuracy (66%) for N stage, although this was not significantly different to the other modalities. The apparent diffusion coefficient was different between surgery-only and chemo-/radiotherapy groups (1.90 vs 1.30 × 10-3 mm2 s-1, respectively; p = 0.005)-optimal cut off for local invasion: 1.33 × 10-3 mm2 s-1 (p = 0.05). Difference in standardized uptake value was also very close to conventional levels of statistical significance (8.81 vs 13.97 g cm-3, respectively; p = 0.05)-optimal cut off: 7.97 g cm-3 (p = 0.44). CONCLUSION: In this pilot study, we have shown that MR with DWI could enrich the current pre-operative work-up for oesophageal cancer and could be used for T and N staging. However, larger studies will need to be carried out before introducing this technique in the standard diagnostic pathway, in order to understand if MR with DWI could change its management and replace more costly or invasive tests such as PET-CT or EUS. Advances in knowledge: This pilot study represents the first effort where the four techniques have been prospectively compared together for oesophageal cancer staging. The combination of MR and DWI could provide important, additional information for staging and initial treatment decision-making.

Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma.

BACKGROUND: Nab-paclitaxel-gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m(-2) every 2 weeks, respectively; PAXG regimen). METHODS: Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m(-2) (level three) every 2 weeks in cohorts of 3-6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma. RESULTS: Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by ⩾49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%. CONCLUSIONS: The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m(-2) every 2 weeks. The preliminary results are promising and warrant further exploration.

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial.

PURPOSE: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. EXPERIMENTAL DESIGN: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. RESULTS: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. CONCLUSIONS: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.

Preoperative locoregional staging of gastric cancer: is there a place for magnetic resonance imaging? Prospective comparison with EUS and multidetector computed tomography.

BACKGROUND: The aim of this study was to prospectively compare the diagnostic performance of magnetic resonance imaging (MRI), multidetector computed tomography (MDCT) and endoscopic ultrasonography (EUS) in the preoperative locoregional staging of gastric cancer. METHODS: This study had Institutional Review Board approval, and informed consent was obtained from all patients. Fifty-two patients with biopsy-proven gastric cancer underwent preoperative 1.5-T MRI, 64-channel MDCT and EUS. All images were analysed blind, and the results were compared with histopathological findings according to the seventh edition of the TNM classification. After the population had been divided on the basis of the local invasion (T1-3 vs T4a-b) and nodal involvement (N0 vs N+), sensitivity, specificity, positive and negative predictive value, and accuracy were calculated and diagnostic performance measures were assessed using the McNemar test. RESULTS: For T staging, EUS showed higher sensitivity (94%) than MDCT and MRI (65 and 76%; p = 0.02 and p = 0.08). MDCT and MRI had significantly higher specificity (91 and 89%) than EUS (60%) (p = 0.0009 and p = 0.003). Adding MRI to MDCT or EUS did not result in significant differences for sensitivity. For N staging, EUS showed higher sensitivity (92%) than MRI and MDCT (69 and 73%; p = 0.01 and p = 0.02). MDCT showed better specificity (81%) than EUS and MRI (58 and 73%; p = 0.03 and p = 0.15). CONCLUSIONS: Our prospective study confirmed the leading role of EUS and MDCT in the staging of gastric cancer and did not prove, at present, the value of the clinical use of MRI.

Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.

Feasibility and safety of EUS-guided cryothermal ablation in patients with locally advanced pancreatic cancer.

BACKGROUND: New therapies are needed for pancreatic cancer. OBJECTIVE: To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor growth measured with CT scan and to find the overall survival. DESIGN: A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. SETTING: San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. PATIENTS: A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. INTERVENTION: Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. MAIN OUTCOME MEASUREMENTS: Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. RESULTS: The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass (P = .07). LIMITATIONS: Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. CONCLUSION: EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.

A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen).

PURPOSE: PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6). METHODS: Chemo-naive patients with stage III or metastatic PA received P (30 mg/m(2) day 1 and 15), G (800 mg/m(2) day 1 and 15), and capecitabine (1,250 mg/m(2)/day days 1-28, without a break) and were randomized to receive either D at 25-30 mg/m(2) day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m(2) day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and ß = 0.10; the study was to enroll 52 patients per arm. RESULTS: Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients' characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%. CONCLUSIONS: The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

Salvage therapy with mitomycin and ifosfamide in patients with gemcitabine-resistant metastatic pancreatic cancer: a phase II trial.

BACKGROUND: At the time of upfront treatment failure, over half of the patients with advanced pancreatic cancer are candidates for further treatment. METHODS: Patients with metastatic gemcitabine-resistant pancreatic cancer were treated with mitomycin 8 mg/m(2) on day 1, ifosfamide 2,500 mg/m(2) and mesna 3,000 mg/m(2) on days 1-3 every 28 days until progressive disease. A positive responder was defined as a patient who was progression free at 6 months from trial enrollment. According to the Fleming design, a sample size of 34 patients was estimated assuming p0 = 0.05 and p1 = 0.20. RESULTS: Between May 2006 and December 2007, 21 patients (median age 56 years; median Karnofsky performance score 80) were enrolled. One patient died before receiving any treatment. Eighteen patients interrupted chemotherapy due to progressive disease (n = 15), toxicity (n = 2) or refusal (n = 1). Grade >2 toxicity consisted of neutropenia in 80% of patients, thrombocytopenia and fatigue in 20% and anemia in 10%. Only 1 patient was progression free at 6 months (5%). One patient had a partial response (5%) and 2 patients had stable disease (10%). Median survival was 3.7 months. CONCLUSION: Based on the poor outcome observed and on the high level of grade 3-4 toxicity, the trial was prematurely stopped and the mitomycin and ifosfamide regimen was considered insufficiently active in gemcitabine-pretreated advanced pancreatic cancer.

XELIRI or FOLFIRI as salvage therapy in advanced pancreatic cancer.

BACKGROUND: More than half of patients with pancreatic adenocarcinoma (PA) are candidates for further treatment when they experience upfront treatment failure. PATIENTS AND METHODS: Patients with gemcitabine-resistant PA, age <76 years and Karnofski performance status (KPS) >50 were treated with a XELIRI or FOLFIRI regimen until progressive disease or a maximum of six months. As this was an observational study, no statistical design was performed. RESULTS: Between July 2007 and December 2009, 34 patients (median age 60 years; median KPS 90) were treated with XELIRI (26) or FOLFIRI (8) regimen. Grade >2 toxicity consisted of neutropenia in 9% of patients, anemia and fatigue in 3% and hand-foot syndrome in 12%. Median progression-free survival was two months (range 1-4). Maximum response was stable disease in four patients (12%). Median survival was 4.2 (range 1-15) months. CONCLUSION: Fluoropyrimidine and irinotecan combination does not seem to have any role in the treatment of gemcitabine-resistant PA.

The cisplatin, epirubicin, 5-fluorouracil, gemcitabine (PEFG) regimen in advanced biliary tract adenocarcinoma.

BACKGROUND: Biliary tract adenocarcinoma (BTA) is an uncommon tumor with a poor prognosis and no standard, systemic chemotherapy. The combined cisplatin, epirubicin, 5-fluorouracil, and gemcitabine (PEFG) regimen is an effective, upfront treatment for advanced pancreatic cancer. In this study, the authors assessed the activity and safety of this combination regimen in patients with advanced BTA. METHODS: PEFG (cisplatin 40 mg/m(2) and epirubicin 40 mg/m(2) on Day 1; gemcitabine 600 mg/m(2) on Days 1 and 8; and 5-fluorouracil [FU] 200 mg/m(2) daily as a continuous infusion) was administered to chemotherapy-naive patients who had a cytologic or histologic diagnosis of locally advanced or metastatic BTA, aged 60 either until they had evidence progressive disease or for a maximum of 6 months. Tumor size was assessed every 2 months during treatment. RESULTS: Between May 1999 and December 2005, 37 patients (62% metastatic) who had a median age of 62 years and a median PS of 90 received the PEFG regimen at the authors' institution. Primary tumor sites were the intrahepatic bile duct in 10 patients (27%), the extrahepatic bile duct in 8 patients (22%), the gallbladder in 12 patients (32%), and the ampulla of Vater in 7 patients (19%). A partial response was observed in 16 patients (43%), and stable disease was observed in 12 patients (32%). The median overall survival (OS) was 12.1 months, and the 1-year OS rate was 52%. The median progression-free survival (PFS) was 7.9 months, and the 6-month PFS rate was 67%. The main grade 3/4 toxicity was neutropenia in 18% of cycles followed by thrombocytopenia in 9% of cycles, nausea/vomiting in 5% of cycles, and febrile neutropenia, fatigue, anemia, and stomatitis in 2% of cycles. CONCLUSIONS: The current results demonstrated that PEFG was an active regimen with a manageable toxicity profile for patients with advanced BTA.