Randomized phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer.

OBJECTIVE: Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer. METHODS: Double-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, ß = 80%, one sided. RESULTS: 120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms. CONCLUSION: The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial.

BACKGROUND: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. PATIENTS AND METHODS: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. RESULTS: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. CONCLUSIONS: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations. CLINICALTRIALS.GOV NUMBER: NCT01704703. EUDRACT NUMBER: 2012-001955-38.

First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

BACKGROUND: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. METHODS: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. MAIN OBJECTIVE: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). RESULTS: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). CONCLUSIONS: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. TRIAL REGISTRATION: This trial was prospectively registered at EudraCT ( 2013-000236-94 ). Date of trial registration: April 9th, 2013.

Cytoprotective and Antioxidant Effects of Steen Solution on Human Lung Spheroids and Human Endothelial Cells.

Respiratory diseases represent a major healthcare burden worldwide. Lung transplantation (LTx) is the "gold standard" for end-stage patients, strongly limited by shortage of available/suitable donor lungs. Normothermic ex vivo lung perfusion (EVLP) has significantly increased the number of lungs suitable for transplantation. Steen solution is used for EVLP, but the mechanisms involved in its beneficial properties remain to be clarified. We investigated the effects of Steen solution in an in vitro protocol of cold starvation and normothermic recovery on human lung spheroids, named pneumospheres (PSs), containing epithelial/basal cells, and on endothelial human umbilical vein endothelial cells (HUVEC). Steen solution significantly preserved the viability of PSs, reduced reactive oxygen species (ROS) release by PSs and HUVECs, decreased NADPH-oxidase (NOX) activity in PSs, and reduced inflammatory cytokines expression levels in HUVECs. Steen solution was able to specifically reduce NADPH oxidase 2 (NOX2) isoform activation, particularly in PSs, as detected by soluble-NOX2 peptide and p47-phosphorylation. Interestingly, a specific NOX2 inhibitor could partly mimic the pro-survival effect of Steen on PSs. We provide the first evidence that Steen solution can preserve lung epithelial/progenitor cells viability partially through NOX2 downregulation, and exert antioxidant effects on parenchymal cells, with consequent ROS reduction. These results suggest that NOX2 inhibition might be an additional strategy to reduce cellular damage during LTx procedures.

Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. PATIENTS AND METHODS: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. RESULTS: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. CONCLUSIONS: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.

Efficacy and safety of tenofovir, entecavir, and telbivudine for chronic hepatitis B in heart transplant recipients.

BACKGROUND: Treatment of chronic hepatitis B (CHB) with polymerase inhibitors is key to prevent disease flares and progression toward advanced liver disease. Efficacy and tolerability of newer agents has been reported anecdotally in transplant recipients. METHODS: In this prospective, observational study, we assessed outcomes of therapy with tenofovir (TDF), entecavir (ETV), and telbivudine (LdT) in 13 heart transplant recipients (HTR) with CHB. RESULTS: Most patients were hepatitis B e antigen negative, had low baseline hepatitis B virus (HBV) DNA, and normal aminotransferases. Liver biopsy showed a median fibrosis score of 1.5 (range 0-4). Glomerular filtration rate (GFR) was <50 mL/min in 7 patients (54%). Two patients were started on de novo ETV before transplant. Eleven previously treated patients were switched to TDF (n = 9) or LdT (n = 2). Median treatment duration was 33 months (range 1-71). HBV DNA remained suppressed in 6 patients and became undetectable in 5. Aminotransferases went down to the normal range in all patients, with a single flare in 1 patient. One patient lost hepatitis B surface antigen. No cases occurred of hepatic decompensation, hepatocellular carcinoma, or liver-related death. The GFR remained largely stable, and no cases of TDF-related hyper-phosphaturia were observed. CONCLUSIONS: This study indicates that newer antivirals are effective and safe in HTR with CHB.

An infrared flash contemporaneous with the gamma-rays of GRB 041219a.

The explosion that results in a cosmic gamma-ray burst (GRB) is thought to produce emission from two physical processes: the central engine gives rise to the high-energy emission of the burst through internal shocking, and the subsequent interaction of the flow with the external environment produces long-wavelength afterglows. Although observations of afterglows continue to refine our understanding of GRB progenitors and relativistic shocks, gamma-ray observations alone have not yielded a clear picture of the origin of the prompt emission nor details of the central engine. Only one concurrent visible-light transient has been found and it was associated with emission from an external shock. Here we report the discovery of infrared emission contemporaneous with a GRB, beginning 7.2 minutes after the onset of GRB 041219a (ref. 8). We acquired 21 images during the active phase of the burst, yielding early multi-colour observations. Our analysis of the initial infrared pulse suggests an origin consistent with internal shocks.

Multidisciplinary approach and multimodal therapy in resected pancreatic cancer. Observational study.

OBJECTIVE: Analysis and evaluation of a multidisciplinary approach, postoperative results and survival of a group of patients with resected pancreatic cancer after a multimodal therapy. DESIGN: DESCRIPTIVE, prospective and observational study. PATIENTS: Between January 2004 and December 2004, 124 patients with pancreatic cancer were evaluated. In 30 patients pancreatic resection was performed, and they are the object of this study. Results of preoperative evaluation, postoperative morbidity and mortality, and long term survival were studied. RESULTS: Diagnostic evaluation was completed in ambulatory basis in 20% of the patients. In 63% of cases, admission was done in the same day of surgery. In 3 patients (9%), tumor resection was not achieved, therefore, concordance between radiological and surgical resectability rate was 91%. Resectability rate was 24.1%. Surgical Mortality was 3.3%, with a global morbidity rate of 56.6%. Survival at one, two, three and, four years was 76.2%, 56.3%, 43%, y 27.3% respectively. CONCLUSIONS: Technological development and coordination of efforts in multidisciplinary teams offer an accurate evaluation of tumor involvement, and may reduce the number of laparotomies without tumor resection. The application of a systematic and generalized multimodal treatment in pancreatic cancer is progressively showing a tendency of progressive increase in resectability and survival rates in pancreatic cancer.

[Sugammadex, efficacious in reversing a neuromuscular block in a woman with Becker muscular dystrophy]. / Eficacia de sugammadex para la reversión del bloqueo neuromuscular en una paciente con distrofia muscular de Becker.

Becker muscular dystrophy affects mainly the musculoskeletal system, causing muscle wasting and progressive weakness. A 61-year-old woman with breast cancer, who had been diagnosed with Becker muscular dystrophy 45 years earlier, was scheduled for right mastectomy. We induced general anesthesia with propofol, fentanyl, and a nondepolarizing muscle blocker (rocuronium). Neuromuscular function was monitored continuously by acceleromyographic train-of-four ratio (TOFr) (Watch-SX monitor). The block was reversed with sugammadex. After preoxygenation with fentanyl and propofol, the device was calibrated and the baseline TOFr was recorded. We injected 1 mg/kg of rocuronium and assessed TOF responses every 15 seconds. The maximum decrease in TOF response (to 0 twitches) was at 52 seconds. Tracheal intubation was uneventful. Anesthesia was maintained by intravenous infusion. The operation lasted 74 minutes. The second TOF twitch (T2) reappeared 86 minutes after the initial dose. After we injected 2 mg/kg of sugammadex, a TOFr of 0.7 was reached at 79 seconds; a TOFr of 0.9 was reached at 108 seconds and a TOFr of 1.0 at 152 seconds. No electrocardiographic or hemodynamic abnormalities occurred during sugammadex administration and there were no signs of residual neuromuscular blockade on awakening or adverse events in the following 24 hours.

Laparoscopic appendectomy for complicated acute appendicitis.

The role of laparoscopic appendectomy in complicated appendicitis is still not widely accepted. The authors report their retrospective study performed to evaluate the effectiveness of the laparoscopic approach in the management of complicated appendicitis. From January 2003 to October 2008, 552 patients underwent appendectomy in our surgical department. Among these, 358 were not complicated appendicitis while 194 were complicated. Of the 194 cases of complicated appendicitis, 121 patients underwent laparoscopic appendectomy while the remaining 73 cases were treated by conventional open surgery. The average length of hospital stay was 5.7 days, with a range from 4 to 13 days. Post-operative complications were observed in a total 11 patients (9.1%), including 3 cases of intra abdominal abscess (2.5%), 2 cases of umbilical wound infection (1.6%) and 6 cases of prolonged ileus (4.9%). Our experience suggests that the laparoscopic procedure is a valid, safe and feasible option to manage acute complicated appendicitis.

Detection of a Compact Radio Source near the Center of a Gravitational Lens: Quasar Image or Galactic Core?

By use of a new, very sensitive interferometric system, a faint, compact radio source has been detected near the center of the galaxy that acts as the main part of a gravitational lens. This lens forms two previously discovered images of the quasar Q09S7+561, which lies in the direction of the constellation Ursa Major. The newly detected source has a core smaller than 0.002 arc second in diameter with a flux density of 0.6 +/- 0.1 millijansky at the 13-centimeter wavelength of the radio observations. This source could be the predicted third image of the transparent gravitational lens, the central core of the galaxy, or some combination of the two. It is not yet possible to choose reliably between these alternatives.

[Primary duodenal adenocarcinoma: report of three cases, prognostic factors and therapeutic approach]. / Adenocarcinoma primitivo del duodeno: tre casi clinici e considerazioni prognostico-terapeutiche.

Three cases of histologically proven primary non-ampullary adenocarcinoma of the duodenum, observed in our Department from 2001 to 2004, are described. The cases were treated by pancreaticoduodenectomy, duodenal resection and transduodenal excision, respectively. The rarity of this pathology is documented by few retrospective studies and justifies discussion about the main prognostic factors and the best therapeutic approach. We analyze diagnostic, therapeutic and prognostic factors after a revision of literature.

[Radiological study of anastomotic leakages following colorectal surgery]. / Il controllo radiologico delle deiscenze anastomotiche in chirurgia colo-rettale.

The anastomotic leakage is one of the most serious complications following colorectal surgery. The incidence rate is between 3% and 21% considering the different experiences, pathology and surgical techniques. Our aim is to verify the role of radiological study in 45 patients with clinical and subclinical colorectal anastomotic leakage total anastomoses = 252). In 31 patients at risk, the operation was concluded with a loop ileostomy. The radiological study gastrografin enema was performed in all patients (26 symptomatic and 19 asymptomatic patients with loop ileostomy). The dehiscence incidence resulted 5.5%: 14 of 252 patients. In our experience the radiological study of selected colorectal anastomoses allowed to show the site and the flow of the leakage and to plan the proper management. In asymptomatic patients the study allowed to programme a specific follow up in patients with higher risk of postinflammatory stenosis or perhaps neoplastic relapse.

First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: Phase II randomised MACRO2 TTD study.

BACKGROUND: This multicentre, randomised, and phase II study evaluated mFOLFOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients (NCT01161316). PATIENTS AND METHODS: Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months. RESULTS: One hundred ninety-three patients (median [range] age 60 [33-74] years) were randomised (2:1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 [52, 69]%/72 [61, 83]%, p [non-inferiority]<0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 [95% CI 7, 10] months/10 [7,13] months, hazard ratio [HR] = 1.19 [0.80, 1.79]) or overall survival (23 [19, 28] months/27 [18, 36] months, HR = 1.24 [0.85, 1.79]) between arms. The objective response rate was also similar (48 [39, 57]%/39 [27, 52]%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade ≥III AEs: 70%/68%). The most common grade ≥III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade ≥III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%). CONCLUSION(S): This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients.

[Surgical timing in bleeding liver adenoma: case report]. / Timing chirurgico nell'adenoma epatico sanguinante: case report.

The diagnosis of liver adenoma, which etiopathogenesis most often involves a prolonged assumption of estrogen (90% of adenomas occurs in women after more than 5 years of estrogen therapy), always imposes a surgical resection. The reason depend from neoplasia characteristics like the malignant evolution (4%) and the high risk of abdominal/intratumoral bleeding (30-50%), that increases during pregnancy and postpartum period. Regression of lesion after discontinuation of hormone therapy is rare and does not remove the degeneration and/or haemorrhagic risk. Liver resection should be performed with appropriate selective endovascular embolization, considering that an inept emergency surgery may impose a greater risk ot the liver, exposing the patient to major risk of morbidity and mortality. The correct timing from embolization to elective surgery is not yet standardized in the literature. The surgeon's personal experience and mainly a careful patient follow-up suggest the timing of surgery after embolization. The authors relate their own experience about the therapeutic strategy and surgical timing in a case of bleeding liver adenoma.

[Covered perforation of solitary cecal diverticulum: case report]. / Perforazione coperta di un diverticolo solitario del cieco: case report.

Acute right lower abdominal pain is often clinically difficult to diagnose. The diagnosis, especially in young patients, is frequently oriented to appendicular disease. Surgical exploration only confirms diagnosis or surprises the surgeon, revealing an unexpected right colon diverticulitis. This emergency condition challenges the surgeon with the dilemma about the best therapeutic choice: conservative or radical treatment? The elective localization of diverticulitis to the right colon is very rare (6.6-14%). The authors report a case of covered perforation of a solitary cecal diverticulum.

Astronomy. ASASSN-15lh: A highly super-luminous supernova.

We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± 0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.

Human mammaglobin mRNA is a reliable molecular marker for detecting occult breast cancer cells in peripheral blood.

Occult carcinoma cells in peripheral blood of breast cancer (BC) patients is generally associated with poor disease prognosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) is a sensitive method for revealing rare circulating cancer cells. The target mRNA must be carefully chosen, as it must be expressed only by malignant cells. In this study, we developed a nested RT-PCR assay for mammaglobin (hMAM) and assessed both its specificity and its sensitivity in the detection of cancer cells in peripheral blood of BC patients. hMAM mRNA was detected by RT-PCR in 156/165 (95%) of fresh BC tissues analyzed. All samples from 66 healthy blood donors and 151 patients with benign breast disease were hMAM negative as assessed by nested RT-PCR. In contrast, hMAM was detected in 16/137 (12%) of peripheral blood samples deriving from BC patients: 0/9 in stage 0, 1/50 (2%) in stage I, 3/33 (9%) in stage II, 1/18 (5%) in stage III and 11/27 (41%) in stage IV. Using nested RT-PCR, we were able to amplify hMAM transcript of one tumour cell/10(6) normal cells. Our data demonstrate that hMAM mRNA detection by RT-PCR is a specific assay potentially suitable for identification of occult cancer cells in peripheral blood of BC patients.

[Kaposi's sarcoma: on its frequent association with lymphoreticular neoplasms and diabetes mellitus]. / Sarcoma di Kaposi: sulla frequente associazione con neoplasie linforeticolari e diabete mellito.

Kaposi's sarcoma (K.S.) is associated relatively frequently with diabetes mellitus and with a second often lymphoreticular neoplasia. On the basis of the three cases reported, which presented an association of diabetes mellitus, chronic lymphatic leukaemia, Hodgkin's lymphoma and K.S., the relationship between neoplastic diseases, immunological and lymphoproliferative disorders and virus infections is considered.