Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

BACKGROUND: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. RESULTS: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. CONCLUSIONS: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. CLINICAL TRIAL NUMBER: NCT02034981.

Delayed allergic dermatitis presenting as a keloid-like reaction caused by sting from an Indo-Pacific Portuguese man-o'-war (Physalia utriculus).

Cnidarian envenomations are common occurrences in the tropics that can affect holidaymakers. The cutaneous reactions are classified as immediate or delayed types. Delayed allergic reactions are persistently recurring dermatitis, which can occur within 1-4 weeks from the initial sting, and may last for several months. Hypertrophic scar-like or keloid-like reactions are rare, and are believed to be a type IV hypersensitivity reaction to sequestered antigens from stinging filaments. We report an unusual case of delayed allergic dermatitis with keloid-like presentation caused by Physalia utriculus.

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia.

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial.

BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy.

BACKGROUND: We recently demonstrated that excision repair cross-complementing group 1 protein (ERCC1) is predictive of adjuvant cisplatin-based chemotherapy benefit in resected non-small-cell lung cancer (NSCLC). Non-squamous cell carcinomas (non-SCCs) carry an increased risk of brain metastases (BMs). We hypothesised that there might be an increased incidence of BMs in ERCC1-negative non-SCCs when treated with adjuvant cisplatin-based chemotherapy. PATIENTS AND METHODS: Incidence of BMs and histoclinical parameters were analysed in a population of 761 patients enrolled in the International Adjuvant Lung Cancer Trial. A subgroup analysis was carried out in patients with ERCC1-negative non-SCCs. RESULTS: Of 761 patients, 98 developed BMs alone or in association with other metastatic sites, with a 5-year incidence rate of 18.0% (14.7%-21.8%). In the multivariate analysis, the clinical parameters associated with the occurrence of BMs were the nodal status (P = 0.02) and histological type [give hazard ratio (HR) for non-squamous to quantify introduction assertion, P = 0.002]. Chemotherapy had no effect on BMs [HR = 1.4 (0.90-2.1), P = 0.14]. In patients with non-SCC histology (n = 335), adjuvant chemotherapy was associated with an increased risk of BMs [HR = 2.1 (1.01-4.3), P = 0.04] for ERCC1-negative tumours, whereas there was no evidence of an effect on BMs for ERCC1-positive tumours [HR = 1.1 (0.38-3.0), P = 0.90]. Nevertheless, these two effects are not different (P = 0.30 for interaction) possibly due to a lack of power in this subgroup. CONCLUSIONS: This study suggests that adjuvant cisplatin-based chemotherapy is associated with an increased risk of BMs in patients with resected chemosensitive non-SCCs. If confirmed, these data could provide a rationale for new follow-up and/or prophylactic strategies.

Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients.

OBJECTIVE: To evaluate the impact of surgery as first-line treatment on event-free survival (EFS) of primary aggressive fibromatosis. PATIENTS AND METHODS: Treatments were categorized into: surgery with or without radiotherapy and nonsurgical strategies with systemic treatment alone or wait and see policy. Eighty-nine patients had initial resection of their primary tumour followed by postoperative radiotherapy in 13 cases. Twenty-three did not undergo surgery but received systemic treatment or watch and wait policy. RESULTS: Median follow-up was 76 months. Overall 3 years EFS was 49%. In the univariate analysis, patients with microscopically complete surgery had a similar outcome to patients in the no-surgery group (3 years EFS of 65% and 68%, respectively). Gender, age, tumour size, treatment period and strategy (surgery versus no-surgery) were not statistically significant. Quality of resection according to margins and the tumour site were the only prognostic factors. There was a significant correlation between tumour site and quality of surgery (p=0.0002). CONCLUSIONS: A subset of patients with extra-abdominal fibromatosis could be managed with a nonaggressive policy, as growth arrest concerned 2/3 of nonoperated patients. When surgery is finally necessary, it should be performed with the aim of achieving negative margins.

Localized lymphatic sporotrichosis after fish-induced injury (Tilapia sp.).

Localized lymphatic sporotrichosis generally develops after the fungus Sporothrix schenckii is traumatically introduced into skin or mucosa by contaminated plant material. An 18-year-old male fisherman was injured by spines of the dorsal fin of a fish on the left third finger. The lesion became ulcerated, edematous and suppurative and did not respond to tetracycline and cephalexin. Fifteen days after the accident, a nodular lymphangitic pattern of swelling was observed. Histopathological findings and an intradermal test were suggestive of sporotrichosis and mycological cultures confirmed the diagnosis. The lesions resolved after oral treatment with potassium iodide. Sporotrichosis is a common subcutaneous mycosis in Brazil, and there is a previous report in the literature of this disease being acquired via trauma involving fish spines.

Randomized comparative study of radial artery and right gastroepiploic artery in composite arterial graft for CABG.

OBJECTIVES: Arterial grafts have been used to achieve better long-term results and improve graft patency in coronary artery bypass grafting. Composite graft was proposed to overcome inconveniences of proximal anastomoses to the aorta and increase the use and surgical options of arterial grafts. However, lack of prospective randomized studies with this kind of grafts is evident. We compare the results of composite Y-grafts of the radial artery (RA) and the right gastroepiploic artery (RGEA) proximally anastomosed to the left internal thoracic artery (LITA) for CABG, evaluated through angiography, in a prospective randomized study. METHODS: Between August 1998 and November 1999, 60 patients were randomly divided into two groups: group I (GI) received RGEA graft and group II (GII), RA graft. LITA was used to graft the left anterior descending artery and RGEA or RA was placed to obtuse marginal or first diagonal branch. The right coronary artery branches was grafted with saphenous vein graft (SVG) when necessary. All coronary arteries receiving arterial grafts had > or =75% proximal stenosis and diameter > or =1.5 mm. RESULTS: GI and GII preoperative data were similar, 63 distal anastomoses were performed with the LITA, 32 with the RA and 32 with the RGEA. There were two perioperative deaths (3.3%), one in each group, none related to cardiac causes. Four (6.6%) q-wave myocardial infarctions were found and two (3.3%) patients showed low cardiac output syndrome. Angiography was performed in all surviving patients from the 8th to 15th postoperative day and showed a patency rate of 96.5% (56/58) for LITA, 89.6% (26/29) for RA and 68.9% (20/29) for RGEA, with a statistically significant difference between RGEA and RA (P=0.025). CONCLUSIONS: Radial artery had better early results than right gastroepiploic artery. Use of the LITA as inflow graft seems not to affect its good patency. Use of the RGEA as composite graft should not be encouraged. Long-term follow-up with objective investigation and randomized trials is required to confirm better results of composite conduits.

Seabather's eruption: report of five cases in southeast region of Brazil.

The authors report five cases of seabather's eruption, a typical dermatitis associated predominantly to the jellyfish Linuche unguiculata (Cnidaria), that causes erythematous and pruriginous papules on areas of the skin of bathers covered by swimsuits. The rash is characteristic and the eruption is commom in the Caribbean, Florida, Mexico and Gulf States of USA. The cases are the first reported in Brazil and larvae of the jellyfish are present in the waters where the accidents happened.

[Primary angioplasty associated with systemic coronary stenting in acute myocardial infarction. Results at the end of the hospitalization period and at 24 months]. / Angioplastie primaire associée à la mise en place systématique d'une endoprothèse en phase aiguë d'infarctus du myocarde. Résultats en fin de période hospitalière et à 24 mois.

A series of 149 consecutive patients admitted for myocardial infarction (excluding cardiogenic shock), dilated and systematically stented in the acute phase before the 12th hour and followed up for a period from 30 days to 2 years, was studied. The criteria of follow-up were: number of asymptomatic patients, deaths, reinfarction, residual ischaemia, cardiac failure, angioplasty or bypass surgery. On admission, 40.9% of the infarcts were anterior, 44.3% inferior and 14.8% lateral. One hundred and eighty-three stents with a diameter of over 3 mm were inserted. The angioplasty success rate was 98.6%. During the hospital period, 90.6% of patients were asymptomatic. 4.7% had recurrent infarction, 4% had cardiac failure, 0.7% had residual ischaemia, and there were 0.7% of cardiac deaths. The survival rate was 97.2% at 2 years: 69.8% of patients were totally asymptomatic: the cumulative major cardiac event rate (death, reinfarction, angioplasties or bypass graft) was 25.9% and the reoperation rate on the culprit vessel was 20.1%. These results show the short and long-term value of angioplasty associated with coronary stenting over other techniques in the acute phase of infarction based on the criteria studied. The long-term results of larger randomised studies using glycoprotein inhibitors (Gp IIb IIIa) associated with angioplasty and stenting are expected for validating the use of these products.

Successful one-stage resection of intravenous leiomyomatosis of the uterus with extension into the heart.

Intravenous leiomyomatosis of the uterus is a rare neoplasm characterized by nodular masses of benign smooth muscles with intraluminal growth to the inferior vena cava and, in some cases, to the heart. It may cause abdominal and cardiovascular symptoms and is a serious risk of death when it reaches the tricuspid valve. Surgery is the best treatment and must be applied as soon as possible using cardiopulmonary bypass. The authors report a new case that had cardiac involvement and was successfully resected. The symptoms, imaging diagnosis, pathological and histopathological findings, tumors that mismatched the intravenous leiomyomatosis (IVL), and the use of circulatory arrest and deep hypothermia are discussed. A review of the literature is included.

Unusual abdominal tumors with intracardiac extension. Two cases with successful surgical resection.

Abdominal tumors that can grow through vascular lumen and spread to the right heart are rare. Although these tumors have different histologic aspects, they may cause similar abdominal and cardiac symptoms and are a serious risk factor for pulmonary embolism and sudden death when they reach the right atrium and tricuspid valve. The best treatment is radical surgical resection of the entire tumor using cardiopulmonary bypass with or without deep hypothermia and total circulatory arrest. We report the cases of two patients, the first with leiomyosarcoma of the inferior vena cava and the other with intravenous leiomyomatosis of the uterus that showed intravascular growth up to right atrium and ventricle, who underwent successful radical resection in a one-stage procedure with the use of cardiopulmonary bypass. We discuss the clinical and histologic aspects and imaging diagnosis and review the literature.

Geometric reconstruction in left ventricular aneurysm. Surgical aspects and early results.

The early results of 79 patients who underwent left ventricular aneurysmectomy with geometric and circular reconstruction in a seven-year experience are analyzed. The most common indication for operation was congestive heart failure (78.4%), either isolated (25.3%) or with angina (53.1%). Sixty patients (76%) were in NYHA class III and 10 (12.6%) in NYHA class IV at the time of surgery. Fifty-eight (73.4%) underwent coronary artery by-pass graft surgery. Hospital mortality was 5.1%, in patients older than 60 (12%), in NYHA class IV (20%), with poor left ventricular function (EF < 0.30-20% and LVED > 25) (14%), and with extensive coronary artery disease (10%) were under increased risk. Low cardiac output and use of intra-aortic balloon pump were also associated risk factors. Other risk factors mentioned in the literature are discussed. There were no deaths from isolated left ventricular aneurysmectomy. The early results of this study and the early and late results of others using the same technique are better than the results obtained in previous studies of different types of correction, suggesting that this is the procedure of choice for treating left ventricular aneurysm.

[Subaortic stenosis caused by anomalous chordae tendineae of the mitral valve ("mitral web")]. / Estenose subaórtica por cordas tendíneas anômalas da valva mitral ("mitral web").

Patient with subaortic stenosis due to the insertion of anomalous chordae tendineae of the mitral valve in the interventricular septum (mitral web) associated with mitral stenosis with diagnosis made by bidimensional echocardiographic study with Doppler and confirmed by hemodynamic study. The patient was submitted to surgical treatment. The anomalous cords were resected and the mitral valve with severe malformation was replaced by a bioprosthesis. The patient had a uneventful recovery and echocardiographic evaluation showed an outflow tract without obstruction, with no gradient, with remnants of the papillary muscles and normo-functioning bioprosthesis.

[Intrapericardial diaphragmatic hernia associated with atrial septal defect]. / Hérnia diafragmática intrapericárdica associada a communicação interatrial.

The authors report the case of a patient with atrial septal defect who was submitted to surgical treatment when an intrapericardial hernia was found. The septal defect was closed with a bovine pericardial patch and the hernia with a pediculated autogenous pericardial graft. They discuss several aspects of the classification of the hernia, its association with other anomalies, embryogenesis, pathophysiology, prognosis and surgical correction.

[Coronary angioplasty in a 12-year-old child]. / Angioplastia coronária em uma criança de 12 anos de idade.

Coronary artery disease is seldom reported in patients under 20 years of age. We present here the case of a 12 years old male, with systemic high blood pressure who had 2 episodes of typical chest pain. He underwent a submaximal exercise treadmill test which was negative. He then underwent cinecoronarography that revealed a 78% (measured by the caliper) obstruction in the proximal segment of the circumflex coronary artery with 3 mm of extension. The left coronary artery and the left ventricle were normal. The patient was subjected to a percutaneous transluminal coronary angioplasty, which was successful and left a 12% (measured by caliper) residual stenosis. The late angiographic restudy (5 months after the procedure) showed the maintenance of the immediate success of the procedure.