Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin.

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials.

BACKGROUND: The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC. PATIENTS AND METHODS: The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies). RESULTS: Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received. CONCLUSION: This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Biliary tract cancers: SEOM clinical guidelines

Biliary tract cancer (BTC) is an uncommon and highly fatal malignancy. It is composed of three main different entities; Gall bladder carcinoma (GBC), intrahepatic cholangiocarcinoma (iCC) and extrahepatic cholangiocarcinoma (eCC) sharing different genetic, risk factors and clinical presentation. Multidetector-row computed tomography (MDCT) and magnetic resonance cholangio-pancreatography (MRCP) are the more important diagnostic techniques. Surgery is the only potentially curative therapy but disease recurrence is frequent. Treatment with chemotherapy, radiotherapy or both has not demonstrated survival benefit in the adjuvant setting. Cisplatin plus gemcitabine constitutes the gold standard in metastatic disease. New ongoing studies mainly in the adjuvant and neoadjuvant setting along with molecular research will hopefully help to improve survival and quality of life of this disease (AU)

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Biliary tract cancers: SEOM clinical guidelines.

Biliary tract cancer (BTC) is an uncommon and highly fatal malignancy. It is composed of three main different entities; Gall bladder carcinoma (GBC), intrahepatic cholangiocarcinoma (iCC) and extrahepatic cholangiocarcinoma (eCC) sharing different genetic, risk factors and clinical presentation. Multidetector-row computed tomography (MDCT) and magnetic resonance cholangio-pancreatography (MRCP) are the more important diagnostic techniques. Surgery is the only potentially curative therapy but disease recurrence is frequent. Treatment with chemotherapy, radiotherapy or both has not demonstrated survival benefit in the adjuvant setting. Cisplatin plus gemcitabine constitutes the gold standard in metastatic disease. New ongoing studies mainly in the adjuvant and neoadjuvant setting along with molecular research will hopefully help to improve survival and quality of life of this disease.

The needle and the damage done: pericardial effusion with tamponade after needle ingestion in an infant.

OBJECTIVE: Paediatric foreign bodies may present with vague and nonspecific symptoms. It is important to have a high index of suspicion when managing such cases. METHOD: We report the case of a nine-month-old infant who presented with a wheeze, cough and fever following ingestion of a needle. RESULTS: This patient developed pericardial tamponade as a consequence of the needle ingestion, and required a thoracotomy for retrieval. We discuss the pathophysiology involved and the surgery required. CONCLUSION: Pericardial tamponade is a rare but potentially fatal manifestation of an ingested foreign body.

Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion.

UNLABELLED: There have been significant changes in the management of neonates and infants undergoing cardiac surgery in the past decade. We have evaluated in this prospective, randomized, double-blinded study the effect of large-dose fentanyl anesthesia, with or without midazolam, on stress responses and outcome. Forty-five patients < 6 mo of age received bolus fentanyl (Group 1), fentanyl by continuous infusion (Group 2), or fentanyl-midazolam infusion (Group 3). Epinephrine, norepinephrine, cortisol, adrenocortical hormone, glucose, and lactate were measured after the induction (T1), after sternotomy (T2), 15 min after initiating cardiopulmonary bypass (T3), at the end of surgery (T4), and after 24 h in the intensive care unit (T5). Plasma fentanyl concentrations were obtained at all time points except at T5. Within each group epinephrine, norepinephrine, cortisol, glucose and lactate levels were significantly larger at T4 (P values < 0.01), but there were no differences among groups. Within groups, fentanyl levels were significantly larger in Groups 2 and 3 (P < 0.001) at T4, and among groups, the fentanyl level was larger only at T2 in Group 1 compared with Groups 2 and 3 (P < 0.006). There were no deaths or postoperative complications, and no significant differences in duration of mechanical ventilation or intensive care unit or hospital stay. Fentanyl dosing strategies, with or without midazolam, do not prevent a hormonal or metabolic stress response in infants undergoing cardiac surgery. IMPLICATIONS: We demonstrated a significant endocrine stress response in infants with well compensated congenital cardiac disease undergoing cardiac surgery, but without adverse postoperative outcome. The use of large-dose fentanyl, with or without midazolam, with the intention of providing "stress free" anesthesia, does not appear to be an important determinant of early postoperative outcome.

Parameters associated with perioperative baffle fenestration closure in the Fontan operation.

OBJECTIVE: To identify clinical parameters indicating perioperative fenestration closure in children who underwent the fenestrated Fontan operation. DESIGN: Retrospective. SETTING: Single children's hospital. PARTICIPANTS: Patients who underwent a fenestrated Fontan operation in 1996 through 1997 (n = 101). INTERVENTION: A fenestrated Fontan operation was performed in children with single-ventricle physiology. MEASUREMENTS AND MAIN RESULTS: Early perioperative closure of the fenestration occurred in 14 patients (group 1), whereas the fenestration remained patent in 87 patients (group 2). The groups were compared by the following parameters: demographics, cardiac catheterization and ultrasound data, and use of aspirin or warfarin preoperatively and intraoperatively by assessing the composition of the cardiopulmonary bypass solution, use of ultrafiltration and antifibrinolytics, protamine dose, last hematocrit on cardiopulmonary bypass, and requirement of blood products. Immediately postoperatively in the intensive care unit (ICU), cardiac filling pressures (central venous and left atrial pressure), coagulation profile, cardiac rhythm, chest tube drainage, length of stay in the ICU, and use of atrial pacing were reviewed. Significant indicators of early fenestration closure in this study as determined by multivariate stepwise logistic regression were a high transpulmonary pressure gradient (p = 0.015) and a higher oxygen saturation (p = 0.001) 1 hour after arrival in the ICU, a low fibrinogen level (p < 0.0001), and the need for temporary atrial pacing (p = 0.029). The fenestration was reopened in 13 patients in group 1. In 101 patients, there was no early mortality, and all patients survived to discharge. CONCLUSION: Factors that correlated with postoperative fenestration closure in the fenestrated Fontan operation in this study were a high transpulmonary pressure gradient and a high oxygen saturation 1 hour after arrival in the ICU, a low fibrinogen level, and the need for temporary atrial pacing.

Intraoperative recurrent laryngeal nerve monitoring during video-assisted throracoscopic surgery for patent ductus arteriosus.

OBJECTIVE: To develop a technique to identify and localize the recurrent laryngeal nerve (RLN) during video-assisted thoracoscopic surgery (VATS) for patent ductus arteriosus. DESIGN: Prospective clinical study. SETTING: Children's hospital. PARTICIPANTS: Sixty infants and children scheduled for elective closure of patent ductus arteriosus. INTERVENTIONS: With parental informed consent, 60 infants and children undergoing elective VATS for patent ductus arteriosus were studied. A thin, pencil-point, Teflon-coated, stimulating probe allowed direct stimulation (<2 mA, 100-msec pulse width) of the left RLN inside the thorax. A commercially available 4-channel neurologic monitor recorded compound evoked electromyograms (EMGs) from the left RLN and right RLN (as control) by needle electrodes placed percutaneously in the neck. Hoarseness, stridor, feeding difficulties, and voice changes were assessed postoperatively. MEASUREMENTS AND MAIN RESULTS: Left RLN EMGs were easily obtained in 59 of the 60 patients. The surgeon correctly identified the RLN visually once in the first 7 patients; this ability subsequently improved. EMG localization of the location or course of the RLN altered dissection, clip size, or clip position in 37 of 59 patients. CONCLUSION: Intraoperative EMG to identify location and route of the RLN was easy to perform, was effective in identifying RLN position, and appeared to facilitate dissection and clipping of the ductus.

Electrocardiographic inscription of diaphragmatic contractions during anaesthesia.

An electrocardiographic artifact was noted on a child under general anaesthesia. The artifact was caused by rhythmic diaphragmatic contractions. A systematic approach to distinguish an artifact from a cardiac electrophysiological event is presented.

Electrocardiographic demonstration of dual atrioventricular nodal pathways in children.

Dual atrioventricular nodal pathways, as evaluated by electrocardiography, were found in two children without arrhythmias over a six year period. Although none have developed tachycardia, they have the substrate to develop atrioventricular reentrant tachycardia.

Induction of wide QRS tachycardia during transthoracic echocardiography.

A wide QRS tachycardia was repeatedly triggered during transthoracic echocardiographic examination in a critically ill premature infant with bilateral chest tubes. The left-sided tube was anterior to the heart. The arrhythmia was not induced after removal of the chest tubes at the follow-up ultrasonographic evaluation. Compression of the thoracic wall and chest tube, and subsequently the heart, by the ultrasound transducer is postulated as the cause for this wide QRS tachycardia.

Mitral valve prolapse in juvenile thyrotoxicosis.

To determine whether there is an association between mitral valve prolapse and juvenile thyrotoxicosis, we studied 13 thyrotoxic patients (3 males, 10 females, ages 8-17 years) by physical examination, chest radiograms, electrocardiograms and echocardiography. Five patients had an apical systolic murmur and two of these had echocardiographic evidence of mitral valve prolapse. The findings of mitral valve prolapse in 15% of the hyperthyroid patients and 1.7% in the control group suggests that this abnormality may be more frequent in hyperthyroid children. Echocardiograms should be performed in hyperthyroid children who present with an apical systolic murmur.

Echocardiographic assessment of the right atrioventricular junction in Ebstein's malformation.

Echocardiographic evaluation of two infants with Ebstein's malformation of the tricuspid valve revealed an echogenic right atrioventricular junction that gave the impression of a divided right atrial cavity. Imaging of this junction resulted in better assessment of the components of the right heart of this malformation.

Cor triatriatum sinister: echocardiographic assessment.

A 16 year old white female presented with paroxysmal cough and hemoptysis of recent onset. Cardiac evaluation was consistent with pulmonary hypertension. Cor triatriatum sinister was diagnosed by echocardiography. The clinical presentation and the echocardiographic features of this anomaly are discussed.