Simona Grozinsky-Glasberg

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.

BACKGROUNDnOptimal antibiotic treatment for sepsis is imperative. Combining a beta lactam antibiotic with an aminoglycoside antibiotic may provide certain advantages over beta lactam monotherapy.nnnOBJECTIVESnOur objectives were to compare beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy in patients with sepsis and to estimate the rate of adverse effects with each treatment regimen, including the development of bacterial resistance to antibiotics.nnnSEARCH METHODSnIn this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11); MEDLINE (1966 to 4 November 2013); EMBASE (1980 to November 2013); LILACS (1982 to November 2013); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2013). We scanned citations of all identified studies and contacted all corresponding authors. In our previous review, we searched the databases to July 2004.nnnSELECTION CRITERIAnWe included randomized and quasi-randomized trials comparing any beta lactam monotherapy versus any combination of a beta lactam with an aminoglycoside for sepsis.nnnDATA COLLECTION AND ANALYSISnThe primary outcome was all-cause mortality. Secondary outcomes included treatment failure, superinfections and adverse events. Two review authors independently collected data. We pooled risk ratios (RRs) with 95% confidence intervals (CIs) using the fixed-effect model. We extracted outcomes by intention-to-treat analysis whenever possible.nnnMAIN RESULTSnWe included 69 trials that randomly assigned 7863 participants. Twenty-two trials compared the same beta lactam in both study arms, while the remaining trials compared different beta lactams using a broader-spectrum beta lactam in the monotherapy arm. In trials comparing the same beta lactam, we observed no difference between study groups with regard to all-cause mortality (RR 0.97, 95% CI 0.73 to 1.30) and clinical failure (RR 1.11, 95% CI 0.95 to 1.29). In studies comparing different beta lactams, we observed a trend for benefit with monotherapy for all-cause mortality (RR 0.85, 95% CI 0.71 to 1.01) and a significant advantage for clinical failure (RR 0.75, 95% CI 0.67 to 0.84). No significant disparities emerged from subgroup and sensitivity analyses, including assessment of participants with Gram-negative infection. The subgroup of Pseudomonas aeruginosa infections was underpowered to examine effects. Results for mortality were classified as low quality of evidence mainly as the result of imprecision. Results for failure were classified as very low quality of evidence because of indirectness of the outcome and possible detection bias in non-blinded trials. We detected no differences in the rate of development of resistance. Nephrotoxicity was significantly less frequent with monotherapy (RR 0.30, 95% CI 0.23 to 0.39). We found no heterogeneity for all these comparisons.We included a small subset of studies addressing participants with Gram-positive infection, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies.nnnAUTHORS CONCLUSIONSnThe addition of an aminoglycoside to beta lactams for sepsis should be discouraged. All-cause mortality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.

Beta‐lactam versus beta‐lactam‐aminoglycoside combination therapy in cancer patients with neutropenia

BACKGROUNDnContinued controversy surrounds the optimal empirical treatment for febrile neutropenia. New broad-spectrum beta-lactams have been introduced as single treatment, and classically, a combination of a beta-lactam with an aminoglycoside has been used.nnnOBJECTIVESnTo compare beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutropenia.nnnSEARCH METHODSnThe Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2012), LILACS (August 2012), MEDLINE and EMBASE (August 2012) and the Database of Abstracts of Reviews of Effects (DARE) (Issue 3, 2012). We scanned references of all included studies and pertinent reviews and contacted the first author of each included trial, as well as the pharmaceutical companies.nnnSELECTION CRITERIAnRandomised controlled trials (RCTs) comparing any beta-lactam antibiotic monotherapy with any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial empirical treatment of febrile neutropenic cancer patients. All cause mortality was the primary outcome assessed.nnnDATA COLLECTION AND ANALYSISnData concerning all cause mortality, infection related mortality, treatment failure (including treatment modifications), super-infections, adverse effects and study quality measures were extracted independently by two review authors. Risk ratios (RRs) with their 95% confidence intervals (CIs) were estimated. Outcomes were extracted by intention-to-treat (ITT) analysis whenever possible. Individual domains of risk of bias were examined through sensitivity analyses. Published data were complemented by correspondence with authors.nnnMAIN RESULTSnSeventy-one trials published between 1983 and 2012 were included. All cause mortality was lower with monotherapy (RR 0.87, 95% CI 0.75 to 1.02, without statistical significance). Results were similar for trials comparing the same beta-lactam in both trial arms (11 trials, 1718 episodes; RR 0.74, 95% CI 0.53 to 1.06) and for trials comparing different beta-lactams－usually a broad-spectrum beta-lactam compared with a narrower-spectrum beta-lactam combined with an aminoglycoside (33 trials, 5468 episodes; RR 0.91, 95% CI 0.77 to 1.09). Infection related mortality was significantly lower with monotherapy (RR 0.80, 95% CI 0.64 to 0.99). Treatment failure was significantly more frequent with monotherapy in trials comparing the same beta-lactam (16 trials, 2833 episodes; RR 1.11, 95% CI 1.02 to 1.20), and was significantly more frequent with combination therapy in trials comparing different beta-lactams (55 trials, 7736 episodes; RR 0.92, 95% CI 0.88 to 0.97). Bacterial super-infections occurred with equal frequency, and fungal super-infections were more common with combination therapy. Adverse events were more frequent with combination therapy (numbers needed to harm 4; 95% CI 4 to 5). Specifically, the difference with regard to nephrotoxicity was highly significant. Adequate trial methods were associated with a larger effect estimate for mortality and smaller effect estimates for failure. Nearly all trials were open-label. No correlation was noted between mortality and failure rates and these trials.nnnAUTHORS CONCLUSIONSnBeta-lactam monotherapy is advantageous compared with beta-lactam-aminoglycoside combination therapy with regard to survival, adverse events and fungal super-infections. Treatment failure should not be regarded as the primary outcome in open-label trials, as it reflects mainly treatment modifications.

Laparoscopic resection of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) are a rare heterogeneous group of endocrine neoplasms. Surgery remains the best curative option for this type of tumor. Over the past two decades, with the development of laparoscopic pancreatic surgery, an increasingly larger number of PNET resections are being performed by these minimally-invasive techniques. In this review article, the various laparoscopic surgical options for the excision of PNETs are discussed. In addition, a summary of the literature describing the outcome of these treatment modalities is presented.

Diagnosing and Managing Carcinoid Heart Disease in Patients With Neuroendocrine Tumors: An Expert Statement

Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is responsible for substantial morbidity and mortality. The pathophysiology of carcinoid heart disease is poorly understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors. Despite recognition, international consensus guidelines specifically addressing the diagnosis and management of carcinoid heart disease are lacking. Furthermore, there is considerable variation in multiple aspects of screening and management of the disease. The aim of these guidelines was to provide succinct, practical advice on the diagnosis and management of carcinoid heart disease as well as its surveillance. Recommendations and proposed algorithms for the investigation, screening, and management have been developed based on an evidence-based review of the published data and on the expert opinion of a multidisciplinary consensus panel consisting of neuroendocrine tumor experts, including oncologists, gastroenterologists, and endocrinologists, in conjunction with cardiologists and cardiothoracic surgeons.

Efficacy of Peptide Receptor Radionuclide Therapy for Functional Metastatic Paraganglioma and Pheochromocytoma

Purpose: Treatment options for unresectable paraganglioma (PGL)/pheochromocytoma (PCC), especially with uncontrolled secondary hypertension (HTN), are limited. Preliminary studies with peptide receptor radionuclide therapy (PRRT) suggest efficacy, but data on HTN control and survival are lacking. We assessed PRRT outcomes in such patients from two referral centers. Methods: Twenty consecutive patients (13 men; age range, 21 to 77 years) with high somatostatin receptor (SSTR) expression treated with 177Lu‐DOTA‐octreotate, nine with radiosensitizing chemotherapy, were retrospectively reviewed. Median cumulative activity was 22 GBq (median 4 cycles). Fourteen patients were treated for uncontrolled HTN and six for progressive or symptomatic metastatic disease or local recurrence. Results: Three months after PRRT, 8 of 14 patients treated for HTN required reduced medication doses, 5 had no change in anti‐HTN doses, and 1 was lost to follow‐up. Eighty‐six percent had serum chromogranin‐A reduction. Of the entire cohort, 36% had disease regression (29% partial and 7% minor response) on computed tomography, with stable findings in 50%. Three other patients had bony disease evaluable only on SSTR imaging (2 partial response and 1 stable). Median progression‐free survival was 39 months; median overall survival was not reached (5 deaths; median follow‐up, 28 months). Four patients had grade 3 lymphopenia; 2 had grade 3 thrombocytopenia. Renal impairment in 2 patients was attributed to underlying disease processes. Conclusions: PRRT achieves worthwhile clinical and biochemical responses with low toxicity and encouraging survival in PGL/PCC. Because PRRT has logistic and radiation‐safety advantages compared to 131I‐MIBG therapy, further prospective evaluation is warranted.

Inhibition of mTOR in carcinoid tumors

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors, whose incidence and prevalence are increasing. The clinical behavior of NEN is variable, ranging from well-differentiated slow growing tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. The term carcinoid is commonly used for the more benign variants of these neoplasms. Most frequently, carcinoids have their origin in the small intestine, followed by in the lung and other sites. Some of these tumors are associated with the carcinoid syndrome. The use of somatostatin analogs has revolutionized the clinical management of patients with carcinoids. However, although symptomatic relief and stabilization of tumor growth for various periods of time are observed in many patients treated with somatostatin analogs, tumor regression is rare. Currently, there is no other powerful antiproliferative agent available for carcinoids. Mammalian target of rapamycin (mTOR), a main protein kinase in the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway, is an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, and angiogenesis. Alterations of the normal activity of mTOR and of mTOR-related kinases in this pathway have been found in a diversity of human tumors, including NEN; therefore, mTOR pathway represents an attractive target for new anticancer therapies. While mTOR inhibitors, such as everolimus, are established therapy in pancreatic NEN, results from recent clinical trials indicate that mTOR inhibitors may be also of value in the management of carcinoids. However, further clinical trials will have to confirm efficacy and elucidate, in which subtypes and in which setting, these drugs might be most usefully applied.

Clinical features of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs), also known as islet cell tumors, are rare neoplasms that arise in the endocrine tissues of the pancreas. Most of pancreatic NETs (50–75%) are nonfunctioning (not associated with a hormonal clinical syndrome); however, in up to one third they can secrete a variety of peptide hormones, including insulin, gastrin, glucagon, vasoactive intestinal peptide, somatostatin etc., resulting in rare but unique clinical syndromes. In this article, the clinical features of the different types of PNETs will be reviewed. Other aspects of the management of these tumors (surgery, treatment of advanced disease, tumor localization) are not dealt with here, as they are covered by other papers in this volume.

Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms

The vast majority of gastrin‐related gastrointestinal neuroendocrine neoplasms (GI‐NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI‐NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI‐NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long‐term follow‐up and potential comorbidities of GNEN1s.

Laparoscopic resection of primary midgut carcinoid tumors

BackgroundLaparoscopic intestinal surgery is the preferable technique for the majority of intestinal surgical disorders. However, no series on laparoscopic resection of intestinal midgut carcinoid tumors (MCTs) has been reported to date. This is related to the rarity of these tumors as well as the technical difficulties resecting the large mesenteric root lymph node mass commonly found with these tumors and the occasional difficulty identifying the primary MCT, which may be small and undetected on preoperative imaging studies. This is the first series to report the results for laparoscopic resection of MCT.MethodsAll consecutive patients with MCT (excluding appendiceal carcinoid tumor) between 2002 and 2012 underwent laparoscopic resection. The patient’s clinical data, preoperative endocrine workup, imaging studies, operative data, final histology, and outcome were recorded and analyzed.ResultsDuring the study period, 35 patients underwent surgery for primary intestinal carcinoid tumor. Of the 35 patients, 20 (12 women and 8 men ages 26–86xa0years) had surgery for primary MCT, and the remainder had a colorectal carcinoid tumor. In the MCT group, ten patients had liver metastases at the time of surgery. In three patients, multiple synchronous MCTs were detected intraoperatively. All the patients underwent a laparoscopic resection with en bloc resection of the corresponding mesenteric root mass. No conversion to open surgery was needed, and no major morbidity occurred. Two patients (10xa0%) each experienced minor morbidity with wound infection and prolonged ileus. The median hospital length of stay was 6xa0days (range 4–9xa0days). During a follow-up period of 3–96xa0months, no patients experienced local or regional recurrence. No distant metastases were detected during the follow-up period in any patients who had surgery with intent to cure.ConclusionAlthough technically difficult, laparoscopic resection of primary MCTs is feasible and safe, with the additional known significant advantages of laparoscopic surgery in general. Similar to the large-scale prospective studies that proved the oncologic safety of laparoscopic surgery for colorectal cancer, this small series showed that the laparoscopic technique also may be oncologically safe for these rare tumors.

Hepatic intra-arterial therapies in metastatic neuroendocrine tumors: lessons from clinical practice

BackgroundLiver metastases are common in patients with neuroendocrine tumors (NETs), having a negative impact on disease prognosis. The options for selective therapy in patients with unresectable multiple liver metastases are limited to TACE (transarterial chemoembolization), TAE (transarterial embolization), or SIRT (selective internal radiation therapy).AimTo explore the clinical outcome, survival and safety of these therapies in NETs patients.MethodsRetrospective case series of consecutive patients (mean age 56.6 years, 59% male) treated at two tertiary university medical centers from 2005 to 2015.ResultsFifty-seven patients with G1, G2, and low G3 NETs with liver metastases were investigated (pancreatic NET (pNET), 24; small bowel, 16; unknown origin (UKO), 9; rectal, 3; lung, 3; and gastric, 2). Fifty-three patients underwent TACE, three patients underwent TAE, and one patient underwent SIRT. Clinical improvement and tumor response were observed in 54/57 patients (95%), together with marked decreased in tumor markers. The median time to tumor progression following the first treatment was 14u2009±u200916 months. The median overall survival was 22u2009±u200918 months, more pronounced in the pNET, followed by small bowel and UKO subgroups. There was a trend for a better survival in patients with disease limited to the liver and in whom the primary tumor was resected.ConclusionHepatic intra-arterial therapies are well tolerated in the majority of patients with NETs and liver metastases and associated with both clinical improvement and tumor stabilization for prolonged periods. These therapies should be always considered, irrespective of the presence of extrahepatic metastasis.