Potential of dietary polyphenols for protection from age-related decline and neurodegeneration: a role for gut microbiota?

Many epidemiological studies have shown the beneficial effects of a largely plant-based diet, and the strong association between the consumption of a Mediterranean-type diet with healthy aging including a lower risk of cognitive decline. The Mediterranean diet is characterized by a high intake of olive oil, fruits and vegetables and is rich in dietary fiber and polyphenols - both of which have been postulated to act as important mediators of these benefits. Polyphenols are large molecules produced by plants to protect them from environmental threats and injury. When ingested by humans, as little as 5% of these molecules are absorbed in the small intestine with the majority metabolized by the gut microbiota into absorbable simple phenolic compounds. Flavan-3-ols, a type of flavonoid, contained in grapes, berries, pome fruits, tea, and cocoa have been associated with many beneficial effects on several risk factors for cardiovascular disease, cognitive function and brain regions involved in memory formation. Both preclinical and clinical studies suggest that these brain and heart benefits can be attributed to endothelial vascular effects and anti-inflammatory properties among others. More recently the gut microbiota has emerged as a potential modulator of the aging brain and intriguingly polyphenols have been shown to alter microbiota composition and be metabolized by different microbial species. However, there is a need for well controlled studies in large populations to identify predictors of response, particularly given the vast inter-individual variation of human gut microbiota.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma.

BACKGROUND: The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer. PATIENTS AND METHODS: Eligible patients with HR+/HER2- stage II-III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025. RESULTS: Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction. CONCLUSION: Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population. CLINICALTRIALS.GOV REGISTRATION: NCT02040857.

Correlation of native T1 mapping with right ventricular function and pulmonary haemodynamics in patients with chronic thromboembolic pulmonary hypertension before and after balloon pulmonary angioplasty.

OBJECTIVES: The aim of this study was to assess native T1 mapping in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) before and 6 months after balloon pulmonary angioplasty (BPA) and compare the results with right heart function and pulmonary haemodynamics. METHODS: Magnetic resonance imaging at 1.5 T and right heart catheterisation were performed in 21 consecutive inoperable CTEPH patients before and 6 months after BPA. T1 values were measured within the septal myocardium, the upper and lower right ventricular insertion points, and the lateral wall at the basal short-axis section. In addition, the area-adjusted septal native T1 time (AA-T1) was calculated and compared with right ventricular function (RVEF), mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). RESULTS: The mean AA-T1 value decreased significantly after BPA (1,045.8 ± 44.3 ms to 1,012.5 ± 50.4 ms; p < 0.001). Before BPA, native T1 values showed a moderate negative correlation with RVEF (r = -0.61; p = 0.0036) and moderate positive correlations with mPAP (r = 0.59; p < 0.01) and PVR (r = 0.53; p < 0.05); after BPA correlation trends were present (r = -0.21, r = 0.30 and r = 0.35, respectively). CONCLUSIONS: Native T1 values in patients with inoperable CTEPH were significantly lower after BPA and showed significant correlations with RVEF and pulmonary haemodynamics before BPA. Native T1 mapping seems to be indicative of reverse myocardial tissue remodelling after BPA and might therefore have good potential for pre-procedural patient selection, non-invasive therapy monitoring and establishing a prognosis. KEY POINTS: • BPA is a promising treatment option for patients with inoperable CTEPH • Native septal T1 values significantly decrease after BPA and show good correlations with right ventricular function and haemodynamics before BPA • Prognosis and non-invasive therapy monitoring might be supported in the future by native T1 mapping.

An observational study of the timing of surgery, use of laparoscopy and outcomes for acute cholecystitis in the USA and UK.

BACKGROUND: Evidence supports early laparoscopic cholecystectomy for acute cholecystitis. Differences in treatment patterns between the USA and UK, associated outcomes and resource utilization are not well understood. METHODS: In this retrospective, observational study using national administrative data, emergency patients admitted with acute cholecystitis were identified in England (Hospital Episode Statistics 1998-2012) and USA (National Inpatient Sample 1998-2011). Proportions of patients who underwent emergency cholecystectomy, utilization of laparoscopy and associated outcomes including length of stay (LOS) and complications were compared. The effect of delayed treatment on subsequent readmissions was evaluated for England. RESULTS: Patients with a diagnosis of acute cholecystitis totaled 1,191,331 in the USA vs. 288 907 in England. Emergency cholecystectomy was performed in 628,395 (52.7% USA) and 45,299 (15.7% England) over the time period. Laparoscopy was more common in the USA (82.8 vs. 37.9%; p < 0.001). Pre-treatment (1 vs. 2 days; p < 0.001) and total ( 4 vs. 7 days; p < 0.001) LOS was lower in the USA. Overall incidence of bile duct injury was higher in England than the USA (0.83 vs. 0.43%; p < 0.001), but was no different following laparoscopic surgery (0.1%). In England, 40.5% of patients without an immediate cholecystectomy were subsequently readmitted with cholecystitis. An additional 14.5% were admitted for other biliary complications, amounting to 2.7 readmissions per patient in the year following primary admission. CONCLUSION: This study highlights management practices for acute cholecystitis in the USA and England. Despite best evidence, index admission laparoscopic cholecystectomy is performed less in England, which significantly impacts subsequent healthcare utilization.

Prospective Risk Factor Analysis for the Development of Post-operative Urinary Retention Following Ambulatory General Surgery.

AIMS: Post-operative urinary retention (POUR) is a common cause of unplanned admission following day-case surgery and has negative effects on both patient and surgical institution. We aimed to prospectively evaluate potential risk factors for the development of POUR following day-case general surgical procedures. METHODS: Over a 24-week period, consecutive adult patients undergoing elective day-case general surgery at a single institution were prospectively recruited. Data regarding urinary symptoms, comorbidities, drug history, surgery and perioperative anaesthetic drug use were collected. The primary outcome was the incidence of POUR, defined as an impairment of bladder voiding requiring either urethral catheterisation, unplanned overnight admission or both. Potential risk factors for the development of POUR were analysed by logistic regression. RESULTS: A total of 458 patients met the inclusion criteria during the study period, and data were collected on 382 (83%) patients (74.3% male). Sixteen patients (4.2%) experienced POUR. Unadjusted analysis demonstrated three significant risk factors for the development of POUR: age ≥ 56 years (OR 7.77 [2.18-27.78], p = 0.002), laparoscopic surgery (OR 3.37 [1.03-12.10], p = 0.044) and glycopyrrolate administration (OR 5.56 [2.00-15.46], p = 0.001). Male sex and lower urinary tract symptoms were not significant factors. Multivariate analysis combining type of surgery, age and glycopyrrolate use revealed that only age ≥ 56 years (OR 8.14 [2.18-30.32], p = 0.0018) and glycopyrrolate administration (OR 3.48 [1.08-11.24], p = 0.0370) were independently associated with POUR. CONCLUSIONS: Patients aged at least 56 years and/or requiring glycopyrrolate-often administered during laparoscopic procedures-are at increased risk of POUR following ambulatory general surgery.

Sex differences in the influence of body mass index on anatomical architecture of brain networks.

BACKGROUND/OBJECTIVES: The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters. SUBJECTS/METHODS: Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age. RESULTS: In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions. CONCLUSIONS: In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.

[Pulmonary embolism]. / Lungenembolie.

Pulmonary embolism is a potentially fatal disorder and frequently seen in critical care and emergency medicine. Due to a high mortality rate within the first few hours, the accurate initiation of rational diagnostic pathways in patients with suspected pulmonary embolism and timely consecutive treatment is essential. In this review, the current European guidelines on the diagnosis and therapy of acute pulmonary embolism are presented. Special focus is put on a structured patient management based on the individual risk of early mortality. In particular risk assessment and new risk-adjusted treatment recommendations are presented and discussed in this article.

Quantitative analysis of technological innovation in minimally invasive surgery.

BACKGROUND: In the past 30 years surgical practice has changed considerably owing to the advent of minimally invasive surgery (MIS). This paper investigates the changing surgical landscape chronologically and quantitatively, examining the technologies that have played, and are forecast to play, the largest part in this shift in surgical practice. METHODS: Electronic patent and publication databases were searched over the interval 1980-2011 for ('minimally invasive' OR laparoscopic OR laparoscopy OR 'minimal access' OR 'key hole') AND (surgery OR surgical OR surgeon). The resulting patent codes were allocated into technology clusters. Technology clusters referred to repeatedly in the contemporary surgical literature were also included in the analysis. Growth curves of patents and publications for the resulting technology clusters were then plotted. RESULTS: The initial search revealed 27,920 patents and 95,420 publications meeting the search criteria. The clusters meeting the criteria for in-depth analysis were: instruments, image guidance, surgical robotics, sutures, single-incision laparoscopic surgery (SILS) and natural-orifice transluminal endoscopic surgery (NOTES). Three patterns of growth were observed among these technology clusters: an S-shape (instruments and sutures), a gradual exponential rise (surgical robotics and image guidance), and a rapid contemporaneous exponential rise (NOTES and SILS). CONCLUSION: Technological innovation in MIS has been largely stagnant since its initial inception nearly 30 years ago, with few novel technologies emerging. The present study adds objective data to the previous claims that SILS, a surgical technique currently adopted by very few, represents an important part of the future of MIS.

[Pulmonary hypertension: Possible genetic causes and therapeutic options]. / Pulmonale Hypertonie : Mögliche genetische Ursachen und therapeutische Optionen.

Pulmonary hypertension (PH) is a severe disease, which is usually only recognized at a late stage. It is characterized by dyspnea and right heart insufficiency. In some forms of pulmonary hypertension, such as the rare pulmonary arterial hypertension (PAH) and PAH associated with congenital heart defects, genetic factors have been identified. This article summarizes the general and supportive therapies for PH, targeted pharmaceutical treatment for PAH and non-operable chronic thromboembolic pulmonary hypertension. To achieve acceptable survival rates, it is essential to transfer patients to an expert center at an early stage for further differential diagnostics and therapy.

Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer.

BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control. PATIENTS AND METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant. RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months. CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.

A combined nutrient and lactulose challenge test allows symptom-based clustering of patients with irritable bowel syndrome.

OBJECTIVES: The aim of the present pilot study was to evaluate the usefulness of a test meal containing lactulose in the non-invasive assessment of visceral sensitivity in irritable bowel syndrome (IBS), and to identify subsets of IBS patients based on gastrointestinal (GI) symptom generation. METHODS: We included 43 patients with IBS (Rome III) and 29 healthy controls. The fasted subjects were served three test meals consisting of a 400-ml liquid breakfast alone or containing lactulose (15 or 25 g) in a double-blind crossover design. Seven GI symptoms, overall digestive comfort, and exhaled H2/CH4 were assessed at baseline and every 15 min during 4 h after meal intake. Anxiety and depression were assessed only at baseline. A mapping of the seven GI symptoms was done using a Principal Component Analysis (4 h mean area under the curve, AUC). Independently, a hierarchical cluster analysis was performed on the same parameters to identify GI symptom-based IBS clusters. RESULTS: All three tests were well tolerated. The 25 g lactulose challenge enabled discrimination of IBS from healthy controls according to the symptom response. This challenge also enabled clustering of IBS subjects in two subgroups based mainly on bloating, distension, and discomfort symptoms (2,457 (2,043-2,872), 2,450 (1,910-2,990), 2,602 (2,126-3,079) vs. 537 (383-691), 619 (458-780), 643 (432-854); 4 h mean AUC; P<0.0001), overall digestive comfort (1807 (1318-2295) vs. 3350 (2942-3758); 4 h mean AUC; P<0.0001), and anxiety at baseline (9.2 (7.0-11.5) vs. 5.5 (4.2-6.9); Hospital Anxiety and Depression scale anxiety mean scores; P=0.003). This clustering was independent of the Rome III subtype and the amount of exhaled H2/CH4. CONCLUSIONS: The lactulose challenge test seems to be a promising tool to assess visceral sensitivity in IBS, and to subgroup IBS patients based on their symptom pattern.

A phase II study of bevacizumab in combination with vinorelbine and trastuzumab in HER2-positive metastatic breast cancer.

We aimed to evaluate the efficacy and feasibility of combining trastuzumab/vinorelbine with bevacizumab in patients with first-or second-line HER2-positive, metastatic breast cancer (MBC). Eligible patients had HER2-positive measureable MBC, with no more than one prior line of chemotherapy, and were treated with trastuzumab (4 mg/kg × 2 mg/kg weekly thereafter), vinorelbine (25 mg/m(2) weekly), and bevacizumab (10 mg/kg every 2 weeks). Co-primary endpoints were (a) the proportion of patients alive and progression-free at 1 year and (b) safety profile/feasibility. Feasibility was defined as a rate of grade 3/4 non-hematologic toxicity attributable to protocol-based therapy <20 %. Twenty-nine patients were enrolled (n = 22 first-line, n = 7 second-line). Median age was 48 years (range 37-68). The median number of cycles received was 8 (1-23) and median duration on treatment was 7.4 months (range 1-22). The study was closed early due to higher-than-expected rates of grade 3/4 non-hematologic toxicities, with 50 events in 20 patients. A total of six patients (21 %) were taken off study for treatment-related toxicity. Most common treatment-related toxicities included fatigue (n = 7), febrile neutropenia (n = 4), and headache (n = 3). At 1 year, 8/22 first-line (36 %) and 2/7 second-line (29 %) patients were alive and progression-free. Median PFS was 9.9 months and 7.8 months in the first- and second-line cohorts, respectively. Objective responses were observed in 16/22 (73 %) and 5/7 (71 %) patients in the first- and second-line settings. Although the combination of vinorelbine, trastuzumab, and bevacizumab showed notable activity in HER2-positive MBC, the proportion of first-line patients alive and progression-free at 1 year was deemed unlikely to reach the pre-defined threshold for declaring success. Additionally, unacceptable toxicity was observed, at rates greater than previously reported with vinorelbine/trastuzumab or vinorelbine/bevacizumab doublet combinations.

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial.

OBJECTIVE: A phase II study was performed to evaluate the efficacy and tolerability of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) patients, and to investigate clinical and molecular predictors of outcome. METHODS: 59 patients with advanced HCC received 10 mg/kg i.v. of bevacizumab every 14 days and 150 mg p.o. of erlotinib daily. The primary endpoint was progression-free survival (PFS) at 16 weeks. Clinical characteristics and plasma biomarkers expression levels were analyzed. RESULTS: PFS at 16 weeks was 64% (95% CI 51-76): 14 patients achieved partial response (24%), 33 had stable disease (56%), 6 progressed (10%), and 6 were not evaluable (10%). Median overall survival was 13.7 months (95% CI 9.6-19.7), and median PFS was 7.2 months (95% CI 5.6-8.3). Grade 3-4 adverse events included fatigue (30%), diarrhea (17%), hypertension (14%), elevated transaminases (12%), and gastrointestinal hemorrhage (10%). High plasma angiopoietin-2, epidermal growth factor receptor, and endothelin-1, and lack of acneiform rash were associated with poor outcome. CONCLUSIONS: The combination of bevacizumab with erlotinib achieved encouraging results in patients with advanced HCC. Current correlatives may help to guide future HCC studies.

Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women.

OBJECTIVE: Alterations in serotonin signalling within the brain-gut axis have been implicated in the pathophysiology of irritable bowel syndrome (IBS) and is a treatment target. Acute tryptophan depletion (ATD) decreases brain serotonin (5-hydroxytryptamine; 5-HT) levels, and increases visceral perception and negative emotional bias in patients with IBS. The aim of the present study was to determine the effect of ATD on brain activity and connectivity during visceral stimuli in healthy women, and to compare the ATD-induced brain connectivity of an arousal circuit in female patients with IBS without ATD. METHODS: 12 healthy females (19-25 years) were studied under placebo (PLA) conditions and ATD. Functional MRI measurements were performed during a rectal barostat protocol, consisting of random non-painful and maximal tolerable distensions. Partial least squares analyses and structural equation modelling were used to evaluate the effect of ATD on functional and effective brain connectivity during distension. Results in healthy controls under ATD were compared with the effective connectivity of brain responses to 45 mm Hg rectal distension in 14 female patients with constipation-predominant IBS (IBS-C) (24-50 years). RESULTS: In healthy controls, ATD resulted in increased response of an extensive brain network to balloon distension, including the amygdala and nodes of emotional arousal and homeostatic afferent networks. The effect was greater during high inflation, suggesting greater engagement of the central serotonion system with more aversive visceral stimuli. Effective connectivity analysis revealed a profound effect of ATD on coupling between emotional arousal network nodes, resulting in loss of negative feedback inhibition of the amygdala. A near-identical pattern was identified in the patients with IBS-C. CONCLUSIONS: The findings are consistent with an ATD-induced disinhibition of and increased connectivity within an emotional arousal network during aversive stimulation. Together with the previous demonstration of ATD-induced visceral hyperalgesia in healthy controls, and the near-identical effective connectivity pattern observed in patients with IBS-C, these findings suggest that dysregulation of this brain network may play a role in central pain amplification and IBS pathophysiology.

Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders.

There is emerging evidence that diet has a major modulatory influence on brain-gut-microbiome (BGM) interactions with important implications for brain health, and for several brain disorders. The BGM system is made up of neuroendocrine, neural, and immune communication channels which establish a network of bidirectional interactions between the brain, the gut and its microbiome. Diet not only plays a crucial role in shaping the gut microbiome, but it can modulate structure and function of the brain through these communication channels. In this review, we summarize the evidence available from preclinical and clinical studies on the influence of dietary habits and interventions on a selected group of psychiatric and neurologic disorders including depression, cognitive decline, Parkinson's disease, autism spectrum disorder and epilepsy. We will particularly address the role of diet-induced microbiome changes which have been implicated in these effects, and some of which are shared between different brain disorders. While the majority of these findings have been demonstrated in preclinical and in cross-sectional, epidemiological studies, to date there is insufficient evidence from mechanistic human studies to make conclusions about causality between a specific diet and microbially mediated brain function. Many of the dietary benefits on microbiome and brain health have been attributed to anti-inflammatory effects mediated by the microbial metabolites of dietary fiber and polyphenols. The new attention given to dietary factors in brain disorders has the potential to improve treatment outcomes with currently available pharmacological and non-pharmacological therapies.

Do national policies for complaint handling in English hospitals support quality improvement? Lessons from a case study.

OBJECTIVES: A range of public inquiries in the English National Health Service have indicated repeating failings in complaint handling, and patients are often left dissatisfied. The complex, bureaucratic nature of complaints systems is often cited as an obstacle to meaningful investigation and learning, but a detailed examination of how such bureaucratic rules, regulations, and infrastructure shape complaint handling, and where change is most needed, remains relatively unexplored. We sought to examine how national policies structure local practices of complaint handling, how they are understood by those responsible for enacting them, and if there are any discrepancies between policies-as-intended and their reality in local practice. DESIGN: Case study involving staff interviews and documentary analysis. SETTING: A large acute and multi-site NHS Trust in England. PARTICIPANTS: Clinical, managerial, complaints, and patient advocacy staff involved in complaint handling at the participating NHS Trust (n=20). MAIN OUTCOME MEASURES: Not applicable. RESULTS: Findings illustrate four areas of practice where national policies and regulations can have adverse consequences within local practices, and partly function to undermine an improvement-focused approach to complaints. These include muddled routes for raising formal complaints, investigative procedures structured to scrutinize the 'validity' of complaints, futile data collection systems, and adverse incentives and workarounds resulting from bureaucratic performance targets. CONCLUSION: This study demonstrates how national policies and regulations for complaint handling can impede, rather than promote, quality improvement in local settings. Accordingly, we propose a number of necessary reforms, including patient involvement in complaints investigations, the establishment of independent investigation bodies, and more meaningful data analysis strategies to uncover and address systemic causes behind recurring complaints.