Cross-Sectional Study on MRI Restaging After Chemoradiotherapy and Interval to Surgery in Rectal Cancer: Influence on Short- and Long-Term Outcomes.

BACKGROUND: The time interval between CRT and surgery in rectal cancer patients is still the subject of debate. The aim of this study was to first evaluate the nationwide use of restaging magnetic resonance imaging (MRI) and its impact on timing of surgery, and, second, to evaluate the impact of timing of surgery after chemoradiotherapy (CRT) on short- and long-term outcomes. METHODS: Patients were selected from a collaborative rectal cancer research project including 71 Dutch centres, and were subdivided into two groups according to time interval from the start of preoperative CRT to surgery (< 14 and ≥ 14 weeks). RESULTS: From 2095 registered patients, 475 patients received preoperative CRT. MRI restaging was performed in 79.4% of patients, with a median CRT-MRI interval of 10 weeks (interquartile range [IQR] 8-11) and a median MRI-surgery interval of 4 weeks (IQR 2-5). The CRT-surgery interval groups consisted of 224 (< 14 weeks) and 251 patients (≥ 14 weeks), and the long-interval group included a higher proportion of cT4 stage and multivisceral resection patients. Pathological complete response rate (n = 34 [15.2%] vs. n = 47 [18.7%], p = 0.305) and CRM involvement (9.7% vs. 15.9%, p = 0.145) did not significantly differ. Thirty-day surgical complications were similar (20.1% vs. 23.1%, p = 0.943), however no significant differences were found for local and distant recurrence rates, disease-free survival, and overall survival. CONCLUSIONS: These real-life data, reflecting routine daily practice in The Netherlands, showed substantial variability in the use and timing of restaging MRI after preoperative CRT for rectal cancer, as well as time interval to surgery. Surgery before or after 14 weeks from the start of CRT resulted in similar short- and long-term outcomes.

Identification of a novel pathway of transforming growth factor-ß1 regulation by extracellular NAD+ in mouse macrophages: in vitro and in silico studies.

Extracellular ß-nicotinamide adenine dinucleotide (NAD(+)) is anti-inflammatory. We hypothesized that NAD(+) would modulate the anti-inflammatory cytokine Transforming Growth Factor (TGF)-ß1. Indeed, NAD(+) led to increases in both active and latent cell-associated TGF-ß1 in RAW 264.7 mouse macrophages as well as in primary peritoneal macrophages isolated from both C3H/HeJ (TLR4-mutant) and C3H/HeOuJ (wild-type controls for C3H/HeJ) mice. NAD(+) acts partially via cyclic ADP-ribose (cADPR) and subsequent release of Ca(2+). Treatment of macrophages with the cADPR analog 3-deaza-cADPR or Ca(2+) ionophores recapitulated the effects of NAD(+) on TGF-ß1, whereas the cADPR antagonist 8-Br-cADPR, Ca(2+) chelation, and antagonism of L-type Ca(2+) channels suppressed these effects. The time and dose effects of NAD(+) on TGF-ß1 were complex and could be modeled both statistically and mathematically. Model-predicted levels of TGF-ß1 protein and mRNA were largely confirmed experimentally but also suggested the presence of other mechanisms of regulation of TGF-ß1 by NAD(+). Thus, in vitro and in silico evidence points to NAD(+) as a novel modulator of TGF-ß1.

Physiologic responses to severe hemorrhagic shock and the genesis of cardiovascular collapse: can irreversibility be anticipated?

BACKGROUND: The causes of cardiovascular collapse (CC) during hemorrhagic shock (HS) are unknown. We hypothesized that vascular tone loss characterizes CC, and that arterial pulse pressure/stroke volume index ratio or vascular tone index (VTI) would identify CC. METHODS: Fourteen Yorkshire-Durock pigs were bled to 30 mmHg mean arterial pressure and held there by repetitive bleeding until rendered unable to compensate (CC) or for 90 min (NoCC). They were then resuscitated in equal parts to shed volume and observed for 2 h. CC was defined as a MAP < 30 mmHg for 10 min or <20 mmHg for 10 s. Study variables were recorded at baseline (B0), 30, 60, 90 min after bleeding and at resuscitation (R0), 30, and 60 min afterward. RESULTS: Swine were bled to 32% ± 9% of total blood volume. Epinephrine (Epi) and VTI were low and did not change in NoCC after bleeding compared with CC swine, in which both increased (0.97 ± 0.22 to 2.57 ± 1.42 mcg/dL, and 173 ± 181 to 939 ± 474 mmHg/mL, respectively), despite no differences in bled volume. Lactate increase rate (LIR) increased with hemorrhage and was higher at R0 for CC, but did not vary in NoCC. VTI identified CC from NoCC and survivors from non-survivors before CC. A large increase in LIR was coincident with VTI decrement before CC occurred. CONCLUSIONS: Vasodilatation immediately prior to CC in severe HS occurs at the same time as an increase in LIR, suggesting loss of tone as the mechanism causing CC, and energy failure as its probable cause.

Novel serum biomarkers in carotid artery stenosis: useful to identify the vulnerable plaque?

OBJECTIVES: Serum biomarkers representing inflammatory activity in vulnerable carotid plaques may be used to identify high-risk patients for cerebral ischemic events. We aimed to analyze the relationship between concentrations of four novel biomarkers and neurological symptoms: Neopterin, PTX3, sCD163, and sTREM-1. In addition, we analyzed the relationship between these markers and the presence of coronary (CAD) and peripheral (PAD) artery disease. DESIGN AND METHODS: Serum biomarker levels were determined in 100 patients undergoing carotid endarterectomy; 33 for stroke, 32 for transient ischemic attack, and 23 for amaurosis fugax. 12 Patients were asymptomatic. Risk factors for atherosclerotic disease and history of CAD and PAD were also assessed. RESULTS: Symptomatic patients did not show significantly elevated biomarker levels compared to asymptomatic patients and levels did not differ among symptomatic subgroups. Neopterin levels were elevated in patients with concomitant coronary and peripheral artery disease (CAD (32%) 10.2 ± 6.6 vs no CAD (68%) 7.6 ± 2.9 nmol/L, PAD (20%) 12.3 ± 7.4 vs no PAD (80%) 7.5 ± 3.0 nmol/L, p<0.05). sTREM-1 was elevated in patients with CAD (50.8 ± 53.2 vs 28.0 ± 31.6 ng/L, p<0.05). PTX3 and sCD163 were not significantly elevated in CAD nor PAD. CONCLUSION: Our findings suggest that serum neopterin and sTREM-1 levels may be related to the presence of atherosclerotic disease, but not to carotid plaque vulnerability.

Carotid endarterectomy: current consensus and controversies.

Stroke is the third most common cause of mortality, and carotid artery stenosis causes 8% to 29% of all ischemic strokes. Best medical treatment forms the basis of carotid stenosis treatment, and carotid endarterectomy (CEA) has an additional beneficial effect in high-grade stenosis. Carotid angioplasty and stenting (CAS) has challenged CEA as a primary carotid intervention. At present, CEA remains the gold standard, but in the future, CAS techniques will evolve and might become beneficial for subgroups of patients with carotid stenosis. This chapter briefly describes the history of carotid interventions and current consensus and controversies in CEA. In the last two years, several meta-analyses were published on a variety of aspects of best medical treatment, CEA, and CAS. It is still a matter of debate as to whether asymptomatic patients with carotid stenosis should undergo a carotid intervention. Especially because medical treatment has dramatically evolved since the early carotid trials. On the other hand, it is clear that carotid interventions in symptomatic patients with a high-grade stenosis should be performed as early as possible after the initial neurological event in order to achieve optimal stroke risk reduction. In CEA, the use of patching is advocated above primary closure, while the role of selective patching is still unclear. No differences in stroke and mortality rates are observed for routine versus selective shunting, for conventional versus eversion CEA, or for local versus general anesthesia. It is anticipated that in the future, there will be several interesting developments in carotid interventions such as plaque morphology analysis, acute interventions during stroke in progress, and further evolvement of CAS techniques.

Carotid plaque formation and serum biomarkers.

Treatment of carotid artery stenosis by endarterectomy or stenting can significantly reduce stroke risk, but is also associated with surgery related mortality and morbidity. At present it is neither possible to assess whether a carotid plaque will become symptomatic or not, nor to define the time when symptoms will occur. Identification of carotid plaques which confer excess risk of neurologic events is fundamental in the selection of patients for vascular intervention. Molecular processes such as inflammation, lipid accumulation, apoptosis, proteolysis, thrombosis and angiogenesis have shown to be highly related with plaque vulnerability. Serum biomarkers reflecting these processes may distinguish unstable from stable carotid artery stenosis and thus be a powerful tool in the selection of patients for carotid surgery. Until now, no serum biomarker has qualified for regular clinical use in carotid artery disease. However, several biomarkers, especially markers of inflammatory or proteolytic activity seem to be promising in the identification of vulnerable carotid plaques. Therefore, it is anticipated that non-invasive risk assessment in carotid artery disease by determination of serum biomarker levels may play an important future role in clinical practice improving better selection criteria for vascular intervention.

An adequately robust early TNF-alpha response is a hallmark of survival following trauma/hemorrhage.

BACKGROUND: Trauma/hemorrhagic shock (T/HS) results in cytokine-mediated acute inflammation that is generally considered detrimental. METHODOLOGY/PRINCIPAL FINDINGS: Paradoxically, plasma levels of the early inflammatory cytokine TNF-alpha (but not IL-6, IL-10, or NO(2) (-)/NO(3) (-)) were significantly elevated within 6 h post-admission in 19 human trauma survivors vs. 4 non-survivors. Moreover, plasma TNF-alpha was inversely correlated with Marshall Score, an index of organ dysfunction, both in the 23 patients taken together and in the survivor cohort. Accordingly, we hypothesized that if an early, robust pro-inflammatory response were to be a marker of an appropriate response to injury, then individuals exhibiting such a response would be predisposed to survive. We tested this hypothesis in swine subjected to various experimental paradigms of T/HS. Twenty-three anesthetized pigs were subjected to T/HS (12 HS-only and 11 HS + Thoracotomy; mean arterial pressure of 30 mmHg for 45-90 min) along with surgery-only controls. Plasma obtained at pre-surgery, baseline post-surgery, beginning of HS, and every 15 min thereafter until 75 min (in the HS only group) or 90 min (in the HS + Thoracotomy group) was assayed for TNF-alpha, IL-6, IL-10, and NO(2) (-)/NO(3) (-). Mean post-surgery+/-HS TNF-alpha levels were significantly higher in the survivors vs. non-survivors, while non-survivors exhibited no measurable change in TNF-alpha levels over the same interval. CONCLUSIONS/SIGNIFICANCE: Contrary to the current dogma, survival in the setting of severe, acute T/HS appears to be associated with an immediate increase in serum TNF-alpha. It is currently unclear if this response was the cause of this protection, a marker of survival, or both. This abstract won a Young Investigator Travel Award at the SHOCK 2008 meeting in Cologne, Germany.

Activation of latent transforming growth factor-beta1 by nitric oxide in macrophages: role of soluble guanylate cyclase and MAP kinases.

The inducible nitric oxide (NO) synthase and the cytokine transforming growth factor-beta1 (TGF-beta1), both central modulators of wound healing, interact reciprocally: TGF-beta1 generally suppresses iNOS expression, while NO can induce and activate latent TGF-beta1. We have shown that chemical NO activates recombinant human latent TGF-beta1 by S-nitrosation of the latency-associated peptide (LAP), a cleaved portion of pro-TGF-beta1 that maintains TGF-beta1 in a biologically-inactive state. We hypothesized that cell-associated TGF-beta1 could be activated by NO via known NO-inducible signaling pathways (soluble guanylate cyclase [sGC] and mitogen-activated protein [MAP] kinases). Treatment of mouse RAW 264.7 macrophage-like cells with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) led to a dose- and time-dependent increase in cell-associated active and latent TGF-beta1, as assessed by quantitative immunocytochemistry for active TGF-beta1 vs. LAP and partially validated by western blot analysis. Treatment with the sGC inhibitor 1,H-[1,2,4]oxadiazole[4,3-a]quinoxalon-1-one (ODQ) reduced both active and latent TGF-beta1 dose-dependently. SNAP, in the presence or absence of ODQ or the MAP kinase inhibitors, did not affect steady-state TGF-beta1 mRNA levels. Treatment with inhibitors specific for JNK1/2, ERK1/2, and p38 MAP kinases suppressed SNAP-induced active and latent TGF-beta1. Treatment with the cell-permeable cGMP analog 8-Br-cGMP increased both active and latent TGF-beta1. However, TGF-beta1 activation induced by 8-Br-cGMP was not blocked by MAP kinase inhibitors. Our findings suggest that NO activates latent TGF-beta1 via activation of sGC and generation of cGMP and separately via MAP kinase activation, and may shed insight into the mechanisms by which both cGMP production and MAP kinase activation enhance wound healing.