Prognostic factors and patterns of locoregional failure after surgical resection in patients with cholangiocarcinoma without adjuvant radiation therapy: optimal field design for adjuvant radiation therapy

Publication date: Available online 5 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Zahra Ghiassi-Nejad, Paola Tarchi, Erin Moshier, Meng Ru, Parissa Tabrizian, Myron Schwartz, Michael Buckstein
PurposeTo identify prognostic factors and patterns of local failure in patients with cholangiocarcinoma, following surgical resection in the absence of adjuvant radiation, for optimal definition of target volumes encompassing the majority of local recurrences.Methods and MaterialsA chart review was performed in patients who underwent resection for primary CCA (intrahepatic, hilar, and distal) between 1999 and 2014. Local failure was defined as recurrence in a theoretical reasonable post-operative radiation volume. This includes the cut surface of liver, biliary anastomosis, hilum, portal nodes, celiac nodes, peri-pancreatic nodes, gastro-hepatic nodes, and retroperitoneal nodes. Patients who received adjuvant radiation were excluded.Results189 patients underwent surgical resection for CCA, of which 145 patients had sufficient follow up. Median follow up was 41.6 months (95% CI: 35.4-48.7). 102 cases were intrahepatic, and 43 were hilar/distal CCA. Adjuvant chemotherapy was given in 38 (26%) of cases, of which 20 (54%) were gemcitabine based. Eighty six patients (59%) had a documented recurrence, of which 44 (51%) had a locoregional component. Among patients that had a recurrence, 23 (27%) had a recurrence at the biliary anastomosis and/or cut liver surface. Twenty eight (32.6%) patients had a recurrence in the regional lymph nodes, most prevalent in the portal (16.3%), and retroperitoneal (17.4%) lymph nodes. Univariable analysis identified tumor size, any vascular invasion, presence of satellites, stage/nodal status and receipt of chemotherapy were significant prognostic factors of overall recurrence among IHC patients. Presence of satellites, and stage 3/Nx status remained statistically significant in multivariable modeling.ConclusionsThe areas at highest risk for locoregional recurrence following surgical resection are the biliary anastomosis/cut liver surface, portal lymph nodes, and retroperitoneal lymph nodes. While these results need to be validated, adjuvant radiation should possibly cover these areas to maximize locoregional control.

Teaser

Locoergional recurrences following surgical resection for cholangiocarcinoma (CCA) cause significant morbidity and mortality. This retrospective analysis explores risk factors for local failures and maps locoregional recurrences in patients who underwent surgery without adjuvant radiation. The recurrence map provides valuable information for delineating optimal planning target volumes for adjuvant radiation.


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Timing Is Everything: Where Status Epilepticus Treatment Fails

Abstract

Status epilepticus is an emergency, however prompt treatment of patients with status epilepticus is challenging. Clinical trials, such as the Established Status Epilepticus Treatment Trial (ESETT), compare effectiveness of antiepileptic medications, and rigorous examination of effectiveness of care delivery is similarly warranted. We reviewed the medical literature on observed deviations from guidelines, clinical significance, and initiatives to improve timely treatment. We found pervasive, substantial gaps between recommended and “real world” practice with regard to timing, dosing, and sequence of antiepileptic therapy. Applying quality improvement methodology at the institutional level can increase adherence to guidelines, and may improve patient outcomes. This article is protected by copyright. All rights reserved.

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Familial mesial temporal lobe epilepsy and the borderland of déjà vu

Abstract

Objective: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly-diagnosed non-lesional MTLE actually represents familial MTLE (FMTLE).

Methods: We identified all consecutive patients presenting to the Austin Heath First Seizure Clinic with MTLE and a normal MRI or MRI-evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by two epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious of epilepsy; or unaffected. Physiological déjà vu was noted.

Results: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9/121 relatives vs 0/121 controls (p=0.008). All affected relatives had seizures with intense déjà vu and accompanying features; 6 relatives had not been previously diagnosed. Déjà vu experiences which were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives vs none of the controls (p=0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%).

Interpretation: FMTLE accounts for almost one-fifth of newly diagnosed non-lesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena which clinically lie in the ‘borderland' between epileptic seizures and physiological déjà vu. This article is protected by copyright. All rights reserved.

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Time-Dependent Risk of Seizures in Critically Ill Patients on Continuous EEG

ABSTRACT

OBJECTIVE: Find the optimal Continuous EEG (cEEG) monitoring duration for seizure detection in critically ill patients.

METHODS: We analyzed prospective data from 665 consecutive cEEGs, including clinical factors and time-to-event emergence of EEG findings over 72-hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for creation of multistate survival model with three states (entry, EEG risk, and seizure). EEG Risk state is defined by emergence of epileptiform patterns.

RESULTS: Clinical variables of greatest predictive value were coma (31% had seizures; OR 1.8; p<0.01) and history of seizures, either remotely or related to acute illness (34% had seizures; OR 3.0; p<0.001). If there were no epileptiform findings on EEG, the risk of seizures within 72-hour was between 9% (no clinical risk factors) and 36% (coma and history of seizures). If epileptiform findings developed the seizure incidence was between 18% (no clinical risk factors) and 64% (coma and history of seizure). In the absence of epileptiform EEG abnormalities, the duration of monitoring needed for seizure risk of <5% was between 0.4hrs (for patients who are not comatose, and no prior seizure) to 16.4hrs (comatose and prior seizure).

INTERPRETATION: The initial risk of seizures on cEEG is dependent on history of prior seizures and presence of coma. The risk of developing seizures on cEEG decays to <5% by 24 hours if no epileptiform EEG abnormalities emerge, independent of initial clinical risk factors. This article is protected by copyright. All rights reserved.

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MMP9 is decreased in natalizumab-treated MS patients at risk for PML

Abstract

Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).

Methods: Relapsing-remitting MS (RRMS) patients who developed PML under NTZ therapy (pre-PML) and non-PML natalizumab-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells (PBMC) and serum samples collected at baseline, at one- and two-year treated time points, and during PML were analyzed for gene expression by RNA-sequencing and for serum protein levels by LUMINEX and ELISA assays respectively.

Results: Among top differentially expressed genes in the RNA-sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: pro-angiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a two-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only MMP9 was validated and, in pre-PML patients MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients and levels remained lower at later time points during NTZ treatment.

Interpretation: The results from this study suggest that the pro-angiogenic factor MMP9 may play a role as biomarker associated with the development of PML in MS patients treated with NTZ. This article is protected by copyright. All rights reserved.

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Microbleeds in the SPS3 Trial: Stroke, Mortality and Treatment Interactions

Abstract

Objectives: To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the SPS3 trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment.

Methods: SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent MRI-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (SBP; 130–149 mmHg vs <130 mmHg; open-label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1278 trial participants who had a baseline axial T2*- GRE MRI sequence allowing for CMB detection.

Results: CMBs were present in 30% of 1278 patients (mean age 63 y). Male gender (OR 1.7, 95%CI 1.3-2.3)·, history of hypertension (1.6, 1.2-2.3), increased systolic blood pressure (1.2 per 20 mmHg, 1.1-1.4), non-diabetic (1.4, 1.1-1.9), multiple old lacunar infarcts(1.9, 1.5-2.5) and moderate(1.7, 1.2-2.3) or severe (4.2, 3.0-5.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 y, overall stroke recurrence was 2.5% per patient-y. Patients with CMBs had an adjusted two-fold increased risk of recurrent stroke (HR 2.1, 1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments.

Interpretation: Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies. This article is protected by copyright. All rights reserved.

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THIRD GENERATION EGFR TKIs IN EGFR-MUTATED NSCLC: WHERE ARE WE NOWAND WHERE ARE WE GOING

Publication date: Available online 5 July 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): A. Russo, T. Franchina, G.R.R. Ricciardi, V. Smiroldo, M. Picciotto, M. Zanghì, C. Rolfo, V. Adamo
The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.



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