Does Loosening the Inclusion Criteria of the CROSS Trial Impact Outcomes in the Curative-Intent Trimodality Treatment of Oesophageal and Gastroesophageal Cancer Patients?

AIM: To determine the efficacy of preoperative chemoradiotherapy as per the CROSS protocol for oesophageal/gastroesophageal junction cancer (OEGEJC), when expanded to patients outside of the inclusion/exclusion criteria defined in the original clinical trial. MATERIALS AND METHODS: Data were collected retrospectively on 229 OEGEJC patients referred for curative-intent preoperative chemoradiotherapy. Outcomes including pathological complete response (pCR), overall survival (OS), cancer-specific survival and recurrence-free survival (RFS) of patients who met CROSS inclusion criteria (MIC) versus those who failed to meet criteria (FMIC) were determined. RESULTS: In total, 42.8% of patients MIC, whereas 57.2% FMIC; 16.6% of patients did not complete definitive surgery. The MIC cohort had higher rates of pCR, when compared with the FMIC cohort (33.3% versus 20.6%, P = 0.039). The MIC cohort had a better RFS, cancer-specific survival and OS compared with the FMIC cohort (P = 0.006, P = 0.004 and P = 0.009, respectively). Age >75 years and pretreatment weight loss >10% were not associated with a poorer RFS (P = 0.541 and 0.458, respectively). Compared with stage I-III patients, stage IVa was associated with a poorer RFS (hazard ratio (HR) = 2.158; 95% confidence interval (CI) = 1.339-3.480, P = 0.001). Tumours >8 cm in length or >5 cm in width had a trend towards worse RFS (HR = 2.060; 95% CI = 0.993-4.274, P = 0.052). CONCLUSION: Our study showed that the robust requirements of the CROSS trial may limit treatment for patients with potentially curable OEGEJC and can be adapted to include patients with a good performance status who are older than 75 years or have >10% pretreatment weight loss. However, the inclusion of patients with celiac nodal metastases or tumours >8 cm in length or >5 cm in width may be associated with poor outcomes.

Repeat resection in recurrent glioblastoma (3rGBM) Trial: A randomized care trial.

BACKGROUND: The prognosis for patients with recurrent glioblastoma (GBM) is dismal, and the question of repeat surgery at time of recurrence is common. Re-operation in the management of these patients remains controversial, as there is no randomized evidence of benefit. An all-inclusive pragmatic care trial is needed to evaluate the role of repeat resection. METHODS: 3rGBM is a multicenter, pragmatic, prospective, parallel-group randomized care trial, with 1:1 allocation to repeat resection or standard care with no repeat resection. To test the hypothesis that repeat resection can improve overall survival by at least 3 months (from 6 to 9 months), 250 adult patients with prior resection of pathology-proven glioblastoma for whom the attending surgeon believes repeat resection may improve quality survival will be enrolled. A surrogate measure of quality of life, the number of days outside of hospital/nursing/palliative care facility, will also be compared. Centers are invited to participate without financial compensation and without contracts. Clinicians may apply to local authorities to approve an investigator-led in-house trial, using a common protocol, web-based randomization platform, and simple standardized case report forms. DISCUSSION: The 3rGBM trial is a modern transparent care research framework with no additional risks, tests, or visits other than what patients would encounter in normal care. The burden of proof remains on repeat surgical management of recurrent GBM, because this management has yet to be shown beneficial. The trial is designed to help patients and surgeons manage the uncertainty regarding optimal care. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov. Unique identifier: NCT04838782.

Risk factors for venous thromboembolism in endometrial cancer.

Background: Venous thromboembolism (vte) in malignancy is associated with poor outcomes. We conducted a retrospective review of vte in patients with endometrial cancer to characterize the vte incidence, identify factors that contribute to vte risk, and compare survival outcomes in patients with and without vte. Methods: A retrospective chart review identified 422 eligible patients who underwent surgery for endometrial cancer (1 January 2014 to 31 July 2016). The primary outcome was vte. Binary logistic regression identified risk factors for vte; significant risk factors were included in a multivariate analysis. Kaplan-Meier estimates are reported, and log rank tests were used to compare the Kaplan-Meier curves. Risk-adjusted estimates for overall survival based on vte were determined using a multivariate Cox proportional hazards model. Results: The incidence of vte was 6.16% overall and 0.7% within 60 days postoperatively. Non-endometrioid histology, stages 3 and 4 disease, laparotomy, and age (p < 0.1) were identified as factors associated with vte and were included in a multivariate analysis. The overall death rate in patients with vte was 42% (9% without vte): hazard ratio, 5.63; 95% confidence interval, 2.86 to 11.08; p < 0.0001. Adjusting for age, stage of disease, and histology, risk of death remained significant for patients with a vte: hazard ratio, 2.20; 95% confidence interval, 1.09 to 4.42; p = 0.0271. Conclusions: A method to identify patients with endometrial cancer who are at high risk for vte is important, given the implications of vte for patient outcomes and the frequency of endometrial cancer diagnoses. Factors identified in our study might assist in the recognition of such patients.

PO-42 - A novel approach to a common problem: after-hours care of cancer patients diagnosed with VTE.

INTRODUCTION: Oncologists often receive phone calls from radiologists after regular working hours or while on call, informing them that a cancer patient has been diagnosed with a blood clot. In these situations, there may not be nursing staff available to contact the patient and provide teaching for Low Molecular Weight Heparin (LMWH) injections. As a result, patients are often sent to the emergency for injection and teaching, taxing an already overburdened emergency department. This problem constitutes an important care gap. AIM: In Alberta, Canada, pharmacists are able to prescribe medications including LMWH. We designed an after-hours program to provide care for cancer patients diagnosed with VTE. MATERIALS AND METHODS: Once the oncologist is made aware of the patient with a clot, a simple one page document is filled out and faxed to a 24-hour outpatient pharmacy outlining the following: patient demographics, clot location, systemic therapy, current anticoagulant and anti-platelet agents. The oncologist has the option to specify desired LMWH. The patient goes to the pharmacy where the pharmacist weighs the patient, reviews blood work electronically and prescribes the LMWH. Also provided are injection teaching and telephone follow-up. A specific algorithm is followed with the pharmacist able to contact the on call oncologist in specific situations where the patient's condition falls outside of the algorithm guideline. The pharmacist is able to order blood work, particularly to evaluate for Heparin Induced Thrombocytopenia. Patients must follow up with their oncologist within 7 days of diagnosis. RESULTS: This program has been run as a pilot and preliminary data will be presented at the ICTHIC meeting. Specifically, we will assess usage of the program, appropriateness of therapy chosen according to Canadian practice guidelines, as well as patient, pharmacist and physician satisfaction with the program. CONCLUSIONS: We believe that this outpatient pharmacy program is innovative, will decrease burden on emergency departments, and takes advantage of our pharmacists' ability to independently assess patients and write prescriptions. This program may serve as a model for other cancer centers looking for a novel way to provide after-hours care of patients diagnosed with VTE.

Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 1: prophylaxis.

Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy has been shown to prevent vte; however, unique clinical circumstances in patients with cancer can often complicate the decisions surrounding the administration of prophylactic anticoagulation. No national Canadian guidelines on the prevention of cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence-informed guideline on the topic. PubMed was searched for clinical trials and meta-analyses published between 2002 and 2013. Reference lists of key articles were hand-searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations. Low molecular weight heparin can be used prophylactically in cancer patients at high risk of developing vte. Direct oral anticoagulants are not recommended for vte prophylaxis at this time. Specific clinical scenarios, including renal insufficiency, thrombocytopenia, liver disease, and obesity can warrant modifications in the administration of prophylactic anticoagulant therapy. There is no evidence to support the monitoring of anti-factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, factor Xa levels could be checked at baseline and periodically in patients with renal insufficiency. The use of anticoagulation therapy to prolong survival in cancer patients without the presence of risk factors for vte is not recommended.

Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 2: treatment.

Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy is used to treat vte; however, patients with cancer have unique clinical circumstances that can often make decisions surrounding the administration of therapeutic anticoagulation complicated. No national Canadian guidelines on the management of established cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence-informed guideline on the topic. PubMed was searched for clinical trials and meta-analyses published between 2002 and 2013. Reference lists of key articles were hand-searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations. Low molecular weight heparin is the treatment of choice for cancer patients with established vte. Direct oral anticoagulants are not recommended for the treatment of vte at this time. Specific clinical scenarios, including the presence of an indwelling venous catheter, renal insufficiency, and thrombocytopenia, warrant modifications in the therapeutic administration of anticoagulation therapy. Patients with recurrent vte should receive extended (>3 months) anticoagulant therapy. Incidental vte should generally be treated in the same manner as symptomatic vte. There is no evidence to support the monitoring of anti-factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, levels of anti-factor Xa could be checked at baseline and periodically thereafter in patients with renal insufficiency. Follow-up and education about the signs and symptoms of vte are important components of ongoing patient care.

Evidence-based guidance on venous thromboembolism in patients with solid tumours.

Venous thromboembolism (vte) is a serious, life-threatening complication of cancer. Anticoagulation therapy such as low molecular weight heparin (lmwh) has been shown to treat and prevent vte. Cancer therapy is often complex and ongoing, making the management of vte less straightforward in patients with cancer. There are no published Canadian guidelines available to suggest appropriate strategies for the management of vte in patients with solid tumours. We therefore aimed to develop a clear, evidence-based guideline on this topic. A systematic review of clinical trials and meta-analyses published between 2002 and 2013 in PubMed was conducted. Reference lists were hand-searched for additional publications. The National Guidelines Clearinghouse was searched for relevant guidelines. Recommendations were developed based on the best available evidence. In patients with solid tumours, lmwh is recommended for those with established vte and for those without established vte but with a high risk for developing vte. Options for lmwh include dalteparin, enoxaparin, and tinzaparin. No one agent can be recommended over another, but in the setting of renal insufficiency, tinzaparin is preferred. Unfractionated heparin can be used under select circumstances only (that is, when rapid clearance of the anticoagulant is desired). The most common adverse event is bleeding, but major events are rare, and with appropriate follow-up care, bleeding can be monitored and appropriately managed.

Does neurologic deterioration help to differentiate between pseudoprogression and true disease progression in newly diagnosed glioblastoma multiforme?

Enlarging or new lesions frequently appear on magnetic resonance imaging (mri) after concurrent administration of radiation therapy and temozolomide in glioblastoma multiforme (gbm) patients. However, in nearly half such cases, the observed radiologic changes are not due to true disease progression, but instead are a result of a post-radiation inflammatory state called "pseudoprogression." Retrospective studies have reported that neurologic deterioration at the time of the post-chemoradiotherapy mri is found more commonly in patients with true disease progression. We report a gbm patient with both radiologic progression on the post-chemoradiotherapy mri and concomitant neurologic deterioration, and we caution against incorporating clinical deterioration into the management schema of patients with possible pseudoprogression.

Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme.

Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re-irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.

Zinc modulation of ionic currents in the horizontal limb of the diagonal band of Broca.

We examined modulation of ionic currents by Zn2+ in acutely dissociated neurons from the rat's horizontal limb of the diagonal band of Broca using the whole-cell patch-clamp technique. Application of 50 microM Zn2+ increased the peak amplitude of the transiently activated potassium current, I(A) (at + 30 mV), from 2.20+/-0.08 to 2.57+/-0.11 nA (n = 27). This response was reversible and could be repeated in 0 Ca2+/1 microM tetrodotoxin (n = 15). Zn2+ shifted the inactivation curve to the right, resulting in a shift in the half-inactivation voltage from 76.4+/-2.2 to -53.4+/-2.0 mV (n = 11), with no effect on the voltage dependence of activation gating (n = 15). There was no significant difference in the time to peak under control conditions (7.43+/-0.35 ms, n = 14) and in the presence of Zn2+ (8.20+/-0.57 ms, n = 14). Similarly, the time constant of decay of I(A) (tau(d)) at + 30 mV showed no difference (control: 38.68+/-3.68 ms, n = 15; Zn2+: 38.48+/-2.85 ms, n = 15). I(A) was blocked by 0.5-1 mM 4-aminopyridine. In contrast to its effects on I(A), Zn2+ reduced the amplitude of the delayed rectifier potassium current (I(K)). The reduction of outward K+ currents was reproducible when cells were perfused with 1 microM tetrodotoxin in a 0 Ca2+ external solution. The amplitude of the steady-state outward currents at +30 mV under these conditions was reduced from 6.40+/-0.23 (control) to 5.76+/-0.18 nA in the presence of Zn2+ (n = 16). The amplitudes of peak sodium currents (INa) were not significantly influenced (n = 10), whereas barium currents (I(Ba)) passing through calcium channels were potently modulated. Zn2+ reversibly reduced I(Ba) at -10 mV by approximately 85% from -2.06+/-0.14 nA under control conditions to -0.30+/-0.10 nA in the presence of Zn2+ (n = 14). Further analyses of Zn2+ effects on specific calcium channels reveals that it suppresses all types of high-voltage-activated Ca2+ currents. Under current-clamp conditions, application of Zn2+ resulted in an increase in excitability and loss of accommodation (n = 13), which appears to be mediated through its effects on Ca2+-dependent conductances.

Vasopressin receptor subtypes differentially modulate calcium-activated potassium currents in the horizontal limb of the diagonal band of Broca.

The actions of vasopressin on acutely dissociated neurons within the rat horizontal limb of the diagonal band of Broca were examined using the whole-cell patch-clamp technique. Vasopressin elicited two distinct responses in 45 of 62 neurons. In one group of cells, 300 nM vasopressin decreased voltage-activated outward currents (26/45 cells) whereas in a second group, vasopressin increased outward currents (19/45 cells). The vasopressin-mediated decrease in outward currents was blocked by 1 microM Manning compound, a V1 receptor antagonist, suggesting that this response was mediated via V1 receptors. In contrast, the vasopressin-induced increase in outward current was blocked by 1 microM d(CH2)5)1,D-Ile2,Ile4,Arg8,Ala9, a V2 receptor antagonist, indicating that V2 receptor activation underlies this second response. When cells were perfused with 0 Ca2+/50 microM Cd2+, application of vasopressin did not cause any change in voltage-activated outward currents, suggesting that vasopressin modulates a calcium-dependent conductance. In the presence of 25 nM charybdotoxin, an Ic channel antagonist, vasopressin application did not influence outward currents, indicating that vasopressin modulates Ic. Currents through voltage-gated calcium channels which are responsible for activation of Ic were unaffected by vasopressin, suggesting a direct effect of vasopressin on Ic channels. These observations indicate a differential modulation of Ic channels by vasopressin via V1 and V2 receptors in the horizontal limb of the diagonal band of Broca. Our data also demonstrate the ionic mechanisms whereby vasopressin may act at V1 for V2 receptors to influence the excitability of the horizontal limb of the diagonal band of Broca neurons.

An electrophysiological study of neurons in the horizontal limb of the diagonal band of Broca.

We examined the morphological and electrophysiological properties of neurons within the horizontal limb of the diagonal band of Broca (hDBB) and investigated the role of excitatory amino acid mediated synaptic transmission in this region. Whole cell patch-clamp recordings were obtained from hDBB neurons in rat forebrain slices. The hDBB cells examined in this study display a morphological and electrophysiological profile that is consistent with the type B, noncholinergic cell type. Cable analysis reveals that hDBB neurons are electrotonically compact and may therefore function as efficient relays for transmission of inputs to other forebrain target sites. Application of agonists for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, N-methyl-D-aspartate (NMDA), and metabotropic receptors all evoke inward currents in hDBB neurons. Pharmacological analyses of synaptic events indicate that evoked excitatory postsynaptic currents (EPSC) are either mediated by non-NMDA receptors alone or a combination of non-NMDA and NMDA receptors. In some neurons, the metabotropic receptor agonist, 1-aminocyclopentane-trans-1, 3-dicarboxylic acid, reduced EPSC amplitude without altering postsynaptic input conductance, thus suggesting a presynaptic locus of action. The electrical and pharmacological properties described for hDBB neurons may be physiologically relevant for the effective transmission of excitatory synaptic inputs to sites that receive projections from the hDBB.

Glutamate receptor subtypes mediate excitatory synaptic responses of rat lateral parabrachial neurons.

We examined the role of specific excitatory amino acid (EAA) receptors in synaptic transmission within the lateral parabrachial nucleus (LPBN) using whole cell patch-recording techniques in a slice preparation. Two types of excitatory postsynaptic responses were observed. The first involved the contribution of non-N-methyl-D-aspartate (NMDA) receptors, which mediated a fast component, and NMDA receptors, which governed the late component of the excitatory postsynaptic current (EPSC). The second EPSC response was mediated solely by non-NMDA receptors. Both EPSC responses reversed near 0 mV. The fast component of the EPSC was attenuated by the non-NMDA antagonists [6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 6-nitro-7-sulfamobenzoquinoxaline-2-3,-dione (NBQX)]. The late component was reduced by D,L-2-amino-5-phosphonovaleric acid (APV) and augmented in Mg(2+)-free external medium. EPSCs mediated solely by non-NMDA receptors were completely blocked by CNQX and NBQX but not affected by APV or Mg(2+)-free external medium. EPSCs were also markedly attenuated by the metabotropic-receptor agonist, trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD). We concluded that intra-LPBN stimulation causes the synaptic release of glutamate, which depolarizes LBPN neurons via non-NMDA and NMDA receptors. We also provide evidence that glutamate can negatively influence its own release via action on presynaptic metabotropic receptors.

Alterations in membrane potential after axotomy at different distances from the soma of an identified neuron and the effect of depolarization on neurite outgrowth and calcium channel expression.

1. Intracellular recordings were made from the soma of an identified neuron B5 within the buccal ganglion of the mollusc, Helisoma trivolvis, during axotomy induced by crushing or cutting the esophageal nerve. Axotomy was associated with a rapid depolarization and occasionally a burst of action potentials (injury discharge). The magnitude of the membrane depolarization in the soma in response to axotomy decayed exponentially when the distance between the soma and site of injury was increased. Input resistance measurements taken during axotomy showed that a barrier to current flow formed rapidly and gradually recovered within 2 h. A barrier to the diffusion of intracellularly injected carboxyfluorescein formed at the site of injury within 15 min of axotomy. 2. To examine the effect of chronic depolarization on neurite outgrowth, the extracellular potassium ion concentration [K+]o was manipulated. The membrane potential of neurons B5 exhibited a 51.8 mV/decade potassium dependence between 20 and 150 mM [K+]o. The initiation of neurite outgrowth from axons crushed 800 microns from the soma and bathed in different concentrations of [K+]o was examined by fluorescence microscopy after filling neurons with Lucifer yellow. We compared the percentage of axons with sprouts 9 and 24 h after organ culture in saline containing [K+]o ranging from 0.1 to 50 mM. Sprouting occurred from 33% of neurons B5 in normal saline (1.7 mM [K+]o) after 9 h and from 100% of neurons after 24 h. No sprouting was observed from neurons B5 9 or 24 h after axotomy when bathed in saline containing reduced or elevated concentrations of [K+]o. 3. To examine the effects of chronic depolarizatin on neurite outgrowth over several days, neurons B5 were axotomized close to the soma and maintained in organ culture in Liebovitz medium (defined medium or medium conditioned with central ganglia). Neurite outgrowth was ranked from 0 to 5 after filling neurons with Lucifer yellow, and our analysis indicated that a small increase in neurite outgrowth occurred in medium supplemented with 10 mM potassium. 4. Elevated potassium did not trigger neurite outgrowth from isolated neurons B5 in cell culture within defined medium, but whole-cell patch-clamp analysis revealed that chronic depolarization associated with elevated potassium altered the expression of calcium currents. Low-voltage-activated (LVA) and high-voltage-activated (HVA) calcium currents were detected in acutely isolated neurons B5.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of sprouting in organ culture after axotomy of an identified molluscan neuron.

We examined a variety of factors that might modulate the initiation of neurite outgrowth in an attempt to identify means by which its initiation might be accelerated. We examined this initiation from an identified molluscan neuron, Helisoma trivolvis buccal neuron B5 after axotomy, and determined whether the site of injury, temperature, ion channel blockers, pH, the second messenger cAMP, and protein synthesis affect the initiation of neurite outgrowth. Neurite outgrowth was assayed from axotomized neurons by filling the neurons intracellularly with Lucifer Yellow and examining the percentage of axons that extended (sprouted) new process after 9 or 24 h in organ culture. About one-third (31%) of axotomized neurons sprouted from the site of injury after 9 h (n = 22), and 88% (n = 20) sprouted after 24 h in saline at 22 degrees-24 degrees C when the injury was located 800 microns from the soma. Elevating the temperature to 32 degrees C or moving the lesion site to 400 or 1500 microns from the soma did not significantly alter the incidence of sprouting. Blocking sodium channels with tetrodotoxin [TTX (2 x 10(-5) M)] did not significantly reduce the incidence of sprouting, whereas the sodium channel agonist, veratridine (10(-5) M) did. The calcium channel blocker lanthanum (10(-6)-10(-4) M), stimulated neurite outgrowth; however, the organic calcium channel blocker verapamil (10(-3)-10(-5) M), and the calcium ionophore A23187 (10(-5) M), had no effect on sprouting. Exposure of neurons to the potassium channel blocker tetraethylammonium [TEA (20 mM)], elevation of intracellular pH with NH4Cl (5 mM), or treatment with the adenylate cyclase activator forskolin (10(-5) M) reduced the incidence of sprouting, whereas dideoxy-forskolin (10(-5) M) had no effect. Inhibition of protein synthesis with anisomycin (2 x 10(-4) to 2 x 10(-6) M) did not significantly suppress sprouting 24 h after axotomy. Both D and L isomers of glutamate (300 microM) stimulated sprouting. The present results suggest that the initiation of sprouting is regulated locally at or near the site of injury, and that blocking specific ion channels may either inhibit or enhance the initiation of neurite outgrowth.