Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Rare Diseases

Pancreatic Neoplasms

Skin Neoplasms

Carcinoma, Non-Small-Cell Lung

Head and Neck Neoplasms

Carcinoma, Renal Cell

Lung Neoplasms

Disease Progression

Kidney Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Analgesics

Nivolumab

Pembrolizumab

Paclitaxel

Albumin-Bound Paclitaxel

Oxaliplatin

Carboplatin

Fluorouracil

Capecitabine

Immune Checkpoint Inhibitors

Immunomodulating Agents

Interleukin-2

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

DK210 (EGFR) will be administered as monotherapy three times per week via subcutaneous (SC) administration. Dose will be escalated from 0.025 mg/kg to 0.3 mg/kg or until unacceptable toxicity, disease progression, or withdrawal of consent. An expansion cohort at the optimal dose will be enrolled in parallel with the combination arms.

In patients with good tolerance of first line systemic therapy, DK210 (EGFR) will be administered three times per week via subcutaneous (SC) administration in combination with second-line intravenous (IV) chemotherapy until unacceptable toxicity, disease progression, or withdrawal of consent

In patients with need of palliative radiation, DK210 (EGFR) will be administered three times per week via subcutaneous (SC) administration in combination with short course radiation therapy (10 fractions or less) until unacceptable toxicity, disease progression, or withdrawal of consent

In patients with good tolerance of first line immunotherapy, DK210 (EGFR) will be administered three times per week via subcutaneous (SC) administration in combination with intravenous (IV) immune checkpoint blockers until unacceptable toxicity, disease progression, or withdrawal of consent

DK210 (EGFR)

Short regimen radiation therapy (10 fractions or less)

Radiation therapy

IV administration of approved PD1 blocker

Immune checkpoint blockers

Single agent or combination of not more than two

Chemotherapy

DEKA Biosciences

Clinical Trials Coordinator

Abishek Tripathi, MD

Clinical Research

Xinhua Zhu, MD, PhD

Clinical Trials Office

Abdul Rafeh Naqash, MD

Douglas Orr, MD

Syed Kazmi, MD

Ashabari Sprenger, PhD

Siqing Fu, MD, PhD

Maryann Poole

Alex Spira, MD

Medical Officer

This study will evaluate safety, pharmacodynamics and biomarkers of subcutaneous (SC) DK210(EGFR) given as monotherapy and in combination with immunotherapy, chemotherapy or radiation.

This study will evaluate DK210(EGFR) as monotherapy and combination in subjects with advanced solid EGFR expressing cancers with documented progressive disease after at least one line of systemic treatment (staging performed by local standard).

Evaluating Safety and Biomarkers Using DK210 (EGFR) for Locally Advanced or Metastatic EGFR+ Tumors

Dose-finding Phase 1 Trial: Evaluating Safety and Biomarkers Using DK210 (EGFR) for Inoperable Locally Advanced and/or Metastatic EGFR+ Tumors With Progressive Disease Failing Systemic Therapy

At this time, IPD sharing has not been defined and/or decided if it will be shared.

Overall response rate (ORR) will be based on clinical examination and investigator review of radiographic images

Based on investigator clinical examination and review of radiographic images

Time from first dose of DK210 (EGFR) to first documentation of clinical or radiographic disease progression or death due to any cause, whichever occurs first.

Time from first dose of DK210 (EGFR) to the time of death

Concentration vs time and standard pharmacokinetic (PK) parameters will be summarized by dose level

Nervous System Diseases

Wounds and Injuries

Inflammation

Brain Injuries

Brain Neoplasms

Central Nervous System Depressants

Platelet Aggregation Inhibitors

Anesthetics

Propofol

Sevoflurane

Anesthetics, Intravenous

Hypnotics and Sedatives

Anesthetics, General

Anesthetics, Inhalation

Jasmina Markovic Bozic, MD, MSC

Blaz Karpe, PHD

Iztok Potocnik, MD, MSC

Ales Jerin, PHD

Andrej Vranič, MD, PHD

Vesna Novak Jankovic, PROF, PHD

Anaesthesia and surgical stress during craniotomy can lead to brain damage and activation of inflammatory response. Consequently inflammatory cytokines (IL6, IL8, IL10) are released. Cell mediated immune balance can increase postoperative complications (infections, wound healing, multiple organ dysfunction). Many studies have shown that volatile anaesthetics reduce systemic and local inflammatory response during major surgery, but animal studies have shown that volatile anaesthetics can induce neuroinflammation (IL6, NF-κB) that leads to decline of cognitive function in rodent and possible human.

Our aim was to investigate how anaesthetic technique for craniotomy influences the release of inflammatory cytokines. Our hypothesis was that when optimal neuroprotective strategies are followed during surgery intravenous anaesthesia attenuates inflammatory response comparing to inhalational anaesthesia.

The investigators included 40 patients anaesthetised with remifentanil based anaesthesia with sevoflurane (S group) or propofol (P group).

Plasma levels of IL6, IL8, IL10 were measured during preoperative, perioperative and postoperative periods of both groups of patients. The investigators also noted emergence parameters, postoperative (pain, shivering, vomiting) and neurological complications after surgery.

Anaesthetic technique for craniotomy has to provide optimal cerebral perfusion, oxygenation and prevent brain oedema (1). It also has to lower the stress response on pain during intubation and surgical manipulation. Emergence from anaesthesia has to be rapid and smooth to permit early postoperative neurological evaluation. The most likely opioid in the last decade is short acting opioid remifentanil that can be easy titrated during the procedure and provides early recovery (2, 3, 4, 5). Currently the propofol-remifentanil and sevoflurane-remifentanil are the most frequently used combinations for craniotomy (6, 7). Recently a multicentre study was published that did not show differences in early recovery between three groups (propofol-remifentanil: TIVA, sevoflurane-remifentanil, sevoflurane-fentanyl). Either technique provided optimal surgical conditions. The group received TIVA had attenuated changes in stress biomarkers (cortizol in plasma and urine, cateholamines. (8).

Anaesthesia and surgical stress during craniotomy can lead to brain damage and activation of inflammatory response (9, 10). Consequently inflammatory cytokines (IL6, IL8, IL10) are released. Cell mediated immune balance can increase postoperative complications (infections, wound healing, multiple organ dysfunction). Many studies have shown that volatile anaesthetics reduce systemic and local inflammatory response during major surgery (11, 12, 13, 14), but animal studies have shown that volatile anaesthetics can induce neuroinflammation (IL6, NF-κB) that leads to decline of cognitive function in rodent and possible human (15,16).

Our aim was to investigate how anaesthetic technique for craniotomy influences the release of inflammatory cytokines. Our hypothesis was that when optimal neuroprotective strategies are followed during surgery intravenous anaesthesia attenuates inflammatory response comparing to inhalational anaesthesia.

Plasma levels of IL6, IL8, IL10 were measured during preoperative, perioperative and postoperative periods of both groups of patients. The investigators also noted emergence parameters, postoperative (pain, shivering, vomiting) and neurological complications after surgery.

Patients and methods

Anaesthesia regimen:

On arrival in the operating room, the patients were randomly assigned to either Group P or Group S. Randomisation was done according to computer-generated order.

All patients were on a regimen of dexamethasone 4x4mg/day with the first dose given at least one day before surgery.

After arriving to the operating room the standard monitoring was instituted. An arterial catheter was placed in the radial artery to continuously monitor blood pressure. For extended haemodynamic monitoring Vigileo system was used.

Patients were premedicated with midazolam (2-3 mg i.v.) and ondansetron (4-8 mg i.v.). Antibiotic prophylaxis with intravenous cefazolin 2g/100 ml 0.9% NaCl was invariably used in all patients.

Anaesthesia induction in Group P was performed with propofol (Propoven, Fresenius Kabi) and in Group S with sevoflurane (Sevorane, Abbott Laboratories). Before intubation all patients received remifentanil (Ultiva, GlaxoSmithKline) and rocuronium (Esmeron, MSD).

After intubation, patient's lungs were ventilated mechanically, with 1:2 oxygen-air mixtures in P and S group. Ventilation was adjusted to maintain normocapnia. Anaesthesia was maintained by continuous infusion of propofol 4-6 mg/kg/h in the P group and with sevoflurane 0,8-1 MAC in the S group. Remifentanil was adjusted regarding to anaesthesia response (0.1 - 2 μg/kg/min). The depth of anaesthesia was measured by a bispectral index (BIS) monitor; BIS values were maintained at 40-60.

For haemodynamic management the following algorithm was used: continuous infusion of 0.9% NaCl 6 mL kg-¹ for the first hour, followed by 2.5 ml kg-¹h-¹ . If CI \< 2 L/min/m2and SVV \> 10%, 6% hydroxyethyl starch (Voluven, Fresenius Kabi) until SVV-10% ; if there is no improvement after 250 ml 6% HES-a, ephedrine (0.5% Efedrin, UMC Ljubljana Pharmacy) 5-10 mg iv or fenilefrin 50-100 μg (0.01%, UMC Ljubljana Pharmacy). If CI \< 2 L/min/m2, SVV \< 10% and heart beat \< 40/min, atropine 0,5 mg. If the mean arterial pressure increases by more than 30% and the heart rate by more than 30% from baseline, the infusion of remifentanil is increased. Any adverse hemodynamic events that did not respond to changes in anaesthetic regimen could be managed with urapidil or metoprolol, as appropriate. Hypotension following blood losses was maintained with colloids (6% HAES) and blood replacement. Hemodynamic parameters were monitored continuously at 5-min intervals from the beginning of induction until the patients were discharged from the PACU.

30 minutes before the end of the surgery (at the time of dura closer) piritramid 5-10 mg was administered. Continuous intravenous infusion of piritramid was started postoperatively as patient control analgesia (PCA). The time of the operation was determined as the time from pin head-holder placement to its removal. The time from the end of the operation to the tracheal extubation was also noted. All patients were extubated in the operating theatre and then transferred to the recovery room.

Postoperative management:

After surgery, the patients stayed in the recovery room for one hour and were then transferred to the intensive care unit of the Department of Neurosurgery.

Standard postoperative monitoring generally used in these procedures was implemented. Oxygen titrated to the lowest level needed to achieve the target arterial oxygen saturation of 96%, was administered via a Venturi mask. Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being, such as hypertension, postoperative nausea and vomiting, pain, neurological complications, in particular if clinical intervention or drug therapy was required.

Hospital stay was also recorded.

Study design:

This prospective randomised single centre study was conducted at the Department of Anaesthesiology and Surgical Intensive Care and at the Department of Neurosurgery, in close cooperation with the Department of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana. The investigators included 40 patients anaesthetised with remifentanil based anaesthesia with sevoflurane (S group) or propofol (P group). The study was approved by the National Medical Ethics Committee of the Republic of Slovenia. All the procedures were performed in accordance with Helsinki declaration. The written informed concern was obtained from all included patients. The patients included in the study were given anaesthesia by the same anaesthesiologist.

The data recorded included demographic characteristics, time of surgery, time to extubation, hemodynamic parameters.

Arterial blood samples for the determinations of cytokines (IL 6, IL 8, IL 10) were drawn at the following time points: 1. before induction, 2. During tumor resection 3. at the end of the surgery, and 4. 24 hours after surgery 5. 48 hours after surgery.

For analyses of serum interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10), blood samples were collected in tubes without additive. After centrifugation serum samples were stored at -20 ºC until analysis. Analyses of samples were performed in one batch. Chemiluminescent immunometric assay (Immulite analyzer; Siemens Healthcare, Erlangen, Germany) was used to measure the concentrations of IL-6, IL-8, and IL-10.

Comparison of Two Anaesthetics on Brain During Brain Tumour Surgery

Phase 1 Study of the Impact of Propofol vs. Sevoflurane on Brain Damage and Inflammatory Response During Brain Tumour Surgery

Drugs consumption, volume loading, blood loss and post anaesthetic adverse events and medication were recorded:

Drugs consumption, volume loading, blood loss and post anaesthetic adverse events and medication were recorded.

Efedrin was used for correction of low blood pressure

Post anaesthetic adverse events and medication:

Fenilefrin was used for low blood pressure correction

The interleukin 10 plasma concentrations during craniotomy (preoperative, perioperative and postoperative periods)

Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being.

Post anaesthetic adverse events and medication in ICU were recorded for a period of 24 h after anaesthesia. Adverse events were defined as any unintended changes in body function or well being, in particular if clinical intervention or drug therapy was required.

University Medical Centre Ljubljana

MD, MSC

Back Pain

Low Back Pain

Necrosis

Pain

Neurologic Manifestations

No manipulative intervention. Phlebotomy for inflammatory biomarker determinations to compare acute versus chronic at baseline.

Inflammatory biomarker determinations after a course of 6 SMT interventions over the period of 2 weeks; a single SMT per treatment.

Asymptomatic subjects. Biomarker determinations at time zero and again two weeks later.

Spinal manipulation will consist of a single high velocity low amplitude thrust to a hypomobile vertebral segment determined by the treating clinician to contribute to the problem.

Spinal manipulation

H. S. Injeyan, PhD, DC

It is expected that mechanical low back pain (LBP) is associated with inflammatory changes localized to the affected tissues. Could such changes be detected in cells involved in the inflammatory process in an in vitro model? The investigators wish to test such a model to compare inflammatory markers in acute and chronic LBP patients and also examine the effect of spinal manipulative treatment (SMT) on changing the level of selected key inflammatory markers. The investigators hypothesize that:

1. Proinflammatory markers will be elevated while antinflammatory markers will be reduced in acute LBP patients relative to chronic back pain patients as well as in healthy study participants who have no LBP or any inflammatory conditions (controls).
2. SMT will cause a reduction in the production of proinflammatory markers while anti-inflammatory markers will increase relative to baseline levels as well as relative to controls

Background: Spinal manipulative treatment(SMT) may work by reducing mechanical irritation to joint tissues (1) and thereby diminishing local inflammation. Evidence for an anti-inflammatory effect of instrument-assisted SMT has been observed in an animal model (2). These findings are consistent with the recently proposed hypothesis that the origin of all pain may be associated with inflammation and augmented production of inflammatory mediators (cytokines), principally TNFα (3). TNFα plays a major role in the pathophysiology of neuropathic pain-associated inflammation (4) and has been implicated in spinal pain syndromes, including intervertebral disc-related low back pain (5, 6) and sciatica (7,8). Our recent studies demonstrated that production of inflammatory mediators is elevated in patients with chronic cervical spine pain, both in vitro and in vivo, and accompanied by up-regulation of chemokine (CC) synthesis (9).

Recent reports on clinical (10), animal (2) and human in vitro models (11) suggest that SMT may exert an anti-inflammatory effect. Thus, Song et al. (2) found that SMT reduced inflammatory neuropathic pain. Teodorczyk-Injeyan et al. (11) demonstrated a significant attenuation of pro-inflammatory cytokine production in vitro, and no changes in serum substance P (SP) levels following SMT. Other studies from our laboratory showed that SMT may enhance both the production of and the response to the immunomodulatory cytokine, IL-2, and IL-2-dependent antibody synthesis (12, 13). Reduction in serum TNFα levels has been reported for cervicogenic headache patients (n=2, case studies) (14, 15). These observations suggest that SMT effects may be transduced into cellular components of the immune system.

Thus far, the clinical relevance of the effect of SMT as a modulator of inflammatory mediator production is unknown. Despite evidence of inflammatory pathophysiology of spinal pain (16), including a subtype of non-specific spinal pain (17), only one clinical study (18) evaluated the correlation between serum TNFα levels, pain intensity and back function.

In this proposed study we intend to use a clinical model to investigate the baseline levels of proinflammatory cytokines in acute and chronic low back pain patients and explore the potential anti-inflammatory effect of SMT following a course of manipulative treatments. Thus, Aim 1 is to determine baseline pro-inflammatory cytokine levels in individuals experiencing acute or chronic lower spinal pain of mechanical etiology, and compare them with asymptomatic controls'. Aim 2 is to explore the relationships between SMT, pain level and functional impairment, and the production of inflammatory mediators relative to baseline.

Anti-inflammatory cytokines (IL-10 and IL-1ra) have been found to be produced alongside, and in parallel, with their respective pro-inflammatory counterparts (TNFα and IL-1β), and act in concert to sustain/restore homeostasis (19). The proposed study will include determinations, in addition to pro-inflammatory cytokine (IL-1, TNFα, IL-6) levels, of the levels of IL-1 receptor antagonist (IL-1ra) and IL-10. Assessment of IL-10 synthesis is particularly relevant as this cytokine up-regulates the production of IL-1ra, which competes with active IL-1 for binding to IL-1 receptors, and which acts as a potent natural anti-inflammatory protein (19, 20).

Study design; Subject Recruitment: Subjects (volunteers) of both sexes, between the ages 20 and 60 years, experiencing acute (less than 4 weeks in duration) or chronic (12 weeks or longer in duration) mechanical low back pain (experienced between spinal levels L1- L5, with or without sacroiliac \[SI\] joint involvement) will be recruited by Canadian Memorial Chiropractic College (CMCC) personnel and posters from CMCC's outpatient clinics, and from the general public through newspaper advertisements . CMCC is in the Greater Toronto Area (GTA), where the population is a diverse ethnic mix (21). Potential participants who have presented to one of the CMCC clinics for the purpose of treatment will be encouraged/recruited by interns/clinicians prior to commencement of treatments. Others who present to participate in the research study will first be assigned to one of the clinic pods for initial assessment prior to entering the study. In no case, however, will participants have received SMT 4 weeks prior to commencement of the study.

Candidates will be interviewed in order to determine eligibility (see exclusion criteria, Appendix 1). They will complete the research intake form (Appendix 2) and be given detailed explanations about the research protocol (Appendix 3). A cohort of matching healthy asymptomatic subjects, recruited from the general population, will serve as controls for the determination of baseline cytokine levels.

Sample size determination: Data published for TNFα levels in chronic neck pain patients versus asymptomatic controls (9) were used to calculate a sample size estimate for this study. The study is powered for the primary outcome measure related to Question 1, looking at the difference between symptomatic and asymptomatic low back pain subjects at baseline (see Statistical Analyses). From Cohen's table (22), based on a power of 0.8, a two-tailed test with a p value \< 0.05, the sample size was estimated to be 17 per group. In order to account for drop-outs and errors that may arise in the blood cultures, the sample size will be increased to 20 per group. As a result, there will be 40 symptomatic subjects and 20 asymptomatic controls, which should provide a more than adequate sample to test the primary outcome.

Subject assessment and group assignment: Qualified subjects will be scheduled. They will be greeted by one of two investigators (depending on recruitment site) , who will brief them and review the intake/eligibility form (Appendix 3) to confirm their eligibility before asking them to sign the informed consent form (Appendix 4). All subjects will then be asked to indicate their pain intensity level on the 10-point visual analogue scale (VAS) and complete the Oswestry functional disability questionnaire. They will then be assessed with standard chiropractic, orthopaedic and neurological tests by their respective chiropractic interns and supervising clinicians, who will assign them to the acute or chronic LBP groups, and who will formulate and explain a treatment plan.. For the duration of the study, treatments will consist of manual SMT and, where needed, manual (not instrument-assisted) soft tissue work provided by the clinician. Other treatment modalities will not be used.

Patients will receive 6 treatments over the course of 2 weeks. (comprised of manipulation of one lumbar or sacroiliac articulation, with or without soft tissue therapy). SMT will consist of a single high velocity, low amplitude (HVLA) thrust intended to cavitate and restore mobility to the joint. If at initial presentation a manipulative segment could not be identified, the patient will be excluded from the study. If on the other hand a manipulable segment is not found at subsequent visits, the clinician will limit the treatment to palpation and some soft tissue work as indicated . In all cases a blood sample will be drawn (see below) after initial assessment and prior to commencement of treatments of patients, in order to establish a baseline level of cytokines for each participant (primary outcome). At their 7th visit (at least 2 days after last treatment), a blood sample will be taken prior to commencement of any further treatment, and they will be asked to complete the exit questionnaire including a VAS (Appendix 5). Should a patient recover following a few treatments, as assessed by subjective feedback from the patient and a VAS result of less than 3/10, then a blood sample will be taken earlier and such will be duly noted. Should a patient require continued treatments beyond the 6 stipulated by the study, s/he will be free to do so under the direction of the clinician in charge of their case.

Interventions: Manipulation: As noted above, each spinal manipulation will consist of a HVLA thrust to an affected segment (23). A clinician will deliver treatments according to his/her assessment findings on a given day.

Venipuncture: On the day of admission into the study and at the completion of SMT therapy, an experienced phlebotomist will perform venipuncture using standard procedures (antecubital fossa, 21gauge needle) in the seated position. Heparinized blood samples (10 ml each) will be collected and transferred (at room temperature) to the laboratory within an hour of collection for the preparation of whole blood cultures as described below .

Laboratory studies

1. Induction of inflammatory cytokines To assess cytokine production in vitro, a whole blood (WB) culture system will be utilized (19). Briefly, multiple sets of WB cultures representing different treatment/culture conditions for each subject will be prepared. Cultures will be stimulated at initiation with 10 μg/ml lipopolysaccharide (LPS) for the induction of TNFα and IL-1β production. Phytohemagglutinin (PHA, 10 µg/ml) alone and in combination with LPS will be used to induce production of the anti-inflammatory cytokine, IL-10 and 2 chemokines, CCL2 and CCL3 . Cultures will be maintained at 37C (Celsius) in a humidified 5% C02 incubator. As clinical conditions involving inflammatory responses may cause a time shift in the capacity for cytokine production (19, 27), the levels of the studied mediators (TNFα, IL-1β, IL-1ra, IL-10, CCL2 and CCL3) will be examined at 24 h intervals in culture supernatants harvested between 24-72h post-initiation. Aliquots of the supernatants will be stored at -76C (Celsius) until tested. This model will allow investigation of the relation between the releases of pro- and anti-inflammatory mediators.
2. Determinations of cytokine levels by enzyme-linked immunosorbent assay The levels of TNFα, IL-1β , and IL-10 and IL-1ra in supernatants from whole blood cultures will be determined by specific enzyme-linked immunosorbent assays (ELISA) using DuoSet ELISA development system for natural and recombinant human cytokines (R\&D Systems, Minneapolis, MN) as described previously (9, 11), and Quantikine Immunoassay Kits will be used for CCL2 and CCL3 determinations. All immunoassay procedures, including reagent and sample diluent preparations, will be carried out as per manufacturer's recommendations. Each of the studied samples will be tested at least twice at 2-4 different dilutions.

Statistical analyses All of the studied mediators will be measured for the LBP patients and asymptomatic subjects at baseline and at the completion of the treatment period. For Question 1 (the primary outcome), baseline comparison for each TNFα and IL-1β will be compared between symptomatic subjects (acute and chronic) versus asymptomatic control subjects. Two unpaired t-tests will be used to test the associated hypothesis. For Question 2, the mean pre-post difference scores will be compared for each of TNFα and IL-1β between the three groups (acute, chronic and asymptomatic) using an ANOVA. If baseline values are significantly different between groups (as hypothesized from Question 1), then ANCOVA will be used to account for this difference. It is anticipated that the sample size is sufficiently large to accommodate this analysis. However, after determining the results for Question 2, a power analysis will be completed. If the study is insufficiently powered for this question, then another sample size estimate will be calculated to inform future work.

For other pro-inflammatory and anti-inflammatory cytokines measured in this study, regression modeling will be used in an attempt to predict cytokine responses. It is understood that any model created during this process will need to be confirmed in a future investigation. Both models created and descriptive data derived from the investigation will be used to inform future work.

Time frame Based on experience, up to 5 subjects per week can be tested. However, based on condition prevalence, we project that patient recruitment and sample collection will take 8-12 months. Cytokine level determinations in cell cultures derived from the three groups of participants will lag behind by 3-4 months, and data analysis will be completed within another 2 months. Preparation of manuscripts will require an additional 4-6 months. Thus we anticipate completing this project within 18 -24 months of initiation of the study.

Effects of Spinal Manipulative Treatment on Inflammatory Markers in Low Back Pain Patients

Changes in Inflammatory Cytokine Levels in Response to Spinal Manipulative Treatment of Low Back Patients: A Single-blind Pilot Clinical Trial.

Parallel bioassays will be done on samples from the same culture supernatants in order to determine the levels of antiinflammatory mediators and chemokines. Changes in the levels of these mediators in response to manipulative treatment may be correlated to changes in proinflammatory mediator levels. Results will be calculated as the difference between baseline and endpoint (i.e. end of two week treatment period).

Supernatants from whole blood cultures are collected 24 or 48 hours postincubation, are dispensed in 0.5-1.0 ml aliquots and stored at 76C. Because subject recruitment occurs over a long period,it is not desirable to process samples sporadically. This approach allows using same-batch reagents/bioassay kits for all samples in an effort to decrease error and enhance internal consistency. Results will be expressed as the difference between the values obtained for acute, chronic and control at baseline.

Postintervention samples (whole blood culture supernatants) will be aliquoted and stored at -76C. proinflammatory cytokine levels will be compared to their respective baselines as well as the asymptomatic controls. These samples will be processed along with those for the primary outcome measure. Results will be expressed as the difference between baseline and endpoint (i.e. end of two week treatment period).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Evaluating Safety and Biomarkers Using DK210 (EGFR) for Locally Advanced or Metastatic EGFR+ Tumors	NCT05704985	Cancer Solid Tumor Colorectal Canc... Pancreas Cancer Non Small Cell ... Head and Neck C... Gynecologic Can... Skin Cancer Kidney Cancer	DK210 (EGFR) Radiation thera... Immune checkpoi... Chemotherapy	18 Years -	DEKA Biosciences
Comparison of Two Anaesthetics on Brain During Brain Tumour Surgery	NCT02229201	Inflammation	Propofol Sevoflurane	18 Years - 80 Years	University Medical Centre Ljubljana
Comparison of Two Anaesthetics on Brain During Brain Tumour Surgery	NCT02229201	Inflammation	Propofol Sevoflurane	18 Years - 80 Years	University Medical Centre Ljubljana
Effects of Spinal Manipulative Treatment on Inflammatory Markers in Low Back Pain Patients	NCT01766141	Low Back Pain	Spinal manipula...	20 Years - 60 Years	Canadian Memorial Chiropractic College

Spots Global Cancer Trial Database for interleukin 10