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Introduction- From clinical IR to clinical trials | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Introduction- From clinical IR to clinical trials | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
HCC and IR oncology treatments | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
HCC and IR oncology treatments | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
ablationadvancedadvancingagentalbuminapproacharterialarterybeadsbilirubinbloodcarcinomacatheterchapterchemochildchroniccirrhosiscirrhoticclinicalconsideredCTcurativediabetesdiagnoseddiagnosisdiameterdiseaseeffectiveembolisationembolizationethanolhcchepatichepatic arteryhepatitishepatocellularincidenceincludeinjectedinjectioninterventionallesionslftslivermeasuresmicrospheresmicrowaveMRImultidisciplinaryNoneobesityoncologyoptimaloptionsoutcomespatientspercutaneouspercutaneouslyperformedportalprocedureprotocolradiofrequencyradiologyraterecurrenceresectionriskscoresscreeningserumsurgerysurgicalsurvivalsystemictasteteststherapiestherapytranstransplanttreatmenttumortumorsultrasoundunresectableutilizedvein
Inclusion Criteria | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Inclusion Criteria | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Exclusion Criteria | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Exclusion Criteria | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Treatment Protocol | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Treatment Protocol | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Transition to Research | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Transition to Research | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Intra Procedure | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)
Intra Procedure | Transforming from Clinical IR to Clinical Trials with Tirapazamine (TPZ)

so I've been a nurse at UC Irvine in interventional radiology for 12 years I'm a part-time employee which has allowed me to pick up additional shifts doing other roles and one of those other roles is allowed me to go into the clinics as a nurse practitioner before

the position was filled with our doctors seeing the outpatients for procedures today I'll be discussing transforming from clinical IR to clinical trials with syrup as me known as tpz and I have nothing to disclose so this is just a

little bit more about me here's our most a family picture of our most recent trip in Arizona and Antelope Canyon and then Utah yeah this is my husband we've been together 30 years two kids 19 year old son and an 18 year old daughter so I've

included a picture here of our team yeah I've got dr. Nadine abhi today she's our principal investigator on the left upper hand corner technologist on and trained on the lower left-hand corner and then there's a group photo which includes our

four attendings dr. Nadine abhi today dr. Carrie Nelson dr. James cat services and dr. diantha Fernando our nurse practitioners in the center Paul he's in the audience we've got three nurse practitioners two fellows residents

approximately 15 nurses 8 technologists a scheduler nurse navigator RN supervisor and RN manager just to give you an idea of what our sizes we have shared staff from CT MRI and anesthesiology we have 5 procedure rooms

available for body cases and we have one neuro room which is shared by three of our neuro I our attendings UCI has the is a 450 bed capacity hospital and we are the only level one trauma center in Orange

County so in August 2015 dr. Nadine OB today began phase one interventional oncology trials and is currently now in Phase two

today's objectives I'll start with reviewing hepatocellular carcinoma HCC

and the current treatment options I'll share the protocol inclusion and exclusion criteria and I will discuss the research treatment protocol briefly and next transitioning to research the preparation taken in the department with

staff members for trial lastly I will talk about what's involved intraoperatively from a nursing standpoint so hepatocellular carcinoma HCC is the most common primary liver manely malignancy and is a leading cause

of cancer-related deaths worldwide cirrhosis is a condition in which there is scarring to the liver causing permanent damage chronic medical conditions such as diabetes mellitus and obesity lead to chronic liver disease

obesity is a risk factor to diabetes and diabetes directly affects the liver because of the essential role the liver plays in glucose metabolism both cirrhosis and chronic liver disease remain the most important risk factor

for the development of HCC a which viral hepatitis and excessive alcohol intake are the leading risk factors of cirrhosis non-alcoholic fatty liver disease and non-alcoholic steatohepatitis which is nash our

conditions in which fat builds up in your liver thus having inflammation and liver cell damage along with fat in your liver these are other risk factors for HCC the incidence of HCC will continue to escalate as hepatitis C and obesity

become more prevalent in the United States so unfortunately the diagnosis of HCC is too often made with advanced liver disease when patients have become symptomatic and have some degree of

liver impairment at this late stage there is virtually no effective treatment that would improve survival in addition the morbidity associated with therapies unacceptably high modalities available for HCC screening include both

radiographic tests and serological markers radiological tests commonly used for surveillance include ultra sonography multi-phase CT and MRI with contrast ultrasound has historically been utilized to identify intrahepatic

lesions since the early 1980s both the photograph above shows a cirrhotic liver versus a normal liver there are visible differences in the portal and hepatic veins between the cirrhotic liver when compared to the non cirrhotic liver so

AFP alpha-fetoprotein has been used as a serum marker for the detection of HCC an AFP level of less than 10 is normal for adults an extremely high level of AFP in your blood greater than 500 could be a sign of liver tumors liver function

tests or lfts look at the part of your liver that is not affected by cancer to see how well your liver is working the lfts will be considered for diagnosis and determining the stage of HCC the tests look for levels of certain

substance in your blood such as bilirubin albumin ALP ast alt and GGT despite advances in prevention techniques screening and new technologies in both diagnosis and treatment incidence and mortality

continue to rise so treatment options for HCC can be divided into three categories surgical options non-surgical options and systemic therapy patients are screened diagnosed and treated accordingly of

these three options interventional radiologists offer the non-surgical approach which include trans arterial embolisation percutaneous ethanol injection radiofrequency ablation and microwave ablation so I want to talk

about the child pu classification the child pious core consists of five clinical measures and is used to assess the prognosis of liver disease and cirrhosis including the required strength of treatment and necessity of

liver transplant the child piu score was originally developed in 1973 to predict surgical outcomes in patients presenting with bleeding esophageal varices today it continues to provide a forecast of the increased increasing severity of

your liver disease and you're expected survival rate the Chao few score is determined by scoring five clinical measures of liver disease the five clinical measures are total bilirubin serum albumin prothrombin time ascites

and hepatic encephalopathy once scores are available in each of the five clinical measures all scores are added and the result is a child piu score their interpretation of the clinical measure is as follows so Class A would

be five to six points lease liver disease with one to five year survival weight at 95 percent Class B seven to nine points moderately severe liver disease one to five year survival rate at seventy five percent and Class C ten

to fifteen points most severe liver disease one to five year survival rate at fifty percent so which child pew scores do I our patients fall into for a research with the CPC and the majority of the HCC child pew scores a and B

seven with the survival rate of one to five years for 95% the best outcomes are achieved when patients are carefully selected for each treatment option regardless of the treatment approach

patients with HCC require a multidisciplinary approach to care to ensure optimal outcomes what we refer to as tumor board tumor board are meetings where specialists from surgery medical oncology radiation oncology

interventional radiology and others collaboratively review a patient's condition and determine the best treatment plan through this multidisciplinary approach patients have access to a diverse team of experts

instead of relying on a single opinion each specialty will have unique contributions to ensure optimal long term outcomes for patients with HCC so there are various algorithms for HCC treatment I actually have one on top of

the other there just to show you that if you're interested in the process you can look it up it's there's a few out there all right so how are the patients selected for treatment like I said tumor board and moving on now to the surgical

options there are two surgical options liver resection and liver transplant surgical resection is currently considered to be the definitive treatment for HCC and the only one that offers the prospect of cure or at least

long-term survival however most patients have unresectable disease at presentation because of poor liver function the overall resect ability rate for HCC is only 10 to 25 percent and even among those who undergo surgical

resection with curative intent there is a recurrence rate of it to 80% at five years post resection survival rates are in the range of 80 to 92% at one year sixty-one to 86 three years and 41 to 74 at five years

the most common sight of post resection recurrence is a remaining liver for patients who are not surgically resectable liver transplant is the only other potentially curative option virtually all patients who are

considered for liver transplant are unresectable because of the degree of underlying liver dysfunction rather than tumor extent down staging using local regional therapies can also be used to increase eligibility for orthotopic

liver transplant while on the transplant list patients disease progress and meeting criteria gets complicated so patients on the transplant list are and do get some other therapies

which I will later discuss so we're surgical resection is not possible for poor liver function liver transplant is a treatment of choice prior to 2008 no systemic therapy was available that demonstrated an improvement in survival

with the publication of two randomized placebo-controlled phase 3 trials the oral multi targeted tyrosine kinase inhibitor sorafenib has become the new standard of treatment for advanced HCC with an increased median survival from

seven point nine months and the placebo group to ten point seven months in the treatment group systemic therapy can be difficult to tolerate because of the side effects dose reduction or treatment interruption is often needed

despite the side-effects treatment is recommended and to be continued into a progression of the tumor is demonstrated the majority of diagnosed patients with HCC present with advanced disease oral therapy has taken two pills twice daily

equaling 400 milligrams B ID so interventional radiology it's like surgery only magic so I I always think about this when patients come in and pre-op beam and they think they're having surgery you know it's well a lot

of benefits to ir what we're doing so interventional radiology is where the magic happens and non-surgical approach procedures are performed percutaneous local ablation include ethanol injection and radiofrequency ablation microwave

ablation is utilized both percutaneously and intraoperatively and lastly there is trans arterial embolisation which depending on the embolization agent can either be chemo bland or radioisotopes percutaneous ethanol injection known as

Pei has a long track record and is very effective in destroying HCC tumors that are less than or equal to 2 centimeters in diameter performed under percutaneous ultrasound guidance a needle is placed into the tumor and absolute alcohol is

injected over recent years radiofrequency ablation referred to as RFA has largely replaced Pei at most centres RFA's also performed percutaneously advancing a specially designed electrode into the tumor and

applying radiofrequency energy to generate a zone of thermal destruction that encompasses the tumor and a 1 centimeter margarine surrounding liver RFA is thus preferable to ethanol injection for patients with solitary

tumors 2 to 4 centimeters in size for tumors smaller than 4 centimeters RFA can achieve initial complete response rates of over 90% in microwave ablation MWA microwaves are created from the needle to create small

regionals regions of heat the heat destroy the liver cancer cells RFA and microwave are effective treatment options for patients who might have difficulty with surgery or those whose tumors are less than one and a half inch

in diameter the success rate for completely eliminating small liver tumors is greater than 85% so can I get a show of hands from the audience on who what facilities are doing chemo embolization everybody pretty much are

you guys doing them next to the gentleman yeah okay so this is gonna be a boring review here alright so trans arterial embolisation a minimally invasive procedure performed to restrict to tumors blood supply it is performed

by advancing and angiography catheter into the branches of the hepatic artery supplying the tumor and injecting an agent mixed with orally contrast followed by a cluding agent known as beads the beads which range from 100 to

300 micrometers in diameter are carried by the circulation into the terminal hepatic arterioles where they lodge and include the vessel resulting in the schema tumor necrosis the procedure is done using moderate sedation patients

are monitored for 23 hours or less for pain and post embolization syndrome trans arterial chemo embolization thus is where the chemo therapeutic agent mixed with beads is injected to the tumor

these particles both blocked the blood supply and induced cytotoxicity attacking the tumor in several ways taste is the treatment of choice when the tumor is greater than four centimeters or there are multiple

lesions within the liver taste takes advantage of the fact that while the liver is refused by both the portal vein and the hepatic artery HCC survives its blood supply almost entirely hepatic artery tastes has been shown to

prolong survival in patients with intermediate stage HCC and objective responses were observed in the majority of patients tear trans arterial radioembolisation is a form of catheter directed internal radiation that

delivers small microspheres with Radio isotopes directly into the tumor y9t microspheres are administered and a procedure similar to taste the procedure has been shown to be safe and effective in cirrhotic patients with HCC the side

effects are usually well title tolerated one major advantage of y9t over taste is that it is indicated in the case of portal vein neoplastic thrombosis while taste traditionally has been considered a contraindication all right so there's

no way around this I'm gonna read to you the inclusion criteria right off the protocol it's kind of long so confirmed diagnosis I wrote some single line there that can help you follow along confirm diagnosis of HCC number two patients

above age 23 patients with single or multiple nodules HCC who are unsuitable or unwilling for surgical resection or RFA the largest tumor nodule should be less than 10 centimeters in the large largest diameter total volume of tumor

cannot exceed 50% of the liver patients are candidates for trans arterial embolisation no tumor invasion to portal vein or thrombosis and main and first branch of the portal vein 5 patients have no lymph node involvement or

distant metastasis 6 ECoG score at 0 to 1 with no known cardiac pulmonary or renal dysfunction 7 child pew score group a and B 7 eight patient should have measurable disease by contrast MRI nine prior local

therapies such as surgical resection radiofrequency ablation and alcohol injection are allowed as long as tumor progresses from the prior treatment and the patients are still candidates for tae 10 patients have normal organ

function based on some labs eleven patients are able to understand and willing to sign the informed consent and twelve men and women of childbearing age need to commit to using two methods of contraception and the exclusion criteria

includes patients with prior t-ae treatment and liver transplant major medical problems such as cardiac pulmonary and renal disease pregnant or lactating women unable to identify the feeding artery at time of procedure

would exclude participants known diagnosis of cancer other than HCC patients are excluded patients with active infectious disease such as HIV or non-healing ulcer ation and poorly controlled HPV infection are

excluded patients on medication for HPV or HCV are allowed in the study that are required to hold medication on day one of procedure patients with congenital QTC syndrome are preferably a social or associated risk of torsades de pointes

and said antiplatelet platelet inhibitors will require washout periods any major GI bleed in the prior two months of enrollment are excluded and lastly patients who have any clinical evidence of hypoxia with o2 saturation

less than 92% on room air and patients with evidence of arterial and sufficiency or micro angio angiography and any organ due to any reason which could lead to distal extremity hypoxia are excluded all right

so the treatment protocol there are multiple plan phases in this trial phase one is a dose defining study for phase two and phase one the problem primary objective is to define the appropriate dose for the Phase two this space is

completed and it had 23 patients enrolled phase two is trans arterial terrapass amine embolization versus trans arterial chemoembolization so far there are an additional 11 patients enrolled there is a phase 2a

which is trans arterial terrapass mean EMBO with antibody which includes patients receiving anti pd-1 monoclonal antibody immunotherapy at an outside facility prior to their first tpz procedure in iron alright so terrapass

mean is a very I'm gonna read this one off for you as well syrup as mean is a very unique cytotoxic agent that is activated under conditions of hypoxia it is a bio reductive agent that is activated by cellular reductase such as

cytochrome p450 reductase to generate nitrox ID radicals through a one-electron reaction in the absence of oxygen nitrox ID radicals include single and double strand break and DNA to cause

cell death because of this property terrapass mean exhibits 15 to 200 times greater toxicity and hypoxic cells compared with oxygenated cells this agent has been shown to be a radiation sensitizer and synergistic with platinum

compounds so tpz is stored at room temperature and must be protected from light during storage and administration so in phase one tpz was originally given our intravenously I've got a photo there of the med fusion pump that we had to

use as the pediatric in future and then the lapel dal and gel foam so patients received intravenous TPC five minutes prior to the injection of the embolizing agent slip iodine gel foam the IV infusion lasted two to four minutes and

was to be completed the five minutes prior so we are currently in Phase two which again is taste versus tape and the primary endpoint is to compare the efficacy of tape versus taste based on progressive free survival progressive

free survival is a duration from randomization to the date of the first evidence of progression

so take a minute to imagine well as ever you guys do anybody doing clinical trials in your facility one two okay and

Paul so take a minute to imagine how you would feel would you be excited worried where do you start and how do you keep everyone involved informed how do you prepare the department so the key to a smooth transition requires a project

manager to develop a project plan adhering to the protocol and task requires knowledge and accountability smooth communication between all involved increases the sense of unity amongst the staff successful clinical

trials should cover the entire scope of the protocol some things we considered for our project or the length of time the trial would take and the number of patients being enrolled what resources were already available and what did we

need in addition who would be responsible for which task and how it would go from one part of the process to the other communication between tasks and ensuring that the ones prior got done and the ones after would continue

problems who would problem solve so I'm not expecting you to see the details but I wanted to show you the schedule of events which was included in the research protocol it's easy to follow and it helps understand the entire

process providing a quick glance of which days the patients would require an appointment or testing to be done the patient's are screened during clinic visits with the MD a nurse practitioner patients can expect a detailed HMP

medication review CT MRI imaging EKG lab work hearing tests consent for research and anesthesia screening the nurse practitioner has helped with scheduling all the screening exams prior term Worman

the NPS had additional work trying to get these patients scheduled themselves they had to override the facility's scheduling process already in place all the patient appointments had to be on specific days and in addition a

convenient time and trying to keep these patients compliant so I was going to show you a video but I wasn't able to to download it if some are you're familiar familiar with the chicken little scene the sky is falling

he basically creates panic from his own fears so this is an example of what could happen when information is not available and the staff are not prepared panic mode so at the start of the trials there was no department manager our

newly hired supervisor was wearing three hats as a manager supervisor and more importantly she was just learning about ir the department was preparing for construction to begin which entailed moving cases to the o.r suite and having

to convince the hospital that our patients would have to recover and another unit by other staff nurses our supervisor offered education and support to ensure the accepting units had what was needed to succeed and feel competent

in recovering the AI our patients but it wasn't easy we were understaffed working on hiring both nursing technologists and nurse practitioners we were also just converting moving over to epic so we had

problems getting our orders in place our nurse navigators took the initiative keeping the information as organized as possible and dr. B today offered an introduction meeting prior to the enrollment of the first patient but

there were ly details left unaddressed and regardless tpz trials began because there are multiple pharmacies at large facilities such as UC Irvine one of our nurses created a diagram to help better on

the process of getting tpz on procedure day so when there's an issue you have to know where the process begins and ends the ten steps involved the research coordinator child cancer center pharmacy which they're in charge of research and

the inpatient pharmacy which is where IR is used to picking up their medications from you can call either of the three involved and not get what you want unless you know what the process stopped the diagram shows the complete process

going from orders confirmations second verifications preparation initiation release and dispensing tpz having the tpz available on the day of the procedure was its own involve tasks so nursing had a lot to be concerned with

the physical exams like I said we were started off and we were having construction done so the big question was who was going to bring these patients back and where were they going to be these were 15-minute exams but we

really didn't know what to do with them it was something as simple as height and weight but to train all the 15 nurses that we had was a little bit stressful patient lay is on these patients were being scheduled on specific days and

they needed specific phone calls no one was really familiar with the protocol except for the NPS and the nurse so our question the nurses was who's going to take care of their calls and their questions and what about insurance and

authorization we had no idea when things came through and said it wasn't approved or wasn't paid for we didn't know what to do about it the tpz orders the pump the IV pump that we needed we had no training on it we

didn't have special tubing we didn't know if there was any risk involved for the nurses and the techs the nursing again the labs the frequency of the labs where the order is going to be an epic epic were they going to be specific or

were they just the standard orders overnight observations hell these patients would be monitored for and what could we expect anything different from the chemo ambos the radiology techs they were concerned with

the positioning bacome being software the radio translucent leads and again special handling of tpz and then recovery any non-standard orders for tpz compared to chemo Ambo there were a few so we were concerned with that it all

appears to be standard and easy however our circumstances were not optimal at the start after several months the department hired a nursing manager and nurse practitioner ir received support from the non clinical research

coordinator and the learning curve plateaued the department now has a defined point person a defined III IR RN to focus on we've initiated a collaborative working team with IR RN + P and research coordinators while

looping in our investigating md guidelines and protocols have been rebus revisited and redone explicitly per trial study the nursing has created a combined a common binder for all the trial studies which include the

protocols and preference and this is continuously being updated increased colleague interactions and communications between the research coordinator the NPS and the RNs for a better patient experience have decreased

delays and service improved communication with PPC U which is where our long-term recovery patients go are now guided and have assistance from the RNs research coordinator communicate via email and they come to our physical

meetings for updates and changes we now see increased participation in the IR staff and the trial studies and cross-training I would expect any clinical challenge any clinical trial to have its

challenges but the better prepared you are at the start the better experience you will have so this is our pre procedure orders this is what was different from the standard clinical trial patients require blood draws and

EKG monitoring so we had a second IV and a second pulse oximetry because because of the comb being imaging we needed to have full socks on both the upper and the lower extremities antiemetics are not

included in the orders as they would be with chemo ambos and because there are eight plus EKG sets required during the procedure the patients will wear two sets of EKG leads one set for the monitoring and the second set used for

EKG recordings for the research the additional work involved with clinical trials was too demanding on one single RN these procedures are now scheduled with to procedural nurses post procedure orders vary some as well the protocol

requires again lab draws and triplicate EKGs these labs and EKGs are time from the time of T Finzi injection the EKG triplicates are at 1 2 4 6 10 and 24 hours post injection various PK labs measuring the pharmo kinetic levels of

tpz are also required post injection at 1 2 4 6 10 and 24 hours post in addition if these patients become free bile with a temperature of greater than 101.5 protocol requires blood cultures be sent and again you must notify doctor Abhijit

a patient requires anti-nausea medication pain a subjective however the clinical trial patients also have a PCA ordered

finally intraoperative considerations positioning for comb bean tpz photo

sensitivity EKG and lab draws and noting the time of tpz injection so i wanted to say a little bit about comb beam all right who has comb beam at their facility just a few less okay comb beam is medical imaging technique consisting

of x-ray computed tomography where the x-rays are divergent forming a cone the scanning software collects the data and reconstructs it producing what is termed a digital volume composed of three dimensional voxels of anatomical data

that can then be manipulated and visualized with specialized software on the left is a standard floral image and on the right is the comb beam so the red shows the vascular angiography the blue is a tumor and the yellow is a feeding

artery to the term or so dr. Abuja lays a B today is heavily involved with research so the procedure room with Combee was exclusively constructed for her so positioning for comb beam I believe

to be the bigger challenge initially comb being requires the patient to have their arms up high and using comb beam technology increases the procedural time it would be difficult for the patients to maintain that position and keep still

without anesthesia we started clinical trials with nurse assisted moderate sedation and soon learned it was very difficult the majority of our HCC embolization --zz are done with with sedation but we're

now using anesthesia for all of it so the lead in this case was Tom the radiology tech which assisted with the placement of the anesthesia equipment and patient positioning our anesthesia personnel are not only out of their

comfort zone in the I are sweet but unfamiliar with tpz trial and how the comb beam equipment rotates completely around the patient the patient is wearing two sets of leads one for anesthesia and the other for research

the leads are radio translucent to reduce artifact and imaging keeping the lid lid lead in the department took some getting used to one set got thrown away one set was found up in the ICU one set was on the

anesthesia equipment it was hard keeping track of our special equipment there so the pulse oximetry and blood pressure are on the lower extremities for cone beam again to avoid artifact and imaging when we first

started using cone beam the nursing staff administering sedation were disconnecting patients from monitoring so there were short interruptions with viewing vital signs it became risky and time-consuming to do

so during the procedure one set of EKGs triplicates are done just prior to tpz injection so the treat the EKG triplicates are basically they're two minutes apart in sets of three and lastly having to keep the tpz in a brown

bag and protected from light during the transfer nurse to position there's the photo on the left upper corner doctor busy day basically draws a tpz through a three-way stopcock under a sterile towel

while the nurse keeps the syringe in the brown bag poking a hole in the bag just to NIF to just enough to expose the tip of the syringe and attach it to the three-way this way the tpz is protected from light these reminder adjustments

however they were difficult from the standard and it took time for all the nurses and techs to adjust all right so this here is just a group photo Tom I've got Tyler on the right Thanh our technologist and ELISA and myself so I

thought this was a good photo to represent radiology many specialties consult two IR but it just isn't quite known yet by the general population and surprisingly by the medical staff as well there is a quote by dr. Rosa be

published quote the reason the public doesn't quite understand is we deal with so many disease entities and so many body parts it's hard to brand us unquote so I don't know if you guys were aware but interventional radiology is now its

own medical specialty so hepatocellular carcinoma is a primary malignancy of the liver and now the third leading cause of cancer deaths worldwide with over

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