In this episode, Lillian Erdahl, MD, FACS, is joined by Fatemeh Shojaeian, MD, MPH, from the Johns Hopkins University School of Medicine. They discuss Dr Shojaeian’s recent article, “Refractory and Recurrent Idiopathic Granulomatous Mastitis Treatment: Adaptive, Randomized Clinical Trial,” in which the authors found that, for resistant or relapsing patients with idiopathic granulomatous mastitis, combining methotrexate and corticosteroids offers a promising strategy. This integration of disease-modifying antirheumatic drugs with corticosteroids not only reduces the necessity for high steroid doses but also effectively alleviates associated side effects.
Disclosure Information: Drs Erdahl and Shojaeian have nothing to disclose.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:03):
You are listening to The Operative Word,
a podcast brought to you by the Journalof the American College of Surgeons.
I'm Dr Lillian Erdahl,and throughout this series, Dr Tom
Varghese and I will speak with recently
published authors about the motivationbehind their latest research
and the clinical implicationsit has for the practicing surgeon.
The opinions expressed in this podcastare those of the participants,
(00:26):
and not necessarilythat of the American College of Surgeons.
Hello,and welcome back to The Operative
Word, the podcast of the Journalof the American College of Surgeons.
I'm your host, Lillian Erdahl, and todayI am joined by Dr Fatemeh Shojaeian.
Welcome, Dr Shojaeian.
Thank you so much,Dr Erdahl, for having me.
(00:48):
Dr Shojaeian is a postdoctoral researchfellow at Johns Hopkins in
the Wood laboratory.
And I wanted to ask, do you
or your authors have anythingto disclose relevant to this work?
No, we don't have anything to disclose.
Great.
Well, thank you for being hereto talk to us about your study,
which is “Refractoryand recurrent idiopathic granulomatous
mastitis treatment (01:09):
Adaptive randomized clinical trial.” And I wonder
if you'll start just by telling usa little bit about this disease.
I'm a breast surgeon, so,it made sense to me when I read it
but tell us about idiopathic granulomatousmastitis and why it's important.
Yes, sure.
So, idiopathic granulomatous mastitis
(01:30):
or IGM, is an inflammatory breast diseasecharacterized
by significant inflammatory changes,within the breast tissue.
And it can presentwith a variety of symptoms,
most importantly, like,
large breast massthat is erythemal, or even fistula,
generally it is not,very common disease all around the world,
(01:55):
but it can be way more commonamong certain patient populations.
So some surgeons may have a patientwith IGM
on a daily basis in their clinics,and some may see it once a year.
With that being said,it's been shown that,
it is a common diseaseamong Middle Eastern population,
(02:17):
including Iranians of course,and Hispanic population as well,
especially in your young,reproductive years.
And, this demographicalso adds another layer
of complexity,since many of these patients,
might be concerned about the possibility
of cancer or, different breast diseases.
(02:40):
So there are some challenges
that can be associated with IGM,
including treatment resistance.
Actually the absence of a proven etiology
for IGM,makes it particularly difficult to achieve
a complete curewithout the risk of remission.
(03:00):
And the other challengeis also the recurrence.
And even after successful treatment,
IGM has a tendency to recur.
And this lack of reliable response
has complicated patient care,
with no general agreementon a standardized approach to treatment.
(03:23):
And as of now,no specific clinical guidelines exist.
Which is leaving patients and clinicians
facing a landscape of trial and error.
Yeah, I,
I canI, I, I feel it as you're describing it
because I do I have seen these patientsin my clinic and,
(03:43):
a lot of timesit takes, quite a bit of time
even before they get the diagnosis.
Because, you know,maybe they have been thought
to have sort of breast abscessor infectious etiology
without recognizing the underlyinginflammatory disease component.
Sometimes they go through big surgeries
because people are tryingto debride the area.
(04:05):
But as you know,when it's this inflammatory disease,
the surgery is typicallynot a curative treatment,
because the underlying process,autoimmune process,
which we maybe don't understandvery well, is still in existence.
And and so I can,you know, just remember patients
as you're talking who have hadthis persistent or recurrent disease.
(04:29):
Yeah.
And exactly as you mentioned,there are like large,
treatment approachesthat is currently being used,
starting from in the observation,
some surgeons like, prefer to only observeand do some, you know,
antibiotics and low level of, treatment,
(04:50):
and some others even do surgery.
So, these treatments often yieldinconsistent results
with some patients responding well,some others do not, as you mentioned.
And also each option carries
its own set of risksand potential side effects as well.
(05:12):
And again we are dealingwith a young patient population
generally,which makes it like even more challenging.
So in this study, that's why we wanted
to address these, pressing needs,focusing on that,
this a specific patient populationwho were resistant and,
or show some sort of recurrence the after,their, like, first line of treatment.
(05:37):
And wewere generally in this patient population,
we were dealing with patients having,
more severe form of IGM and,
some sort of failureto response to therapy.
Okay.
And you used, a database or a researchcollaborative to identify patients.
Can you tell us a little bitabout how you identified them
(05:59):
and how you defined the the disease?
Yes. So, the the,
this study was done on a, breast,
research centerin Tehran, Iran, from 2017 to 2020.
And it was done,
as a like prospectiveadaptive clinical trial.
(06:23):
So the center was kind of,
only breast diseasesand a lot of the patients were referred
from, other surgeons due to like,you know,
due to resistance to therapy.
So, that's how we recruited
(06:43):
patients, from 2017 to 2020.
In the, Breast Cancer Research Center.
Okay.
And it sounds like, this also was a groupof clinicians who were motivated,
as you are,to figure out how to address this disease.
And so then you had, specific criteriafor defining,
(07:04):
the IGM,and making sure that you're looking at,
as homogenous a population as possible or,you know, the disease pattern.
Yeah. So all the patients.
So how would you find a patient was,first of all, the patient undergoing,
histopathological confirmation.
So they had a biopsy and, in our center.
(07:27):
So, the breast pathologist,
sees the slides and confirm,
the diagnoses of IGM, histopathologically.
And then, how we define recurrence
or resistance was,
no response to therapy
(07:47):
after eight weeks of treatmentas, okay, resistance
and recurrence of
the disease was defined as,
reappearance of
the signs and symptoms within eight weeks,
of the completion, of the therapyAnd they usually like the first line,
(08:12):
that, most of them were getting was,and say
antibiotics, drainage and, some dressings.
So they were like most mostly,some sort of supportive care
as the first lineand, all the patient population
were kind of either resistant or recurrentthrough these, therapeutic approaches.
(08:35):
Okay. Yeah.
And again, I think, at any age, but,
seeing patients who have persistent woundsand pain,
I, you know, not everybody has painas their first presenting symptom.
But again, I've certainly seena significant amount of pain
and and again, the, the challenge and the,
life-limiting need to have dressings
(08:57):
and, you know, add that into your dailyroutine is very challenging.
Yeah.
Exactly.
And so most of the patients were actually,
really annoyed with their signsand symptoms.
Yeah. Being unresponsive.
And I think the other thingthat you highlight in
the paper is the importanceof ruling out other causes.
(09:18):
So when we define someone as having IGM,making sure that they don't have
tuberculosis or non-tuberculosismycobacterial infection,
it can be associated also
with other autoimmune diseasesto have inflammation in the breast.
So uncontrolled diabetes
sometimes is a precipitor of inflammationin the breast as well.
So I know you spent some, some timelooking at that.
(09:41):
And then you also lookedat the inflammatory
markers in these patients.
Yes. So,
all the patients underwent
tuberculosisPCR to make sure that they don't have TB
and they don't have any,
you know, contraindicationfor getting corticosteroid as well,
(10:02):
because that was one of the main, mainstem of the clinical trial.
And, all the
like, clinical and demographic
characteristics of the patient, including,
blood test or,
angiotensin converting enzyme,
and antinuclear, antibodies
(10:24):
were also assessed,in their blood, in their blood test.
Okay.
And so then you defined thisgroup of patients and tell me about the,
escalating therapy or the the adaptiveresponsive therapy methodology, how
you kind of picked which therapy to useand how the patients were monitored.
Okay. So,
(10:46):
everything that's been said,
there there were no, like,specific therapy that well,
we kind of know that it's going to workfor these patient populations.
So for the interest of patientand controlling their symptoms
as well as possible,we decided to conduct this study
(11:06):
in an adaptive manner, which, we like thethe whole clinical trial on three phases.
And, we started with three arms.
First arm was including,
supportive carebecause, all the patients were referrals.
And we also wanted to have that armto compare with the others,
(11:30):
the rest of the arms, the second arm was,
high-doseprednisolone, 50 milligram/m² per day.
And the last arm was the lower doseof corticosteroid or prednisolone,
which was 12.5mg/m²
per day, in addition to methotrexate.
(11:51):
So we randomized in the first phase,
we included like ten patients in each
study arm.
And the first point of evaluation
was after 1 to 2 months,
because it was a like,it was patient dependent.
Basically some of them were okaynow, like not going back.
(12:14):
But the general endpoint
was after a month and for the first phase.
And after that, after the first
point of
evaluation, we saw thatalmost none of the patients
in, arm of supportive care
getting drainage was not responding.
(12:36):
So we decided to terminate that arm
and recruited more patients in,
in the other two arms,
meaning we continued with, high doseprednisolone.
And the other arm was methotrexateplus prednisolone.
So we accept more patient.
And the second point of evaluation,
(13:00):
was after six month and after six months,
we generally, the goal was after
seeing remission of the signsand symptoms clinically,
we started tapering the drugs,
in each patient population.
Interestingly,
most of the patients in high-doseprednisolone group
(13:24):
was kind of,responding to the therapy well.
But once we started tapering the drug,
we saw, the remission of the symptoms.
Okay. After six months. Yeah.
So that's why, again,that was kind of failure to therapy.
And in the second phase will be terminatedgroup B, which was high prednisolone.
(13:49):
And we only continued with methotrexate
in addition to lower dosage,
of prednisolone.
So you took those patientswho had relapse of symptoms
after tapering their high doseprednisolone
and moved them over to do the lower dosewith the methotrexate.
Exactly.
So, we continue with 12.5mgof prednisolone
(14:14):
in addition to methotrexate again
until complete remission, achieved.
And then we start tapering the drug.
So generally, on average,the whole time of the treatment in group
B, which was high-doseprednisolone, was about six months.
And in the last group, which were alsotaking methotrexate was about 18 months.
(14:38):
So they continue getting methotrexatefor over a year,
on a weekly basis.
But, the good thing about the lastgroup was
they were able to taper out
the, prednisolone very soon.
And so the prednisolone was not not neededfor symptom control
(14:58):
as long as the methotrexate was. Exactly.
And the reason that we do not have,
the like,
methotrexate aloneand we added prednisolone to that group
is it generally took time for methotrexateto take action.
And these patientswere really like in pain.
And we wanted to take advantageof quick symptom relief of prednisolone.
(15:23):
But generally, after quick symptom relief.
And if you're able to taper outprednisolone and continue
with methotrexate only.
And so then you followed these patientsout 3 to 5 years from their treatment.
How did they do?
Did they have to go back on treatmentagain?
Or how often didthey have recurrence of symptoms. Yes.
(15:44):
So, for the remaining arm,
which was methotrexate,and for these alone,
we saw about 94 to 97%,
complete cure.
So we, we just we didn't.
Yeah.
We didn't, have patients coming backto the clinics with their recurrence.
(16:07):
When they’re
getting, like,
complete, methotrexate course. And.
Yeah, that was the, like the besttreatment arm that we had in this study.
So that the other arms, as you said,
the observation and supportive carereally didn't lead to disease control.
Right.
(16:27):
And then in the patientswith the high-dose prednisolone,
did you have some of those patientsachieve control?
Yeah, we had about, 14
to 15% of the patients
respond to the therapy.
And in this patient population,I would say
14 to 15%
(16:51):
had this as their sign and symptom,
cured without recurrence
because, that'sthe kind of treatment failure that we saw
in this patientpopulation was mainly a recurrence.
So we had about,
15 patients, 15% of the patients
(17:12):
without recurrenceof their signs and symptoms.
And then how did the patients in these twotreatment arms do in terms of side
effects of medications or other, symptomsthat they experienced during treatment?
Yeah. Actually
there were not...
no significant differencesin terms of the side effects
(17:34):
among the groups getting,
methotrexate,methotrexate, on the prednisolone.
So generally supportive care,
they,they didn't have that much of side effects
because like, they were getting, regular,maybe antibiotics.
Yeah. Yeah.
And also, it didn't, like,take longer than 1 to 2 months,
(17:58):
so they're not under like long,of course, of treatment.
But, in the other two groups,
we obviously saw some patients with
high level of,
blood glucose,which was still like lower than 120
and we had some weight gain, about three,four kilogram.
(18:20):
But, generally we didn't have, much,
or severe side effects.
And they were all back to get backto normal after,
the, course of that,
their treatment,and the most frequent, symptom
that we had amongmethotrexate patients was,
(18:43):
some GI
symptoms, and some sort of headaches,so that I will say
there were nothing, bad that we had tojust,
you know, discontinue the drugs.
Well, I think that's good news,because, again, I worry about patients,
particularly being on steroids,corticosteroids
for a long period of time,but autoimmune modulating drugs as well.
(19:07):
So it's good to hear that overall, itsounds like it was pretty well tolerated.
And then maybethere are a couple of options.
I suppose if someone couldn'ttake methotrexate
that you could try the high-dose steroids.
It's just, not as good at achievingtrue remission of the disease.
Yeah.
What do you think about sort of,the longer term follow up?
(19:27):
Do we need longer term follow up to seeif these patients recur ten years later?
Have you have you seen,you know, that that the disease recurs?
Afterthat in some patients, in other studies
or literature reports?
Not actually most of the if,
(19:48):
any recurrence would happenmost of them would be within five years.
So in our patient population, I mean, it'sobviously not after ten years,
but in other studies in our institute,
as well as the literature reviewthat were done
and also, a great surgeon
(20:08):
that I was,I had the pleasure to work with
and their experience, it'susually within five years.
So there, there seems to be like,
no need for ten years
or longer termfollow up for these patients.
That's great to hear.
So, you know, over 90% cure rate,
(20:29):
of this disease.
It is a significant timeto be on treatment 18 months.
But to hear that you're able to achievecure in most of the patients I think is a
great outcome.
And particularly
knowing thatthis can be a difficult disease to treat,
I don't know that the paper, fullycan capture that the experience
(20:50):
of the clinician at the bedsidewho's seeing the patient back and,
evaluatingwhether they need an additional drainage
for an abscess or anothercourse of antibiotics and reassuring them,
when they're on the medication,
that we expect their symptomsto get better.
I mean, there's a lot of helping themthrough the the stress and anxiety
(21:11):
and the symptoms that they're experiencing
from the disease that you kind of talkedabout in the beginning.
Yeah, I also likethese 18 months is kind of the average.
So you can after complete remissionyou can always start tapering
the drugs first of all.
And then also I want to again point outthat these patients were kind of,
you know, more toward more severe side of,
(21:35):
the disease and kind of, you know,unresponsive to.
Yeah.
So it's possible,
I think I hear you saying thatin other patients, you might not need
to keep them on medication for as longthat you intentionally selected,
a group of patientswith more severe granulomatous mastitis.
Exactly, exactly.
And it's a good number.
We talk a lot in research studies, right,about the the,
(21:59):
numbers and the power of the study,but the 300 patients with severity
of that granulomatous mastitis,I think that's a pretty good number
for this uncommon disease of the breast.
So you were able to collect a good,
a good number of patientsfrom the specialized hospital.
Yeah,we exactly were kind of a referral center.
(22:21):
So we take advantage. Yeah. And,
are there any,
caveats about applying these study results
to patient populationsor things that you do?
For instance,do we need to worry about patients
being on these medications,if they're pregnant or lactating?
(22:43):
Do you have any experience or suggestionsfor applying their results?
Yeah.
So, some other parallel studies
that are being done, in our institution,
we are trying to find other, waysfor those patient
that may might have some contraindicationfor getting methotrexate.
(23:05):
Exactly as you mentioned, such as pregnant
women or, women in their lactation.
So it seems, what we found
and, is like another option can be,
azathioprine, other, yeah,that azathioprine can be replaced.
So the thing was, patients, are not,tolerating,
(23:29):
azathioprine as well as methotrexate, but
it can be an alternative,
for patients who have contraindicationfor getting methotrexate.
Another option
is intralesional, like injection,
of the steroid into the lesion.
Also another promptwhich can help to reduce
(23:51):
the dosage.
And the exposure up the whole body
and system to corticosteroid therapy,
but againthe another problem with that again
is that complaints of the patient,which can be a bit painful for them for.
But these two other alternatives
also can be considered for patients.
(24:16):
It's good to knowthat there are additional options.
And again, I've seen, some studiesreporting that use of intralesional
steroids such as triamcinolonealong with the systemic therapies,
or for patients who are, havingpersistent symptoms with systemic therapy.
And as you mentioned,the systemic effects of a corticosteroid
or azathioprine or methotrexatemay be hard for patients to tolerate.
(24:39):
So having a number of different optionsthat can help us control
this difficult diseasemakes a lot of sense to me.
Well,I want to thank you for your time today
and, to you and all of your research team.
I think that what I have experiencedand what I've heard from colleagues
is that this is often a clinical dilemma.
(24:59):
And, andit requires a lot of investment of time
to be able to care for patientsexperiencing granulomatous
mastitis or idiopathicgranulomatous mastitis, particularly
those who are refractory to treatmentor have relapsing disease.
So thank you for helping us knowhow to take care of our patients better.
Thank you so much for your interestin the study.
(25:20):
Thank you for listening
to the Journal of the American Collegeof Surgeons Operative Word podcast.
If you enjoyed today's episode,spread the word on social media
by using the hashtag #JACSOperativeWord.
Subscribe to The Operative Wordwherever podcasts are available,
or listen on the American Collegeof Surgeons website at facs.org/podcast.
You are listening to The Operative Word,
a podcast brought to you by the Journalof the American College of Surgeons.
I'm Dr Lillian Erdahl,and throughout this series, Dr Tom
Varghese and I will speak with recently
published authors about the motivationbehind their latest research
and the clinical implicationsit has for the practicing surgeon.
The opinions expressed in this podcastare those of the participants,
(00:26):
and not necessarilythat of the American College of Surgeons.
Hello,and welcome back to The Operative
Word, the podcast of the Journalof the American College of Surgeons.
I'm your host, Lillian Erdahl, and todayI am joined by Dr Fatemeh Shojaeian.
Welcome, Dr Shojaeian.
Thank you so much,Dr Erdahl, for having me.
(00:48):
Dr Shojaeian is a postdoctoral researchfellow at Johns Hopkins in
the Wood laboratory.
And I wanted to ask, do you
or your authors have anythingto disclose relevant to this work?
No, we don't have anything to disclose.
Great.
Well, thank you for being hereto talk to us about your study,
which is “Refractoryand recurrent idiopathic granulomatous
mastitis treatment (01:09):
Adaptive randomized clinical trial.” And I wonder
if you'll start just by telling usa little bit about this disease.
I'm a breast surgeon, so,it made sense to me when I read it
but tell us about idiopathic granulomatousmastitis and why it's important.
Yes, sure.
So, idiopathic granulomatous mastitis
(01:30):
or IGM, is an inflammatory breast diseasecharacterized
by significant inflammatory changes,within the breast tissue.
And it can presentwith a variety of symptoms,
most importantly, like,
large breast massthat is erythemal, or even fistula,
generally it is not,very common disease all around the world,
(01:55):
but it can be way more commonamong certain patient populations.
So some surgeons may have a patientwith IGM
on a daily basis in their clinics,and some may see it once a year.
With that being said,it's been shown that,
it is a common diseaseamong Middle Eastern population,
(02:17):
including Iranians of course,and Hispanic population as well,
especially in your young,reproductive years.
And, this demographicalso adds another layer
of complexity,since many of these patients,
might be concerned about the possibility
of cancer or, different breast diseases.
(02:40):
So there are some challenges
that can be associated with IGM,
including treatment resistance.
Actually the absence of a proven etiology
for IGM,makes it particularly difficult to achieve
a complete curewithout the risk of remission.
(03:00):
And the other challengeis also the recurrence.
And even after successful treatment,
IGM has a tendency to recur.
And this lack of reliable response
has complicated patient care,
with no general agreementon a standardized approach to treatment.
(03:23):
And as of now,no specific clinical guidelines exist.
Which is leaving patients and clinicians
facing a landscape of trial and error.
Yeah, I,
I canI, I, I feel it as you're describing it
because I do I have seen these patientsin my clinic and,
(03:43):
a lot of timesit takes, quite a bit of time
even before they get the diagnosis.
Because, you know,maybe they have been thought
to have sort of breast abscessor infectious etiology
without recognizing the underlyinginflammatory disease component.
Sometimes they go through big surgeries
because people are tryingto debride the area.
(04:05):
But as you know,when it's this inflammatory disease,
the surgery is typicallynot a curative treatment,
because the underlying process,autoimmune process,
which we maybe don't understandvery well, is still in existence.
And and so I can,you know, just remember patients
as you're talking who have hadthis persistent or recurrent disease.
(04:29):
Yeah.
And exactly as you mentioned,there are like large,
treatment approachesthat is currently being used,
starting from in the observation,
some surgeons like, prefer to only observeand do some, you know,
antibiotics and low level of, treatment,
(04:50):
and some others even do surgery.
So, these treatments often yieldinconsistent results
with some patients responding well,some others do not, as you mentioned.
And also each option carries
its own set of risksand potential side effects as well.
(05:12):
And again we are dealingwith a young patient population
generally,which makes it like even more challenging.
So in this study, that's why we wanted
to address these, pressing needs,focusing on that,
this a specific patient populationwho were resistant and,
or show some sort of recurrence the after,their, like, first line of treatment.
(05:37):
And wewere generally in this patient population,
we were dealing with patients having,
more severe form of IGM and,
some sort of failureto response to therapy.
Okay.
And you used, a database or a researchcollaborative to identify patients.
Can you tell us a little bitabout how you identified them
(05:59):
and how you defined the the disease?
Yes. So, the the,
this study was done on a, breast,
research centerin Tehran, Iran, from 2017 to 2020.
And it was done,
as a like prospectiveadaptive clinical trial.
(06:23):
So the center was kind of,
only breast diseasesand a lot of the patients were referred
from, other surgeons due to like,you know,
due to resistance to therapy.
So, that's how we recruited
(06:43):
patients, from 2017 to 2020.
In the, Breast Cancer Research Center.
Okay.
And it sounds like, this also was a groupof clinicians who were motivated,
as you are,to figure out how to address this disease.
And so then you had, specific criteriafor defining,
(07:04):
the IGM,and making sure that you're looking at,
as homogenous a population as possible or,you know, the disease pattern.
Yeah. So all the patients.
So how would you find a patient was,first of all, the patient undergoing,
histopathological confirmation.
So they had a biopsy and, in our center.
(07:27):
So, the breast pathologist,
sees the slides and confirm,
the diagnoses of IGM, histopathologically.
And then, how we define recurrence
or resistance was,
no response to therapy
(07:47):
after eight weeks of treatmentas, okay, resistance
and recurrence of
the disease was defined as,
reappearance of
the signs and symptoms within eight weeks,
of the completion, of the therapyAnd they usually like the first line,
(08:12):
that, most of them were getting was,and say
antibiotics, drainage and, some dressings.
So they were like most mostly,some sort of supportive care
as the first lineand, all the patient population
were kind of either resistant or recurrentthrough these, therapeutic approaches.
(08:35):
Okay. Yeah.
And again, I think, at any age, but,
seeing patients who have persistent woundsand pain,
I, you know, not everybody has painas their first presenting symptom.
But again, I've certainly seena significant amount of pain
and and again, the, the challenge and the,
life-limiting need to have dressings
(08:57):
and, you know, add that into your dailyroutine is very challenging.
Yeah.
Exactly.
And so most of the patients were actually,
really annoyed with their signsand symptoms.
Yeah. Being unresponsive.
And I think the other thingthat you highlight in
the paper is the importanceof ruling out other causes.
(09:18):
So when we define someone as having IGM,making sure that they don't have
tuberculosis or non-tuberculosismycobacterial infection,
it can be associated also
with other autoimmune diseasesto have inflammation in the breast.
So uncontrolled diabetes
sometimes is a precipitor of inflammationin the breast as well.
So I know you spent some, some timelooking at that.
(09:41):
And then you also lookedat the inflammatory
markers in these patients.
Yes. So,
all the patients underwent
tuberculosisPCR to make sure that they don't have TB
and they don't have any,
you know, contraindicationfor getting corticosteroid as well,
(10:02):
because that was one of the main, mainstem of the clinical trial.
And, all the
like, clinical and demographic
characteristics of the patient, including,
blood test or,
angiotensin converting enzyme,
and antinuclear, antibodies
(10:24):
were also assessed,in their blood, in their blood test.
Okay.
And so then you defined thisgroup of patients and tell me about the,
escalating therapy or the the adaptiveresponsive therapy methodology, how
you kind of picked which therapy to useand how the patients were monitored.
Okay. So,
(10:46):
everything that's been said,
there there were no, like,specific therapy that well,
we kind of know that it's going to workfor these patient populations.
So for the interest of patientand controlling their symptoms
as well as possible,we decided to conduct this study
(11:06):
in an adaptive manner, which, we like thethe whole clinical trial on three phases.
And, we started with three arms.
First arm was including,
supportive carebecause, all the patients were referrals.
And we also wanted to have that armto compare with the others,
(11:30):
the rest of the arms, the second arm was,
high-doseprednisolone, 50 milligram/m² per day.
And the last arm was the lower doseof corticosteroid or prednisolone,
which was 12.5mg/m²
per day, in addition to methotrexate.
(11:51):
So we randomized in the first phase,
we included like ten patients in each
study arm.
And the first point of evaluation
was after 1 to 2 months,
because it was a like,it was patient dependent.
Basically some of them were okaynow, like not going back.
(12:14):
But the general endpoint
was after a month and for the first phase.
And after that, after the first
point of
evaluation, we saw thatalmost none of the patients
in, arm of supportive care
getting drainage was not responding.
(12:36):
So we decided to terminate that arm
and recruited more patients in,
in the other two arms,
meaning we continued with, high doseprednisolone.
And the other arm was methotrexateplus prednisolone.
So we accept more patient.
And the second point of evaluation,
(13:00):
was after six month and after six months,
we generally, the goal was after
seeing remission of the signsand symptoms clinically,
we started tapering the drugs,
in each patient population.
Interestingly,
most of the patients in high-doseprednisolone group
(13:24):
was kind of,responding to the therapy well.
But once we started tapering the drug,
we saw, the remission of the symptoms.
Okay. After six months. Yeah.
So that's why, again,that was kind of failure to therapy.
And in the second phase will be terminatedgroup B, which was high prednisolone.
(13:49):
And we only continued with methotrexate
in addition to lower dosage,
of prednisolone.
So you took those patientswho had relapse of symptoms
after tapering their high doseprednisolone
and moved them over to do the lower dosewith the methotrexate.
Exactly.
So, we continue with 12.5mgof prednisolone
(14:14):
in addition to methotrexate again
until complete remission, achieved.
And then we start tapering the drug.
So generally, on average,the whole time of the treatment in group
B, which was high-doseprednisolone, was about six months.
And in the last group, which were alsotaking methotrexate was about 18 months.
(14:38):
So they continue getting methotrexatefor over a year,
on a weekly basis.
But, the good thing about the lastgroup was
they were able to taper out
the, prednisolone very soon.
And so the prednisolone was not not neededfor symptom control
(14:58):
as long as the methotrexate was. Exactly.
And the reason that we do not have,
the like,
methotrexate aloneand we added prednisolone to that group
is it generally took time for methotrexateto take action.
And these patientswere really like in pain.
And we wanted to take advantageof quick symptom relief of prednisolone.
(15:23):
But generally, after quick symptom relief.
And if you're able to taper outprednisolone and continue
with methotrexate only.
And so then you followed these patientsout 3 to 5 years from their treatment.
How did they do?
Did they have to go back on treatmentagain?
Or how often didthey have recurrence of symptoms. Yes.
(15:44):
So, for the remaining arm,
which was methotrexate,and for these alone,
we saw about 94 to 97%,
complete cure.
So we, we just we didn't.
Yeah.
We didn't, have patients coming backto the clinics with their recurrence.
(16:07):
When they’re
getting, like,
complete, methotrexate course. And.
Yeah, that was the, like the besttreatment arm that we had in this study.
So that the other arms, as you said,
the observation and supportive carereally didn't lead to disease control.
Right.
(16:27):
And then in the patientswith the high-dose prednisolone,
did you have some of those patientsachieve control?
Yeah, we had about, 14
to 15% of the patients
respond to the therapy.
And in this patient population,I would say
14 to 15%
(16:51):
had this as their sign and symptom,
cured without recurrence
because, that'sthe kind of treatment failure that we saw
in this patientpopulation was mainly a recurrence.
So we had about,
15 patients, 15% of the patients
(17:12):
without recurrenceof their signs and symptoms.
And then how did the patients in these twotreatment arms do in terms of side
effects of medications or other, symptomsthat they experienced during treatment?
Yeah. Actually
there were not...
no significant differencesin terms of the side effects
(17:34):
among the groups getting,
methotrexate,methotrexate, on the prednisolone.
So generally supportive care,
they,they didn't have that much of side effects
because like, they were getting, regular,maybe antibiotics.
Yeah. Yeah.
And also, it didn't, like,take longer than 1 to 2 months,
(17:58):
so they're not under like long,of course, of treatment.
But, in the other two groups,
we obviously saw some patients with
high level of,
blood glucose,which was still like lower than 120
and we had some weight gain, about three,four kilogram.
(18:20):
But, generally we didn't have, much,
or severe side effects.
And they were all back to get backto normal after,
the, course of that,
their treatment,and the most frequent, symptom
that we had amongmethotrexate patients was,
(18:43):
some GI
symptoms, and some sort of headaches,so that I will say
there were nothing, bad that we had tojust,
you know, discontinue the drugs.
Well, I think that's good news,because, again, I worry about patients,
particularly being on steroids,corticosteroids
for a long period of time,but autoimmune modulating drugs as well.
(19:07):
So it's good to hear that overall, itsounds like it was pretty well tolerated.
And then maybethere are a couple of options.
I suppose if someone couldn'ttake methotrexate
that you could try the high-dose steroids.
It's just, not as good at achievingtrue remission of the disease.
Yeah.
What do you think about sort of,the longer term follow up?
(19:27):
Do we need longer term follow up to seeif these patients recur ten years later?
Have you have you seen,you know, that that the disease recurs?
Afterthat in some patients, in other studies
or literature reports?
Not actually most of the if,
(19:48):
any recurrence would happenmost of them would be within five years.
So in our patient population, I mean, it'sobviously not after ten years,
but in other studies in our institute,
as well as the literature reviewthat were done
and also, a great surgeon
(20:08):
that I was,I had the pleasure to work with
and their experience, it'susually within five years.
So there, there seems to be like,
no need for ten years
or longer termfollow up for these patients.
That's great to hear.
So, you know, over 90% cure rate,
(20:29):
of this disease.
It is a significant timeto be on treatment 18 months.
But to hear that you're able to achievecure in most of the patients I think is a
great outcome.
And particularly
knowing thatthis can be a difficult disease to treat,
I don't know that the paper, fullycan capture that the experience
(20:50):
of the clinician at the bedsidewho's seeing the patient back and,
evaluatingwhether they need an additional drainage
for an abscess or anothercourse of antibiotics and reassuring them,
when they're on the medication,
that we expect their symptomsto get better.
I mean, there's a lot of helping themthrough the the stress and anxiety
(21:11):
and the symptoms that they're experiencing
from the disease that you kind of talkedabout in the beginning.
Yeah, I also likethese 18 months is kind of the average.
So you can after complete remissionyou can always start tapering
the drugs first of all.
And then also I want to again point outthat these patients were kind of,
you know, more toward more severe side of,
(21:35):
the disease and kind of, you know,unresponsive to.
Yeah.
So it's possible,
I think I hear you saying thatin other patients, you might not need
to keep them on medication for as longthat you intentionally selected,
a group of patientswith more severe granulomatous mastitis.
Exactly, exactly.
And it's a good number.
We talk a lot in research studies, right,about the the,
(21:59):
numbers and the power of the study,but the 300 patients with severity
of that granulomatous mastitis,I think that's a pretty good number
for this uncommon disease of the breast.
So you were able to collect a good,
a good number of patientsfrom the specialized hospital.
Yeah,we exactly were kind of a referral center.
(22:21):
So we take advantage. Yeah. And,
are there any,
caveats about applying these study results
to patient populationsor things that you do?
For instance,do we need to worry about patients
being on these medications,if they're pregnant or lactating?
(22:43):
Do you have any experience or suggestionsfor applying their results?
Yeah.
So, some other parallel studies
that are being done, in our institution,
we are trying to find other, waysfor those patient
that may might have some contraindicationfor getting methotrexate.
(23:05):
Exactly as you mentioned, such as pregnant
women or, women in their lactation.
So it seems, what we found
and, is like another option can be,
azathioprine, other, yeah,that azathioprine can be replaced.
So the thing was, patients, are not,tolerating,
(23:29):
azathioprine as well as methotrexate, but
it can be an alternative,
for patients who have contraindicationfor getting methotrexate.
Another option
is intralesional, like injection,
of the steroid into the lesion.
Also another promptwhich can help to reduce
(23:51):
the dosage.
And the exposure up the whole body
and system to corticosteroid therapy,
but againthe another problem with that again
is that complaints of the patient,which can be a bit painful for them for.
But these two other alternatives
also can be considered for patients.
(24:16):
It's good to knowthat there are additional options.
And again, I've seen, some studiesreporting that use of intralesional
steroids such as triamcinolonealong with the systemic therapies,
or for patients who are, havingpersistent symptoms with systemic therapy.
And as you mentioned,the systemic effects of a corticosteroid
or azathioprine or methotrexatemay be hard for patients to tolerate.
(24:39):
So having a number of different optionsthat can help us control
this difficult diseasemakes a lot of sense to me.
Well,I want to thank you for your time today
and, to you and all of your research team.
I think that what I have experiencedand what I've heard from colleagues
is that this is often a clinical dilemma.
(24:59):
And, andit requires a lot of investment of time
to be able to care for patientsexperiencing granulomatous
mastitis or idiopathicgranulomatous mastitis, particularly
those who are refractory to treatmentor have relapsing disease.
So thank you for helping us knowhow to take care of our patients better.
Thank you so much for your interestin the study.
(25:20):
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