George From China - Dx 2007

[Olga]

It is possible for the metastasis to invade the bone but it usually takes long time to penetrate it. You can ask someone to re-review the ECT done in Mar 2014 and 2015 (if you have a time and money and feels like it), to see if it was missed. 8 cm is a big bone met to grow in such a short time.

[D.ap]

Hi Lynette
I hope this day finds George recovering.
Looks like MRgFUS was used with uterine fibroids and some liver tumors.
As I understand it, the ultrasound is limited to 12cm's deep and has recently been used with a brain tumor.

J Ther Ultrasound. 2014 Oct 16;2:17. doi: 10.1186/2050-5736-2-17. eCollection 2014.

First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound.


http://www.ncbi.nlm.nih.gov/pubmed/25671132

Is it possible the scan read incorrectly as positive to cancer?

Found when I searched for limations of ECT.

What are the limitations of Chest Radiography?Bone scans cannot identify some types of cancer.

You may need additional tests like CT, MR imaging, blood tests or a biopsy in addition to bone scans to help distinguish between normal and abnormal bone.

Nuclear medicine procedures can be time consuming. It can take several hours to days for the radiotracer to accumulate in the body part of interest and imaging may take up to several hours to perform, though in some cases, newer equipment is available that can substantially shorten the procedure time.

The resolution of structures of the body with nuclear medicine may not be as high as with other imaging techniques, such as CT or MRI. However, nuclear medicine scans are more sensitive than other techniques for a variety of indications, and the functional information gained from nuclear medicine exams is often unobtainable by other imaging techniques.

Link to radiology of bone tumors-

http://www.ncbi.nlm.nih.gov/books/NBK12539/

My thought is that even biopsies can conclude benign tumors so why can't scans be wrong in concluding malignancies?


SKELETAL METASTASES FROM SOFT-TISSUE SARCOMAS
INCIDENCE, PATTERNS, AND RADIOLOGICAL FEATURES

http://www.boneandjoint.org.uk/highwire ... l-text.pdf

The radiological study of 227 bone metastasis included 9 patients with ASPS--5 definitively dx



Write when you can

Love
Debbie

[Jorge]

Olga,
The bone met on George's humerus is like a mushroom with spindly stipe of 3~4cm. But the bone near the met became very thin that there is fracture risk that's the primary reason that a surgery is needed.


Debbie,
Thank you so much for searching and sharing the info about MR-guided focused ultrasound. Looks like we're having more and more local treatments
I've discussed it with some other renal cancer patient about the ECT, they also found the smaller bone mets can't be detected by ECT...

Not sure what systme treatments can be used now... Some TKI only work for the lung mets, new mets keeps coming out from other part of the body... Do you think the PD1 antibody worth a try now?
Any inputs will be highly appreciated.

Thanks,
Lynette

[D.ap]

Lynette

Melanoma FDA approved PD1

FDA Approves Second PD-1 Inhibitor, Nivolumab, for Melanoma - See more at: http://www.cancernetwork.com/melanoma/f ... Ft1Ha.dpuf

http://www.cancernetwork.com/melanoma/f ... b-melanoma

Ps Lynette
a great article on drug resistance and mutations and caner

Abstract.


Although targeted therapy is yielding promising results in the treatment of specific cancers, drug resistance poses a problem. We develop a mathematical framework that can be used to study the principles underlying the emergence and prevention of resistance in cancers treated with targeted small-molecule drugs. We consider a stochastic dynamical system based on measurable parameters, such as the turnover rate of tumor cells and the rate at which resistant mutants are generated. We find that resistance arises mainly before the start of treatment and, for cancers with high turnover rates, combination therapy is less likely to yield an advantage over single-drug therapy. We apply the mathematical framework to chronic myeloid leukemia. Early-stage chronic myeloid leukemia was the first case to be treated successfully with a targeted drug, imatinib (Novartis, Basel). This drug specifically inhibits the BCR-ABL oncogene, which is required for progression. Although drug resistance prevents successful treatment at later stages of the disease, our calculations suggest that, within the model assumptions, a combination of three targeted drugs with different specificities might overcome the problem of resistance.

Keywords: multiple-drug therapy, mutations, stochastic models

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1172248/

[D.ap]

Therapeutic uses of anti-PD-1 antibodies
Authors
George K. Philips1⇑ and
Michael Atkins2
1Georgetown University Hospital – Medicine, 3800 Reservoir Road NW Washington District of Columbia 20007, USA, T: 202-444-0545 F: 202-444-9429
2Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA
Corresponding author: George K. Philips Contact email: george.k.philips@gunet.georgetown.edu
Received September 4, 2014.
Pg 6
-nivolumab
http://m.intimm.oxfordjournals.org/cont ... u095.short

[Olga]

Lynette, I just found an article re. anti-PD-1 and PD-L1 targeting drugs side effects profile and management, posted it in
Board index ‹ Systemic Treatment ‹ Side effects of systemic treatments
here:
http://www.cureasps.org/forum/viewtopic.php?f=46&t=1102

we have someone participating in a trial for one of these drugs (there are several from different big pharma co in trials now) but they do not want to share an information, unfortunately.
If someone starts the treatment with one of these class of drugs, could you please open a new topic in the systemic drugs treatment in addition to a brief note in the patient's updates.

[Bonni Hess]

Dear Lynette, My heart breaks for the new challenges dear George and you are facing with George's newly diagnosed bone and kidney mets, but I am grateful that you are.moving pro-actively forward with treatments to shrink and destroy the mets and also searching for a new more effective systemic treatment to try to stabilize the progression of George's disease. I wish that we had more data and anecdotal information about the promising new PDL-1 immunotherapy drug, but as Olga said in her response to Jen who is also considering and exploring possible treatment with PDL-1, the family of the one ASPS patient who we are personally aware of who is currently being treated with PDL-1 is unfortunately unwilling to share any of the patient's anecdotal treatment experience or results at this time. Hopefully other patients who may be receiving PDL-1 treatment will be willing to share and post on the Board so that we can all learn from their experience. Hopefully too, PDL-1 will.prove to be a VERY effective and successful ASPS treatment. Please take care, give George and yourself special hugs from me, and keep in touch as you are able. With deepest caring, healing wishes, much love, and continued Hope, Bonni

[Jorge]

Thanks all for the reply and info sharing.

There are 2 Chinese patients will start Keytruda, actually tomorrow, as they didn't respond well to the TKIs. I will ask them if they would like to share the side effect and response of using PD1, and post on the PD1/PDL1 page.

For us, there is some change. We were told yesterday George has very strong expression of GD2 in the gene test of his lung mets, that he can join the GD2 CAR-T clinical trial which is led by Prof. Lung-ji Chang in University of Florida. There are some very successful cases (complete responses) of lymphoma treated with Prof. Lung-ji Chang's technique. We understand CAR-T is very new and cutting-edge, only a few neuroblastoma patients were treated with it... But it's still very attractive to us

So now we have 2 options: Keytruda or GD2 CAR-T. Following are the advantage and disadvantage of the 2 treatments that I can think of:
Keytryda:
Side effects are known to be slight and controllable.
The ORR of stage 2 or 3 clinical trials of some cancers is between 15%~40%. ORR of RCC is ~22% for Opdivo.
High price, ~$10000 per course of 3 weeks. Usually, it needs 3 or 4 course to evaluate the response.

GD2 CAR-T:
Most concern of side effect is cytokine storm. But Prof. Chang says his treatment is safe and controllable.
Unknown effect for solid tumor. CAR-T targets specifically, in this case GD2.
Also high price, ~$10000 per course. whether it works or not, can be evaluated after 1 course.

What do you guys think? Any input or suggestion will be highly welcome.

[Jorge]

I just find this article about PD-1 and PD-L1 expression on Soft Tissue Sarcomar. ASPS is not in the study samples, but I think there is still some meaning for reference?

Tumor Infiltrating PD1-Positive Lymphocytes and the Expression of PD-L1 Predict Poor Prognosis of Soft Tissue Sarcomas
Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859621/

[edwardchee]

Lynette,

My name is Ed. My wife Rene had putative synovial sarcoma mets ablated by Dr. Littrup. Just want to chime in on the immunotherapies. We specifically chose cryoablation, even of primary tumor, in order to harness immune effect. After cryoablation of recurrence of her primary (infratemporal fossa), we followed it up with multiple dendritic vaccinations. Eventually, there was re-recurrence in one spot just outside the cryoablation boundary. This re-recurrence was surgically resected with radical surgery.

Interestingly, what was found was the re-recurrent lesion (1cm) looked well defined on MRI. However, during surgery, surgeon could not visually identify. SUbsequent pathology explained why: the "lesion" was actually a large number of immune cells - basically many little microscopic islands of synovial sarcoma cells, surrounded by a lot of T-cells. It is a high probability that the immune system (cryoablation + dendritic) was exerting some level of immune control. The nature of immunotherapy is it takes time. Lesions seem to initially grow bigger on scans (thought to be due to the immune cells infiltrating the tumor). If we had waited to scan later, the lesion may have completely disappeared. However, we did not want to take chances, hence the radical surgery.

The point of sharing this is there is a lot of literature supporting immune effect of cryoablation, including creation of T-cells that can target your tumor. It's like doing a vaccine specific for your tumor.

Secondly, there is no point doing PD1 unless the pt has T-cells that can target the tumor (study the papers).

Put two and two together, this strongly implies the benefit of doing cryoablation shortly before PD-1. Dr. Littrup mentioned to us before he thought the T-cells would stick around for around 6 weeks after cryoablation. Our own studies give us the impression that sooner is better - perhaps 2-3 weeks after cryo.

The CART therapy is also a strong scientifically valid alternative. However, it can have more side effects. We would do that if tumors are out of control and rapidly growing. We think of it as the "big guns". However, there is no guarantee it will work either. His tumors must express whatever the T cells are engineered to target. Above that, there seem to be issues with tumors escaping T-cells. Looks like doctors are looking into combining PD-1 with CART to address that problem. I would imagine the side effects would be even potentially higher.

In summary, if we were in your position, if things are "out of control", we would likely go for CART. However, cryo of one or two "safely located" lesions in order to create the vaccine effect, followed soon by PD-1 is a safer option if you have 3 months to evaluate. (BTW we have a friend with refractory Lymphoma who was referred to hospice after trying everything under the sun. Her oncologist agreed to try PD-1 and within a couple of months, most of her tumors were clearly shrinking. 3 months later, even more shrinkage). So THERE IS HOPE.

[D.ap]

Ed and family
Thank you so much for sharing. I can't speak for everyone however
I've learned a lot from your post
I hope all is well with you and your family
Love the P family , Debbie

[Jorge]

Hi Edward,

Thank you very much for your input and sharing of Rene's experience with immunotherapy after cryoablation--very encouraging!
What exact dendritic vaccinations were used after Rene's cryoablation?

George just finished Cyber Knife to his kidney met in the weekend. My understanding is the gradually necrosis of this met would also release tumor antigen, which will also harness the PD1 injection.
However, a last Cryoablation is also needed and was planned before the Cyber Knife treatment. But George needs sometime to recovery from the Cyber Knife that we don't consider doing it recently.
Or maybe we can take some low dosage interferon or interleukin when he is in the recovery, and do the cryoablation later and then PD1?

The reason we were thinking of CAR-T is because George has strong expression of GD2, which is the target point of the CAR-T. I read some article in the weekend, the biggest weeknesses is that the GD2 CAR-T cells can't go inside the tumor and the cells fade too quickly. Didn't see a sucessful case with Dr. Chang's GD2 CAR-T technics yet...

Lynette

[edwardchee]

Lynette (and Debbie),

We went to germany (Thomas Nesselhut) for unprimed DCs - the idea being the unprimed immature DCs, if injected in strategic spots near the affected area, can pick up bits of the tumor and go on to train the T-Cells.

To make an already complicated history more complicated, Rene was also getting Coley Fluid injections into the post-surgical bed as well as intravenous administrations. Coley Fluid is a non-specific dead bacterial vaccine that has a very, very old history with sarcoma. Unfortunately, the company (MBVax in Canada) has since stopped making the fluid available. Basically, during our time, we did not have access to PD-1, let alone CART. The best we had was CTLA-4, but the cost and side effect profile was unacceptable to us. So we chose DC + Coley Fluid + cryo. I know this makes it hard to know which immunotherapy did what. But our goal was not a science experiment, only to stay alive at all cost. The immuno therapy field has since matured a lot and to their best knowledge, PD-1 with some vaccine effect prior should be a very good, or perhaps superior alternative to what we did.

I don't know about interleukins and interferons. Generally speaking, these have not been shown to have much benefit. I would make a beeline straight to PD-1. By the way, yes, radiation also has been seen to create T-cells in some cases. Probably not as strong as cryoablation though. You can google it. So his Cyber Knife might be "good enough" for the purpose of creating those T-Cells. An example article is as follows:
http://cancerimmunolres.aacrjournals.or ... d=aacrjnls
PD-1 generally has very low side effect rate. So, if the money issues can be surmounted, it is quite the "no brainer" from our perspective, especially if the situation is not pressingly urgent (out of control tumors) that may necessitate the "big gun" CART approach.

A related layman article by one of the pioneers in the field :
http://www.onclive.com/publications/Onc ... unotherapy
"Administered intravenously, ipilimumab, also known as CTLA-4 blockade, works best if an anticancer therapy—such as radiation, chemotherapy, freezing, or targeted therapy—is first used to stimulate T cells to go on the attack, Allison said. Once that has been accomplished, the scientist said, the drug could be widely useful.

Yes, if George's tumor was shown to strongly exhibit GD2, then it makes sense to go for CART. However, you have to bear in mind the potential serious toxicity, and weight that against how pressing the situation is. It is important to see some successful prior cases, because the doctor's technique may not be optimized, may not work (at all) or may be dangerous (cytokine storm, autoimmune attack of organs). Have you looked at trials in the USA? (I know it will be a burden to travel for you - but that's one option to consider). Trials such as this one:
https://clinicaltrials.gov/ct2/show/NCT02107963
I also seem to remember there was one in Texas (Baylor or MD Anderson...)

Also, I want to report that Rene is doing well. Her last lung cryo with Dr. Littrup was July 2013. At that point, we were all ready to go for CTLA-4 (as PD-1 was not yet approved). However, we chose to immediately, and quite suddenly stop all immunotherapy and "switch" to very high dose Omega3, low Omega6 dietary regimen, partly suspecting it may also have immunological effect. ("too much" immunotherapy / too much inflammation can actually be counter productive, as it may up-regulate all sorts of negating factors such as IL-10 etc. We felt omega3 could potentially stop those and make the already-created T-Cells from the tons of DC / cryo / Coley treatments actually get into the tumor). On top of immune effect, Omega3/6 is believed by Pardini and others to have direct tumor kill. It is very logical - you are what you eat - especially when it comes to fats that actually stay in your body because they incorporate directly into cell membranes (versus vitamins or even chemo that gets pumped out / excreted).

Our primary inspiration at that point was Dr. Ron Pardini's research / case study of an MFH patient. We have been in contact with the patient and he was VERY MUCH alive and well (last contact a few months ago), with completely ZERO tumors after something like 12-13 years? following this nutritional intervention. We have a lot of theories how this may work, but all that matters to us is Rene's tumors (which were popping up every 3 months in the lung, in an accelerating time pattern) stopped popping up after that last cryo, and starting this regimen. That was almost 2 years ago.
http://www.thedcasite.com/Omega3_Fatty_ ... _Lungs.pdf
We do not know whether the omega3/omega6 stopped the tumors, or whether the accelerating lung tumors were merely a manifestation of her immune system making these lesions "more visible" on scan (and hence cryo-ablated). So we can't say for sure whether it was the immunotherapy vs the OMega3,6 that did it. But we don't really care, and Rene has been on the omega3,6 regimen for almost 2 years now with little problem. Hopefully she continues this way, but if the tumors do come back, without a doubt, we will definitely be going for cryoablation followed with PD-1 antibodies as our first choice.


Hang in there,
Ed

[Jorge]

Hi Edward,
Rene and you were doing great in the past few years. I'm happy for you!

Here I have a question about the following description. The suspicious lesion was found to be " a large number of immune cells ", is it possible the immune cells gathered there due to the inflammation or necrosis by the cryoablation?
I mean, can this phenomenon be taken as immune system attacking tomor?


"Interestingly, what was found was the re-recurrent lesion (1cm) looked well defined on MRI. However, during surgery, surgeon could not visually identify. SUbsequent pathology explained why: the "lesion" was actually a large number of immune cells - basically many little microscopic islands of synovial sarcoma cells, surrounded by a lot of T-cells. It is a high probability that the immune system (cryoablation + dendritic) was exerting *some* level of immune control. The nature of immunotherapy is it takes time. Lesions seem to initially grow bigger on scans (thought to be due to the immune cells infiltrating the tumor). If we had waited to scan later, the lesion may have completely disappeared. However, we did not want to take chances, hence the radical surgery. "

[edwardchee]

Lynette,

To recap:

1) subsequent radical resection showed everything within Dr. Littrup's cryo ball to be completely dead.
2) only that 1cm "lesion", which had a lot of T-Cells, also contained microscopic (no macroscopic) islands of tumor

This is what we feel was happening at the cryo periphery:

We think the cryo killed everything within the zone. However, the re-recurrence was at a spot where Dr. Littrup just couldn't get the probes close enough / deep enough. It was in an area close to the carotid artery in the head (near the skull base). I actually "knew" it was a very high risk that re-recurrence would happen there, based on obsessive analysis of the pre/post scans and probe placement.

Also, in literature, there is documented concern of inflammation caused by cryo to accelerate remnant disease. This inflammation is 2 edged. On one hand, needed to create the "right" kind of immune response (T-Cell activation). On the other hand, bad in that it can accelerate tumor growth if the cryo did not kill it all. This is what we think happened:- that yes, the cryo & other immunotherapy caused T-Cells to surround and attack the tumor - but at the same time, the inflammation in that area may have been working to promote tumor regrowth.

Furthermore, there is significant amount of literature that implicates the "wrong" kind of inflammation from making immunotherapy ineffective (maybe also in the area immediately surrounding the tumor to make it hard for the T-Cells to get in). It's not fully understood, but the general gist is you don't want chronic persisting inflammation. Acute is needed in the context of creating T-Cells, but chronic is thought not to be good.

There is no way for us to know whether, had we left the "lesion" alone, that the T-Cells would eventually overpower and eliminate that last bastion of tumor. Without waiting another 3 months and re-scanning to see if the lesion would "die down", there's just no way to know.

However, what I can tell you with certainty is that after radical resection, all margins were negative. Given the location -- very very close to carotid, we strongly suspect that had Rene not done all that immunotherapy and cryo, leading to T-Cells "surrounding" the remnant tumor, she may not be alive today. Once the carotid is involved, it would probably be game over. THe data also speaks for itself - that recurrent sarcomas in tight locations such as in the head/jaw have exceedingly poor prognosis. We highly doubt that surgery alone would have achieved the negative margins (we consulted 3 leading H&N surgeons - the top guy at MSKCC went so far as to say 100% no way to get it all - yet he wanted to embed brachytherapy seeds intra-surgically to "extend life longer"... we ran away from there).

So, in a sense, we retrospectively view her cryo/dc/immunotherapy regimen as a low toxicity, perhaps superior in efficacy neo-adjuvant treatment to subsequent radical resection.

I would go so far as to strongly recommend that whatever immunotherapy you do, sieze the opportunity to cryo or resect any problematic tumors that may shrink from the immunotherapy. As you know, the science is still not fully mature and relapses do occur, including in CART and PD1.