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Protocol for Stage 4 Intracranial mesenchymal chondrosarcoma with metastatis in 2 distant location  

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asafsh
(@asafsh)
Eminent Member
Joined: 5 months ago
Posts: 66
09/01/2020 1:33 am  

Dears, i will appreciate if you can share your opinions about mesenchymal chondrosarcoma treatment which is started originally in intraorbital location as extrasceletal-soft tissue but after wrong surgery (incomplete resection without biopsy) propagated into face and right side of brain and appeared in 2 distant locations too (according to latest PET scan).

Patient undergo 2 surgical operations - first for partial tumor resection, and second for complete right eye resection and surrounding tissue and small part of skull bone for safety margin. Before second operation she had 3 cycles of VAC chemotherapy with no changes in tumor size (during July this year). Then later tumor started to grow (during August to October) and decision for complete resection was done. One month since last operation tumor recurred and started to grow. Recently, she got first cycle of IE and seems (subjective visual based  opinion with MR measurement) tumor responded partially to this protocol. But we know that after few cycles tumor may gain resistance to IE protocol and need to prepare ourselves for further fight. 

Chemo is proposed using conventional approach as shown here though we already informed (oncologist) that life expectancy is about less than 2-5 months. Of course we are determined to change this and trying to find alternative ways.

Seems original tumor first showed itself about 14 years ago but didn't grow till 2018.

Thank you very much


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asafsh
(@asafsh)
Eminent Member
Joined: 5 months ago
Posts: 66
09/01/2020 12:24 pm  

There is an article Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A related to the sarcoma cell line SW1353 "LDHA is highly activated in chondrosarcoma cells. Cancer cells, unlike their normal counterparts, use aerobic glycolysis with reduced mitochondrial oxidative phosphorylation for glucose metabolism (11). Since LDHA is an important key enzyme of glycolysis, we first measured the LDHA expression in two malignant chondrosarcoma cell lines compared with benign human chondrocyte cell lines, CHON-001 and
CHON‑002. Notably, LDHA was significantly upregulated in chondrosarcoma cells (Fig. 1A).
"

Is there chance that the behavior is the same for mesenchymal chondrosarcoma, and if so may the targeting glycolysis is a way to go? They got the LDHA expression result through 3rd party lab. May be i may try to ask them for quotation and send them samples to do the same.

First VAC treatment with doxorubicine in our case did't shrink tumor, unfortunately.

Thanks


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Daniel
(@daniel)
Member Admin
Joined: 5 years ago
Posts: 722
09/01/2020 6:07 pm  

@asafsh

Dear asafsh,

Targeting glycolisis is good for all cancer and cells types that are visible on PET (most cases) and if that is done in an effective manner, it will at least slow down a lot cancer evolution. In addition, that will also reduce acidity around the tumors and in turn will make more effective chemo-therapies that are of weak-base type such as Doxorubicin.

I am sorry to hear that the oncologist speaks about 2-5 months, but based on personal experience with re-purposed drugs, supplements and intravenous treatments, we can go way beyond that.

If I can help with anything, please let me know.

Kind regards,
Daniel


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asafsh
(@asafsh)
Eminent Member
Joined: 5 months ago
Posts: 66
13/01/2020 2:44 pm  

@daniel

Thank you very much for your response and for invaluable information on this web site. 

Was busy with patient relocation and doctor visits these days.

I have tried to collect information from internet based on naive relationship guided extraction.

I apologise in advance for any possible mistakes due to my limited knowledge in medical field. 

We are going to visit physician this week and trying to prepare information for him about adjuvant treatment possibilities we can ask him to combine with standard chemo. Unfortunately this disease is very rare and most clinics do not posses systematic information on sarcoma treatment, yet there is no single sarcoma multidisciplinary center in Turkey similar to those in Europe and USA. 

Appreciate very much if you can share your opinions on below (if you have a time of course)

So here it is:

1. Biopsy genetic analysis findings from Foundation 1 lab report

Biomarker Findings Microsatellite status -MS-Stable
Tumor Mutational Burden TMB-Intermediate (6 Muts/Mb)
Genomic Findings HEY1 HEY1-NCOA2 fusion
PD-L1 IMMUNOHISTOCHEMISTRY (IHC) ANALYSIS (Dako 22C3 pharmDx™) Tumor Proportion Score (TPS) (%) 0

Conclusion: No therapies or clinical trials are associated with the Genomic Findings for
this sample.

2. Conventional treatment and clinical trials including mesenchymal chondrosarcoma

Information below is gathered from numerous articles from Pubmed and others online information sources (only few articles are mentioned here). Due to absence of knowledge in molecular biology/chemistry/medicine fields i can't validate them.

Summary and case studies on this disease states importance of surgical resection with wide margin and some benefits from chemo and radiotherapy. But unfortunately we failed to do so due to physician mistake.

Unlike other chondrosarcomas, mesenchymal chondrosarcoma respond to the chemotherapy:

"Advanced chondrosarcomas: role of chemotherapy and survival"

"Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma."

According to Outcome of First-Line Systemic Treatment for Unresectable Conventional, Dedifferentiated, Mesenchymal, and Clear Cell Chondrosarcoma
the best chemotherapy for the mesenchymal chondrosarcoma is VIDE (vincristine, ifosfamide, doxorubicin,etoposide) resulted in 37 months PFS.

For antiangiogenic therapy Clinical benefit of antiangiogenic therapy in advanced and metastatic chondrosarcoma Patient 7 (mesenchymal chondrosarcoma) achieved stable disease for 8 months by pazopanib.

Trabectedin. There were 2 or 3 trials of Trabectedin use on chondrosarcomas in Japan. In few places it was mentioned as effective for mesenchymal chondrosarcoma treatment. Though mixed stable disease or partial response figures were mentioned  (6 months, 15 months, 2 years).  Still i don't have clear clue on this drug, yet it might have serious side effects.

 

3. Lab research found through pubmed and other science online resources

- Literature is saying that mesenchymal chondrosarcoma is to be regarded as a different pathology compared to other chondrosarcomas.
- There is not much research done on mesenchymal chondrosarcoma. Most of them are in-vitro.
- The only cell line used in newest research is MCS170
- Another cell line for mesenchymal chondrosarcoma was used in older research (more than 20 years old) and it isn't mentioned in newer articles.

3.1 A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival
the MCS170 cell line showed moderate sensitivity to Volasertib. (experimental drug)

3.2 BCL-2 family
3.2.1 2013 Screening for Potential Targets for Therapy in Mesenchymal, Clear Cell, and Dedifferentiated Chondrosarcoma Reveals Bcl-2 Family Members and TGFb as Potential Targets
"In the present study, Bcl-2 expression was generally high in mesenchymal and clear cell chondrosarcoma, whereas Bcl-xl expression was high in dedifferentiated chondrosarcoma."

3.2.2 2016 "Inhibition of Bcl-2 family members sensitizes mesenchymal chondrosarcoma to conventional chemotherapy: report on a novel mesenchymal chondrosarcoma cell line
"The antiapoptotic proteins Bcl-2 and Bcl-xL were found to be highly expressed in chondrosarcoma, especially in the mesenchymal subtype" "Bcl-2 was expressed in MCS170 (Figure 3a) cells, although variable staining intensities were observed between different cells. Bcl-xl was highly expressed
in MCS170 cells (Figure 3c), however, only very weak Bcl-w expression was observed (Figure 3e)"

3.2.3 2018 "Bcl-xl as the most promising Bcl-2 family member in targeted treatment of chondrosarcoma"
If i interpret the information in this article correctly then BCL-2 expression for MCS170 cell line in figure 2 (A) isn't visible. I guess answer is in the 3.2.2 where it is mentioned that:
"Bcl-2 was expressed in MCS170 (Figure 3a) cells, although variable staining intensities were observed between different cells." "Unfortunately inhibition of Bcl-2 family members with the orally available
derivative of ABT-737, ABT-263 resulted in a high toxicity rate (most significantly thrombocytopenia) in lymphoid malignancies and solid tumors3."
afaiu ABT-263 is Navitoclax and there are couple of clinical trials going on this drug.

3.2.4 "A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress"
The drug used was ACDB - 2-allyloxy-4-chloro-N-(2-diethylaminoethyl)benzamide hydrochloride
The cell line used isn't mesenchymal chondrosarcoma. ACDB almost completely stopped tumor growth in mouse.

3.2.5 "Direct Binding of Bcl-2 Family Proteins by Quercetin Triggers Its Pro-Apoptotic Activity"
"It may be concluded that, quercetin binds directly to the BH3 domain of Bcl-2 and Bcl-xL proteins, thereby inhibiting their activity and promoting cancer cell apoptosis"
Can quercetin be a valid candidate for treatment?

3.3 "Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3"
"combination of MDM2 inhibition and cyclin D1 knockdown had greater anti-proliferative effects, compared to either intervention alone in ... a chondrosarcoma (MCS170)..."
Cell viability for MCS170 was around 40% after treatment with Nutlin-3 for 48 hours and infection with lentiviral CCND1 shRNA for 72 hours is presented on Figure 3.

3.4 "Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation"
Results for repurposed drugs are presented in this article for different cell lines including mesenchymal chondrosarcoma:
Table 1, IC50 :
CB-839 (μM) Metformin (mM) Phenformin (μM) Chloroquine (μM)
>50                  10.5                         294.7                       14.4

3.5 "Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A"

Article is not directly related to mesenchymal chondrosarcoma cell line. In-vivo mouse with chondrosarcoma SW1353 cell line treated with oxamate and doxorubicin almost stopped tumor growth after 50 days since treatment (Figure 7)

3.6 Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer
"Inhibition of key enzymes in glycolysis and glutaminolysis pathways with small molecules has provided a novel but emerging area of cancer research and has been proven effective in slowing the proliferation of cancer cells, with several inhibitors being in clinical trials."
Does this mean that approaches in 3.4 and 3.5 can be used synergisticaly for better treatment outcome?

3.7 Anti-cancer potential of a specific mixture of phytonutrients in chondrosarcoma SW-1358 cells 
Not directly related to mesenchymal chondrosarcoma. May it be relevant as supplement to main treatment?
Seems like the formulation mentioned in article is already used in commercial products.

3.8 "Paeonol Suppresses Chondrosarcoma Metastasis through Up-Regulation of miR-141 by Modulating PKCδ and c-Src Signaling Pathway"

4. Misc.

4.1 Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients
"Cytotoxicity of peripheral NK cells is impaired in STS patients but can be restored by ex vivo stimulation with IL-2" "We attempted to gain insight into the mechanisms that might cause the NK cells’ functional deficit, as this might reveal means of intervention that could help prevent the development of dysfunction or restore activity. Surgery has been described to cause NK cell dysfunction,50 but these effects were of limited
duration, with cytotoxic capacity returning to pre-surgery values after approximately 30 d.47 In our cohort of STS patients, blood samples were taken at least 4 weeks after surgery. Therefore, post-surgical effects seem unlikely as explanation of impaired NK cell-specific cytotoxicity"

4.2 Colloidal Silver
Going to order pair of 99.99 grade silver electrodes to produce it in-house.

Thank you very much 

p.s We have a friend in Germany who can help with drugs. 
p.s. Is it possible to share your email for matter not directly related to this thread?

 


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asafsh
(@asafsh)
Eminent Member
Joined: 5 months ago
Posts: 66
13/01/2020 2:49 pm  

I don't know whether we can benefit from whole body or local hyperthermia as literature is saying that tumor achieves thermotolerance after few treatments. In one of the articles on this subject mentions that no significant differences found between 2 and 6 hyperthermia treatment outcomes. 


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asafsh
(@asafsh)
Eminent Member
Joined: 5 months ago
Posts: 66
01/02/2020 4:37 am  

869 Successful aggressive chemotherapy in patients with chondrosarcoma: A report of four cases

The first p.t, a 35 ys. old female with a local recurrence and multiple lung metastases of a mesenchymal CS showed a CR of all detectable tumor manifestations after 6 cycles and is disease free for 14+ month. The second pt., a 28 ys. old male with multiple lung mets. of a CS is in continuous complete remission for 3+ month. Two additional patients with multiple lung mets. of a CS showed a stable disease for 13 and 3 months respectively after completion of 4 cycles. Both patients were put on oral chemotherapy with trofosfamide and are still under treatment.

 


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asafsh
(@asafsh)
Eminent Member
Joined: 5 months ago
Posts: 66
05/02/2020 3:29 am  

Effect of a nutrient mixture on matrix metalloproteinase-9 dimers in various human cancer cell lines
https://www.spandidos-publications.com/ijo/44/3/986

Strong clinical and experimental evidence demonstrates association of elevated levels of matrix metalloproteinase MMP-9 with cancer progression, metastasis and shortened patient survival, as it plays a key role in tumor cell invasion and metastasis by digesting the basement membrane and ECM components.

Our objective was to study the relative secretion patterns of MMP-9 monomer and dimer in a variety of cancer cell lines and the effect of a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract on MMP-9 secretion.

Chondrosarcoma SW-1353 MMP-9 and dimer secretion
Untreated chondrosarcoma cell line SW-1353 showed moderate MMP-9 and no MMP-9 dimer secretion. PMA (100 ng/ml) strongly induced MMP-9 and MMP-9 dimer, as shown in Fig. 4.

NM inhibited the secretion of both in a dose-dependent manner with total block of MMP-9 dimer at 250 μg/ml (linear trend R2=0.843) and MMP-9 at 500 μg/ml (linear trend R2=0.729). Secretion of MMP-9 dimer was found to be 25% that of MMP-9.


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