Showing posts with label melanoma. Show all posts
Showing posts with label melanoma. Show all posts

Friday, April 19, 2013

Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor

*T-cell therapy, that is genetically engineered T-cells, is a valid modality of cancer treatment.  Porter et al updated their finding at the ASH describing response rate in refractory CLL and ALL.  Patients were given a lentiviral vector that expressed a chimeric antigen receptor "with specificity for the B cell Antigen CD19 paired with CD137 and CD3-zeta." (hemonc today) some of the reported results where positively dramatic.
The experience with MAGE 11 for treatment refractory melanoma did not go so well.

Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor 

What you pick to attack should not be in the brain (attack to the brain by T cell is likely), and involving a "crazy gene" the like of Androgen Receptor will have many unexpected consequences.  patient died with coma and seizures!   T-cell tissue penetration is bound to occur because it is what T cell do so your task is to pick the receptor carefully!

and don't go out there and pick p300, a potent and ubiquitous transcriptional regulator, because it is Ubiquitous!  Tissue specificity as done above in Hematologic malignancies would be more appropriate!


Infusion of Autologous dendritic cell Immunotherapy  (AGS-003) given with SUNITINIB extended survival in Metastatic Renal cell cancer!   Think Immunotherapy when the going get tough we told recently... congrats to NC researcher to have proven the point!   Follow this principle in tough Myeloma cases.  May be drendritic cell infusion will work in Myeloma!

Wednesday, February 27, 2013



1.   In Breast cancer


2.   In Prostate  cancer

-Abiraterone (Zytiga)
-Enzalutmide (Xtandi)
-Alpharadin (Radium 223)

3.   Other

4.   Melanoma

-GDC- 0973
-Vemurafenib (Zelboraf)

5.   Lung cancers

- Selumetinib

5.   Thyroid cancer


Friday, February 22, 2013


Based on what we know now, it is easy to see that in those diseases where Avastin has failed FDA approval, Anti-MEK will do better.  MEK is down stream and MEK is involved in much more, including VEGF expression.  MEK is part of the MEK/MAPK pathways, it is the door to Mesenchymal transformation (that is it the door to epithelial-mesenchymal transition), and therefore to angiogenesis, and to metastatic spread.
Anti-MEK also removes the negative inhibitory effect of the PTEN driven forces of the PI3K/MTOR pathways.

PTEN inhibits insulin-stimulated MEK/MAPK activation andcell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model

Watch it now as Cabozantinib, Selumtinib, and Trametinib will rise in anything Avastin has touched.
Metastatic Colon Cancer is the Primary target!

Only the MTOR inhibitors add to these drugs

Inability of Doxorubicin to add to DTIC in Melanoma is due to amplification of these 2 pathways.

Anti-MEK and MTOR combination will do far better in Melanoma and Pancreatic cancers, mark my words.  We just need to brace ourselves to a new set of side effects.

Monday, January 14, 2013

Lack of Clear Evidence for Sentinel Node Biopsy in Melanoma?

Roxanne Nelson
Jan 11, 2013
Sentinel lymph node (SLN) biopsy has become a common procedure in melanoma and has been endorsed by professional guidelines. It is considered to be a minimally invasive and highly accurate procedure that allows for appropriate regional nodal staging and identification of patients without nodal metastases.
However, in a feature published online January 8 in BMJ, freelance journalist Ingrid Torjesen, from London, United Kingdom, describes SLN biopsy as an "expensive and invasive procedure" and reports that thousands of melanoma patients around the world are having it done despite a lack of clear evidence that it will improve outcomes.
She focuses on the Multicenter Selective Lymphadenectomy Trial (MSLT-I), which was designed to determine the ability of SLN biopsy to identify patients with clinically occult nodal metastases and to evaluate the effectiveness of immediate completion lymph node dissection (CLND) in patients with positive SLNs.
The 5-year follow-up of the MSLT-I, published in 2006 ( N Engl J Med. 2006;355:1307-1317), failed to show a survival advantage from SLN biopsy. However, it did confirm that SLN biopsy was highly accurate in identifying positive nodes in patients with melanomas 1.2 to 3.5 mm thick, and that SLN biopsy followed by CLND was associated with prolonged disease-free survival.
In addition, clinically node-negative patients with SLN metastases who underwent CLND had significantly better melanoma-specific 5-year survival rates than those who had delayed CLND for clinically detected nodal relapse.
SLN biopsy is now commonly used in Australia, Canada, the United States, and Western Europe, but is not routinely used in the United Kingdom.
A guideline issued jointly by the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SOS) recommends SLN biopsy for patients with melanomas of intermediate thickness. The procedure has also been endorsed by the American Joint Committee on Cancer as a valuable staging procedure for those at risk of developing clinically occult nodal metastases.
Why No Interim Results?
In her report, Torjesen states that the results of the MSLT-I were controversial, and that critics said it was not surprising "to see an improved disease-free survival in the biopsy arm [because] patients whose disease was most likely to progress had had their regional nodes removed."
She notes that the fourth interim analysis of the MSLT-I data (showing 7-year follow-up data), which was expected in 2008, and the fifth and final analysis (with 10-year data), expected in 2011, will settle the question once and for all.
So why haven't they been published, Torjesen asks.
"A minimum of 10 years of follow-up is required to see the full benefit of the technique," said Alistair Cochran, MD, MB ChB, distinguished professor of pathology, laboratory medicine, and surgery at the University of California Los Angeles School of Medicine.
"The 10-year data have been analyzed and are being prepared for submission, hopefully within the next month or so," Dr. Cochran told Medscape Medical News.
Dr. Cochran was involved in developing the technique, is a coauthor of the ASCO/SOS guidelines, and has worked with Donald Morton, MD, lead author of the MSLT-I.
Sandra Wong, MD, associate professor of surgery at the University of Michigan Health Systems in Ann Arbor, and lead author of the ASCO/SOS guidelines, agrees. "In a lot of studies, the follow-up time just isn't long enough," she told Medscape Medical News. "Melanoma is not like a lot of other cancers, where you start seeing recurrences within the first 2 years. I have patients who are a decade out and they are having a recurrence. It's just a very different disease process," she explained.
Lacking Balance
Dr. Cochran pointed out that Torjesen relies heavily on comments from J. Meiron Thomas, MS, FRCP, FRCS, who is a consultant surgeon at the Royal Marsden Hospital London and chair of surgical oncology at Imperial College, London, United Kingdom.
Dr. Thomas has been very vocal in his criticism of SLN biopsy and has published maybe 15 or 16 papers on the subject, Dr. Cochran explained. "This is a picture of a tennis match.... We publish something and then Dr. Thomas prints a rebuttal. We have eventually left him to it and figured time will tell," he noted.
"I don't know if bias is the right word, but the paper seems to only represent 1 side of the debate," said Dr. Wong. "That side is a very minority opinion, and Dr. Thomas is a vocal critic," she added.
Dr. Wong noted that when "we try to set up debates at national meetings, we can never get anyone to take the con side. Not even a 'soft' con."
This report is not offering any new information or insight, said Daniel Coit, MD, a surgical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. It "is really just a rehash of arguments and commentaries that have been made for quite some time," he explained.
Dr. Coit emphasized Donald Morton, who introduced the technique and who has, so to speak, the biggest stake in it "is the one person who has done more than anyone else to critically evaluate the technique, with these 2 large randomized prospective trials.... While there are many critics — and Steve Rosenberg [mentioned in the report] and Meiron Thomas have an absolute right to interpret the data of others — neither has actually created any data of their own to contribute to this," he explained.
"It is very easy to take pot shots, but very hard to create new data," Dr. Coit added. "And Don Morton has created a wealth of data."
All of the arguments made in the report are cogent. "This is not a procedure that affects survival, it is a procedure that provides important prognostic information," he noted.
"As a society, we have to decide if we want to pay for it, just as we decide if we are going to pay for CT scans or PET scans," Dr. Coit added.
Professional Advancement and Company Profits?
Torjesen implies that the uptake of SLN biopsy has been largely driven by professional advancement and commercial profit. She states that "whole professional careers and businesses have been built on sentinel node biopsy for melanoma. Professional pride and company profits are now at stake."
Dr. Cochran explained that it is highly doubtful that the use of SLN biopsy has been endorsed simply to advance careers or to generate profit. "I don't think that the popularity of the technique can be put down to the commercialization," he said. "I'm sure that there is some money to be made, but nothing like the money that can be made by pharmaceutical companies from some of their new drugs."
Dr. Wong agrees that there is some cost associated with the procedure, but it is not very expensive overall and not a huge profit maker. "It's not like chemotherapy or using excessive imaging," she noted.
"If you're really cynical, you can say that if melanoma surgeons stopped doing this, they would lose a large part of their practice," she added. "But that's cynical because this is a procedure that can help overall survival or help make an accurate diagnosis," she said.
Harms of Overtreatment
Torjesen raises concerns about overtreatment in her report. "It is generally accepted that only 20% of patients who have sentinel node biopsy will have positive sentinel nodes, and only 20% of those will have metastatic disease in the nonsentinel nodes," she states. "Therefore, 96% of patients who have sentinel node biopsy will have unnecessary surgery," she writes.
Dr. Cochran agrees that the prophylactic removal of lymph nodes can cause serious morbidity, but pointed out that some people can be saved by it. "The other alternative is to watch and wait, but we've found that the number of involved lymph nodes in patients who have been observed is about 3 times as high as those treated with sentinel node biopsy," he said. "We know that with time, the disease progresses. I think most physicians are uncomfortable with letting things be and letting nature take its course," he explained.
Dr. Cochran added that at some point it will be possible to tell which patients with a positive SLN have metastatic disease, "but we are not there yet."
It is hoped that the follow-up MSLT-II will answer some of those questions. That study is also being run by Dr. Morton, and will evaluate the potential benefits of regional lymphadenectomy for melanoma patients with positive sentinel nodes.
The MSLT-II will establish whether "every patient with a positive SLN needs a full dissection," said Dr. Wong.
If lymph node surgery in melanoma is ultimately scaled back, it would not be without precedent. In recent years, surgical oncologists have learned that not all women with positive sentinel axillary lymph nodes need completion dissection. The Z0011 trial, conducted by the American College of Surgeons Oncology Group, showed that women with minimal lymph node involvement did not suffer from inferior survival when they only underwent sentinel node biopsy and did not undergo completion dissection.
In addition, new agents have been shown to be very effective in metastatic disease; that's why the staging is so important, Dr. Wong explained. "You may have a patient who walks in with a stage I melanoma clinically, but may actually be a stage III once we do the procedure. If we lose these data, we won't know which patients will benefit from these new treatments," she noted.
In general, the jury is still out as far as SLN biopsy goes. "But everyone is doing it, and I don't think there is too much debate," Dr. Wong said. "It is hard to tell a patient that you don't want to do it if they are in the 1 to 4 mm stage. They want to know."
Dr. Coit agrees. "I don't think any clinicians regularly using this procedure propose it to patients as anything other than a method that will provide more information on how likely melanoma is to occur," he said.
The main question right now is which patients are least likely to benefit from the procedure, he added. "We are taking a long hard look at who this prognostic information will likely help, this procedure will help, but also who it will not be of benefit to."
Medscape Medical News requested a comment on this report from BMJ, but had not received a response by press time.
BMJ. 2013;346:e8645. Full text

Sunday, November 18, 2012

Quantia / Brain tumors and methylated C-MET

Nice presentation on Quantia. They presented a case of a "disruptive Doctor" who was reported by staff as being "late", "not responsive to call" and "being rude to staff". Pretty much led me to agree with them. But through due process, heard the Dr's response to these accusations, I was able to give him some slack and another chance. Often we rush to condemnation without knowledge of other people's values and perspective. The key to finding the truth is due diligence! The lack of institutional due diligence led to misconstruction and mistakes!
We also attended a talk on Brain tumor, one of the resistant cancers, about importance of finding methylated C-MET as it gives a positive prognosis, responsiveness to treatment, and high pseudo-progression rate on MRI. This all is relevant to our Targeting therapy. An interesting observation to make is that, in cancers that are resistant, the response rate is consistently hovering around 15-30%. This is seen with Avastin in Brain cancers and Ipilimumab in Melanoma. This is pointing to the fact that we still have not reached the main target to apoptosis, or that we need sequential additional hits, or have not closed a loophole! We need to go back to the drawing board!