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Wednesday, June 5, 2013
FROM PRACTICE UPDATE, ASCO NEWS
Tuesday, June 4, 2013
HUGE NEWS FROM MEDSCAPE! PRACTICE CHANGING! IN ALL FAIRNESS GO TO MEDSCAPE FOR A FULL REPORT!
This coverage is not sanctioned by, nor a part of, the American Society of Clinical Oncology.
CHICAGO, Illinois — The common practice of
administering intravenous calcium and magnesium along with oxaliplatin
to reduce the side effect of neuropathy should be stopped, experts
say.
The first placebo-randomized phase 3 trial of this practice has shown no benefit. The results were presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®) by Charles Loprinzi, MD, from the Mayo Clinic in Rochester, Minnesota.
The trial was conducted in 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (5-fluorouracil, oxaliplatin, and leucovorin), who were randomized to receive intravenous CaMg (1g calcium gluconate, 1 mg magnesium sulfate) or placebo before and after oxaliplatin. There was also a third arm in the trial, in which patients received CaMg before and placebo after the oxaliplatin.
The results showed no differences between the groups in either acute neurotoxicity or cumulative sensory neurotoxicity, as assessed both by patient and physician questionnaires."
"Medscape Medical News from the:
Stop Using Calcium and Magnesium With Oxaliplatin
The first placebo-randomized phase 3 trial of this practice has shown no benefit. The results were presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®) by Charles Loprinzi, MD, from the Mayo Clinic in Rochester, Minnesota.
The trial was conducted in 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (5-fluorouracil, oxaliplatin, and leucovorin), who were randomized to receive intravenous CaMg (1g calcium gluconate, 1 mg magnesium sulfate) or placebo before and after oxaliplatin. There was also a third arm in the trial, in which patients received CaMg before and placebo after the oxaliplatin.
The results showed no differences between the groups in either acute neurotoxicity or cumulative sensory neurotoxicity, as assessed both by patient and physician questionnaires."
EVIDENCES MOUNT THAT UNIVERSITIES ARE COMING TOGETHER TO TAKE ALL THE MONEY FOR CANCER RESEARCH
READ FOR YOUR SELF!
BIG CANCER RESEARCH CONSORTIUM (from ONCOLOGY TIMES)
READ FOR YOUR SELF!
BIG CANCER RESEARCH CONSORTIUM (from ONCOLOGY TIMES)
CHICAGO
– In a new venture, 11 university-based matrix cancer centers are
uniting “to transform cancer research through collaborative oncology
trials that leverage the scientific and clinical expertise of the Big
Ten universities.”
The
consortium will allow universities with similar missions, visions, and
cultures to create a regional cancer team science initiative to advance
research by sharing resources and strengths to form what is hoped will
be a lean, efficient, and collaborative effort that will focus on Phase 0
to II clinical trials accruing patients with specific diseases and
molecular characteristics.
The
news releases sent out on Friday by the individual institutions all had
the same information but included no clear direction as to who was the
designated point person or spokesperson, which was perhaps in deference
to the consortium’s sensitivity to having any one institution overshadow
the others.
However,
the mention toward the end of the release that the Indianapolis-based
Hoosier Oncology Group (HOG) would serve as the administrative
headquarters for the Big Ten Cancer Research Consortium (BTCRC) provided
a clue that Indiana University’s Melvin and Bren Simon Cancer Center
might be a good place to start.
It
was, and since the official kickoff of the initiative was slated for
June 1 during the time of the American Society of Clinical Oncology’s
Annual Meeting in Chicago, I met with Simon Cancer Center Director
Patrick J. Loehrer Sr., MD. He explained that part of the impetus for
the initiative was related to helping save the “endangered species of
assistant professors,” who under current circumstances might have to
wait for years to lead a clinical trial through the cooperative group
mechanism.
“I
remember when I had finished my medical oncology fellowship at Indiana
and was a newly minted medical oncologist eager to get involved in
clinical trials,” he said, adding that he was dismayed by the limited
opportunities.
In
1984, following discussions with Larry Einhorn, MD, and others at
Indiana, Loehrer helped establish the Hoosier Oncology Group, aka, the
HOG, as it is affectionately called by proud citizens of the Hoosier
State, which was modeled to involve more community oncologists in
clinical trials.
He
said there was originally some resistance from oncologists concerned
about losing patients to academic cancer centers, but that the HOG was
designed so patients could be treated the same way in their hometowns.
According
to Loehrer, every HOG study had co-chairs from both the community and
academic centers, and community oncologists were selected to deliver
ASCO presentations.
“These were non-NCI funded trials and community oncologists got involved in the whole process. It
was wonderful,” he said, adding that over subsequent years it became
more difficult to secure industry funding for clinical trials, and that
BTCRC studies will need at least three institutions involved, with one
of the principal investigators being a junior faculty member.
So
when Steven T. Rosen, MD, Director of the Robert H. Lurie Comprehensive
Cancer Center at Northwestern University, suggested in 2011 using the
Big Ten’s athletic conference model to bring cancer centers together,
the idea resonated with Loehrer and other cancer center directors.
Within
a few months the HOG was selected as BTCRC administrative headquarters
and by July 2012, 10 cancer centers were committed to participating in
the consortium (with an 11th joining later), and a steering committee
was formed. Noah Hahn, MD, Associate Professor of Medicine at Indiana
University’s Simon Cancer Center and Chief Medical and Scientific
Officer with HOG, was named interim Executive Officer of the Big Ten
cancer consortium.
HOG,
Loehrer said, will serve strictly in a contract research organization
(CRO) capacity, providing comprehensive study management and support,
and benefits for consortium members including:
- A single, common contract for all institutions;
- A planned streamlined IRB review consolidation;
- Organized clinical trial working groups;
- Sharing specimens with clinically annotated data;
- Development of junior faculty; and
- The opportunity to open trials faster among member institutions.
The venture will also be limited to members of the Big Ten, Loehrer said, and currently includes:
• Indiana University (Indiana University Melvin and Bren Simon Cancer Center);
• Northwestern University (Robert H. Lurie Comprehensive Cancer Center);
• Penn State University (Penn State Hershey Cancer Institute);
• Purdue University (Purdue University Center for Cancer Research;
• Rutgers
University (the Cancer Institute of New Jersey becomes part of Rutgers
on July 1, but Rutgers doesn’t officially join the Big Ten athletic
conference until next year);
• University of Illinois (University of Illinois Cancer Center) ;
• University of Iowa (Holden Comprehensive Cancer Center);
• University of Michigan (University of Michigan Comprehensive Cancer Center);
• University of Minnesota (Masonic Cancer Center);
• University of Nebraska (Fred & Pamela Buffett Cancer Center); and
• University of Wisconsin (Carbone Comprehensive Cancer Center).
When
I first saw the list, Ohio State University’s James Cancer Hospital and
Solove Research Institute seemed conspicuous by its absence. I called
center head Michael A. Caligiuri, MD (a member of OT’s Editorial
Board), who said that OSU had been asked to join, but was “currently
involved in another endeavor that precludes participating at this time.”
He did not disclose the nature of that endeavor.
Cross-referencing
the cancer Big Ten with its athletic counterpart, I also noticed the
absence of Michigan State University’s Breslin Cancer Center, and noted
that the University of Maryland was slated to join the athletic
conference in 2014 at the same time as Rutgers, but its Greenebaum
Cancer Center was not yet on the list.
Loehrer
said that all Big Ten members current and future had been asked to join
the cancer consortium and the 11 institutions listed above had
committed to joining, with each agreeing to pay $14,000 a year over a
proposed three-year period to cover infrastructure costs. He also
acknowledged that this was a work in progress and that more specific
directions would be developed over time.
At
the June 1 kick-off event I spoke with Chandra Belani, MD, who
represents Penn State University’s Hershey Cancer Institute on the BTCRC
steering committee. Belani shared Loehrer’s excitement about the
consortium, and the prospect of developing more early phase trials that
would also help train the next generation of physician-scientists.
He
also talked about the idea of using the Big Ten’s athletic
infrastructure to increase awareness about cancer research and clinical
trials and the potential of raising funds through small contributions by
the thousands of fans attending Big Ten sporting events.
This
model, similar to Stand Up To Cancer’s relationship with Major League
Baseball, may prove an additional avenue to provide outreach and
awareness about cancer research and clinical trials to yet another major
grassroots demographic group.
========================================================
YOU GOT IT RIGHT, YOU PAY $14,000 TO "I DON'T KNOW WHO" AND GET ADMITTED TO THIS CLOSE LEAGUE, WHERE IS THE SUPREME COURT ON THIS! AND WE KNOW WHAT HAPPENED IN TEXAS WITH CPRIT! IF YOU DON'T GET IT, WELL YOU DON'T GET IT!
RANDOM NEWS/THE SUPREME COURT IS NOW INVOLVED WITH YOUR GENES!
*ONARTUZUMAB (METMAb) is being USED NOW IN MET positive lung cancer in combination with Erlotinib in a GENENTECH supported trial, cal to register patients 888-662-6728.
*What makes prostate cancer cell so suited to proliferate in the bone environment? Bone metastasis is the primary site of metastasis in prostate cancer and it has been reported that mortality is 5 times as likely in those with Bone Metastatsis! so this is the single most important event that leads to patient's death. It is a critical issue to address!
*Tivozanib has failed drastically to cross the first hurdle (ODAC) and no one believes it will win approval of the FDA on July 28. will wait and see!
*THE SUPREME COURT HEARD ORAL ARGUMENT ABOUT WHETHER OR NOT GENES COULD BE PATENTED! SOON OR LATER, YOU MAY NOT BE ABLE TO LOOK AT YOUR OWN GENES WITHOUT PAYING A FEE TO A COMPANY! THAT'S HOW UGLY THIS WILL GET!
LET SEE YOU COME TO ME WITH LUNG CANCER, AND I WANT TO CHECK YOUR ROS-1 BUT I CAN'T BECAUSE SEE ROS-1 HAS BEEN PATENTED BY COMPANY X, WE NEED SOME FORM OF CLEARANCE BY A THIRD PARTY BECAUSE THEY HAVE A PATENT ON THAT GENE! CRAZY DOES NOT SEEM TO EVEN BEGIN TO DESCRIBE THE WORLD OF LEGALESE!
*ONARTUZUMAB (METMAb) is being USED NOW IN MET positive lung cancer in combination with Erlotinib in a GENENTECH supported trial, cal to register patients 888-662-6728.
*What makes prostate cancer cell so suited to proliferate in the bone environment? Bone metastasis is the primary site of metastasis in prostate cancer and it has been reported that mortality is 5 times as likely in those with Bone Metastatsis! so this is the single most important event that leads to patient's death. It is a critical issue to address!
*Tivozanib has failed drastically to cross the first hurdle (ODAC) and no one believes it will win approval of the FDA on July 28. will wait and see!
*THE SUPREME COURT HEARD ORAL ARGUMENT ABOUT WHETHER OR NOT GENES COULD BE PATENTED! SOON OR LATER, YOU MAY NOT BE ABLE TO LOOK AT YOUR OWN GENES WITHOUT PAYING A FEE TO A COMPANY! THAT'S HOW UGLY THIS WILL GET!
LET SEE YOU COME TO ME WITH LUNG CANCER, AND I WANT TO CHECK YOUR ROS-1 BUT I CAN'T BECAUSE SEE ROS-1 HAS BEEN PATENTED BY COMPANY X, WE NEED SOME FORM OF CLEARANCE BY A THIRD PARTY BECAUSE THEY HAVE A PATENT ON THAT GENE! CRAZY DOES NOT SEEM TO EVEN BEGIN TO DESCRIBE THE WORLD OF LEGALESE!
Monday, June 3, 2013
NEWS FROM ASCO
*Avastin added to progression free and overall survival achieved by chemotherapy in cervical cancers in recurrent and metastatic settings (17 Vs 13.3 months). But it did fail to improve anything in Glioblastoma when given in first line ,
*Sorafenib (NEXAVAR)Showed Benefit in Radioactive Iodine-Refractory Differentiated Thyroid Cancer, as reported by Medical News Today,
"The researchers reported that:
*Extending Tamoxifen to 10years is better than 5 years
ASCO News:
"
Compared with 5 years of tamoxifen, a 10-year regimen was associated with a significant 15% reduction in the risk of recurrence (relative risk, 0.85; p = 0.003) and a significant 25% reduction in the risk of breast cancer mortality starting at year 10 (relative risk, 0.75; p = 0.007). These findings aligned closely with those from the recently published ATLAS trial."
*Avastin added to progression free and overall survival achieved by chemotherapy in cervical cancers in recurrent and metastatic settings (17 Vs 13.3 months). But it did fail to improve anything in Glioblastoma when given in first line ,
*Sorafenib (NEXAVAR)Showed Benefit in Radioactive Iodine-Refractory Differentiated Thyroid Cancer, as reported by Medical News Today,
"The researchers reported that:
- 12% of the sorafenib patients experienced tumor shrinkage
- 0.5% of those on placebo experienced tumor shrinkage
- 42% of patients in the sorafenib group had stable disease after 6 months
- 33% of patients in the placebo group had stable disease after 6 months
- PFS (progression-free survival) in the sorafenib arm was 10.8 months
- PFS among the placebo patients was 5.8 months
- In this cross-over trial, 70% of the placebo patients switched over to sorafenib"
*Extending Tamoxifen to 10years is better than 5 years
ASCO News:
"
Compared with 5 years of tamoxifen, a 10-year regimen was associated with a significant 15% reduction in the risk of recurrence (relative risk, 0.85; p = 0.003) and a significant 25% reduction in the risk of breast cancer mortality starting at year 10 (relative risk, 0.75; p = 0.007). These findings aligned closely with those from the recently published ATLAS trial."
Known Targets in Sarcoma and various malignancies!
*"In addition, variations in CD44 are reported as cell surface markers for some breast and prostate cancer stem cells.In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics.[15] and has been seen as an indicator of increased survival time in epithelial ovarian cancer patients.[16]
Endometrial cells in women with endometriosis demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells.[17]
CD44 variant isoforms are also relevant to the progression of head and neck squamous cell carcinoma.[18][19]
Monoclonal antibodies against CD44 variants include bivatuzumab for v6." wikipedia
*
-----------------------------------------------------------------------------------------------------------
TEC Very significant target because down the stream of this gene is DOK1,and most impressively ARHGEF which has activity with 2 well recognised therapeutic targets CD44 and P110 alpha, remember P110alpha deficiency can induce Malformation (Macrocephaly) and you know how we feel about gene inducing malformation
" non-receptor protein-tyrosine kinases containing a pleckstrin homology domain. Tec family kinases are involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein coupled receptors, and integrin molecules. They are also key players in the regulation of the immune functions. Tec kinase is an integral component of T cell signaling and has a distinct role in T cell activation. This gene may be associated with myelodysplastic syndrome.[2]wikipedia
Anti CD44 has just been used in a recent publication
adding a booster of c-AMP may intensify the effect (PRKAR1A related).
*"In addition, variations in CD44 are reported as cell surface markers for some breast and prostate cancer stem cells.In breast cancer research CD44+/CD24- expression is commonly used as a marker for breast CSCs and is used to sort breast cancer cells into a population enriched in cells with stem-like characteristics.[15] and has been seen as an indicator of increased survival time in epithelial ovarian cancer patients.[16]
Endometrial cells in women with endometriosis demonstrate increased expression of splice variants of CD44, and increased adherence to peritoneal cells.[17]
CD44 variant isoforms are also relevant to the progression of head and neck squamous cell carcinoma.[18][19]
Monoclonal antibodies against CD44 variants include bivatuzumab for v6." wikipedia
*
-----------------------------------------------------------------------------------------------------------
TEC Very significant target because down the stream of this gene is DOK1,and most impressively ARHGEF which has activity with 2 well recognised therapeutic targets CD44 and P110 alpha, remember P110alpha deficiency can induce Malformation (Macrocephaly) and you know how we feel about gene inducing malformation
" non-receptor protein-tyrosine kinases containing a pleckstrin homology domain. Tec family kinases are involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein coupled receptors, and integrin molecules. They are also key players in the regulation of the immune functions. Tec kinase is an integral component of T cell signaling and has a distinct role in T cell activation. This gene may be associated with myelodysplastic syndrome.[2]wikipedia
Anti CD44 has just been used in a recent publication
adding a booster of c-AMP may intensify the effect (PRKAR1A related).
Sunday, June 2, 2013
GENES IN SARCOMA (LISTED FIRST AND THEN WE GO TO WORK!)
THE C-KIT CASE
ACTIVATES THE FOLLOWING GENES
PIK3R1
PLCG1
SH2B2/APS
CBL
THE POTENT GRB2
RAS/MAPK
PTPN6/SHP1
PTPRU
CRK
LYN
SRC
SHC1
DOK1
-----------------------------------------------------------------------------------------------------------
TEC Very significant target because down the stream of this gene is DOK1,and most impressively ARHGEF which has activity with 2 well recognised therapeutic targets CD44 and P110 alpha, remember P110alpha deficiency can induce Malformation (Macrocephaly) and you know how we feel about gene inducing malformation
" non-receptor protein-tyrosine kinases containing a pleckstrin homology domain. Tec family kinases are involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein coupled receptors, and integrin molecules. They are also key players in the regulation of the immune functions. Tec kinase is an integral component of T cell signaling and has a distinct role in T cell activation. This gene may be associated with myelodysplastic syndrome.[2]wikipedia
Anti CD44 has just been used in a recent publication
adding a booster of c-AMP may intensify the effect (PRKAR1A related)
-----------------------------------------------------------------------------------------------------------
PREDISPOSING GENES
NF1
LI-FRAUMENI
HELICASE GENES
P53
CYTOKINES/KITLG/SCF
SPECIFIC GENES FOR SOME SPECIFIC SARCOMA
1.GIST C-KIT, CD 117, PDGFR-ALPHA
2.ALVEOLAR RHABDOMYOSARCOMA PAX3-FOXO1A
3.EWING SARCOMA EWSR1-FLI1 AND EWSR-ERG
4.LIPOSARCOMA CDK4,HDM2
5.SYNOVIAL SYT-SSX1,2
6.MYXOID FUS-CHOP DDIT3
THE C-KIT CASE
ACTIVATES THE FOLLOWING GENES
PIK3R1
PLCG1
SH2B2/APS
CBL
THE POTENT GRB2
RAS/MAPK
PTPN6/SHP1
PTPRU
CRK
LYN
SRC
SHC1
DOK1
-----------------------------------------------------------------------------------------------------------
TEC Very significant target because down the stream of this gene is DOK1,and most impressively ARHGEF which has activity with 2 well recognised therapeutic targets CD44 and P110 alpha, remember P110alpha deficiency can induce Malformation (Macrocephaly) and you know how we feel about gene inducing malformation
" non-receptor protein-tyrosine kinases containing a pleckstrin homology domain. Tec family kinases are involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein coupled receptors, and integrin molecules. They are also key players in the regulation of the immune functions. Tec kinase is an integral component of T cell signaling and has a distinct role in T cell activation. This gene may be associated with myelodysplastic syndrome.[2]wikipedia
Anti CD44 has just been used in a recent publication
adding a booster of c-AMP may intensify the effect (PRKAR1A related)
-----------------------------------------------------------------------------------------------------------
PREDISPOSING GENES
NF1
LI-FRAUMENI
HELICASE GENES
P53
CYTOKINES/KITLG/SCF
SPECIFIC GENES FOR SOME SPECIFIC SARCOMA
1.GIST C-KIT, CD 117, PDGFR-ALPHA
2.ALVEOLAR RHABDOMYOSARCOMA PAX3-FOXO1A
3.EWING SARCOMA EWSR1-FLI1 AND EWSR-ERG
4.LIPOSARCOMA CDK4,HDM2
5.SYNOVIAL SYT-SSX1,2
6.MYXOID FUS-CHOP DDIT3
Medscape Medical News from the:
Sorafenib Potent New Tx for Advanced Thyroid Cancer
Topic Alert
Receive an email from Medscape whenever new articles on this topic are available.
Drug & Reference Information
CHICAGO — The targeted agent sorafenib (Nexavar,
Bayer HealthCare Pharmaceuticals) could become the first new drug for
metastatic thyroid cancer in 40 years and opens up a new field in
medical oncology, says the lead author of a study presented here at a
plenary session of the 2013 Annual Meeting of the American Society of
Clinical Oncology.
"Up until now, patients in this population haven't even come to medical oncology because there wasn't any treatment for them," commented Marcia Brose, MD, PhD, an assistant professor of otolaryngology and head and neck surgery in the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
She explained that this is really the beginning of a new field in medical oncology. Previously, thyroid cancer was generally treated by endocrinologists because medical oncology had no effective treatments once a patient became resistant to radioactive iodine.
Thyroid cancer has a reputation of being a "good cancer" because it can be easily cured, Dr. Brose explained. "But that's only for 90% of the patients, and for the other 10%, it will kill them eventually. Once surgery can no longer be used and the tumor no longer takes up radioactive, overall survival drops to about 2 and a half to 3 years."
"It is now important for the doctors who see these patients early on to refer them to medical oncologists, because now we have a treatment," said Dr. Brose. "For medical oncologists, it is important for them to know that we now have a treatment, and hopefully our data will lead to FDA approval."
Dr. Brose presented results from a phase 3 clinical trial, known as DECISION, in 417 patients with progressive RAI-refractory differentiated thyroid cancer. The results show a significant improvement in median progression-free survival to 10.8 months in the sorafenib group compared with 5.8 months in the placebo arm.
Sorafenib has been used off label for this purpose, Dr. Brose noted, but some physicians are not comfortable prescribing off label. "But the added level of rigor from a pivotal phase 3 study that is not just positive but highly significant — a doubling of progression-free survival — will hopefully help more physicians feel comfortable prescribing it," she said.
Chemotherapy Not Effective
"Conventional cytotoxic chemotherapy has not been effective in the management of differentiated thyroid cancers in spite of significant toxicities," commented Yujie Zhao, MD, PhD, assistant professor of oncology, Roswell Park Cancer Institute, Buffalo, New York.
"This randomized, placebo-controlled phase 3 study confirmed previous phase 2 results and also demonstrated a statistically significant progression-free survival improvement of 5 months compared with the placebo arm," said Dr. Zhao, who was not involved in the study.
Dr. Zhao noted that because stable disease of 6 months or longer was also seen in 33% of patients who received placebo, this suggests the importance of proper selection of patients who need treatment.
Sorafenib blocks the enzyme RAF kinase, which is a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation, and it also inhibits the VEGFR-2/PDGFR-beta signaling cascade. It is currently approved to treat hepatocellular carcinoma and advanced renal cell carcinoma.
The primary endpoint of the study was progression-free survival, which was assessed every 8 weeks. Secondary endpoints included overall survival, response rate (complete and partial response), and drug safety.
Within the cohort, tumor histology was 57% papillary, 25% follicular, and 10% poorly differentiated, and the vast majority (96%) of patients had metastatic disease. The most common target lesions were lung (71%), lymph node (40%), and bone (14%).
The authors note that their primary endpoint of progression-free survival was met (hazard ratio, 0.58; P < .0001). The median overall survival has not yet been reached in either study arm, and 70% of placebo patients have started open-label sorafenib.
All reported responses were partial — 12.2% in the sorafenib group vs 0.5% for placebo (P < .0001). Stable disease ≥ 6 months was 42% and 33%, respectively.
Tolerability was consistent with the known sorafenib safety profile, the authors note. The most common any-grade treatment-emergent adverse events in the sorafenib arm included hand–foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension. There was 1 death in each study arm that was attributed to sorafenib use.
For Select Patients
"There is a huge unmet need for an effective treatment in this population," said Lori Wirth, MD, who was approached by Medscape Medical News for an independent commentary. "While this is a relatively uncommon disease, patients do live for years with it, so there is a sizeable population in need of treatment."
"This was a positive study, and I believe that it will be adapted as standard of care in this population," said Dr. Wirth, medical director, Center for Head and Neck Cancers, Massachusetts General Cancer Center, Boston.
However, Dr. Wirth pointed out that this study was designed for
patients with progressive disease. "That means that there is a caveat to
the excitement over these results," she said. "There was toxicity
associated with this treatment, and so it may not be suitable for every
patient."
This type of cancer is a "grab bag of different pathologies," she continued, and she noted that some patients will have a low disease burden and be asymptomatic. "Disease progression may not occur for a while, and while sorafenib may shrink the tumor, it can affect their quality of life."
"Patients with a large tumor burden, and for those with symptoms, they will need treatment, and we can justify the side effects," Dr. Wirth explained. "But we need to differentiate who needs to be treated and who doesn't."
This research was supported in part by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc. Dr. Brose and several coauthors report relationships with industry, including Bayer and Onyx, as noted in the abstract.
2013 Annual Meeting of the American Society of Clinical Oncology. Abstract 4. Presented June 2 2013.
"Up until now, patients in this population haven't even come to medical oncology because there wasn't any treatment for them," commented Marcia Brose, MD, PhD, an assistant professor of otolaryngology and head and neck surgery in the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
She explained that this is really the beginning of a new field in medical oncology. Previously, thyroid cancer was generally treated by endocrinologists because medical oncology had no effective treatments once a patient became resistant to radioactive iodine.
Thyroid cancer has a reputation of being a "good cancer" because it can be easily cured, Dr. Brose explained. "But that's only for 90% of the patients, and for the other 10%, it will kill them eventually. Once surgery can no longer be used and the tumor no longer takes up radioactive, overall survival drops to about 2 and a half to 3 years."
"It is now important for the doctors who see these patients early on to refer them to medical oncologists, because now we have a treatment," said Dr. Brose. "For medical oncologists, it is important for them to know that we now have a treatment, and hopefully our data will lead to FDA approval."
Dr. Brose presented results from a phase 3 clinical trial, known as DECISION, in 417 patients with progressive RAI-refractory differentiated thyroid cancer. The results show a significant improvement in median progression-free survival to 10.8 months in the sorafenib group compared with 5.8 months in the placebo arm.
Sorafenib has been used off label for this purpose, Dr. Brose noted, but some physicians are not comfortable prescribing off label. "But the added level of rigor from a pivotal phase 3 study that is not just positive but highly significant — a doubling of progression-free survival — will hopefully help more physicians feel comfortable prescribing it," she said.
Chemotherapy Not Effective
"Conventional cytotoxic chemotherapy has not been effective in the management of differentiated thyroid cancers in spite of significant toxicities," commented Yujie Zhao, MD, PhD, assistant professor of oncology, Roswell Park Cancer Institute, Buffalo, New York.
"This randomized, placebo-controlled phase 3 study confirmed previous phase 2 results and also demonstrated a statistically significant progression-free survival improvement of 5 months compared with the placebo arm," said Dr. Zhao, who was not involved in the study.
Dr. Zhao noted that because stable disease of 6 months or longer was also seen in 33% of patients who received placebo, this suggests the importance of proper selection of patients who need treatment.
Sorafenib blocks the enzyme RAF kinase, which is a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation, and it also inhibits the VEGFR-2/PDGFR-beta signaling cascade. It is currently approved to treat hepatocellular carcinoma and advanced renal cell carcinoma.
The primary endpoint of the study was progression-free survival, which was assessed every 8 weeks. Secondary endpoints included overall survival, response rate (complete and partial response), and drug safety.
Within the cohort, tumor histology was 57% papillary, 25% follicular, and 10% poorly differentiated, and the vast majority (96%) of patients had metastatic disease. The most common target lesions were lung (71%), lymph node (40%), and bone (14%).
The authors note that their primary endpoint of progression-free survival was met (hazard ratio, 0.58; P < .0001). The median overall survival has not yet been reached in either study arm, and 70% of placebo patients have started open-label sorafenib.
All reported responses were partial — 12.2% in the sorafenib group vs 0.5% for placebo (P < .0001). Stable disease ≥ 6 months was 42% and 33%, respectively.
Tolerability was consistent with the known sorafenib safety profile, the authors note. The most common any-grade treatment-emergent adverse events in the sorafenib arm included hand–foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension. There was 1 death in each study arm that was attributed to sorafenib use.
For Select Patients
"There is a huge unmet need for an effective treatment in this population," said Lori Wirth, MD, who was approached by Medscape Medical News for an independent commentary. "While this is a relatively uncommon disease, patients do live for years with it, so there is a sizeable population in need of treatment."
"This was a positive study, and I believe that it will be adapted as standard of care in this population," said Dr. Wirth, medical director, Center for Head and Neck Cancers, Massachusetts General Cancer Center, Boston.
How do some physicians
get paid faster than 75% of multi-specialty group practices nationwide
as surveyed by the Medical Group Management Association and Healthcare
Billing Management Association for Days Revenue in AR?
Information from Industry
This type of cancer is a "grab bag of different pathologies," she continued, and she noted that some patients will have a low disease burden and be asymptomatic. "Disease progression may not occur for a while, and while sorafenib may shrink the tumor, it can affect their quality of life."
"Patients with a large tumor burden, and for those with symptoms, they will need treatment, and we can justify the side effects," Dr. Wirth explained. "But we need to differentiate who needs to be treated and who doesn't."
This research was supported in part by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc. Dr. Brose and several coauthors report relationships with industry, including Bayer and Onyx, as noted in the abstract.
2013 Annual Meeting of the American Society of Clinical Oncology. Abstract 4. Presented June 2 2013.
THE CURE IS WITHIN REACH,
DON'T GET DISTRACTED, FOCUS ON WHAT IS AT STAKE
ONE CLEAR PATH, THE ROLE OF BIM GENE FOR THE CURE!
===========================================================
Past use of chemotherapy and early interventions have shown us that cancer killing is possible by chemotherapy drug use, by radiation, by infection induced Cytokines, and by the immune system itself. One of the major pathway to death, is the CELLULAR PROGRAMMED DEATH CALLED APOPTOSIS.
We have now sufficient compelling evidences that all the cancer cell needs to die is to be provided critical circumstances or message that given these conditions pathway to Apoptosis is the logical attitude to adopt!
Aside from chemotherapy and target therapies, severe sepsis delivers the same message to our white cells and other cells, with death of the individual as a result.
Cellular nature provides us with several opportunities to kill the cell, but our knowledge is at present not enough to talk to cell appropriately, and give instructions for Apoptosis. So for now we try the rough ways! We kind of brutalize the cell and see what comes out! And we are still doing so because our knowledge of how the cell work remains rudimentary and fragmented at best.
With our fragmented knowledge, we know now that when we give Etoposide, one of the cell protection mechanism at Mitochondrial level is Bcl-2, and we call this molecule ANTI-APOPTOTIC MOLECULE because it protects the cell against programmed cell death.
But to be fair, nature also gives a chance to cell killing by providing a close Molecule to Bcl-2 called Bcl2L11, which has that BH-3 characteristic, and is PRO-APOPTOTIC, this is the BIM. Increase this and you have a higher self destruction of cancer cells! Now how to tell cancer cell, "increase your BIM please!" that where the challenge is!
We have preliminary knowledge, but it needs to be more focused, coordinated and understandable to the cell!
ie. while reviewing MITF gene, we clearly told you that MITF activates RUNX3 and RUNX3 activates BIM, that's the way to do this simply. But don't kill the messenger, we know this but we really don't know how to every time and effectively achieve this today!
We know a all lot today but not enough ...
Here is what we know!
======================================================================
ATLAS
*BIM is a pro-apoptotic member of the Bcl-2 family important in mediating apoptosis in response to various intrinsic stimuli. Studies using BIM knockout mice showed that it plays a large part in maintaining hematopoietic homeostasis. (THIS GIVE US INSIGHT THAT IN THE BLOOD CELL LINEAGE DISEASE, BIM IS OF A TREMENDOUS IMPORTANCE, AND ACTION AT BIM SHOULD HELP US CONTROL HEMATOLOGIC DISEASES)
*shown to mediate apoptosis in response to stimuli such as cytokine deprivation, deregulated calcium flux and microtubule perturbation. In vivo, BCL2L11/BIM is essential for hematopoietic homeostasis, thymocyte negative selection and as a barrier against autoimmunity. (WHEN STIMULATION OF NERVE CEASES UNDER DEPRIVATION OF NERVE GROWTH FACTOR, BIM GOES TO WORK TO KILL THE NERVE CELL)
*are either bound to DLC1 cytoplasmic dynein light chain and sequestered to the microtubule-associated dynein motor complex or associated with the pro-survival proteins on the mitochondria. A C-terminal hydrophobic domain present in all three major isoforms of BIM localizes the protein to intracytoplasmic membranes. (Making DLC1 a target, IF YOU REMOVE DLC1 FROM THE EQUATION, 2 THINGS MAY HAPPEN, ONE BIM IS FREE TO ACT OR WATCH OUT IT MAY BE MORE DESTROYED BY IBIQUITINATION POTENTIALLY OR "MISLOCATED" MISSING ITS POINT OF ACTION, THESE ARE FACTS WE STILL NEED TO CLEARLY ESTABLISH)
*Gaviraghi et al
E2F, a characterized transcriptional regulator of BCL2L11 expression. (CHECK OUR BLOG, WE SPOKE ABOUT E2F EXTENSIVELY, HERE IT IS COMING BACK TO REEMPHASIZE ITS "PLAYER STATUS", THIS IS A BOOSTER TO BIM!)
Expression of BCL2L11 is induced by a diverse range of apoptotic stimuli such as deprivation of growth factors/cytokines, ionizing radiation, and cytotoxic peptides [2,6,14,22].
Interestingly, the analysis presented in this manuscript indicates that the highest expression levels of BCL2L11 transcripts were detected in pancreas, placenta and thyroid tissue, suggesting an important role for BCL2L11 in the normal physiology of these tissues. With respect to P1-derived transcripts, up to 70% of total BCL2L11 transcripts are contributed from the newly identified promoter in the testis, an organ where BCL2L11 activity was shown to contribute critically to spermatogenesis [25], suggestive for a prominent role for the putative BCL2L11 P1 in the expression of BCL2L11 in this tissue. (IN WHICH CANCERS AGAIN THIS BIM CAN HAVE A ROLE?)
*atlas!
"BIM-deficient mice developed a fatal systemic lupus erythematosus (SLE)-like disease. Lymphocytes lacking BIM are refractory to a number of stimuli including cytokine deprivation, deregulated calcium ion flux. BIM is also important in turning off immune responses following acute viral infection. BIM cooperates with the death ligand Fas (which triggers the extrinsic pathway) to shut down immune responses following chronic viral infection and to prevent autoimmunity. Experiments using mice deficient for both BIM and pro-survival Bcl-2 demonstrated that Bcl-2 is an essential guardian of BIM. Indeed, removal of just one allele of BIM prevented polycystic kidney disease and restored normal growth of Bcl-2-deficient mice. Loss of both alleles restored a robust hematopoietic system and prevented graying." (LET'S REEMPHASIZE THAT YOU INDEED HAVE READ THE ROLE OF BIM IN POLYCYSTIC KIDNEY DISEASE, DOES METHYLATING ONE ALLELE A THERAPEUTIC OPTION?)
REGULATION (atlas)
" BIM is regulated by transcriptional control which differs with cell types by transcription factors including FOXO-3a and c-JUN . BIM is also controlled via alternative splicing that produces many different isoforms. BIM is regulated as well by post-translational modifications such as phosphorylation by ERK1, ERK2 and JNK. Phosphorylation-dependant ubiquitylation is thought to regulates BIM's half life.
Interactions:
Unlike some BH3-only proteins, BIM is a promiscuous binder of pro-survival proteins and can bind BCL2, BCLX, BCLW , MCL1 and BCL2A1 with high affinity. There are also some reports that BIMS is able to bind BAX (multidomain pro-apoptotic effector of the pathway) and activate it directly, but whether this binding occurs physiologically is unclear.
BIM belongs to the Bcl-2 family of proteins and contains the BH3 domain which is homologous to the BH3 domains of:" (EVERY TIME c-JUN IS MENTIONED, I THINK CYTOKINE PRODUCTION, AND CYTOKINES/GROWTH FACTOR DEPENDENT PROCESSES, BLOCKAGE AT RECEPTORS MAY HAVE SIGNIFICANT EFFECTS)
*1. Hughes et al
"Bim protein and that NF-Y is important for apoptosis following NGF withdrawal. Furthermore, I found that the transcriptional coactivators CBP/p300 are required for the activation of bim-LUC following NGF withdrawal and that CBP/p300 may interact with NF-Y to enhance bim transcription. In addition to this, the prosurvival MEK/ERK pathway has been found to inhibit bim expression independently of the PI3-K/Akt pathway. 3' RACE and experiments in sympathetic neurons with a new bim-LUC+3'UTR reporter construct revealed that this negative regulation is mediated through the bim 3' UTR. Mutational analysis and RNA stability experiments have been employed to further investigate this mechanism."
(block NGF all the way, and see what happens!)
*2. Gilley et al.
We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons.
(WE HAVE SAID, BEHIND THE FOXO LAYS THE PUMA (gene))
Ong et al.
Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.
(RE-EMPHASIZING THE NEED TO HAVE THE RIGHT BIM!)
IN sepsis Bim is upregulated Weber et al
PLENTY OF TARGETS OFFERED HERE!
DON'T GET DISTRACTED, FOCUS ON WHAT IS AT STAKE
ONE CLEAR PATH, THE ROLE OF BIM GENE FOR THE CURE!
===========================================================
Past use of chemotherapy and early interventions have shown us that cancer killing is possible by chemotherapy drug use, by radiation, by infection induced Cytokines, and by the immune system itself. One of the major pathway to death, is the CELLULAR PROGRAMMED DEATH CALLED APOPTOSIS.
We have now sufficient compelling evidences that all the cancer cell needs to die is to be provided critical circumstances or message that given these conditions pathway to Apoptosis is the logical attitude to adopt!
Aside from chemotherapy and target therapies, severe sepsis delivers the same message to our white cells and other cells, with death of the individual as a result.
Cellular nature provides us with several opportunities to kill the cell, but our knowledge is at present not enough to talk to cell appropriately, and give instructions for Apoptosis. So for now we try the rough ways! We kind of brutalize the cell and see what comes out! And we are still doing so because our knowledge of how the cell work remains rudimentary and fragmented at best.
With our fragmented knowledge, we know now that when we give Etoposide, one of the cell protection mechanism at Mitochondrial level is Bcl-2, and we call this molecule ANTI-APOPTOTIC MOLECULE because it protects the cell against programmed cell death.
But to be fair, nature also gives a chance to cell killing by providing a close Molecule to Bcl-2 called Bcl2L11, which has that BH-3 characteristic, and is PRO-APOPTOTIC, this is the BIM. Increase this and you have a higher self destruction of cancer cells! Now how to tell cancer cell, "increase your BIM please!" that where the challenge is!
We have preliminary knowledge, but it needs to be more focused, coordinated and understandable to the cell!
ie. while reviewing MITF gene, we clearly told you that MITF activates RUNX3 and RUNX3 activates BIM, that's the way to do this simply. But don't kill the messenger, we know this but we really don't know how to every time and effectively achieve this today!
We know a all lot today but not enough ...
Here is what we know!
======================================================================
ATLAS
*BIM is a pro-apoptotic member of the Bcl-2 family important in mediating apoptosis in response to various intrinsic stimuli. Studies using BIM knockout mice showed that it plays a large part in maintaining hematopoietic homeostasis. (THIS GIVE US INSIGHT THAT IN THE BLOOD CELL LINEAGE DISEASE, BIM IS OF A TREMENDOUS IMPORTANCE, AND ACTION AT BIM SHOULD HELP US CONTROL HEMATOLOGIC DISEASES)
*shown to mediate apoptosis in response to stimuli such as cytokine deprivation, deregulated calcium flux and microtubule perturbation. In vivo, BCL2L11/BIM is essential for hematopoietic homeostasis, thymocyte negative selection and as a barrier against autoimmunity. (WHEN STIMULATION OF NERVE CEASES UNDER DEPRIVATION OF NERVE GROWTH FACTOR, BIM GOES TO WORK TO KILL THE NERVE CELL)
*are either bound to DLC1 cytoplasmic dynein light chain and sequestered to the microtubule-associated dynein motor complex or associated with the pro-survival proteins on the mitochondria. A C-terminal hydrophobic domain present in all three major isoforms of BIM localizes the protein to intracytoplasmic membranes. (Making DLC1 a target, IF YOU REMOVE DLC1 FROM THE EQUATION, 2 THINGS MAY HAPPEN, ONE BIM IS FREE TO ACT OR WATCH OUT IT MAY BE MORE DESTROYED BY IBIQUITINATION POTENTIALLY OR "MISLOCATED" MISSING ITS POINT OF ACTION, THESE ARE FACTS WE STILL NEED TO CLEARLY ESTABLISH)
*Gaviraghi et al
E2F, a characterized transcriptional regulator of BCL2L11 expression. (CHECK OUR BLOG, WE SPOKE ABOUT E2F EXTENSIVELY, HERE IT IS COMING BACK TO REEMPHASIZE ITS "PLAYER STATUS", THIS IS A BOOSTER TO BIM!)
Expression of BCL2L11 is induced by a diverse range of apoptotic stimuli such as deprivation of growth factors/cytokines, ionizing radiation, and cytotoxic peptides [2,6,14,22].
Interestingly, the analysis presented in this manuscript indicates that the highest expression levels of BCL2L11 transcripts were detected in pancreas, placenta and thyroid tissue, suggesting an important role for BCL2L11 in the normal physiology of these tissues. With respect to P1-derived transcripts, up to 70% of total BCL2L11 transcripts are contributed from the newly identified promoter in the testis, an organ where BCL2L11 activity was shown to contribute critically to spermatogenesis [25], suggestive for a prominent role for the putative BCL2L11 P1 in the expression of BCL2L11 in this tissue. (IN WHICH CANCERS AGAIN THIS BIM CAN HAVE A ROLE?)
*atlas!
"BIM-deficient mice developed a fatal systemic lupus erythematosus (SLE)-like disease. Lymphocytes lacking BIM are refractory to a number of stimuli including cytokine deprivation, deregulated calcium ion flux. BIM is also important in turning off immune responses following acute viral infection. BIM cooperates with the death ligand Fas (which triggers the extrinsic pathway) to shut down immune responses following chronic viral infection and to prevent autoimmunity. Experiments using mice deficient for both BIM and pro-survival Bcl-2 demonstrated that Bcl-2 is an essential guardian of BIM. Indeed, removal of just one allele of BIM prevented polycystic kidney disease and restored normal growth of Bcl-2-deficient mice. Loss of both alleles restored a robust hematopoietic system and prevented graying." (LET'S REEMPHASIZE THAT YOU INDEED HAVE READ THE ROLE OF BIM IN POLYCYSTIC KIDNEY DISEASE, DOES METHYLATING ONE ALLELE A THERAPEUTIC OPTION?)
REGULATION (atlas)
" BIM is regulated by transcriptional control which differs with cell types by transcription factors including FOXO-3a and c-JUN . BIM is also controlled via alternative splicing that produces many different isoforms. BIM is regulated as well by post-translational modifications such as phosphorylation by ERK1, ERK2 and JNK. Phosphorylation-dependant ubiquitylation is thought to regulates BIM's half life.
Interactions:
Unlike some BH3-only proteins, BIM is a promiscuous binder of pro-survival proteins and can bind BCL2, BCLX, BCLW , MCL1 and BCL2A1 with high affinity. There are also some reports that BIMS is able to bind BAX (multidomain pro-apoptotic effector of the pathway) and activate it directly, but whether this binding occurs physiologically is unclear.
BIM belongs to the Bcl-2 family of proteins and contains the BH3 domain which is homologous to the BH3 domains of:" (EVERY TIME c-JUN IS MENTIONED, I THINK CYTOKINE PRODUCTION, AND CYTOKINES/GROWTH FACTOR DEPENDENT PROCESSES, BLOCKAGE AT RECEPTORS MAY HAVE SIGNIFICANT EFFECTS)
*1. Hughes et al
"Bim protein and that NF-Y is important for apoptosis following NGF withdrawal. Furthermore, I found that the transcriptional coactivators CBP/p300 are required for the activation of bim-LUC following NGF withdrawal and that CBP/p300 may interact with NF-Y to enhance bim transcription. In addition to this, the prosurvival MEK/ERK pathway has been found to inhibit bim expression independently of the PI3-K/Akt pathway. 3' RACE and experiments in sympathetic neurons with a new bim-LUC+3'UTR reporter construct revealed that this negative regulation is mediated through the bim 3' UTR. Mutational analysis and RNA stability experiments have been employed to further investigate this mechanism."
(block NGF all the way, and see what happens!)
*2. Gilley et al.
We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons.
(WE HAVE SAID, BEHIND THE FOXO LAYS THE PUMA (gene))
Ong et al.
Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.
(RE-EMPHASIZING THE NEED TO HAVE THE RIGHT BIM!)
IN sepsis Bim is upregulated Weber et al
Available online
http://ccforum.com/content/12/5/R128
Page 5 of 10
(page number not for citation purposes)
ciitis (n = 2), faecal peritonitis (n = 8) and pneumonia (n = 6).
Nine of the ten critically ill non-septic patients were included in
their post-operative period afte
r trauma, abdominal or pharyn-
geal cancer, or aortic aneurysm rupture with a delayed recov-
ery. These patients received prophylactic antibiotic treatment
with no signs of infection in the perioperative phase. One
patient had abacterial pancreatiti
s and did not receive antibiot-
ics. Patients did not receive immunosuppressants or drotrec-
ogin alfa (activated) before or during their treatment. Eight
patients with severe sepsis
received 3 mg/kg hydrocortisone
before or at the time of sampling. No difference in white blood
cells counts was found comparing critically ill patients with
patients with sepsis. However, lymphocyte counts were
decreased in severe sepsis as compared with critically ill
patients and dropped below the local reference range of 1–4
G/l (Table 1).
Phosphatidylserine externalisation and caspase-3
activation
Phosphatidylserine externalisation marks cells for phagocyto-
sis as an early event of the apoptotic process. Cells were con-
sidered early apoptotic when phosphatidylserine was
externalised on cells with a still intact membrane, as indicated
by negative staining for 7-AAD. CD4
+
and CD8
+
T-cells and
CD19
+
B-cells exhibited significantl
y raised portions of phos-
phatidylserine-positive population
s in severe sepsis, but not in
critically ill patients (Figure 1a).
Caspase-3 is the central executioner caspase. Activation of
caspase-3 leads to de
gradation of multiple intracellular sub-
strates and to the typical morphological features of classical
apoptosis. In the current study,
activation of caspase-3 was
measured by an antibody specific to the active fragment of
cleaved caspase-3 (Figures 1b and 1c). In patients with
severe sepsis, the subpopulation
with active caspase-3 was
elevated in CD4+ T-cells and CD8+ T-cells compared with
critically ill patients or healthy
controls. Also, B-
cells from sep-
tic patients were found to cont
ain significantly more activated
caspase-3 than B-cells from critically ill patients or healthy
controls.
Bcl-2 expression
Since the Bcl-2 family of proteins is known to regulate the
mitochondrial integrity, we analysed the expression of Bcl-2
(Figure 2). The amount of Bcl-2 in CD4
+
T-cells of critically ill
non-septic patients did not differ significantly from healthy con-
trols. However, in patients with sepsis, Bcl-2 protein levels
dropped by about 25%. In CD8
+
T-cells, no significant change
between the three groups could be observed. The decrease in
mitochondrial Bcl-2 was most pronounced in B-cells, where
Bcl-2 dropped by 36% when compared with healthy controls.
mRNA expression of Bcl-2 family members
When investigating the mRNA expression of mobile pro-apop-
totic BH3-only proteins of the Bcl-2 family, massive induction
was observed in severe sepsis (Figure 3a). When compared
with healthy controls and critically ill patients, mRNA expres-
sion of Bim was upregulated.
This corresponds to a 310.5-fold
increase compared with critically ill patients and a 51.7-fold
rise compared with healthy controls. While Bid was decreased
in critically ill patients, it was markedly upregulated in severe
sepsis.
WE THANK THE RESEARCHER FOR THEIR WORKS WHICH HAVE BROUGHT US CLOSER TO THE CURE, CRBCM RAISES ITS HAT TO YOUR HONOR! THIS IS REAL SCIENCE DEVOID OF POLITICAL INTRIGUES, JUST PURE PROGRESS, THANK YOU FROM THE BOTTOM OF OUR HEARTS!PLENTY OF TARGETS OFFERED HERE!
INTERNET BASED MEDICAL SURVEY INCREASINGLY A FALSE TRAP!
=======================================================
Criminals have gotten in the medical survey business. So until you know where it is coming from it is not worth your time to take them. They will get information from you, but at the end, there is "looping" where you come back to the same question until you get tired, and never complete the survey. Or simply a message that you did not qualify to take the survey in the first place. and "thank you".
The surveyor by then has gotten questions answered and may be paid to do that.
You end up frustrated and a bit "violated". So please keep your Blood pressure in check by just deleting these so called "offers".
=======================================================
Criminals have gotten in the medical survey business. So until you know where it is coming from it is not worth your time to take them. They will get information from you, but at the end, there is "looping" where you come back to the same question until you get tired, and never complete the survey. Or simply a message that you did not qualify to take the survey in the first place. and "thank you".
The surveyor by then has gotten questions answered and may be paid to do that.
You end up frustrated and a bit "violated". So please keep your Blood pressure in check by just deleting these so called "offers".
Saturday, June 1, 2013
VARIOUS NEWS.
*FROM ASCO, ABOUT PROSTATE CANCER/EXCERPT
"
Despite its challenges, PSA remains the best serum-based biomarker in prostate cancer. Variations of PSA such as free-to-total PSA ratio may be used to risk stratify patients. Assessment of urine PCA3 (Progensa PCA3 assay), or assessment of prostate biopsy tissue GSTP1 methylation (ConfirmMDx assay), are marketed to help avoid unnecessary repeat biopsies.
The Oncotype DX prostate biopsy-based genomic test recently became commercially available, and is marketed to identify the presence of an aggressive genotype to aid initial treatment decision making.
Notably, none of these novel tests has been prospectively evaluated to assess effect on clinically meaningful outcomes such as survival or quality of life.
In the United States, there is limited regulatory oversight of molecular diagnostic tests. The FDA regulates “companion” diagnostic assays that are used to predict patient responses to approved products (e.g., KRAS). But for non-companion tests, there is no requirement prior to marketing that benefits be demonstrated in survival or quality of life."
*METASTATIC MELANOMA TREATMENT
AGENTS
1. Ipilimumab - antagonist of CTLA-4
2.Nivolumab - antagonist of PD-1
3. MK-3475- antagonist of PD-1
4. Vemurafenib- (this is Zelboraf) - positive BRAF Mutation
5. Dabrafenib - positive BRAF Mutation
6. Trametinib - MEK is the target
7. Combination of Trametinib and Dabrafenib have been successfully combined for greater effect
8. Nexavar, Sutent, Gleevec, Sprycel, Tasigna are used in c-KIT positive Mutation
9. Adoptive T cell therapy
Adapted from YUSHAK et al.
*FROM ASCO, ABOUT PROSTATE CANCER/EXCERPT
"
Despite its challenges, PSA remains the best serum-based biomarker in prostate cancer. Variations of PSA such as free-to-total PSA ratio may be used to risk stratify patients. Assessment of urine PCA3 (Progensa PCA3 assay), or assessment of prostate biopsy tissue GSTP1 methylation (ConfirmMDx assay), are marketed to help avoid unnecessary repeat biopsies.
The Oncotype DX prostate biopsy-based genomic test recently became commercially available, and is marketed to identify the presence of an aggressive genotype to aid initial treatment decision making.
Notably, none of these novel tests has been prospectively evaluated to assess effect on clinically meaningful outcomes such as survival or quality of life.
In the United States, there is limited regulatory oversight of molecular diagnostic tests. The FDA regulates “companion” diagnostic assays that are used to predict patient responses to approved products (e.g., KRAS). But for non-companion tests, there is no requirement prior to marketing that benefits be demonstrated in survival or quality of life."
*METASTATIC MELANOMA TREATMENT
AGENTS
1. Ipilimumab - antagonist of CTLA-4
2.Nivolumab - antagonist of PD-1
3. MK-3475- antagonist of PD-1
4. Vemurafenib- (this is Zelboraf) - positive BRAF Mutation
5. Dabrafenib - positive BRAF Mutation
6. Trametinib - MEK is the target
7. Combination of Trametinib and Dabrafenib have been successfully combined for greater effect
8. Nexavar, Sutent, Gleevec, Sprycel, Tasigna are used in c-KIT positive Mutation
9. Adoptive T cell therapy
Adapted from YUSHAK et al.
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