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Old 04-10-2014, 01:28 PM   #1
gdpawel
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Triple Negative Breast Cancer: Worse or Just Different?

Robert A. Nagourney, M.D.

The term “triple negative breast cancer” (TNBC) is applied to a subtype of breast cancers that do not express the estrogen or progesterone receptors. Nor do they overexpress the HER2 gene. This disease constitutes 15 – 20 percent of all breast cancers and has a predisposition for younger women, particularly those of black and Hispanic origin. This disease may becoming more common; although, this could reflect the greater awareness and recognition of this disease as a distinct biological entity.

On molecular profiling, TNBC has distinct features on heat maps. The usual hormone response elements are deficient, while a number of proliferation markers are upregulated. Not surprisingly, this disease does not respond to the usual forms of therapy like Tamoxifen and the other selective estrogen response modifiers known as SERMs. Nonetheless, TNBC can be quite sensitive to cytotoxic chemotherapy. Indeed, the responsiveness to chemotherapy can provide these patients with complete remissions. Unfortunately, the disease can recur. Complete remission maintained over the first three to five years is associated with a favorable prognosis, with recurrence rates diminishing over time and late recurrences more often seen in estrogen receptor-positive cancers.

Triple negative breast cancer is not one, but many diseases.

Among the subtypes are those that respond to metabolic inhibitors such as the PI3K and mTOR directed drugs. Another subset may respond to drugs that target epidermal growth factor. There are basal-types that may be somewhat more refractory to therapy, while a subset may have biology related to the BRCA mutants, characterized by DNA repair deficiencies and exquisite sensitivity to Cisplatin-based therapies. Finally, a last group is associated with androgen signaling and may respond to drugs that target the androgen receptor.

Some years ago, we used the EVA-PCD platform to study refractory patients with breast cancer and identified exquisite sensitivity to the combination of Cisplatin plus Gemcitabine in this patient group. We published our observations in the Journal of Clinical Oncology and the combination of Cisplatin or Carboplatin plus Gemcitabine has become an established part of the armamentarium in these patients.

http://www.rationaltherapeutics.com/...tin-Breast.pdf

The I-SPY-2 trial has now used genomic analyses confirming our observations for the role of platins in TNBC. This is part reflects the DNA repair deficiency subtype associated with the BRCA-like biology. More recently, we have examined TNBC patients for their sensitivity to novel therapeutic interventions. Among them, the PI3K and mTOR inhibitors, as well as the glucose metabolism pathway inhibitors like Metformin. Additional classes of drugs that are revealing activity are the cyclin-dependent kinase inhibitors, some of which are moving forward through clinical trials.

One feature of triple negative breast cancer is avid uptake on PET scan. This reflects, in part, the proliferation rate of these tumors, but may also reflect metabolic changes associated with altered glucose metabolism. In this regard, the use of drugs that change mitochondrial function may be particularly active. Metformin, a member of the biguanide family influences mitochondrial metabolism at the level of AMP kinase. The activity of Metformin and related classes of drugs in triple negative breast cancer is a fertile area of investigation that we and others are pursuing.

When we examine the good response of many triple negative breast cancers to appropriately selected therapies, the potential for durable complete remissions and the distinctly different biology that TNBC represents, the question arises whether TNBC is actually a worse diagnosis, or simply a different entity that requires different thinking. We have been very impressed by the good outcome of some of our triple negative breast cancer patients and believe this a very fertile area for additional investigation
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Old 04-10-2014, 01:30 PM   #2
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Cancer is not a genomic disorder, but a metabolic disorder

Robert A. Nagourney, M.D.

A study conducted by Canadian investigators and reported in the September 1, 2013 issue of the Journal of Clinical Oncology examined the impact of Metformin use on mortality in men with diabetes and prostate cancer (Margel D. Urbach DR., Lipscombe LL, Metformin Use and All-Cause and Prostate Cancer-Specific Mortality Among Men with Diabetes, Journal of Clinical Oncology, volume 31, #25, pgs 3069-3075, 2013). The investigators examined 3837 patient with a median age of 75 years. They conducted a retrospective analysis examining the Ontario Province heath care records. The intent was to examine duration of exposure to Metformin as a diabetes management in patients with prostate cancer to assess the impact on all-cause and prostate cancer-specific mortality.

The results are impressive and instructive. There was a significant decrease in the risk of prostate cancer-specific and all-cause mortality, which related to the dose and duration of exposure to Metformin. The adjusted hazard ratio for the study of 0.76 indicates that there is a 24% reduction in mortality for prostate cancer-specific events with the use of Metformin. This study was not perfect, as it was retrospective, there was no randomization and it was impossible to control for all other variables such as exercise, smoking history and clinical parameters of prostate cancer. Nonetheless, there is a clear and important trend toward reduced prostate cancer and even overall mortality. This is but one of a series of clinical studies that have examined the impact of Metformin upon not only prostate cancer but also breast cancer. Much of this work was originally pioneered by Dr. Michael Pollack from McGill University in Montreal.

Metformin and the closely related Phenformin are members of the class of drugs known as biguanides. While the exact mode of action of the biguanides is not fully understood, they are known to disrupt mitochondrial respiration at complex I. This upregulates an enzyme known as adenosine monophosphate kinase (AMPK) thereby altering energy metabolism within the cell and down regulating mTOR. In diabetics, this drives down blood glucose to control the disease. However, in cancer patients, a profound effect is observed that suppresses synthetic pathways necessary for energy metabolism, cellular survival and cellular proliferation. These effects appear responsible for the impact upon prostate cancer. Interestingly, these drugs are more effective in controlling already transformed cells and less effective in the prevention of cancer. This is consistent with the observation that malignantly transformed cells change their state of metabolism.

This article is interesting on many levels. The first and most obvious is that this relatively inexpensive and well-tolerated drug can have an impact on prostate cancer.

Secondly, these effects appear to cross the lines of different cancer types, such that breast cancer and other forms of cancer might also be successfully treated.

The third note of interest shows that even patients without diabetes can tolerate Metformin, suggesting this as an adjunct to many different treatments. Finally and most importantly this represents the new and important recognition that cancer is not a genomic disorder, but a metabolic disorder. Cancer may utilize normal genetic elements to its own advantage. AMP kinase, LKB1 and mTOR are not unique to cancer, but instead, are found in every cell. These normal proteins are simply altered in their function in malignantly transformed cells. Metformin is one of what will soon be a large number of metabolomic agents entering the clinical arena as cancer research moves from the nucleus to the mitochondrion.

http://jco.ascopubs.org/content/31/25/3069.abstract
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Old 04-10-2014, 01:31 PM   #3
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Palbociclib stymies cancer progression but falls short on survival

Palbociclib doubled the average amount of progression-free survival (PFS) time among patients with advanced breast cancer. But in the first detailed glimpse of its impact on overall survival (OS) - a key feature to the future prospects of this flagship program - the therapy has failed to demonstrate a statistically significant improvement in extending patients' lives after an initial assessment. Palbociclib is on of the cyclin-dependent kinase inhibitors.

Patients with hormone receptor-positive metastatic breast cancer enjoyed a median PFS rate of 20.2 months when taking a combination of palbociclib and the antiestrogen drug Femara (letrozole), compared to 10.2 months for letrozole alone, according to researchers presenting the latest data at the American Association for Cancer Research (AACR)meeting in San Diego. The OS rate, though, was 37.5 months for the combo versus 33.3 months for the solo therapy. That was an improvement, but not a big enough one to qualify as significant enough to meet the secondary endpoint.

Investigators were quick to note that there haven't been enough patient deaths in the study to firm up the OS numbers, happy at this stage to point to a trend in the drug's favor. But investors were left feeling somewhat deflated over the shortfall on OS, especially after seeing signs of a dramatic improvement in PFS earlier on. At the interim point, patients taking palbociclib saw a delay in disease progression of 26.1 months, compared to only 7.5 months in the control arm.

Financial analysts had expected the PFS rate over the letrozole arm to balance out a bit in the follow-up. And they expect the results are sufficient for a regulatory application soon, which is what investors have been gambling on. Pfizer (the drug's manufacturer), though, hasn't come right out and said whether they're going for an early approval.

Palbociclib is a CDK-4/6 inhibitor. And it's not alone. Last December, Novartis pushed its rival program for LEE011 into Phase III, setting up a showdown over a market that could deliver billions in potential revenue. Both therapies target a pair of cyclin dependent kinases that play a role in cancer. Eli Lilly also has a contender in the pipeline, LY2835219. But the pharma giant is well behind the leaders in this race, and Lilly suffers from a reputation for carefully regimented development programs that often lag well behind those of rivals.

Lilly's investigators reported at AACR that of the 47 patients with metastatic breast cancer in the study, 9, or 19%, had a partial response while 24, 51%, had stable disease. "Disease progressed despite treatment in 11 patients," according to a release from Lilly. "All of the nine patients who had a partial response, and 20 of the 24 patients who had stable disease, had HR-positive disease, which meant that the partial response and stable disease rates for patients with HR-positive disease were 25 percent and 55 percent, respectively."

Schoenebaum takes a positive view on Lilly's come-from-behind position in the race for an approval. "Overall, these data seem to indicate that (Lilly's) drug is clearly active," he wrote. "Whether it's actually MORE active than Pfizer's palbociclib remains an open question as you must be very careful when comparing across different trials with small patient numbers. As a reminder, Lilly has argued that their drug might work better because it can be dosed continuously (vs palbociclib's 3 weeks on; 1 week off regimen) due to less severe neutropenia. Lilly plans on announcing next steps later in the first half of 2014 - we believe it's possible that a phase 3 could begin by year 2014's end or in early 2015. There is very little, if anything, in Lilly consensus estimates for this drug - so in theory, at least, it represents all upside."

The view from Pfizer's investigators remained upbeat, despite the setback on OS rates.

"This is an exciting data set that shows a major clinical benefit for patients who have hormone receptor-positive, metastatic breast cancer," said UCLA Professor Dennis Slamon. "The potential impact of this study could be huge. We are doing further Phase III work with the drug, but the current data are as exciting as the initial studies we were involved in when testing Herceptin for HER2-positive breast cancers."

Source: FierceBiotech
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Old 04-10-2014, 01:32 PM   #4
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Bemaciclib Seems Safe, Effective for Advanced Disease

In an early trial, an experimental breast cancer drug stopped disease growth and shrank tumors by more than 30 percent in some patients.

The pill, bemaciclib, was safe and well-tolerated by women with breast cancer that had spread, or metastasized, to other parts of the body, according to the results of this phase 1 trial.

"This is a novel oral treatment for patients with metastatic breast cancer," said lead researcher Dr. Amita Patnaik, the associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio.

If these results are replicated in future trials, it's conceivable that the pill might extend survival for women with terminal breast cancer, experts suggested.

The drug was particularly effective for the most common type of breast cancer, called hormone receptor-positive breast cancer. In this type of cancer, cancer cells grow in response to signals from the hormones estrogen and/or progesterone.

The study included more than 130 women. Overall, Patnaik said half of them had cancer growth controlled and 25 percent had shrinkage of their tumors.

Unlike standard cancer drugs, this is a twice-daily pill that allows women to go on with their daily lives. In contrast, other cancer drugs are given intravenously at a hospital or doctor's office. Another difference, Patnaik said, is that bemaciclib is a targeted therapy, a newer type of drug that is better able to identify and attack specific cells.

"Our results show that it can be given safely over a long period of time, and patients are able to go on with their routine activities and have a good quality of life," she said.

Side effects of the drug include diarrhea, nausea and vomiting. For study participants, most of these problems were mild or moderate, Patnaik said.

The trial results were presentated on Sunday at the annual meeting of the American Association for Cancer Research (AACR) in San Diego. The study was funded by Eli Lilly and Co., the maker of bemaciclib.

"It is important to remember that this is a first-time evaluation of the drug and these results will have to be confirmed in later studies," Patnaik cautioned. More trials are being planned, she said.

Dr. Neelima Denduluri, a medical oncologist at Virginia Cancer Specialists in Arlington, pointed out that metastatic breast cancer is generally incurable. "Goals of therapy include maintaining quality of life while administering effective therapy," said Denduluri, who was not involved in the study.

She said she hopes bemaciclib and other new drugs will make a difference in the treatment of advanced breast cancer.

For hormone receptor-positive breast cancer, doctors often use anti-estrogen therapies. However, tumor cells stop responding to these drugs, so alternatives are often needed, Denduluri said.

"Bemaciclib's trial results are very exciting and confirm that developing this class of drugs is very promising for patients with advanced breast cancer," Denduluri added.

For the study, Patnaik's team tested the drug on 132 women with breast cancer. Forty-seven of them with metastatic cancer had tried as many as seven other drugs before bemaciclib.

The women took bemaciclib pills twice daily for 28 days.

Thirty-six of the 47 patients with metastatic breast cancer had hormone receptor-positive disease, the researchers noted. Nine of the 47 patients had a partial response, and 24 of the 47 patients saw the growth of their cancer stopped.

Among the metastatic breast cancer group, 11 patients had their cancer progress despite treatment, the researchers said.

Among women with hormone receptor-positive breast cancer, 81 percent had a complete response, partial response or stable disease, and their cancer didn't progress for an average of nine months, the study found. For study participants overall, progression-free survival was nearly 6 months.

The trial lasted 28 days, but women who benefited from the drug could continue on it in 28 day cycles as long as they continued to benefit. Eighteen of the hormone receptor-positive breast cancer patients are still being treated with bemaciclib, said Patnaik.

Dr. Myra Barginear, an oncologist at North Shore-LIJ Cancer Institute in Lake Success, N.Y., is also excited about the potential of this drug and others like it.

"As a breast cancer doctor, I am thrilled to potentially have a new agent for my patients with advanced hormone receptor-positive breast cancer. This is the most common type of breast cancer -- representing approximately 80 percent of all cases," she said.

Data and conclusions presented at meetings are typically considered preliminary until published in a peer-reviewed medical journal.

Source: HealthDayNews
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Old 04-10-2014, 01:33 PM   #5
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The cyclin-dependent kinase inhibitors

These kinase inhibitors can work across various types of cancer, but often only extend life by around three to six months. However, researchers believe they can unlock the true potential of these drugs by changing the way they are used, after uncovering a hidden way that they work. Those researchers had planned to conduct clinical trials using kinase inhibitors at higher doses, but with rest periods to take advantage of the new mechanism, and believe the new method has the potential to keep cancers at bay for much longer.

Some private laboratory oncologists have found that high-dose kinase inhibitors can be effective for central nervous system (CNS) disease, so long as resistance has not developed. It may have something to do with entry into the cell; efflux out of the cells; inactivation, or whatever. They have often recommend higher dose, pulse/intermittent therapy, in combination with other agents. Palbociclib is being looked at right now, because of its advancement in clinical trials, but I'm sure they will be ready for Bemaciclib when it becomes available.

One of those private laboratory oncologists, Dr. Robert A. Nagourney, will be attending the upcoming American Society of Clinical Oncology trade show in Chicago, where he will present early studies on Cyclin-dependent kinases as therapeutic targets: examination of palbociclib (PD0332991) and flavopiridol in human tumor primary culture microspheroids.
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Old 04-10-2014, 04:02 PM   #6
dawny
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Re: Triple Negative Breast Cancer: Worse or Just Different?

Thank you gdpawel, as always for your informative posts!

Dawn
__________________
Dx May 27 2011, age 43
Stage 1V 3.6cm breast lump, spot on lung nodes chest + neck
HER2+ ER/PR-
Abraxane weekly - 16 weeks
Herceptin every third week
September 26 2011 N.E.D!
Herceptin ongoing
8th Dec 2011 Brain MRI - clear
20th Dec 2011 bone/cat scan clear still NED
April 2012 scans show axillary node lump - ? what to do...
June 2012 Axillary node dissection 1/11 nodes affected, a wide local excision shows DCIS. Now what to do again? Watch and scan 3 monthly
April 2013, two spots in nodes to chest wall, start TDM1 as part of clinical trial
July 2013 stable
Oct 2013 progression off TDM-1
Nov 2013 radiation to lymph nodes in sternum
Dec 2013. Mastectomy right side, pathology shows tumour was HER-2 negative, no wonder TDM-1 didn't work!
April 2014 NED. On Herceptin only
August 2014 NED. On Herceptin only
March 2015. NED. On Herceptin only
September 2015 NED on Herceptin only
March 2016. Pulmonary embolism, Clexane injections daily forever. Still NED On Herceptin only
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Old 05-12-2014, 10:16 PM   #7
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Palbociclib Extends PFS in ER-positive/HER2-negative Breast Cancer

Treatment with palbociclib combined with letrozole resulted in significantly improved progression-free survival (PFS) compared with letrozole alone in patients with hormone receptor-positive metastatic breast cancer, according to a phase 2 trial presented at the American Association of Cancer Research Annual Meeting in San Diego, CA, on April 6, 2014.

Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6.

The study design comprised 2 parts. In part 1, researchers recruited 66 postmenopausal patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and, in part 2, they recruited 99 postmenopausal patients with the same diagnosis who had been found to have CCND1 amplification and/or loss of p16, which are markers of sensitivity to palbociclib. Patients continued to receive medication until disease progression, unacceptable toxicity, or withdrawal from the study, and their tumors were assessed every 2 months.1

PFS in patients treated with palbociclib plus letrozole was almost double that of patients treated with letrozole alone: 20.2 versus 10.2 months (P=0.0004). There was a 51% reduction in the risk of disease progression in patients who received palbociclib.1

“This study grew out of a strong initial preclinical observation made a few years ago that hormone receptor-positive breast cancer cells are dependent on CDK-4/CDK-6 for their growth, and that these cancers are sensitive to inhibition of CDK-4/CDK-6,” said lead researcher Richard S. Finn, MD, associate professor of medicine at the University of California in Los Angeles.

The risk for disease progression did not decrease further in patients who were recruited in part 2 of the study, whose tumors had the molecular targets specific for the drug: risk decreased by 70% for those in part 1, compared with 49% for those in part 2. “The challenge with any targeted drug is identifying patients who are dependent on the target,” said Dr. Finn. “Having an intact Rb pathway seems to be the most critical factor for this drug to be effective, because most hormone-positive tumors are dependent on this pathway.”

Overall survival was 37.5 months in patients treated with palbociclib and letrozole and 33.3 months in patients treated with letrozole alone, a difference that was not significant.1

“A small lead-in phase 1 study conducted prior to this phase 2 trial showed that palbociclib and the antiestrogen drug letrozole could be given safely as a combination, with manageable side effects,” said Dr. Finn. The most common adverse events associated with palbociclib treatment were neutropenia, leukopenia, fatigue, and anemia. “It is important that we not only improve the efficacy of the compound, but also that we do not add an undue burden in toxicity, and we are happy that the drug was well tolerated overall.”

Two important reasons for the success of this trial, Dr. Finn explained, were that hormone receptor-positive/HER2-negative patients are more likely than other patients to benefit from palbociclib and that the compound is highly specific in its ability to block CDK-4 and CDK-6, leading to less toxicity.

Palbociclib is being tested in phase 3 trials in combination with letrozole (PALOMA-2) and fulvestrant (PALOMA-3) for late-stage, metastatic breast cancers, and in combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.

Reference

Finn RS, Crown JP, Lang I, et al. Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) [Abstract CT101]. Presented at the American Association for Cancer Research, San Diego, CA, April 6, 2014.

Source: Chemotherapy Advisor
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Old 05-13-2014, 08:33 AM   #8
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Re: Triple Negative Breast Cancer: Worse or Just Different?

Thank you GDP for answering my question: What's next.

I am very excited about the upcoming ASCO conference in Chicago. I know one study I participated in is about to share some exciting news. Another will likely have good news for the SABCS.

It seems we need new lingo. The days of ER +/-, PR +/-, Her2 +/- are about to be left behind. Triple Positive, Triple Negative are too simple with cancer.

I can't believe there are women with lower expressions of Her2 who could have benefited from Herceptin. Yet with the current system it is a decade past the original FDA approval and these women are still grouped in the Triple Negative category, progressing and dying.

Thanks heavens for Research Rebels like Nagourney.
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Old 06-12-2014, 09:53 PM   #9
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Cyclin-dependent kinases as therapeutic targets

Cyclin-dependent kinases as therapeutic targets: Examination of palbociclib (PD 0332991) and flavopiridol in human tumor primary culture microspheroids.

Author(s): Robert Alan Nagourney, Eknath A. Deo, Nilesh L. Vora, Milan Rohit Sheth, Paula J Bernard, Federico R Francisco, Steven S Evans; Rational Therapeutics, Long Beach, CA; Malcolm Todd Cancer Institute, Long Beach, CA; Todd Cancer Institiute, Long Beach, CA; UC Irvine Medical Center, Long Beach, CA

Abstract:

Background:

The cyclin dependent kinases (CDK) are a family of enzymes that mediate cell cycle progression. CDK dysregulation is a common event in human carcinogenesis, making CDK inhibition an attractive target for therapy. Palbociclib (PD) is a selective CDK 4/6 inhibitor, while flavopiridol (FL) is non-specific. CDK inhibitors are now in clinical trials.

Methods:

To examine the activity and compare the profiles of PD & FL, we used Ex Vivo Analyses of Programmed Cell Death (EVA/PCD) in human tumor primary cultures isolated from surgical specimens. After disaggregation, microspheroids, isolated by precise density centrifugation were exposed to PD or FL for 72 hours and drug induced cell death then measured by delayed-loss-of-membrane integrity and/or ATP content (luciferase).Dose response curves were interpolated to LC50 values. Twenty nine PD, 68 FL and 20-both specimens were studied.

Results:

PD & FL reveal activity in a broad array of tumors including upper GI, NSCLC, Breast, Ovary & Hematologic. No activity was observed for FL or PD in Head & Neck. Similar profiles were observed except in prostate where FL was more active than PD. Correlations by Pearson Moment revealed an R = 0.58 P<0.01 (2-tailed T).

Conclusions:

Findings confirm activity for the CDK inhibitors and suggest disease specific profiles. With culture conditions established, further analyses are now comparing PD with other classes of drugs, to examine combinations, synergy & sequence dependence, as will be reported. Supported in part by the Vanguard Cancer Foundation and the Memorial Medical Center Foundation.

Citation: J Clin Oncol 32, 2014 (suppl; abstr e13504)

http://abstracts.asco.org/144/AbstView_144_129973.html
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Old 08-25-2015, 10:22 AM   #10
Marko Skoric
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Re: Triple Negative Breast Cancer: Worse or Just Different?

Thanks your for your good post. It is really helpful.
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