Poster Discussion III
Robert G. Maki, MD PhD
Memorial Hospital
New York, NY, USA
Focus on just a few of the
quality posters from this session
• Basic Science
– 34824 Leiomyosarcoma phosphokinome (El Sayadi)
• Neoadjuvant therapy
– 34844 Volume change after neoadjuvant chemo in extremity
sarcomas (Lackman)
– 35131 Preop imatinib for GIST (Trent)
• Novel therapeutics
– 35010 Apomab phase II (Chawla)
– 34863 HDAC inhibitors and chemotherapy (Lopez)
• Controversy
– 35001 Pleomorphic RMS therapy (Whelan)
– 35060 Three EOI osteosarcomas studies (Whelan)
The Theatre
• 1st successful theatre (2nd overall, after the Red Lion), built 1576
by James Burbage and John Brayne in Shoreditch
• After Thomas Nashe's play, Isle of Dogs, all London theatres were
closed in summer of 1597. The Theatre did not reopen.
• Dismantled by carpenter Peter Street in 1598, parts became
• …the Globe Theatre: 1599
• 6 August 2008: Portions found again in an excavation on New Inn
Broadway
The Theatre, 1576
Question 1
How do you distinguish aneuploid
sarcomas of a given histology?
34824 Leiomyosarcoma phosphokinome
(page 71 of program)
• El Sayadi et al. examined 13 LMS frozen samples with a
multiplex (652 protein) kinase assay (Kinexus)
– ~380 protein-specific antibodies
– 270 phosphorylation site specific antibodies
• Elevated levels of PKC, Tyro3, MSH2 in LMS vs normal
muscle
• Two clusters of LMS: One more like normal muscle, another
with distinct Rb and other phosphoprotein expression
• Correlation to CGH and miRNA arrays underway
• Could well have prognostic or predictive consequences for
therapy
The variability of leiomyosarcomas
• Aneuploid karyotype
• Somewhat different pattern of metastasis based on
anatomic primary site
• Different sensitivity to chemotherapy: Uterine >
retroperitoneum/extremity > GI
• How can we predict who will do well and who might
benefit from adjuvant chemotherapy?
Henry V, III, vi (1598-99)
Fluellen: By your patience, Aunchient (Ensign) Pistol. Fortune is
painted blind, with a muffler afore her eyes, to signify to you
that Fortune is blind; and she is painted also with a wheel, to
signify to you, which is the moral of it, that she is turning,
and inconstant, and mutability, and variation: and her foot,
look you, is fixed upon a spherical stone, which rolls, and rolls,
and rolls: in good truth, the poet makes a most excellent
description of it: Fortune is an excellent moral.
• We have much to learn regarding the biological heterogeneity
of even the most common of the sarcomas we treat.
Question 2
Can we use something other than RECIST
to determine radiological outcome for
sarcoma patients?
34844 Lackman et al.: MRI tumor volume, neoadjuvant
chemotherapy, and outcome (p. 71)
•
•
•
•
•
3-dimensional MRI measurements used
12 month follow up minimum, pts from 1998-2007
Doxorubicin based therapy employed in 90% of patients
RT typically given after chemotherapy, before surgery
Definitions employed:
– Progression ≡ Tumor volume increase ≥ 10%
– Response ≡ Tumor volume decrease ≥ 10%
– Stable ≡ Everything else
• N = 41 of 92 met criteria for analysis
– MFH (12), Lipo (9), Synovial (7), NOS (5), LMS (4)
– Most missing patients excluded for lack of volume data
Outcomes
• Median follow up 41.5 months (12-118).
• n = 41 :
– Response 22 (54%)
– Progression 15 (36%)
– Stability in 4 (10%)
Median volume change: -19 cm3(-18%); mean +134 cm3 (+20%)
LR: 4 (2 responders, 2 progressors)
Mets: 8 (4 from each group)
Death: 8 (6 from progression group, 1 from response and 1 from stable
group)
• Patients with poor outcome had shorter OS than other two groups
(p=0.02 Cox, p=0.005 K-M)
• DFS similar for both groups (p~0.45-0.5)
• Degree of tumor necrosis did correlate with outcome
•
•
•
•
Volume change and OS
p=0.01
No correlation between volume change and necrosis
250%
R2 = 0.003
Percent Volume Change
200%
150%
100%
50%
0%
-50%
-100%
0%
20%
40%
60%
80%
100%
Percent Histopathologic Tumor Necrosis
*One outlier
(85%,+931%)
is not shown
on the graph.
Comments
• We’ve got the information, why not use it?!
• Would be interesting to see sensitivity analysis to see
how volume change (percentage) would affect these
cutoffs
• Correlation with PET or DCE MRI would also be
intriguing
King John, V, vii (1595-6)
Ay, marry, now my soul hath elbow-room;
It would not out at windows nor at doors.
There is so hot a summer in my bosom,
That all my bowels crumble up to dust:
I am a scribbled form, drawn with a pen
Upon a parchment, and against this fire
Do I shrink up.
• Even those these changes are small (3√10 = 2.15
mm), they appear to be meaningful, and are worth
examining with respect to PET and other metrics of
response in a larger study.
Question 3
How quickly do GIST patients respond to
imatinib in the neoadjuvant setting?
35131 Trent et al.: Preop imatinib for GIST (p.
87)
• n=20 patients randomized to 3, 5, or 7 days of
imatinib preop at 600 mg oral daily, then completed
2 years therapy.
• Efficacy evaluated by PET, dynamic contrast CT,
TUNEL, DFS
• ~70% of patients showed signs of PET or CT response
• Apoptosis increased mean 12% on Rx (0-33%)
• Median DFS in this cohort: 44 mo
• Tumor size predicted recurrence risk (p=0.02)
Disease free survival curve
The Tempest, II, i (approx. 1611)
• Antomo:
. . . Who's the next heir of Naples?
• Sebastian:
Claribel.
• Antonio:
She that is Queen of Tunis; she that dwells
Ten leagues beyond man's life; she that from Naples
Can have no note, unless the sun were post—
The Man i' th' Moon's too slow—till new-born chins
Be rough and razorable; she that from whom
We all were sea-swallow'd, though some cast again
(And by that destiny) to perform an act
Whereof what's past is prologue; what to come,
In yours and my discharge.
• We will see further data fairly regarding the utility of adjuvant imatinib
Question 4
What are promising new combinations of
targeted and cytotoxic systemic
therapeutics?
34863 Lopez et al. Synergy of HDAC inhibitors
and chemotherapy (p. 72-73)
• HDAC inhibition interesting novel therapeutic in synovial and
other sarcomas (T. Nielsen, Vancouver)
• PCI-24781 examined against 4 STS cell lines
• 44 genes showed significant change in expression at mRNA
and protein levels, including RAD51 (reduction)
• Chemotherapy + HDACi more effective than either alone
• Interesting owing to the central role of RAD51 in repairing
DNA damage (double strand DNA breaks)
• One of a family of proteins, any others affected?
• Interacts with BRCA1 and BRCA2; are these affected?
HDAC vs. sarcoma cell lines
(colony formation)
RAD51 expression decreased upon exposure to HDACs;
tumor weight in vivo lower with combination Rx with
chemotherapy
• Suggestive of a synergistic approach to treat adult sarcomas
• Drawback has been longer exposure to HDACi may not be clinically tolerable
Hamlet, V, ii (1600-01)
• Hamlet: Come on, sir.
• Laertes: Come, my lord.
[They play and Hamlet scores a hit]
• Hamlet: One.
• Laertes: No.
• Hamlet: Judgment.
• Osric: A hit, a very palpable hit.
• Laertes: Well, again.
• King Claudius: Stay, give me drink. Hamlet, this pearl is thine.
Here's to thy health! Give him the cup.
Question 5
What is the follow up on a promising
proapoptotic antibody?
35010 Chawla et al. anti-DR5 mAb phase II (p. 80)
• Phase I data indicated 2 responders with conventional
chondrosarcoma and one with synovial sarcoma (SS)
• Phase II 15 mg/kg mAb loading, 10 mg/kg dose q3wk
• 14 chondrosarcomas: 0 RECIST PR; 8/14 SD best result;
resection of two patients’ tumors: 50, 60% necrosis
35010 Chawla et al. anti-DR5 mAb phase II
• 1 pt with SS: lung involvement, Rx x 1 → resp
distress, Rx with anticoagulation for pulmonary
embolus, G5 hemoptysis. Postmortem: necrotic
tumor
• Not dissimilar from patients with SS treated with
sorafenib at our hospital
• Clearly an issue with further development of drug;
anti-DR4? TRAIL/Apo2L ligand itself in development
Two quotations
All’s Well that Ends Well, II, i (1602-03)
• Helena: "Oft expectation fails, and most oft there
Where most it promises; and oft it hits
Where hope is coldest, and despair most fits.”
Romeo and Juliet, V, iii (1594-96, 1st perf. 1662)
• Romeo: "O true apothecary!
Thy drugs are quick. Thus with a kiss I die."
Question 6
What remains controversial regarding
sarcoma management?
35001 Whelan et al. Rx of Pleo RMS (p.79)
• 17 of 23 physicians queried had responded as to how
best to treat 7 cm thigh pleomorphic RMS in adults
• 9 recommended extra staging beyond chest CT
• 13 recommended chemotherapy without a
consistent regimen noted
• RT suggested by 11
• Not a lot of consensus!
Midsummer Night’s Dream, IV, I (1595-1596)
• Hippolyta: I was with Hercules and Cadmus once,
When in a wood of Crete they bay'd the bear
With hounds of Sparta: never did I hear
Such gallant chiding: for, besides the groves,
The skies, the fountains, every region near
Seem'd all one mutual cry: I never heard
So musical a discord, such sweet thunder.
35060 Whelan et al. Three EOI randomized studies (p.84)
• 1067 patients in three studies, MRC/EORTC BO02/80831,
BO03/80861 , BO06/80931
• All three used standard arm [Cis 100/m2 + Dox 75 mg/m2] x 6
• Experimental arms: (1) + HD MTX, (2) + T10-like, (3) Dose
compressed
• Median follow up 9+ years, 533 treated in standard arms
• Survival was 56% and 52% at 5 and 10 years respectively.
Limb salvage rate 69%.
• No improved survival in the experimental arms
Overall survival data
As discussed in JCO, 9/2008
Jaffe N and Gorlick R, JCO 2008; 26: 4365
A Midsummer Night’s Dream, I, i (1595-96)
• Lysander: Ay me! for aught that I could ever read,
Could ever hear by tale or history,
The course of true love never did run smooth;
But either it was different in blood—
• Hermia: O cross! too high to be enthrall'd to low.
• Lysander: Or else misgraffèd in respect of years—
• Hermia: O spite! too old to be engag'd to young.
• Lysander: Or else it stood upon the choice of friends—
• Hermia: O hell! to choose love by another's eyes.
• These data suggest that while active, HD MTX may not add to the dox-cis
backbone. Are we selecting the already sensitive tumors?
• Can new data move the field? (Maybe not late on the last day of the
meeting.)
Finale
KLEMKE WINS!
Democrat Alan Klemke Becomes Wichita's 4th District Alderman
WICHITA, KS, 4 November 2008—In a thrilling conclusion to one of the longest and most anticipated
elections in U.S. history, charismatic Democrat Alan Klemke defeated opponent Carl Ferguson
to become the new alderperson for Wichita's 4th District.
Latest Cheney Tape May Contain Evidence Of
His Whereabouts
WASHINGTON, 6 November 2008—Reports surfaced Tuesday
that the New York–based Fox News Channel has obtained a tape
which purportedly features another cryptic video message from
U.S. vice president and known extremist Dick Cheney, widely
regarded as the most feared man in America.
International Con Man Barack Obama Leaves U.S. With $85
Million In Campaign Fundraising (11 Nov 2008)
Next year is just around the corner
Othello, III, iii (1604)
Othello: Excellent wretch! Perdition catch my soul
But I do love thee! and when I love thee not, Chaos is
come again.
London, 2008?
MacBeth, I, i (1605-06, 1st perf. 1611 Globe Theatre)
• 1st Witch: "When shall we three meet again
In thunder, lightning, or in rain?"
Miami, 2009
Sonnet XVIII (1609)
Shall I compare thee to a summer's day?
Thou art more lovely and more temperate:
Rough winds do shake the darling buds of May,
And summer's lease hath all too short a date:
Sometime too hot the eye of heaven shines,
And often is his gold complexion dimm'd;
And every fair from fair sometime declines,
By chance or nature's changing course untrimm'd;
But thy eternal summer shall not fade
Nor lose possession of that fair thou owest;
Nor shall Death brag thou wander'st in his shade,
When in eternal lines to time thou growest:
So long as men can breathe or eyes can see,
So long lives this and this gives life to thee.
Also moving from London to Miami…
• The limpid words of England give way to the
doggerel of Tin Pan Alley
• The Taming of the Shrew was incorporated into Cole
Porter’s Kiss Me, Kate (Book: Samuel and Bella
Spewack), opening December 30, 1948
• In one scene, the boss of the mobsters, with a debt
to collect from one of the principals, is killed. The
mobsters then have no bone to pick with the
principal, but don’t leave without singing:
CTOS 2009
Eden Roc Hotel
November 4 – 7, 2009