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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

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Poster discussion iii

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
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
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



Question 1

Question 1

How do you distinguish aneuploid sarcomas of a given histology?


34824 leiomyosarcoma phosphokinome page 71 of program
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
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
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

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
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
Outcomes chemotherapy, and outcome (p. 71)

Median follow up 41.5 months (12-118).

n = 41 :

Response22 (54%)

Progression15 (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
Volume change and OS chemotherapy, and outcome (p. 71)

p=0.01


No correlation between volume change and necrosis
No correlation between volume change and necrosis chemotherapy, and outcome (p. 71)

*One outlier (85%,+931%) is not shown on the graph.


Comments
Comments chemotherapy, and outcome (p. 71)

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
King John chemotherapy, and outcome (p. 71), 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

Question 3 chemotherapy, and outcome (p. 71)

How quickly do GIST patients respond to imatinib in the neoadjuvant setting?


35131 trent et al preop imatinib for gist p 87
35131 Trent et al.: Preop imatinib for GIST (p. 87) chemotherapy, and outcome (p. 71)

  • 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
Disease free survival curve chemotherapy, and outcome (p. 71)


The tempest ii i approx 1611
The Tempest, II, i chemotherapy, and outcome (p. 71)(approx. 1611)

  • Antomo:. . . Who's the next heir of Naples?

  • Sebastian:Claribel.

  • Antonio:She that is Queen of Tunis; she that dwellsTen leagues beyond man's life; she that from NaplesCan have no note, unless the sun were post—The Man i' th' Moon's too slow—till new-born chinsBe rough and razorable; she that from whomWe all were sea-swallow'd, though some cast again(And by that destiny) to perform an actWhereof 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

Question 4 chemotherapy, and outcome (p. 71)

What are promising new combinations of targeted and cytotoxic systemic therapeutics?


34863 lopez et al synergy of hdac inhibitors and chemotherapy p 72 73
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
HDAC vs. sarcoma cell lines chemotherapy (p. 72-73)(colony formation)


RAD51 chemotherapy (p. 72-73) 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, V, ii chemotherapy (p. 72-73)(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

Question 5 chemotherapy (p. 72-73)

What is the follow up on a promising proapoptotic antibody?


35010 chawla et al anti dr5 mab phase ii p 80
35010 Chawla et al. anti-DR5 mAb phase II (p. 80) chemotherapy (p. 72-73)

  • 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
35010 Chawla et al. anti-DR5 mAb phase II chemotherapy (p. 72-73)

  • 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
Two quotations chemotherapy (p. 72-73)

All’s Well that Ends Well, II, i (1602-03)

  • Helena: "Oft expectation fails, and most oft thereWhere most it promises; and oft it hitsWhere 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

Question 6 chemotherapy (p. 72-73)

What remains controversial regarding sarcoma management?


35001 whelan et al rx of pleo rms p 79
35001 Whelan et al. Rx of Pleo RMS (p.79) chemotherapy (p. 72-73)

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
Midsummer Night’s Dream, IV, I (1595-1596) chemotherapy (p. 72-73)

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
35060 Whelan et al. Three EOI randomized studies (p.84) chemotherapy (p. 72-73)

  • 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
Overall survival data chemotherapy (p. 72-73)


As discussed in jco 9 2008
As discussed in JCO, 9/2008 chemotherapy (p. 72-73)

Jaffe N and Gorlick R, JCO 2008; 26: 4365


A midsummer night s dream i i 1595 96
A Midsummer Night’s Dream, I, i chemotherapy (p. 72-73)(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

Finale chemotherapy (p. 72-73)


Klemke wins democrat alan klemke becomes wichita s 4th district alderman
KLEMKE WINS! chemotherapy (p. 72-73)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
Latest Cheney Tape May Contain Evidence Of His Whereabouts chemotherapy (p. 72-73)

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
International Con Man Barack Obama Leaves U.S. With $85 Million In Campaign Fundraising (11 Nov 2008)


Next year is just around the corner
Next year is just around the corner Million In Campaign Fundraising (11 Nov 2008)

Othello, III, iii (1604)

Othello: Excellent wretch! Perdition catch my soulBut I do love thee! and when I love thee not, Chaos is come again.


London 2008
London, 2008? Million In Campaign Fundraising (11 Nov 2008)

MacBeth, I, i (1605-06, 1st perf. 1611 Globe Theatre)

  • 1st Witch: "When shall we three meet againIn thunder, lightning, or in rain?"


Miami 2009
Miami, 2009 Million In Campaign Fundraising (11 Nov 2008)

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
Also moving from London to Miami… Million In Campaign Fundraising (11 Nov 2008)

  • 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

CTOS 2009 Million In Campaign Fundraising (11 Nov 2008)

Eden Roc Hotel

November 4 – 7, 2009


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