Raphael E. Pollock

A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors

KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.

Solitary fibrous tumor: a clinicopathological study of 110 cases and proposed risk assessment model

Solitary fibrous tumor represents a spectrum of mesenchymal tumors, encompassing tumors previously termed hemangiopericytoma, which are classified as having intermediate biological potential (rarely metastasizing) in the 2002 World Health Organization classification scheme. Few series have reported on clinicopathological predictors with outcome data and formal statistical analysis in a large series of primary tumors as a single unified entity. Institutional pathology records were reviewed to identify primary solitary fibrous tumor cases, and histological sections and clinical records reviewed for canonical prognostic indicators, including patient age, tumor size, mitotic index, tumor cellularity, nuclear pleomorphism, and tumor necrosis. Patients (n=103) with resected primary solitary fibrous tumor were identified (excluding meningeal tumors). The most common sites of occurrence were abdomen and pleura; these tumors were larger than those occurring in the extremities, head and neck or trunk, but did not demonstrate significant outcome differences. Overall 5- and 10-year metastasis-free rates were 74 and 55%, respectively, while 5- and 10-year disease-specific survival rates were 89 and 73%. Patient age, tumor size, and mitotic index predicted both time to metastasis and disease-specific mortality, while necrosis predicted metastasis only. A risk stratification model based on age, size, and mitotic index clearly delineated patients at high risk for poor outcomes. While small tumors with low mitotic rates are highly unlikely to metastasize, large tumors ≥15u2009cm, which occur in patients ≥55 years, with mitotic figures ≥4/10 high-power fields require close follow-up and have a high risk of both metastasis and death.

Epithelioid sarcoma: results of conservative surgery and radiotherapy.

PURPOSEnTo determine the outcome and prognostic factors for patients with localized epithelioid sarcoma treated with conservative surgery and radiotherapy (RT).nnnMETHODS AND MATERIALSnThe medical records of 24 patients with nonmetastatic epithelioid sarcoma treated with conservative surgery and RT were reviewed. Preoperative RT was given to 3 patients (median 46.4 Gy) and postoperative RT to 21 patients (median 64.5 Gy). A local (limb-sparing) surgical procedure was performed in all patients.nnnRESULTSnAt a median follow-up of 131 months, 14 patients had relapsed and 13 patients had died. The actuarial overall and disease-free survival rate at 10 years was 50% and 37%, respectively. Local, nodal, and metastatic failure occurred in 7, 4, and 10 patients, respectively, yielding a 10-year actuarial local, nodal, and metastatic control rate of 63%, 81%, and 56%, respectively. Univariate analysis revealed that size < or =5 cm and extremity location were favorable prognostic factors for overall, disease-free, and metastasis-free survival. The actuarial 5-year overall, disease-free, and metastasis-free survival rate was 79% vs. 25% (p = 0.002), 51% vs. 13% (p = 0.03), and 79% vs. 13% (p <0.001), respectively, for lesion size < or =5 vs. > 5 cm. The actuarial 5-year overall, disease-free, and metastasis-free survival rate was 77% vs. 39% (p = 0.002), 56% vs. 0% (p = 0.01), and 78% vs. 17% (p = 0.01), respectively, for extremity vs. nonextremity location. Multivariate analysis of the factors correlating with the overall, disease-free, and metastasis-free survival confirmed the favorable prognostic significance of small lesion size. The prognostic significance of extremity location on univariate analysis was explained by an imbalance in the mean tumor sizes.nnnCONCLUSIONSnEpithelioid sarcoma is an aggressive soft-tissue sarcoma, with high rates of local and distant relapse. Local control with conservative surgery and RT compares favorably to published surgical series. The poor outcome for tumors > or =5 cm in size emphasizes the need for effective systemic therapy.

A prospective evaluation of isolated limb perfusion with doxorubicin in patients with unresectable extremity sarcomas

S: PLENARY and PARALLEL SESSIONS 2 of 5 animals showing a complete response out to 60 days). There was no significant change in tumor LPAM concentration with addition of heat. Average proliferation index following ILP with saline, saline + HT, LPAM, or LPAM + HT was 40%, 28%, 27%, and 16% respectively. CONCLUSIONS: Administration of LPAM with increasing amounts of localized heat yielded increasing growth delay and decreased proliferative index. This demonstrates that the application of hyperthermia, rather than the prevention of hypothermia, is the cause for enhanced therapeutic effect in HILE The interaction between HT and melphalan was synergistic. This interaction could not be explained by increased uptake of drug with the addition of heat. These findings underscore the importance of the use of HT in regional chemotherapy.

Soft Tissue Sarcoma of the Head and Neck

Risk Assessment Models The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Soft Tissue Sarcoma of the Trunk and Extremities

Risk Assessment Models The AJCC has recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step forward towards the goal of precision medicine, this work was only very recently published. For this reason, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Training for careers in academic surgical oncology: The future is bright

Heslin and colleagues have examined the academic status, clinical activities, and practice patterns of surgeons who graduated from the Memorial Sloan-Kettering Cancer Center Surgical Oncology Fellowship between 1983 and 1996. The purpose of this analysis, presented in this issue of Annals of Surgical Oncology, was to test the hypothesis that surgical oncology fellowships are a viable pathway to academic surgical careers. Grist for the analytic mill was derived from a questionnaire sent to all fellowship graduates from the years listed above. A response rate of 99% was obtained, indicating the interest of nearly all of the former fellows to “stand up and be counted.” Evidence of success in training academic surgeons can be derived from a careful read of the data. While most former fellows are working 70–75 hours a week, their overall mean job satisfaction was 4.2 on a scale of 1–5, with a median value of 5.0. Seventy-one percent are still employed in their first job, and 72% were still in academic positions 8 years after finishing their fellowship. Moreover, 27% are now associate professors, which suggests that a definable academic career trajectory is being pursued. The data from the Memorial Sloan-Kettering Cancer Center remarkably parallels the experience at the University of Texas MD Anderson Cancer Center, where 79 fellows have graduated from the Surgical Oncology Fellowship from 1986 through 1999. Of these 79 fellows, 63 (80%) are in geographic full-time academic surgical positions. Thirteen (16%) of 79 fellows switched positions at least once, with only 5 (38%) of these 13 moving from academic to private practice opportunities. Moreover, 28 (44%) of the 63 former Anderson fellows in academic positions have received or are currently funded by peer reviewed extramural mechanisms such as grants from the NIH, the American Cancer Society, or other professional organizations. Why do young surgeons aspire to fellowship positions? There seem to be both positive and negative motivators. Among the positive factors is a desire to increase knowledge and clinical management skills for certain specific diseases. Another consideration may be to focus academic pursuits and gain the clinical and research skills needed to succeed in the academic arena. On the negative side, Heslin et al. suggest that during the standard 5 years of general residency training, applicants realize that it is difficult to develop a focused clinical and academic identification with one or two malignant diseases. We suggest that there are additional positive drives for fellowship training that are now emerging. Preeminent among these goals is the desire to learn contemporary multimodality oncology care. This intent is fueled by the realization that as we enter the next millenium, solid tumor care is unequivocally multimodality. Increasingly, those in academic surgical oncology will find that they are under pressure (much of it self-imposed) to define themselves as oncologists who use surgery as their therapeutic modality rather than as surgeons who happen to operate on cancer patients. Surgical oncologists must understand all aspects of multimodality cancer management to maintain a leadership role in patient care and treatment planning. The second major goal of surgical oncology fellowship training must be to acquire familiarity with molecular medicine if one is interested in being a part of the “cutting edge” in the next generation of academic surgical oncologists. Knowledge about how genes regulate (or dysregulate) cognate protein production is necessary to understand molecular diagnostics as well as gene-based therapies that will become an integral part of the cancer Received June 10, 1999; accepted June 11, 1999. From the Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas. Address correspondence to: Raphael E. Pollock, MD, PhD, Department of Surgical Oncology, Box 106, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; Fax: 713-792-4689; E-mail: rpollock@notes.mdacc.tmc.edu Annals of Surgical Oncology, 6(6):517–518 Published by Lippincott Williams & Wilkins

Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs

Risk Assessment Models The AJCC has recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step forward towards the goal of precision medicine, this work was only very recently published. For this reason, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Soft Tissue Sarcoma – Unusual Histologies and Sites

Emerging Prognostic Factors for Clinical Care The Cancer Genome Atlas and other efforts have genomically characterized several sarcomas. These data, however, do not yet have an impact on prognosis or definitive predictive value for response to treatment to date. For example, it is recognized that mutations in TP53 and CDKN2A are common in aneuploid tumors, but the data regarding these alterations and their impact on staging and treatment remain too sparse to form any recommendations.