Haesun Choi

Correlation of Computed Tomography and Positron Emission Tomography in Patients With Metastatic Gastrointestinal Stromal Tumor Treated at a Single Institution With Imatinib Mesylate: Proposal of New Computed Tomography Response Criteria

PURPOSE Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating gastrointestinal stromal tumors (GISTs) treated with imatinib. This study evaluates whether computed tomography (CT) findings of GIST after imatinib treatment correlate with tumor responses by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and develops reliable, quantitative, CT response criteria. PATIENTS AND METHODS A total of 172 lesions selected by RECIST were evaluated in 40 patients with metastatic GISTs treated with imatinib. All patients had pretreatment and 2-month follow-up CTs and FDG-PETs. Multivariate analysis was performed using tumor size and density (Hounsfield unit [HU]) on CT and maximum standardized uptake value (SUVmax) on FDG-PET. Patients were observed up to 28 months. RESULTS Mean baseline tumor size and density on CT were 5.3 cm and 72.8 HU, respectively, and mean baseline SUVmax on FDG-PET was 5.8. Thirty-three patients had good response on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST. Good responders on CT at 2 months had significantly longer time to progression than those who did not respond (P = .01). CONCLUSION Small changes in tumor size or density on CT are sensitive and specific methods of assessing the response of GISTs. If the prognostic value of our proposed CT response criteria can be confirmed prospectively, the criteria should be employed in future studies of patients with GIST.

We Should Desist Using RECIST, at Least in GIST

PURPOSE Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating imatinib-treated gastrointestinal stromal tumors (GISTs). Response by Choi criteria, a 10% decrease in size or a 15% decrease in density on contrast-enhanced CT, correlated well in a small training set of patients who showed response as measured by positron emission tomography, and was more predictive of time to tumor progression (TTP) than response by RECIST. This study was designed to validate these observations in an independent data set. PATIENTS AND METHODS Fifty-eight patients with imatinib-treated GISTs were evaluated by RECIST and Choi criteria. TTP was compared with TTP in the training set. Patients were analyzed initially with follow-up to 28 months, extended to 60 months for survival analysis. RESULTS Patients who met Choi response criteria on CT at 2 months had significantly better TTP than those who did not (P = .0002), whereas response group by RECIST was not significantly correlated with TTP. Even when the 98 patients from both sets were analyzed together, the response group by RECIST did not correlate significantly with TTP, whereas response group by Choi criteria did correlate significantly with TTP. Disease-specific survival (DSS) was also significantly correlated with response group by Choi criteria (P = .04), but not with response group by RECIST. CONCLUSION Choi response criteria are reproducible, more sensitive, and more precise than RECIST in assessing the response of GISTs to imatinib mesylate. Response by Choi criteria, unlike response by RECIST, correlates significantly with TTP and DSS. Response by Choi criteria should be incorporated routinely into future studies of GIST therapy. We should desist using RECIST, at least in GIST.

Early and late complications after radiofrequency ablation of malignant liver tumors in 608 patients

Background:Radiofrequency ablation (RFA) has become a common treatment of patients with unresectable primary and secondary hepatic malignancies. We performed this prospective analysis to determine early (within 30 days) and late (more than 30 days after) complication rates associated with hepatic tumor RFA. Methods:All patients treated between January 1, 1996 and June 30, 2002 with RFA for hepatic malignancies were entered into a prospective database. Patients were evaluated during RFA treatment, throughout the immediate post RFA course, and then every 3 months after RFA to assess for the development of treatment-related complications. Results:A total of 608 patients, 345 men (56.7%) and 263 women (43.3%), with a median age of 58 years (range 18–85 years) underwent RFA of 1225 malignant liver tumors. Open intraoperative RFA was performed in 382 patients (62.8%), while percutaneous RFA was performed in 226 (37.2%). The treatment-related mortality rate was 0.5%. Early complications developed in 43 patients (7.1%). Early complications were more likely to occur in patients treated with open RFA (33 [8.6%] of 382 patients) compared with percutaneous RFA (10 [4.4%] 226 patients, P < 0.01), and in patients with cirrhosis (25 [12.9%] complications in 194 patients) compared with noncirrhotic patients (31 [7.5%] complications in 414 patients, P < 0.05). Late complications arose in 15 patients (2.4%) with no difference in incidence between open and percutaneous RFA treatment. The combined overall early and late complication rate was 9.5%. Conclusions:Hepatic tumor RFA can be performed with low mortality and morbidity rates. Though relatively rare, late complications can develop and physicians performing hepatic RFA must be cognizant of these delayed treatment-related problems.

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.

Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor

Hemangiopericytomas and malignant solitary fibrous tumors (HPC/SFT) are rare, closely related sarcomas with unpredictable behavior that respond infrequently to chemotherapy. An optimal systemic treatment strategy for advanced HPC/SFT has not yet been identified.

MR Imaging for Preoperative Evaluation of Primary Rectal Cancer: Practical Considerations

High-resolution magnetic resonance (MR) imaging plays a pivotal role in the pretreatment assessment of primary rectal cancer. The success of this technique depends on obtaining good-quality high-resolution T2-weighted images of the primary tumor; the mesorectal fascia, peritoneal reflection, and other pelvic viscera; and superior rectal and pelvic sidewall lymph nodes. Although orthogonal axial high-resolution T2-weighted MR images are the cornerstone for the staging of primary rectal cancer, high-resolution sagittal and coronal images provide additional value, particularly in tumors that arise in a redundant tortuous rectum. Coronal high-resolution T2-weighted MR images also improve the assessment of nodal morphology, particularly for superior rectal and pelvic sidewall nodes, and of the relationship between advanced-stage tumors and adjacent pelvic structures. Rectal gel should be used in MR imaging examinations conducted for the staging of polypoid tumors, previously treated lesions, and small rectal tumors. However, it should not be used in examinations performed to stage large or low rectal tumors. Diffusion-weighted imaging is useful for identifying nodes and, occasionally, the primary tumor when the tumor is difficult to visualize with other sequences. Three-dimensional T2-weighted imaging provides multiplanar capability with a superior signal-to-noise ratio compared with two-dimensional T2-weighted imaging.

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

Germ‐line mutations in the KIT receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). There is limited information from large kindreds regarding median age at diagnosis, detailed histopathology, clinical effects of imatinib therapy and chromosomal abnormalities of the KIT gene. We identified a large kindred with GIST. Each family member was interviewed and appropriate medical records and radiographic imaging were obtained. Archival tumor tissue was obtained to confirm diagnosis, extract genomic DNA and perform fluorescent in situ hybridization cytogenetics of the KIT gene. Fifteen of 79 individuals with GIST were identified in this kindred. There were 8 males, the mean age at diagnosis was 53.9 (range 45–71) years. Histopathology revealed microscopic proliferation and nodularity in the myenteric plexus, spindled morphology, diffuse Kit but variable CD34 staining and low mitotic rates in the setting of metastatic disease. A deletion of codon 579 in exon 11 of the KIT gene was identified in tumor and normal tissue of this family. Mutation and cytogenetic analysis revealed homozygous loss of the wild‐type KIT sequence in tumor from one individual. Four of 4 individuals treated with imatinib are alive and without progression while 9 of 11 individuals not treated with imatinib are deceased. This study describes a kindred with a propensity to develop GIST in an autosomal dominant pattern. Germ‐line deletion of KIT codon 579 in GIST is associated with clinical benefit from imatinib, limited utility of mitoses to predict malignant potential, and a novel homozygous deletion of this codon in one individual.

MR Imaging of Prostate Cancer in Radiation Oncology: What Radiologists Need to Know

Radiation therapy (RT) is one of the principal treatment modalities for localized or locally advanced prostate cancer. The two major forms of RT for prostate cancer are external-beam RT (EBRT) with a photon or proton beam and brachytherapy. With modern conformal techniques for EBRT (three-dimensional conformal RT, intensity-modulated RT, and image-guided RT) and advanced computer-based planning systems for brachytherapy, the dose can be more precisely delivered to the prostate while reducing unnecessary radiation to normal tissue. The dominant intraprostatic tumor can be targeted with a higher dose, so-called dose painting. Magnetic resonance (MR) imaging plays a pivotal role in pretreatment assessment of prostate cancer. Multiparametric MR imaging, a combination of anatomic and functional MR imaging techniques (diffusion-weighted imaging, dynamic contrast material-enhanced imaging, and MR spectroscopy), significantly improves the accuracy of tumor localization and local staging. For pretreatment planning, anatomic MR imaging provides highly accurate local staging information, particularly about extraprostatic extension and seminal vesicle invasion. The dominant intraprostatic tumor and local recurrence in the prostatectomy bed can be better localized with multiparametric MR imaging for dose painting. MR imaging allows excellent delineation of the contours of the prostate and surrounding structures. It can also be used in early posttreatment evaluation after brachytherapy.

Optimization of MR Imaging for Pretreatment Evaluation of Patients with Endometrial and Cervical Cancer

Endometrial and cervical cancer are the most common gynecologic malignancies in the world. Accurate staging of cervical and endometrial cancer is essential to determine the correct treatment approach. The current International Federation of Gynecology and Obstetrics (FIGO) staging system does not include modern imaging modalities. However, magnetic resonance (MR) imaging has proved to be the most accurate noninvasive modality for staging endometrial and cervical carcinomas and often helps with risk stratification and making treatment decisions. Multiparametric MR imaging is increasingly being used to evaluate the female pelvis, an approach that combines anatomic T2-weighted imaging with functional imaging (ie, dynamic contrast material-enhanced and diffusion-weighted imaging). MR imaging helps guide treatment decisions by depicting the depth of myometrial invasion and cervical stromal involvement in patients with endometrial cancer and tumor size and parametrial invasion in those with cervical cancer. However, its accuracy for local staging depends on technique and image quality, namely thin-section high-resolution multiplanar T2-weighted imaging with simple modifications, such as double oblique T2-weighting supplemented by diffusion weighting and contrast enhancement.

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

Activating mutation in KIT or platelet-derived growth factor-α can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6–13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S- and G2 phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination.