Publications: Peer reviewed
To date over 500 Peer Review articles have been published on the clinical findings supporting the clinical efficacy of PathFinderTG®. For your reference we have provided a .pdf file of the complete list of all the clinical publications.
In addition, we have cataloged and listed related articles in specialty bibliographies for the following areas:
- Topographic Genotyping
- Fractional Allelic Loss
- Barrett's Esophagus
- Molecular/Genetic Analysis of Glioma
- Molecular/Genetic Analysis of Pancreatic Cancer
- Molecular/Genetic Analysis of Liver Cancer
The following are a few sample synopses of articles in the area of Pancreas, Brain and Metastatic vs. New Primary:
Lapkus O, Gologan O, Liu Y, Swalsky P, Wilson M, Finkelstein S, Silverman J. Determination of sequential mutational accumulation in pancreas and bile duct brushing cytology. Modern Pathology 2006 19, 907-913
This was a retrospective single center study involving archived cytology specimens from 61 patients with pancreaticobiliary disease (40 pancreatic and 21 biliary duct brushings). Microdissection, PCR amplification and loss of heterozygosity determination/gene sequencing were performed detecting and quantifying the extent of mutational change for each marker. The analysis included cytology cohorts diagnosed microscopically as normal, atypical cells, suspicious for cancer and definitively cancer. Findings of surgical excision were included in the correlative analysis.
- All cytology brushings definitively diagnosed as cancer showed four or more, high amplitude (significantly clonally expanded) mutations.
- All cases assessed by cytology as atypical or suspicious could be definitively and objectively assigned to categories of no dysplasia, low grade dysplasia, high grade dysplasia or malignancy based on cumulative amounts and extent of clonal expansion.
- A significant proportion of patients with normal appearing or atypical appearing cytology showed acquired mutation sufficient for classification as low grade dysplasia.
- Mutation acquisition, in general, preceded the overt morphologic expression of neoplasia.
Khalid A. Pal R. Sasatomi E. Swalsky P. Slivka A. Whitcomb D. Finkelstein S. Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples. Gut. 2004: 53 (12):1860-5
PathFinderTG analysis was performed on 26 patients with pancreaticobiliary strictures. The reference standard was subsequent surgical resection performed on all patients. Brush cytology diagnosed malignancy in 8, was indeterminate in 10 and was negative for cancer in 8.
- Nine patients confirmed to have malignancy were correctly diagnosed as having cancer by PathFinderTG using objective molecular criteria.
- Remaining patients proving not to have cancer were correctly diagnosed as such by PathFinderTG as their cytology failed to meet the minimum molecular criteria for malignancy.
Khalid A, McGrath K, Zahid M, Wilson M, Brody D, Swalsky P, Moser A, Lee K, Slivka A, Whitcomb D, Finkelstein S. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clinical Gastroenterology and Hepatology 2005:3: 967-973
This study was prospective and involved endoscopic ultrasound guided pancreatic cyst aspirates collected over a 19 month period. 31 of these patients ultimately underwent surgery allowing for a comparison of pathology results after surgery and assessment of earlier cyst fluid aspirate analysis. Technical characteristics of molecular analysis were evaluated. Molecular parameters including DNA amount and quality, as well as k-ras-2 oncogene point mutation and allelic imbalance (LOH) mutations of a broad panel of associated tumor suppressor genes in pancreatic neoplasia were compared to traditional predictors of disease such as carcinoembryonic antigen.
- Malignant cyst fluid provided enough DNA to perform mutational analysis in an accurate and reliable manner complementing with, and not interfering with, cytology and/or histopathology evaluation.
- Molecular analysis was statistically superior to conventional diagnosis based on cytology and cyst fluid levels of carcinoembryonic antigen.
- K ras mutation followed by allelic loss was predictive of a malignant cyst (91% sensitivity 93% specificity). Molecular determination of the temporal sequence of k-ras-2 oncogene point mutation acquisition in relationship to other acquired allelic
- Imbalance (LOH) mutations was found to be a powerful indicator of cystic disease etiology and biological aggressiveness.
- PathFinderTG analysis provided discriminating information otherwise not available by current pathology evaluation of aspirated pancreatic cyst fluid.
Mohan D, Finkelstein S, Swalsky P, Sasatomi E, Wiley C, Hamilton R, Leiberman F, Couce M Microdissection of gliomas: therapeutic and prognostic considerations. Modern Pathology 2004 17 1346-1358
197 gliomas from the three institutions (University of Pittsburgh Medical Center, Allegheny General Hospital, and Duke University Medical Center) were prospectively analyzed by PathFinderTG. All these samples had histological classification and WHO grading assigned. Topographic genotyping was performed involving five genomic regions in proximity to known tumor suppressor genes. Also evaluated were genomic loci known or suspected to undergo deletional damage in gliomas and associated with anaplastic transformation. Deletions affecting chromosome arms 1p and 19q were also assessed using a panel of markers capable of discriminating between interstitial versus telomeric deletion of 1p. The reference standard to which PathFinderTG was compared was histopathology, as well as clinical and imaging features supporting either high grade or low grade status. The reference standard also included outcome as determined by response to therapy reflected by tumor size on imaging at six months.
- The level of anaplasia on histology correlates in a highly significant manner with the extent of mutational acquisition (p<.0001).
- This study confirmed the established role of 1p/19q loss as a predictor of treatment responsiveness, however the study demonstrated that 1p loss is more accurately ascertained by determining its temporal sequence and genomic extent of mutation acquisition.
- PathFinderTG accurately predicted treatment responsiveness and biological aggressiveness better than histopathology alone.
McLendon, R 1; Swalsky, P 2; Finkelstein, S. Relationship of the pattern of 1p/19q allelic loss to the histological type of glioma. Journal of Neuropathology & Experimental Neurology. 2004: 63(5):551
This prospective analysis of 54 patients from Duke University correlated PathFinderTG with outcomes, including disease free interval and overall survival for patients with cerebral gliomas. The study was specifically designed to determine whether the additional molecular analysis of genomic extent of 1p deletion could significantly improve prediction of favorable treatment responsiveness in glioma patients as measured on two year follow-up.
- Patients whose gliomas showed telomeric deletion across the terminal half of chromosome 1p manifested a significantly better outcome than patients whose glioma either lacked 1p/19q deletion or 1p deletion was present but limited to a single interstitial genomic site.
- The use of a four marker panel from 1p22 to 1pter was sufficient to fully separate favorable and unfavorable responsiveness groups with respect to interstitial versus telomeric 1p deletion.
- It was not possible to predict the genomic extent of 1p/19q deletion by microscopic examination alone.
Rolston, R K 1; Maciunas, R 1; Finkelstein, S D 2; Swalsky, P A 3; Sagar, S 1; Cohen, M L. Topographic distribution, genomic pattern and timing of 1p allelic loss predicts treatment responsiveness in gliomas. Journal of Neuropathology & Experimental Neurology. 2004: 63(5):550
A retrospective analysis of gliomas from Case Western Reserve University correlated the presence and extent of 1p genomic deletion as measured by broad panel mutational analysis for allelic imbalance versus fluorescent in-situ hybridization (FISH) using a single probe (Vysis) situated at 1p36. Molecular findings were correlated with outcome as determined by survival and tumor recurrence following initial treatment.
- FISH failed to detect interstitial genomic deletion in gliomas that fell outside of 1p36 leading to a significant false negative error rate.
- FISH failed to account for oligodendroglial growth in a glioma whereas LOH analysis identified at least interstitial deletion in all cases with such growth.
- LOH analysis was objective and avoided sampling errors that were major limitations in the application of FISH.
Metastatic vs. New Primary
Dacic S. Ionescu DN. Finkelstein S. Yousem SA. Patterns of allelic loss of synchronous adenocarcinoma of the lung. American Journal of Surgical Pathology. 2005: 29(7):897-902
This study addresses a fundamental weakness in the current pathology staging of lung cancer. When two or more nodules of lung cancer are present synchronously or metachronously, current staging assumes this to represent metastatic spread of one cancer. The study involved 80 lung cancer patients with individual and multiple tumors undergoing PathFinderTG genotyping using a broad panel of markers associated with lung cancer formation.
- A significant proportion of patients with multiple nodules of lung cancer, in fact, could be shown to have multicentric new primary cancer formation and not metastatic spread.
- The current pathologic staging of lung cancer should recognize the reality of multiple primary cancer formation with appropriate downstaging for better treatment.
Hunt JL. Finkelstein SD. Microdissection techniques for molecular testing in surgical pathology. Archives of Pathology & Laboratory Medicine. 2004: 128(12):1372-8
This review describes the valuable role that PathFinderTG plays in fully resolving indeterminate diagnosis and the need for better information in modern surgical pathology practice.
- PathFinderTG is described in its capacity to fully define the relationship between two or more separate sites of cancer formation.
- PathFinderTG is described with respect to the information derived from specific cancers to resolve issues such as grade of dysplasia, reactive versus neoplastic cell proliferation and to effectively predict the biological aggressiveness of cancer.
- PathFinderTG is used to fully resolve issues related to floater contamination and labeling mix-ups of specimens.
Finkelstein PA, Finkelstein SD, Wilson MM, Vogel VG, Definitive discrimination of cancer recurrence/metastasis versus de novo cancer formation: New primary versus metastasis discrimination. American Society of Clinical Oncology Abstract, San Diego, 2005
The report was presented as an oral presentation at this national meeting. PathFinderTG was performed prospectively on 278 patients in whom the diagnosis of recurrence/metastasis versus new primary cancer remained in doubt after full microscopic examination, including special stains. The reference standard was clinical follow-up which extended up to 5 years.
- PathFinderTG accurately resolved the diagnostic issue in all cases.
- Microscopic examination was unreliable and subjective in interpretation. Comparative mutational profiling should serve as the gold standard for addressing this issue.