KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4132-4132 ◽  
Author(s):  
W. De Roock ◽  
J. De Schutter ◽  
G. De Hertogh ◽  
M. Janssens ◽  
B. Biesmans ◽  
...  
Keyword(s):  
Tumor Size ◽  
Kras Mutation ◽  
Objective Response ◽  
Complete Response ◽  
Rapid Onset ◽  
Colorectal Cancers ◽  
Tumor Shrinkage ◽  
Kras Mutations ◽  
Exon 2 ◽  
Early Tumor

4132 Background: A recent study has shown that the presence of a KRAS mutation is associated with the absence of objective response to cetuximab (CTX) in advanced colorectal cancers (mCRC). Our hypothesis was that CTX cannot induce any tumor shrinkage in KRAS mutant mCRC. Methods: We analyzed KRAS exon 2 mutation status by Taqman, PCR and sequencing on 37 available tumor samples from patients with mCRC progressive on chemotherapy. Twenty patients received CTX combined with irinotecan (BOND) and 17 received CTX in monotherapy (7 BOND, 10 SALVAGE). We measured the change in tumor size between baseline and the consecutive evaluations. At week 12 and at week 24, we statistically tested the change from baseline between the groups with KRAS wild type (WT) and KRAS mutation (MUT) using the t-test. RECIST criteria for tumor response were used. Results: 3 patients had progressive disease (PD), 26 stable disease (SD), 8 partial response (PR) and 0 complete response. A KRAS MUT was found in 17 tumors (46%): 2 in PD (66.7%), 15 in SD (57.7%) and none in PR patients (p<0.01; responders vs. non responders). At 12 weeks there was a mean decrease in tumor size of 23.1% (SE=7.38) in the KRAS WT and an increase of 2.6% (SE=4.13) in the KRAS MUT mCRC. At 24 weeks KRAS WT and MUT mCRC had a 45.8% (SE=8.61) and a 1.3% (SE=6.67) mean decrease respectively (p= 0.0081 at 12 weeks; p=0.0015 at 24 weeks). The mean tumor size of the KRAS WT did not decrease further after 24 weeks. In the subgroup of SD tumor size regression was observed but only in WT patients. Mean time to progression was 32 (range 12–96) and 30 weeks (range 12–84) for KRAS WT (SD + PR) and MUT respectively. Conclusion: We confirmed KRAS MUT precludes objective response to CTX in mCRC. In addition we found tumor size regression in SD patients being restricted to WT patients. We observed rapid onset of these differences suggesting an important role of KRAS MUT status in early tumor shrinkage. However the onset of progression was not different according to KRAS MUT status. [Table: see text]

scholarly journals KRAS gene mutation in patients with primary colorectal cancer

Acta Medica ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 20-25
Author(s):  
Minh Thuc Vu Thi ◽  
Van Thieu Le ◽  
Quang Huy Huynh ◽  
Minh Duc Nguyen
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Kras Mutation ◽  
Pcr Amplification ◽  
Colorectal Cancers ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Keywords Colorectal Cancer

Objective: KRAS mutation occurs in 30% to 50% of colorectal cancers. The aim of our study was to determine the frequency of KRAS mutations among patients with colorectal cancer; and the relationship with clinicopathologic features. Materials and Methods: 79 colorectal cancer cases at a hospital in Hai Phong of Vietnam were collected, including 45 colon cancer and 34 rectal cancer during January 2010 and July 2012. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene. The study was based on informed consent and approval by the Ethics Committee of Viet Tiep Hospital. Results: KRAS mutation was found in 40.4% (225/557) colorectal cancer. All mutation locations were in codon 12. There was significant association (p < 0.05) between KRAS mutations, tumor size and tumor stage. No significant association was observed between KRAS mutations and gender, tumor location, tumor grade or histologic presence of mucin (p>0.05). Conclusion: Determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers Keywords: colorectal cancer, KRAS gene mutation, clinicopathology.

scholarly journals IMPACT OF KRAS MUTATIONS IN CLINICAL FEATURES IN COLORECTAL CANCER

2020 ◽  
Vol 33 (3) ◽  
Author(s):  
Renato Morato ZANATTO ◽  
Gianni SANTOS ◽  
Júnea Caris OLIVEIRA ◽  
Eduardo Marcucci PRACUCHO ◽  
Adauto José Ferreira NUNES ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Kras Mutation ◽  
Direct Sequencing ◽  
Colorectal Carcinogenesis ◽  
Kras Mutations ◽  
Primary Tumor Site ◽  
Exon 2 ◽  
Metastatic Site ◽  
Colorectal Cancer Patients

ABSTRACT Background: KRAS mutations are important events in colorectal carcinogenesis, as well as negative predictors of response to EGFR inhibitors treatment. Aim: To investigate the association of clinical-pathological features with KRAS mutations in colorectal cancer patients treated. Methods: Data from 69 patients with colorectal cancer either metastatic at diagnosis or later, were retrospectively analyzed. The direct sequencing and pyrosequencing techniques were related to KRAS exon 2. The mutation diagnosis and its type were determined. Results: KRAS mutation was identified in 43.4% of patients. The most common was c.35G>T (p.G12V), c.35G>A (p.G12D) and c.38G>A (p.G13D). No correlation was found between KRAS mutation and age (p=0.646) or gender (p=0.815). However, mutated group had higher CEA levels at admission (p=0.048) and codon 13 mutation was associated with involvement of more than one metastatic site in disease progression (p=0.029). Although there was no association between primary tumor site and mutation diagnosis (p=0.568), primary colon was associated with worse overall survival (p=0.009). Conclusion: The KRAS mutation was identified in almost half of patients. Mutated KRAS group had higher levels of CEA at admission and the mutation at codon 13 was associated with involvement of more than one metastatic site in the course of the disease. Colon disease was associated with the worst overall survival.

scholarly journals KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1514 ◽  
Author(s):  
Ghimessy ◽  
Gellert ◽  
Schlegl ◽  
Hegedus ◽  
Raso ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kras Mutation ◽  
Antiangiogenic Therapy ◽  
Hazard Ratio ◽  
Wild Type ◽  
First Line ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Platinum Based Chemotherapy

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

scholarly journals Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 754 ◽  
Author(s):  
Aya Takahashi ◽  
Michihisa Moriguchi ◽  
Yuya Seko ◽  
Toshihide Shima ◽  
Yasuhide Mitsumoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Characteristic Curve ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Treatment Decision ◽  
Progression Free Survival ◽  
Tumor Shrinkage ◽  
Discrimination Ability ◽  
Early Tumor Shrinkage ◽  
Early Tumor

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.

Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with FOLFOX4 with or without cetuximab: Lessons from the OPUS trial.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 398-398 ◽  
Author(s):  
H. Piessevaux ◽  
C. Bokemeyer ◽  
M. Schlichting ◽  
S. Heeger ◽  
S. Tejpar
Keyword(s):  
Tumor Size ◽  
Tumor Shrinkage ◽  
First Line ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Kras Status ◽  
Early Tumor Shrinkage ◽  
Tumor Measurements ◽  
Early Tumor

398 Background: The measurement of tumor shrinkage at the first evaluation (8 weeks) was reported to predict long-term outcome in mCRC treated with irinotecan-based chemotherapy (CT) + cetuximab (cet) in first-line and chemorefractory patients (pts). The predictive power of early tumor measurements was restricted to pts treated with CT + cet compared with CT alone but isn't known for cet with other CT regimens. This was investigated in pts treated with the FOLFOX4 regimen ± cet in the OPUS trial. Methods: Based on the 8-weekly radiological assessments reported by the investigator and reviewed by an independent review committee, relative changes in tumor size from baseline were computed and dichotomized using a 20% relative decrease cut-off value. Kaplan-Meier curves were constructed for progression-free survival (PFS) and overall survival (OS), stratified by treatment arm and KRAS status. Results: Tumor measurements at week 8 with KRAS status were available in 297 pts. Tumor shrinkage ≥20% was associated with significantly better PFS and OS in KRAS wild-type (wt) pts treated with FOLFOX4 + cet but not in those treated with CT alone (Table). Conclusions: When combining cet with FOLFOX4 in first-line KRAS wt mCRC, early tumor shrinkage is associated with long-term outcome. This finding is specific for the effect of cet, confirming this drug to have distinctive and rapid effects on tumor size leading to long-term outcome measures unrelated to the effect of CT. [Table: see text] [Table: see text]

scholarly journals Frequency and Spectrum of KRAS Mutations in Moroccan Patients with Lung Adenocarcinoma

ISRN Oncology ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Ibrahim Elghissassi ◽  
Hanane Inrhaoun ◽  
Anwar Boukir ◽  
Fouad Kettani ◽  
Lamia Gamra ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kras Mutation ◽  
Mutation Frequency ◽  
Asian Population ◽  
Wild Type ◽  
North African ◽  
Kras Mutations ◽  
Exon 2 ◽  
Lung Adenocarcinomas ◽  
Moroccan Patients

Background. In lung adenocarcinoma, the frequency of KRAS mutations is ethnicity dependent with a higher proportion in African Americans and white Caucasians than in Asians. The prevalence of these mutations among North Africans patients is unknown. The objective of this study was to report the frequency and spectrum of KRAS mutations in a group of Moroccan lung adenocarcinoma patients. Methods. Tumor specimens from 117 Moroccan patients with lung adenocarcinoma were selected to determine frequency and spectrum of KRAS mutations. KRAS mutations in codons 12 and 13 of exon 2 were analyzed using conventional DNA sequencing. Results. The overall frequency of the KRAS mutations was 9% (11/117). In the population with KRAS mutations, there was a trend towards more male (P=0.06) and more smokers (P=0.08) compared to patients with wild type KRAS. KRAS mutations were located at codon 12 in 10 out of 11 patients (91%). The G12C mutation was the most frequent KRAS mutation (73%). Conclusion. This is the first study to date examining the frequency and spectrum of KRAS mutations in lung adenocarcinomas in North African and Arab populations. KRAS mutation frequency in Moroccan patients was comparable with the frequency observed in East-Asian population. KRAS mutations are more likely observed in males and smokers and to be transversions. Further studies, in larger numbers of patients, are needed to confirm these findings.

KRAS/NRAS/BRAF genotyping in patients with mestastatic colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 718-718 ◽  
Author(s):  
Nuria Rodriguez Salas ◽  
Jesus Miranda ◽  
Lorena Ostios ◽  
Mario Muñoz ◽  
Alberto Borobia ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Logistic Model ◽  
Mutational Analysis ◽  
Array Analysis ◽  
Nras Mutation ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Exon 2 ◽  
World Development ◽  
Codon 61

718 Background: mCRC is the 2º cause of death in the world. Development of targeted therapies has increased the survival. The efficacy of these drugs (such Bevacizumab and monoclonal antibodies against EGFR) depends on the use of genetic biomarkers such as KRAS and NRAS. The BRAF status acts as prognostic factor. The objective of this study was to perform a mutational analysis of KRAS/NRAS/BRAF in a cohort of 326 Spanish patients, and correlate the findings with clinical factors. Methods: We analyzed KRAS by chip-array analysis (Infiniti System, USA), NRAS using pyrosequencing on a Pyromark Q96MD instrument (Qiagen, USA) and BRAF mutations (in 80 of these samples) by means of Infiniti System (AutoGenomics, USA). Results: KRAS mutations 129/326 patients had KRAS mutation (31.2% in codon 12 and 6.7% in codon 13). The median age was 68.9, 55% male, 66.4% had left-sided tumor, 83% histologically grade 2 tumor. The pattern of spread was liver (51.1%), lung (33.3%) and peritoneum (11.6%). There were 6 types of mutation in codon 12 (p.Gly12Asp, p.Gly12Cys, p.Gly12Val, p.Gly12Arg, p.Gly12Ser, p.Gly12Ala) and 1 type in codon 13 (p.Gly13Asp). We apply a logistic model (age&sex corrected) to location, and we found association between KRAS wild type and left location, OR 1.73 [CI:1.03-2.9] p = 0.035 NRAS mutations: 13 patients had NRAS mutation (3.98%), 8 male, 92% had left-sided, 46% liver metastasis and 53.9% lung metastasis. Type of NRAS mutation: 1.6% in exon 2 (1.2% in codon 12 and 0.4% in codon 13) and 1.8% in exon 3 (0.2% in codon 59 and 1.6% in codon 61). In exon 2 we found 2 types of changes, 1 in codon 12 (p.Gly12Asp) and 1 in codon 13 (p.Gly13Arg). In exon 3 we found 5 types of changes, 1 in codon 59 (p.Ala59Thr) and 4 in codon 61 (p.Gln61Glu; p.Gln61Leu; p.Gln61Arg; p.Gln61His). BRAF mutation: 9/80 patients harboured mutations, all of them at the residue V600E. Conclusions: In our cohort 39.5% had mutations in KRAS, 3.98% in NRAS and 11% in BRAF. KRAS mutation is associated to right-sided location.

Evolution of Sub-Clones with KRAS Mutations In Pediatric Patients with MLL-AF4 Rearrangements

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2454-2454
Author(s):  
Silvia Bresolin ◽  
Emanuela Giarin ◽  
Luca Trentin ◽  
Lueder Hinrich Meyer ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Kras Mutation ◽  
Lymphoblastic Leukemia ◽  
Mutation Screening ◽  
Selective Advantage ◽  
Human Leukemia ◽  
Kras Mutations ◽  
Specific Patient ◽  
Exon 2 ◽  
Ras Genes

Abstract Abstract 2454 Mixed Lineage Leukemia (MLL) gene rearrangements are common genetic translocations occurring in human leukemia. Numerous MLL-partner genes have been identified so far; of these MLL-AF4 was found to characterize the largest subgroup of fusion proteins in pediatric acute lymphoblastic leukemia (ALL). A recent study reported that mutations in kras accelerate leukemo-lymphogenesis in a MLL-AF4 transgenic mouse model. Activating mutations in RAS genes, frequently occuring in codons 12, 13 and 61, prevent the hydrolysis of RAS-GTP and result in the constitutive activation of the RAS proteins enhancing cell survival and proliferation. Mutations in RAS genes were found in several types of human cancers, including leukemia and ALL with MLL rearrangements. We analyzed the presence of KRAS mutations in pediatric MLL-AF4 rearranged ALL samples at diagnosis and relapse with the aim to establish the frequency of KRAS mutations in MLL-AF4 leukemia and to tentatively associate RAS mutations to the leukemogenic process. In this study 40 ALL patients were included (23 infant and 17 non infant); of these, 14 pairs at diagnosis and relapse, 22 at diagnosis only and 4 samples at relapse only. The study was approved by the institutional ethical committee and informed consent was obtained in accordance with the Declaration of Helsinki. Mutation screening was performed for exon 2 and exon 3 of KRAS by 454 technology (Roche Applied Science) with GS Junior Sequencing Instruments; to recognize each specific patient, primer pairs included a 10-base molecular identifier barcode sequence (MID). We generated amplicon ultra-deep sequencing of the 2 amplicons with a median coverage per amplicon of 1800 reads per sample. Twenty patients (55,6%) out of 36 with t(4;11) at diagnosis harbored KRAS mutations (range of penetrance of 0,4–29,7% for mutated sequences). Interestingly, in some patients more than one clone with different mutations at difference penetrance in KRAS codons were present. Of the 18 relapse samples 4 (22%) harbor KRAS mutations (penetrance of 1.3–38% of reads). Sanger sequencing was used to validate the presence of mutations in patients with more of 20% of penetrance identified with 454 technology. To evaluate the role of KRAS mutations in the leukemogenic process we analyzed matched paired diagnostic and relapse samples; in patients with mutations at diagnosis, 3 distinct situations were identified in the relapsed samples, pointing different changes between diagnosis and relapse: (1) presence of KRAS mutations in a specific codon at diagnosis and disappearance of this clone at relapse (6 of 9 cases, 67%); (2) decrease of the penetrance of a mutation between diagnosis and relapse and appearance of a new different mutation at relapse (2 of 9 cases, 22%); (3) clonal evolution of the same mutation and increase of the percentage of the mutated sequence from diagnosis to relapse (1 of 9 cases, 11%). Apparently, patients with MLL-AF4 rearrangements at diagnosis and relapse presented with subclones and during the relapse phase previous clones disappeared while new clones appeared and only in one case we can assume a selective advantage of the clone with the KRAS mutation. To further explore the propagation of KRAS mutated subclones in MLL-AF4, we transplanted 2 patients at diagnosis into a NOD/SCID xenograft mouse model. Xenografted samples obtained from leukemia bearing mice transplanted further onto subsequent recipients in serial passages. KRAS mutations were analyzed for each of the passages as mentioned above. One of the diagnostic samples used for transplantation harbored KRAS G12S mutation. The human cells of this patient isolated after the first passage in the mouse carried the same mutation of the diagnosis but with a very low penetration, suggesting a minority clone that decreased further in the second passage. No trace of mutations was found in the third passage. The other diagnostic sample for which serial transplanted samples were analyzed had no KRAS mutation at diagnosis and no new mutations appeared during further passages in the mice. The disappearance of the mutated KRAS subclone during passages in the recipient mice seems to reflect the negative selection for mutated clones observed in patients between diagnosis and relapse. Overall, these data showed that KRAS mutations are frequently occurring in MLL-AF4 leukemias at diagnosis however these mutations do not seem to add a selective advantage to the blast cells. Disclosures: No relevant conflicts of interest to declare.

Colorectal Cancers with the Uncommon Findings of KRAS Mutation and Microsatellite Instability

2015 ◽  
Vol 146 (4) ◽  
pp. 261-267
Author(s):  
Peter Zauber ◽  
Stephen Marotta ◽  
Marlene Sabbath-Solitare
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Kras Mutation ◽  
Immunohistochemical Staining ◽  
Colorectal Cancers ◽  
Repair System ◽  
Wild Type ◽  
Braf Gene ◽  
Genetic Changes ◽  
Exon 2

Sporadic colorectal cancers with microsatellite instability (MSI) frequently contain a mutation of the BRAF gene. Additionally, it has been shown that BRAF mutations in colorectal cancers are mutually exclusive of KRAS mutation. We evaluated 14 cases of colorectal cancer with MSI that were BRAF wild type but demonstrated a KRAS mutation. The codon 12/13 region in exon 2 of the KRAS oncogene and the codon 600 region in exon 15 of the BRAF gene were analyzed with standard PCR methods. MSI was evaluated by using the Bethesda panel of markers. The methylation status of the mismatch repair system was ascertained using the SALSA® MS-MLPA® methylation-specific DNA detection. The mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 were evaluated by immunohistochemical staining. A total of 530 colorectal cancers were studied for MSI and KRAS gene mutation. Fourteen (2.6%) cancers with both MSI and a KRAS mutation were identified, and all cancers were BRAF wild type. Methylation was present in 7 (50%), 5 demonstrated methylation of MLH1, 1 showed methylation of MGMT, and 1 showed methylation of MSH2. Four patients had simultaneous cancers, some of which showed different genetic changes. Immunohistochemical staining suggested a germ line mutation for 4 of 10 cases with complete staining information. KRAS mutation may occur with MSI in colorectal cancers with wild-type BRAF. If a mutation in KRAS co-exists with MSI, then strong methylation of the MLH1 gene is unlikely. These tumors demonstrate that a small number of colorectal cancers will develop with atypical patterns of molecular genetic changes, suggesting that a specific pattern of genetic changes may not be as crucial as the overall accumulation of changes, consistent with the ‘unique tumor principle'.

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