Evaluation of T2-W MR imaging and diffusion-weighted imaging for the early post-treatment local response assessment of patients treated conservatively for cervical cancer: a multicentre study

Objectives: To compare MR imaging with or without DWI and clinical response evaluation (CRE) in the local control evaluation of cervical carcinoma after radiotherapy. Methods: In a multicentre university setting, we prospectively included 107 patients with primary cervical cancer treated with radiotherapy. Sensitivity and specificity for CRE and MR imaging (with pre-therapy MR imaging as reference) (2 readers) were evaluated using cautious and strict criteria for identifying residual tumour. Nested logistic regression models were constructed for CRE, subsequently adding MR imaging with and without DWI as independent variables, as well as the pre- to post-treatment change in apparent diffusion coefficient (delta ADC). Results: Using cautious criteria, CRE and MR imaging with DWI (reader 1/reader 2) have comparable high specificity (83% and 89%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (63%/53%) than CRE. Using strict criteria, CRE and MR imaging with DWI both showed very high specificity (99% and 92%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (89%/77%) than CRE. All sensitivities were not significantly different. Addition of MR imaging with DWI to CRE has statistically significant incremental value in identifying residual tumour (reader 1: estimate, 1.06; p = 0.001) (reader 2: estimate, 0.62; p = 0.02). Adding the delta ADC did not have significant incremental value in detecting residual tumour. Conclusions: DWI significantly increases the specificity of MR imaging in the detection of local residual tumour. Furthermore, MR imaging with DWI has significant incremental diagnostic value over CRE, whereas adding the delta ADC has no incremental diagnostic value. Key Points: • If MR imaging is used for response evaluation, DWI should be incorporated• MR imaging with DWI has diagnostic value comparable/complementary to clinical response evaluation• Inter-reader agreement is moderate to fair for two experienced radiologist readers• Quantitative measurements of ADC early post-therapy have limited diagnostic valu

Histopathological and molecular features of late relapses in non-seminomas

What's known on the subject? and What does the study add? Late relapses from germ cell tumors respond poorly to systemic chemotherapy. This feature has been partly attributed to their presumed derivation from mature teratomas giving rise to secondary non-germ cell histologies that have lost the original germ cell-like behaviour. Our series demonstrates the occurrence of non-germ cell malignancies in the absence of mature teratoma and points towards microsatellite instability and BRAF-mutations as the biologic basis for chemotherapy resistance in about half of the cases. OBJECTIVE center dot To describe the histopathological types of late relapses of germ cell tumours and to search for molecular markers associated with chemotherapy resistance. PATIENTS AND METHODS center dot Samples from 14 patients with late relapse from a non-seminoma were analysed. center dot Archival tumour tissue was gathered at intial diagnosis (n = 9) and at relapse (n = 9), mostly after previous treatment with chemotherapy. center dot In addition to routine histopathology, tumours were analysed for microsatellite instability and screened for mutations in the KRAS and BRAF genes. RESULTS center dot Relapse occurred after 76.5 months (median, range: 24-209 months). center dot The histology in relapse was pure yolk sac tumour in four of the nine patients analysed. center dot Three had a non-germ cell malignancy, one was a mixed non-seminoma and one was a pure mature teratoma. center dot One sample with non-germ cell malignancy originated from a yolk sac tumour without any evidence of teratoma. center dot In four of 12 evaluable patients, high-level microsatellite instability was observed. center dot All patients were KRAS wild-type but four showed a BRAF mutation at V600E. CONCLUSIONS center dot Many late relapses of germ cell tumours show pure yolk sac histology. center dot Non-germ cell malignancies do not necessarily develop from teratoma but can also arise from yolk sac histology. center dot The biology underlying chemotherapy resistance in late relapse could be related to a high incidence of microsatellite instability and BRAF mutation V600E, which were found in half of the patients

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P<.0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P<.0001). BRAF mutations were highly correlated with MSI (P=.006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P=.017 and P=.008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P<.001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P=.001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P=.068). Conclusion We report for the first time a correlation between a gene mutation-BRAF V600E-and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed