A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial.

BACKGROUND: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response. METHODS: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion. RESULTS: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes. CONCLUSION: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.

Ipilimumab-induced thrombocytopenia in a patient with metastatic melanoma.

A 57-year-old man with metastatic melanoma developed grade 4 thrombocytopenia during treatment with ipilimumab (anti-CTLA-4 antibody). Bone marrow examination confirmed increased megakaryocytes, which supported a diagnosis of drug-induced, immune-mediated thrombocytopenia and he received 1 mg/kg prednisolone and 1 g/kg intravenous immunoglobulin. There was a delayed response to treatment, with the first evidence of rise in platelet count seen after 9 days. This was followed by a complete and sustained resolution of thrombocytopenia. Hematological toxicity has rarely been associated with ipilimumab and to our knowledge this is the first report of isolated grade 4 thrombocytopenia. This case demonstrates the importance of monitoring full blood count in all patients receiving ipilimumab.

Accuracy of unidimensional and volumetric ultrasound measurements in predicting good pathological response to neoadjuvant chemotherapy in breast cancer patients.

Pathological complete response (pCR) is an important predictor of long-term survival in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). At present, the accuracy of traditional radiological assessments during treatment in predicting pCR is poor. Unidimensional and 3D volumetric ultrasound measurements prior to, after 4 cycles (mid-treatment), and at the end of 8 cycles (end-treatment) of chemotherapy were available from a subset of 55 patients enrolled in Neo-tAnGo, a National Cancer Research Network (NCRN) UK neoadjuvant chemotherapy breast cancer trial. Proportional changes in longest diameter (LD) and volume as well as absolute residual size thresholds were examined for their ability to predict pCR or pCR plus minimal residual disease (pCR/MRD). Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) and likelihood ratios (LRs) were calculated. Receiver-operator characteristic (ROC) curves and logistic regression models were also constructed. At mid-treatment, neither complete radiological response, nor proportional LD or volume changes were found predictive of final pCR. A small residual tumour volume (≤ 1 cm³ vs. > 1 cm³) at mid-treatment, however, was associated with pCR/MRD (P = 0.014). Sensitivity, specificity, PPV, NPV, LR+ and LR- values were 61%, 77%, 61%, 77%, 2.62 and 0.51, respectively. The area under the ROC curve was 0.689 (P = 0.03). Volume ≤ 1 cm³ at mid-treatment was found significant in a logistic regression (OR: 0.194, P = 0.011). At end-treatment, no ultrasound measurements were found predictive of pCR or pCR/MRD. In conclusion, proportional tumour size changes (the basis of the RECIST criteria) were not found predictive of good pathological response, although residual volume ≤ 1 cm³ at mid-treatment was found to be predictive of pCR/MRD. However, multiple volume and LD thresholds were examined and uncorrected P values presented, increasing the possibility of type I errors. Replication in an independent dataset is required.

Considerations for the processing and analysis of GoldenGate-based two-colour Illumina platforms.

Illumina's GoldenGate technology is a two-channel microarray platform that allows for the simultaneous interrogation of about 1,500 locations in the genome. GoldenGate has proved a flexible platform not only in the choice of those 1,500 locations, but also in the choice of the property being measured at them. It retains the desirable properties of Illumina's BeadArrays in that the probes (in this case 'beads') are randomly arranged across the microarray, there are multiple instances of each probe and many samples can be processed simultaneously. As for other Illumina technologies, however, these properties are not exploited as they might be. Here we review the various common adaptations of the GoldenGate platform, review the analysis methods that are associated with each adaptation and then, with the aid of a number of example data sets we illustrate some of the improvements that can be made over the default analysis.

Long Term Survival and Continued Complete Response of Vemurafenib in a Metastatic Melanoma Patient with BRAF V600K Mutation.

Introduction. BRAF kinase inhibitors such as Vemurafenib have shown improvement in overall survival, progression-free survival, and response rates in patients with metastatic melanoma with BRAF V600K mutation. However, there were no cases of complete remission reported in patients with V600K mutation before. Case Presentation. A 53-year-old man with metastatic melanoma and dialysis dependent end stage renal failure was treated safely with Vemurafenib for a BRAF V600K mutation positive melanoma and the case was reported elsewhere. After a long follow-up of the same patient treated with Vemurafenib, a complete radiological response was observed and the renal functions remained stable throughout the treatment. Main toxicities reported were grade 1 photosensitivity and skin cancers. Vemurafenib was discontinued but patient remains disease free 12 months after stopping treatment and the clinical review is ongoing. Conclusion. This is the first reported case of complete radiological response to a BRAF inhibitor in metastatic melanoma with BRAF V600K mutation and remains disease free even after discontinuation of treatment. This also shows clinical safety of Vemurafenib in end stage renal failure and highlights the need for closer look at the subgroup of patients with BRAF V600K mutation and its tumour biology.