PurposeCurrent TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome.MethodsPatients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors.ResultsDTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45–2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02–4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR.ConclusionsOur data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

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BackgroundLarge number of patients with colorectal liver metastasis show recurrent disease after curative surgical resection. Identification of these high-risk patients may guide therapeutic strategies. The aim of this study was to evaluate whether the presence of disseminated tumor cells in bone marrow from patients undergoing surgical resection of colorectal liver metastases can predict clinical outcome.MethodsSixty patients with colorectal liver metastases were planned for a curative resection between 2001 and 2007. All patients underwent bone marrow aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC) combined with automated microscopy or indirectly using reverse transcription-polymerase chain reaction (RT-PCR).ResultsDisseminated tumor cells were found in 15 of the 46 patients (33%) using CK-ICC and in 9 of 44 of the patients (20%) using RT-PCR. Patients with negative results for RT-PCR had a significant better disease-free survival after resection of their liver metastases (p = 0.02). This group also showed significant better overall survival (p = 0.002). CK-ICC did not predict a worse clinical outcome.ConclusionsThe presence of disseminated tumor cells in bone marrow detected using RT-PCR did predict a worse clinical outcome. The presence of cells detected with CK-ICC did not correlate with poor prognosis.

Rapidly progressive hip disease (RDHD) is a rare condition of the hip joint, causing destruction of the femoral head. The pathogenesis is unknown. The disease is self-limiting, there is no treatment to stop the disease. Hip arthroplasty is a successful way to relieve pain and restore function. We present a case where both hips were involved and analysed. A favourable result was obtained by bilateral total hip arthroplasty.

Introduction: Determining expression of tumor proliferation by mitotic index or Ki67 expression is one of the strongest prognostic factors in breast cancer, but its reproducibility is not optimal. Recently, phosphohistone H3 (PHH3) was proposed as a novel marker specific for mitosis. For the present study, we hypothesized that counting PHH3 positive cells would be more reproducible than mitoses counting in H&E sections (MAI) and Ki67. Methods: Tumor samples of 159 early breast cancer patients were immunohistochemically stained for Ki67 and PHH3. MAI and PHH3 scores were assessed by three breast cancer dedicated pathologists. Ki67 scores were assessed separately by two breast cancer pathologists. We used for Ki67 a threshold of 20% and for PHH3 the threshold score was 13. Intraclass correlation coefficient (ICC) and Cohen’s κ statistics were used to assess inter-observer agreement. The impact of swapping mitotic index with PHH3 in histologic grading was assessed. Results: The ICCs of PHH3 as a measure for inter-observer agreement on a continuous scale were 0.78 (obs. 1 vs. 2), 0.76 (obs. 2 vs. 3) and 0.97 (obs. 1 vs. 3). The PHH3 kappa scores (κ 0.78, 0.80, 0.68, table 1) were contrasted by fair to moderate inter-observer variation for Ki67 and MAI: Ki67, k 0.55 (obs. 1 and 2) and MAI k 0.38 (obs. 1 vs. 2), k 0.26 (obs. 2 vs. 3), k 0.56 (obs. 1 vs. 3). When using PHH3 in the Nottingham grading score instead of MAI, variation in histologic grading decreased (MAI k 0.43, 0.35, 0.32 vs. PHH3 k 0.52, 0.48, 0.52), while the proportion of grade III tumors increased (table 2). Conclusion: PHH3 seems to outperform Ki67 and MAI as a reproducible measure for tumor proliferation in breast cancer. Variation in histologic grading might be improved by using PHH3, but the resulting increase of high-grade cancers remains to be addressed. Table 1 The inter-observer agreement of PHH3 scored by three different breast cancer pathologistsObs. 2Obs. 3Obs. 3Obs. 1PHH3<13PHH3 ≥13PHH3<13PHH3 ≥13Obs. 2PHH3<13PHH3 ≥13PHH3<13583905PHH3<13597PHH3 ≥138371054PHH3 ≥13931Kappa0.780.800.67Abbreviations: PHH3, phosphohistone H3, Obs, observer.The concordance between obs. 1 & 2, obs. 1 & 3 and obs. 2 & 3 was 90%, 91% and 85%, respectively. Table 2. The impact of swapping mitotic index with PHH3 in histologic gradingGrade I n(%)Grade II n(%)Grade III n(%)Observer 1H&E42(26)104(65)13(8)PHH330(19)77(48)52(33)Observer 2H&E35(33)62(58)9(8)PHH323(22)57(54)26(24)Observer 3H&E25(16)101(64)33(21)PHH320(13)90(56)49(31)Abbreviations: PHH3, phosphohistone H3, H&E, hematolylin and eosin Citation Format: Julia E.C. van Steenhoven, Anne Kuijer, A. M. van Leeuwen, Joost M. van Gorp, Paul J. van Diest, Thijs van Dalen. Assessment of tumor proliferation by mitotic activity index, phosphohistone H3 and Ki67 in early stage ER+/Her2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-11.