Tumor Ki-67 Index Research Articles

Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study

IntroductionHistorically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown. MethodsThe data of all patients with mACC (2005–2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics. ResultsIn total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <.001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032). ConclusionOS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not significantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenalectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.

Correlation of morphologic findings and apparent diffusion coefficient values with Ki-67 proliferation index in patients with glioblastoma

Objectives: Glioblastoma is the most common primary neoplasm of the central nervous system (CNS) and has a very poor prognosis. Ki-67 proliferative index is a value that reflects the mitotic index of the tumor and is associated with poor prognosis. The radiological features of the tumors can predict the course of the disease. The aim of this study is to evaluate the relationship between the morphology and the apparent diffusion coefficient (ADC) values of the tumor with the Ki-67 index on preoperative magnetic resonance imaging (MRI). Methods: Preoperative MRI images of 52 patients with pathological diagnosis of glioblastoma were evaluated retrospectively. A score ranging from 1 to 3 was assigned to each of the morphological features of the tumors (peritumoral edema, necrosis, contrasting pattern, heterogeneity, hemorrhage, mass effect, tumor contour irregularity), and was added up to obtain the total score. In addition, the ADC values of each tumor were measured at the workstation. ADC value and total score of each tumor, and Ki-67 values obtained histopathologically were compared. Results: There was a negative correlation between Ki-67 index of tumors and ADC values (r=-0.895, p = 0.0001). A significant positive correlation was found between the morphological features of the tumors and their total scores (r=0.772, p = 0.0001). A statistically significant negative correlation was found between total score and ADC values (r=-0.780, p = 0.0001). Heterogeneity and necrosis were the features most closely associated with Ki-67. These were followed by mass effect, hemorrhage and contour irregularity, respectively. Conclusions: The morphological findings and ADC values obtained from preoperative MRI are related to the Ki-67 value, and thus can be used to predict prognosis and guide treatment in the early period.

Macrophage CCL22 expression in the tumor microenvironment and implications for survival in patients with squamous cell carcinoma of the tongue.

CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines. CCR4, the receptor for CCL22, is expressed in regulatory T cells (Tregs) and Th2 cells. The Yamamoto-Kohama (YK) mode of invasion has been associated with tumor prognosis. Herein, we investigated the role of CCL22 in the tumor microenvironment and its effect on the overall survival rate in patients with tongue squamous cell carcinoma (SCC). Tumor sections obtained from 92 patients with tongue SCC were graded based on the mode of invasion according to the YK classification. The expressions of several markers (CCL22, CD8, and Ki-67 by immunohistochemistry; CCR4 and FoxP3 by immunofluorescent staining) were evaluated. Student's t test and chi-square tests were used to compare differences between numerical variables and groups, respectively. Survival curves were plotted according to the Kaplan-Meier method and compared using a log-rank test. Hazard ratios and 95% confidence intervals were estimated using univariate or multivariate Cox proportional hazard models. The expression of CCL22 was significantly correlated with YK classification, overall survival rate (P<0.001), a decrease in the number of CD8-positive cells, and an increase in the tumor Ki-67 index. In addition, CCR4-positive cells were observed around CCL22-positive macrophages. These findings indicate that the expression of CCL22 in the tumor microenvironment led to a deterioration in the prognosis of patients with tongue SCC by influencing the balance of M1- and M2-like macrophages.

Nephrometry score correlated with tumor proliferative activity inT1 clear cell renal cell carcinoma

ObjectiveTo evaluate the association between the RENAL nephrometry score (RNS) and tumor proliferative activity assessed by immunohistochemistry in patients with localized renal cell carcinoma. MethodsThe current study included 145 pathological T1 (pT1) clear cell renal cell carcinomas (ccRCC). Tumor proliferative activity was assessed with the Ki67 index and microvessel density (MVD). RNS was retrospectively assessed in the present study. We divided patients into 3 groups according to RNS (RNS 4–6: low-complexity, 7–9: moderate complexity, and 10–12: high-complexity tumors) and compared the Ki67 index as well as MVD among the 3 groups. The association between the Ki67index/MVD and each component (R, E, N, A, L, h) was also evaluated. ResultsThere were 56 low, 84 moderate, and 5 high-complexity tumors. The median Ki67 index of all tumors was 5.34% (interquartile range: 3.28–8.57). The median Ki67 index of low, moderate, and high-complexity tumors was 3.97%, 6.39%, and 11.27%, respectively, with a significant difference among the 3 groups (Kruskal–Wallis test, P = 0.0004). On the other hand, the median MVD of low, moderate, and high-complexity tumors was 14.11%, 14.42%, and 21.22%, respectively, and there were no significant differences among the 3 groups. In terms of each RNS component, there were significant differences in the Ki67 index among the 3 groups in N (P = 0.0101) and L (P = 0.0280) components, respectively. ConclusionsThe revealed association between RNS and the Ki67 index in pT1 clear cell renal cell carcinomas further supports the previous findings that the anatomy of renal cell carcinoma is associated with the malignant potential of localized clear cell renal cell carcinoma, which may provide additional information for treatment decision.

Number, not size, of mesenteric tumor deposits affects prognosis of small intestinal well-differentiated neuroendocrine tumors

Mesenteric tumor deposits are an adverse prognostic factor for small intestinal well-differentiated neuroendocrine tumors. Per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (eighth edition), any mesenteric tumor deposit larger than 2 cm signifies pN2 disease. This criterion has not been critically evaluated as a prognostic factor for small intestinal neuroendocrine tumors, nor have multifocality or histologic features of mesenteric tumor deposits. We evaluated 70 small intestinal neuroendocrine tumors with mesenteric tumor deposits for lesional contour, sclerosis, inflammation, calcification, entrapped blood vessels, and perineural invasion. Ki67 proliferative indices of the largest mesenteric tumor deposit from each case were calculated, and number of tumor deposits and size of the largest deposit were recorded. Associations between these factors (along with patient age, primary tumor Ki67 index, and AJCC stage) and development of liver metastases and overall survival were assessed. Median mesenteric tumor deposit size was 1.5 cm (range: 0.2–7.0 cm); median deposit number was 1 (range: 1–13). Primary and tumor deposit Ki67 indices within a given patient were discordant in 40% of cases but showed similar hazard ratios for disease-specific survival. Size of tumor deposits had no significant effect on prognosis, whether analyzed on a continuous scale or dichotomized using the recommended 2 cm cutoff. In contrast, increasing number of deposits was associated with poor prognosis, with multiple deposits conferring an 8.19-fold risk of disease-specific death compared to a single deposit (P = 0.049). Morphologic features of deposits had no prognostic impact. Size of mesenteric tumor deposits does not affect prognosis in small intestinal neuroendocrine tumor patients; instead, deposit multifocality is associated with shorter disease-specific survival and should be incorporated into future staging criteria.

Toxicities, safeties and clinical response of dacarbazine-based chemotherapy on neuroendocrine tumors in Taiwan population

BackgroundCurrently, the role of dacarbazine (DTIC) based chemotherapy in neuroendocrine tumors (NETs) in Asia is unclear. Here, we report the outcomes of dacarbazine (DTIC)-based chemotherapy in Taiwan population. MethodsDTIC alone (250 mg/m2/day), or 5-fluorouracil (5-FU, 500 mg/m2/day) and DTIC (200 mg/m2/day) with or without epirubicin (200 mg/m2/day), for 3 days, every 3–4 weeks. Subgroups were analyzed by grading, and by Ki-67 index. Results48 patients were reviewed in this study, including 3 had grade 1 tumors, 23 had grade 2, while 22 were grade 3. In grade 3 NEC patients, the tumor Ki-67 index of 21–55% were noted in 8 patients, and >55% in 14 patients. Progression-free survival (PFS) was 5.1 months, and overall survival (OS) was 31.6 months. The PFS (in months) were 12.5 and 1.8 for patients with NETs and neuroendocrine carcinomas (NECs), respectively (p < 0.001). The OS were not reached and 5.9 months for patients with NETs and NECs, respectively (p = 0.001). Patients with NECs were divided into two groups, according to their Ki-67 index. In patients with a tumor Ki-67 index of 21–55%, PFS was 4.1 months, and OS was not reached; in those with a tumor Ki-67 index of >55%, they were 1.5 and 1.8 months, respectively (p < 0.001 and p = 0.013). ConclusionNETs, and grade 3 NECs, with Ki-67 indices of 20–55% had good responses to DTIC-based chemotherapy, with acceptable side effects. Ki-67 index could predict prognosis for grade 3 NEC patients, and guide further chemotherapy choices.

Correlation Between Ki-67 Index, World Health Organization Grade and Patient Survival in Glial Tumors With Astrocytic Differentiation.

BackgroundGlioblastoma multiforme (GBM) is a class IV astrocytic tumor, the most malignant of the four groups of World Health Organization (WHO) tumors with astrocytic differentiation.AimThe aim of this study was to estab­lish whether a correlation exists between the Ki-67 index of tumors with astrocytic differentiation, WHO grade, and patient survival.Materials and methodsA retrospective non-clinical approach to patient selection was chosen for the aim of the study. A total of 47 patients diagnosed and treated for CNS tumors with astrocytic differentiation in the St. Marina University Hospital, Varna, Bulgaria, from September 2012 to July 2016 were retrospectively included into the study cohort. The cases were tested for their immunohistochemistry (IHC) reaction with Ki-67 after their original Hematoxylin and Eosin and IHC slides were reviewed by a single author and blind coded. The Ki-67 positivity index of the nuclei was estimated after digitalization of the slides and calculated by the ImmunoRatio automated count­ing tool. The individual Ki-67 index and patient survival of each case were statistically compared.ResultsThe histopathological groups, after the blind Ki-67 index automated calculation was carried out, revealed no WHO grade I, two WHO grade II samples, four WHO grade III samples and 41 WHO grade IV cases, and these were included in the analysis. The two samples of WHO grade II astrocytic tumors had a mean Ki-67 index of 25%; however, they comprised tumors with an individual index of 43% and 7%, both individual values with a highly unlikely index for this group. The four samples of WHO grade III had a mean Ki-67 index of 4%, standard deviation ±2.16 (p>0.05), with the lowest index being 1% and the highest one being 6%. Both WHO grade II and III did not include enough samples to allow for a proper statistical analysis of patient survival. The 41 GBM cases had a mean Ki-67 index of 17.34%, standard deviation ±10.79 (p>0.05). Statistical analysis of the Ki-67 index divid­ed dichotomously into two groups and patient survival revealed that cases with a high Ki-67 index had no significant difference in survival when compared to those with low expression.ConclusionsBased on the reported results, the mean Ki-67 percentage of positive nuclei in GBM tumor sam­ples cannot be used to estimate the survival of patients. However, Ki-67 remains a valuable IHC pathological tool.

Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice.

Chronic inflammation is involved in cancer growth in esophageal squamous cell carcinoma (ESCC), which is a highly refractory cancer with poor prognosis. This study investigated the antitumor effect and mechanisms of SOCS1 gene therapy for ESCC. Patients with ESCC showed epigenetics silencing of SOCS1 gene by methylation in the CpG islands. We infected 10 ESCC cells with an adenovirus-expressing SOCS1 (AdSOCS1) to examine the antitumor effect and mechanism of SOCS1 overexpression. SOCS1 overexpression markedly decreased the proliferation of all ESCC cell lines and induced apoptosis. Also, SOCS1 inhibited the proliferation of ESCC cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). Additionally, we established two xenograft mouse models in which TE14 ESCC cells or ESCC patient-derived tissues (PDX) were subcutaneously implanted. Mice were intra-tumorally injected with AdSOCS1 or control adenovirus vector (AdLacZ). In mice, tumor volumes and tumor weights were significantly lower in mice treated with AdSOCS1 than that with AdLacZ as similar mechanism to the in vitro findings. The Ki-67 index of tumors treated with AdSOCS1 was significantly lower than that with AdLacZ, and SOCS1 gene therapy induced apoptosis. These findings demonstrated that overexpression of SOCS1 has a potent antitumor effect against ESCC both in vitro and in vivo including PDX mice. SOCS1 gene therapy may be a promising approach for the treatment of ESCC.

Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors

BackgroundBetter prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors—controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage—was investigated.MethodsA total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed.ResultsPatients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168–281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61–140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24–71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90).ConclusionsHigh expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

Cox proportional hazard analysis of sunitinib (SU) efficacy across subgroups of patients (pts) with progressive pancreatic neuroendocrine tumors (NET).

4031 Background: Sunitinib (SU) improved median progression-free survival (PFS) vs. placebo in pts with pancreatic NET (11.4 vs 5.5 months for SU [n = 86] vs placebo [n = 85], hazard ratio [HR] 0.418; 95% CI 0.263, 0.662; p = 0.0001) in a phase III, randomized, double-blind trial (NCT00428597). We report exploratory subgroup analyses evaluating the impact of baseline characteristics on the efficacy of SU treatment, which may aid future study design. Methods: Pts with advanced, well-differentiated pancreatic endocrine tumors and disease progression in the past 12 months were randomized (1:1) to SU 37.5 mg daily or placebo, each with best supportive care (primary endpoint: PFS). The influence of baseline characteristics on treatment effect was assessed using Cox proportional hazards analysis. Results: The treatment effect was statistically significant regardless of age (< 65 vs. ≥ 65 yrs), race (White vs. non-White), gender, ECOG status (0 vs. 1 or 2), number of metastatic sites (≤ 2 vs. ≥ 3) or time from diagnosis to study enrolment (< 3 vs. ≥ 3 yrs). SU showed benefit over placebo in nonfunctioning tumors, with a trend for benefit in functioning pancreatic NET. Somatostatin analogs (SSAs) were allowed before and/or during the study; HR favored SU both in pts with no SSA treatment and those who received SSAs before and/or during the study. Similarly, SU improved PFS in chemo-naïve pts as well as those previously treated with chemotherapy. Baseline characteristics were also evaluated as potential prognostic factors. Multivariate analysis (Cox model) found only time from diagnosis (≥ 3 vs. < 3 yrs; HR 0.603; 95% CI 0.382, 0.952; p = 0.0299) was a potential independent prognostic variable. The PFS advantage with SU was greater when adjusting for time from diagnosis (HR 0.374; 95% CI 0.234, 0.599; p < 0.0001). Exploratory analysis of the 72 pts with available Ki-67 data showed a statistically significant improvement in PFS for the subset of pts with tumor Ki-67 index ≤ 5% (n = 43; HR 0.378; p = 0.0259). Conclusions: Sunitinib resulted in a clinically meaningful improvement in PFS vs placebo across all subgroups studied, supporting its use in pancreatic NET pts independent of baseline characteristics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer

Ki-67 as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer

The choice of adjuvant systemic therapy is based on targeted therapy in line with the St. Gallen Consensus meeting. In addition to the traditional parameters, the panel recommended the use of proliferation markers and multigene assays. The purpose of the present study was to evaluate the clinical significance of proliferative activity using the Ki-67 index as a prognostic marker and as a predictor of recurrence time in breast cancer patients. The Ki-67 index was measured in 3,652 cases with primary breast cancer from 1987 to 2009. Out of these patients, 2,638 cases were evaluated simultaneously for estrogen receptor, progesterone receptor and HER2 from 1997, and these were analyzed as a prognostic factor according to their subtypes. The Ki-67 index exhibited a wide range of 1-99%, with a median of 20%, and cases were divided into 2 or 3 index groups; <20% and ≥20% (and ≥50%). The median Ki-67 index of tumors with luminal A was 17%, and that of luminal B type tumors was 29%. The Ki-67 index of HER2 tumors was 40% and that of triple negative tumors was 50%. A higher Ki-67 index significantly correlated with a higher grade of malignancy. Patients with a higher Ki-67 index had significantly lower disease-free survival (DFS) and overall survival rates. Moreover, there was a significant difference in the recurrence time. Multivariate analysis revealed that the Ki-67 index was a significant factor for DFS, irrespective of nodal status, and that Ki-67 was a significant marker only in luminal A type tumors. Furthermore, luminal A type cases with high Ki-67 had a similar DFS as the luminal B type cases. A higher Ki-67 index (≥20%) significantly correlated with other biological markers, poorer prognosis and early recurrence, particularly in luminal A type tumors. It is important to take the Ki-67 index into consideration in the treatment and follow-up of breast cancer patients.

Randomized Phase II Trial of Letrozole and Letrozole Plus Low-Dose Metronomic Oral Cyclophosphamide As Primary Systemic Treatment in Elderly Breast Cancer Patients

To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.