Ki-67 proliferative marker in lymph node aspirates of patients with non-Hodgkin's lymphoma

Proliferative activity of lymphoma cells was tested by immunocytochemical staining with Ki-67 monoclonal antibody in 63 aspirates of peripheral lymph nodes sampled from patients suffering from non-Hodgkin's lymphoma. Referring to the dominant cell population in nodal aspirates, a rising trend of Ki-67 proliferative marker was noted from the small cells and small cells with notched nucleus and large cells with histopathologic equivalents corresponding to aggressive lymphoma. Statistical testing of the difference in the Ki-67 proliferative marker against demographic and clinical-laboratory characteristics of the studied patients revealed the levels of significance for the performance status, bone marrow infiltration, and albumin serum value. Correlation of cytomorphological and immunocytochemical results was tested against International Prognostic Index (IPI). Statistically significant correlation of Ki-67 with cytomorphology and REAL-immunocytochemical classification of lymphoma was confirmed, but not with the IPI index. In order to determine the prognostic importance of Ki-67 marker, the patients were classified into those with low Ki-67 (<20% of proliferating cells), mean proliferation index Ki-67 (range 20–59%), and high proliferative index Ki-67 (positive in over 60% of lymphoma cells). Testing Ki-67 with survival we have found that the low proliferative index was associated with the longest survival, median about 36 mo; for proliferative marker values ranging between 20 and 59%, the median survival was 30.4 mo; and survival of patients with the high proliferative index was only 12.9 mo.     

p27kipl和Ki-67蛋白在非霍奇金淋巴瘤中的表达及临床意义

目的 探讨p27^kipl和Ki-67蛋白在非霍奇金淋巴瘤(non-Hodgkin’s lymphoma，NHL)中的表达及临床意义。方法 采用免疫组化方法检测100例NHL及20例反应性增生淋巴结中p27^kipl和Ki-67蛋白的表达情况，结合临床及病理资料进行统计分析。结果 p27^kipl蛋白在反应性增生淋巴结(不包括生发中心)中的阳性率明显高于NHL，随着肿瘤侵袭性的增加，p27^kipl表达水平下降。Ki-67蛋白在反应性增生的淋巴结(不包括生发中心)中的阳性率明显低于NHL，其表达水平随着肿瘤的侵袭性增加而上升。NHL中p27^kipl蛋白的阳性率与Ki-67表达水平呈负相关。结论 p27^kipl与NHL的发生发展有关，联合检测p27^kipl及Ki-67蛋白水平可为NHL的临床诊断和治疗提供参考。     

Pharmacokinetic profile and first preliminary clinical evaluation of bendamustine in Taiwanese patients with heavily pretreated indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Prior studies found bendamustine is efficacious in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL). To date, no studies have reported the efficacy of bendamustine in a Chinese population. This multicentre phase II trial evaluated the pharmacokinetics (PK), safety and efficacy of bendamustine monotherapy in Chinese patients in Taiwan with pretreated indolent B‐cell NHL or mantle cell lymphoma (MCL). For PK assessments, patients were randomized (n = 16; 11 with indolent B‐cell NHL and five with MCL) to 90 or 120 mg/m² of bendamustine for the first cycle. Plasma levels of bendamustine and its two metabolites were analyzed. For efficacy and safety evaluations, bendamustine 120 mg/m² was given to all patients every 3 weeks starting at cycle 2 for a minimum of a total of six cycles. The median age of patients was 61.7 years, and the majority were men (75%). The median number of prior treatments was 4 (range, 1–9 regimens), and all patients were previously treated with rituximab. Bendamustine plasma concentration peaked near the end of infusion and was rapidly eliminated with a mean elimination half‐life (t_1/2) of 0.67–0.8 h. Of the evaluable patients (n = 14), the overall response rate was 78.6%, including 7.2% of patients having a complete response. Mean progression‐free survival was 27.5 weeks. The most common grade 3–4 adverse events were leucopenia (56.3%), neutropenia (56.3%) and thrombocytopenia (25%). In conclusion, bendamustine was efficacious and well tolerated in Taiwanese patients with indolent NHL and MCL with a similar PK profile to that of other populations. Copyright © 2014 John Wiley & Sons, Ltd.     

Prognostic significance of histologic grade and Ki-67 proliferation index in follicular lymphoma

The prognostic value of histologic grading and the Ki-67 proliferation index in follicular lymphoma (FL) is controversial. This study investigated the clinical usefulness of these two factors in Asian FL patients. Four hundred and thirty-three patients diagnosed with FL were retrospectively reviewed with a median follow-up time of 47.0 months (range, 24.0-168.0). The 10-year overall survival (OS) rate and progression-free survival (PFS) rate were 91.0% and 47.1%, respectively. Grade 3B and grade 3B with diffuse large B cell lymphoma (DLBCL) showed a better PFS than grade 1-3A (P < 0.001), and similar findings were noted in patients who received rituximab-containing regimens (P = 0.002). In contrast, no significant differences in terms of OS or PFS were observed between grades 1-2 and 3A. In addition, patients with Ki-67 ≥ 30% had a significantly better PFS than patients with Ki-67 < 30% (P = 0.014), although the difference was eliminated in the multivariate analysis. Both grade and Ki-67 index had no impact on prognosis in patients who did not receive rituximab treatment. In conclusion, grade 3A is closely related to grade 1-2, as reflected by a similar indolent clinical course and a lower PFS rate than grade 3B/3B + DLBCL. In addition, a higher Ki-67 index seems to have a positive effect on PFS in FL patients.     

Using primary site as a predictor of survival in mantle cell lymphoma

BACKGROUND:

Mantle cell lymphoma (MCL) is a rare B cell lymphoma that varies in clinical behavior with some patients experiencing aggressive disease with short survival, whereas others have indolent behavior. We examined the association between primary disease site and survival in MCL patients to identify subgroups with distinct characteristics.

METHODS:

We analyzed the United States Surveillance, Epidemiology and End Results Program database for MCL cases reported from 2000 through 2009. Kaplan‐Meier curves and Cox proportional hazard models were used to estimate the effect of primary site on survival.

RESULTS:

Among 4477 cases included in our study, 19.6% of patients presented with an extranodal primary site. The most common extranodal primary sites were of the gastrointestinal (GI) tract (7.8%), the head and neck (6.2%), and the hematologic/reticuloendothelial systems (3.6%). Asians/Pacific Islanders were more likely than whites or blacks to have GI tract or head and neck disease (P < .0001 and P = .002, respectively). Advanced disease and B symptoms were less common in those with primary disease of the GI tract or head and neck than in those with primary disease of the lymph nodes (both P < .0001). In a multivariate Cox regression model, patients with primary disease of the GI tract and head and neck had superior survival compared to those with primary disease of the lymph nodes; hazard ratios 0.75 (95% CI = 0.62‐0.90) and 0.68 (95% CI = 0.55‐0.85), respectively.

CONCLUSIONS:

Primary site of disease may be an important prognostic factor for patients with MCL. Further studies elucidating a biological basis for these differences are needed. Cancer 2013. © 2013 American Cancer Society.     

Minichromosome maintenance 2 (MCM2) immunoreactivity in stage III human gastric carcinoma: clinicopathological significance

Background The origin licensing factor minichromosome maintenance 2 (MCM2) has recently been identified as a critical regulator of proliferation in both normal and neoplastic cells. This study examined whether MCM2 expression was of prognostic relevance in patients with stage III gastric carcinoma and whether the expression of this marker showed any correlation with clinicopathological characteristics. In addition, we evaluated whether the expression of this proliferation marker was correlated with that of another marker, Ki-67, in gastric carcinoma. Methods We examined the immunohistochemical expression of MCM2, Ki-67, and p53 in 103 surgically removed stage III gastric carcinomas, which consisted of 60 intestinal-type and 43 diffuse-type carcinomas. The labeling indices (LIs) of MCM2 and Ki-67 in cancer cells were compared with clinicopathological characteristics, p53 expression, and overall survival rates. Results The mean MCM2 and Ki-67 LIs were 69.1 ± 11.8% and 48.2 ± 14.5%, respectively, in the intestinal carcinomas, and 43.7 ± 9.9% and 24.9 ± 11.0%, respectively, in the diffuse carcinomas. The LIs of these proteins revealed no significant association with clinicopathological characteristics or with p53 expression in the carcinomas. Kaplan-Meier survival curves showed that, in the patients with diffuse carcinoma, those with higher MCM2 LIs had a poorer prognosis (P < 0.05), but the MCM2 LI was not correlated with prognosis for those with intestinal carcinoma (P = 0.25). Ki-67 expression had no significant correlation with prognosis in either intestinal-type or diffuse-type carcinomas. Multivariate Cox regression analysis confirmed that MCM2 was an independent prognostic factor in patients with diffuse carcinoma. Conclusion Our data suggest that MCM2 is a useful prognostic marker in patients stage III diffuse-type gastric carcinoma.     

T细胞淋巴瘤中MUM1蛋白的表达及其与细胞增殖的关系

目的：探讨T细胞淋巴瘤中MUM1蛋白的表达及其与肿瘤细胞增殖的关系。方法：收集诊断及分型均明确的T细胞淋巴瘤患者的石蜡包埋组织58例,其中T淋巴母细胞性淋巴瘤/白血病（precursor Tlymphoblastic lymphoma/leukemia,T-LBL/L）9例、间变性大细胞淋巴瘤（anaplastic large Tcell lymphoma,ALCL）12例和外周T细胞性淋巴瘤（peripheral Tcell lymphoma,PTL）37例。另选2例反应性增生性淋巴结炎组织作对照。应用免疫组织化学法检测各组织中MUM1蛋白、ki-67的表达,并分析肿瘤组织中MUM1蛋白表达与ki-67增殖指数的关系。结果：1例T-LBL/L（1/9,11.11%）、9例ALCL（9/12,75.0%）和26例PTL（26/37,70.27%）组织中MUM1蛋白的表达呈阳性。MUM1蛋白在T-LBL/L中的阳性表达率明显低于ALCL组和PTL组（P〈0.05）,而在ALCL与PTL间的差别无统计学意义（P〉0.05）。MUM1蛋白阳性病例的ki-67增殖指数（53.61±23.83）%与MUM1阴性组（53.27±21.23）%相比,其差异无统计学意义（P〉0.05）。结论：MUM1蛋白在T细胞淋巴瘤中的表达可能与细胞活化有关,与肿瘤细胞的增殖可能无直接关系。     

Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer

Background

Minichromosome maintenance (MCM) proteins 2-7 form a complex essential for the initiation of DNA replication. In the process to screen expression changes related to growth suppression of non-small cell lung cancer (NSCLC) cells by a cJun dominant-negative mutant, we found that reduced expression of MCM4 was correlated with this growth suppression.

Method

We determined the relevance of MCM4 in proliferation of NSCLC by downregulating its expression with small-interfering RNA in three NSCLC cell lines. We then immunohistochemically analyzed MCM4 expression in 156 surgically resected NSCLCs to correlate clinicopathologic characteristics.

Results

MCM4 downregulation reduced proliferation in two cell lines. MCM4 expression was higher in cancer cells than in adjacent normal bronchial epithelial cells (p < 0.001). High MCM4 expression was correlated with male gender, heavy smoking, poorer differentiation and non-adenocarcinoma histology (p < 0.001, respectively). High MCM4 expression was also correlated with proliferation markers, Ki-67 and cyclin E expression (p < 0.001, respectively). MCM4 expression was not associated with survival.

Conclusion

MCM4 may play an essential role in the proliferation of some NSCLC cells. Taken together with higher expression in NSCLCs and its correlation with clinicopathologic characteristics such as non-adenocarcinoma histology, MCM4 may have potential as a therapeutic target in certain population with NSCLCs.     

CD44v6和Ki-67蛋白表达与大肠癌浸润转移的关系

目的探讨CD44v6、Ki-67蛋白表达与大肠癌浸润转移的关系及相关性。方法采用微波-LSAB免疫组化染色方法检测60例大肠癌组织中CD44v6、Ki-67的表达情况并分析其与大肠癌浸润转移的关系。结果大肠癌CD44v6和Ki-67蛋白阳性表达率分别为81.7%和86.7%。二者阳性表达均与肿瘤临床Dukes分期、浸润程度和淋巴结转移密切相关(P<0.05),而与患者性别及肿瘤分化程度无关(P>0.05)。在大肠癌中CD44v6和Ki-67蛋白阳性表达具有密切相关性(P<0.01)。结论大肠癌CD44v6、Ki-67表达与其发生发展和浸润转移密切相关,联合检测对了解大肠癌的生物学行为和判断患者预后有一定的实用价值。     

Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role

Background:

Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts.

Methods:

Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. Results were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC).

Results:

Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007).

Conclusions:

Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.     

bcl-6和Ki-67在弥漫大B细胞淋巴瘤中的表达及其意义

 【摘要】 目的 研究bcl-6和Ki-67在弥漫大B细胞淋巴瘤（DLBCL）中的表达及其临床意义。方法 应用免疫组织化学方法检测90例DLBCL标本中bcl-6和Ki-67的表达情况。以20例淋巴结反应性增生（RH）标本作为对照。结果 bcl-6在DLBCL组织中阳性表达率为54.44 %（49／90）, 在RH组织中为15.00 %（3／20）,两者差异有统计学意义（χ2＝10.214,P＝0.001）;其表达与临床分期、乳酸脱氢酶水平、B症状及Hans分型相关 (χ2值分别为5.257、5.257、4.704、16.024,均P＜0.05)。Ki-67在DLBCL组织中的高表达率为80.00 %（72／90）,而在RH组织中为20.00 %（4／20）,两者差异有统计学意义（χ2＝27.585,P＝0.000）,其表达与临床分期、国际预后指数（IPI）及近期疗效相关（χ2值分别为5.889、6.451、6.024,均P＜0.05)。结论　bcl-6和Ki-67的异常表达与DLBCL的临床分期、IPI及Hans分型等相关,可为其临床治疗及预后判断等提供参考依据。     

A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma.

BACKGROUND: Protein kinase C beta (PKCbeta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCbeta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. PATIENTS AND METHODS: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. RESULTS: Sixty patients, median age 66 years (range 45-85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3-5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for > or =3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. CONCLUSION: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.     

Proliferation predicts failure‐free survival in mantle cell lymphoma patients treated with rituximab plus hyperfractionated cyclophosphamide,vincristine, doxorubicin,and dexamethasone alternating with rituximab plus high‐dose methotrexate and cytarabine

BACKGROUND:

It has been demonstrated that the tumor proliferation index has prognostic significance in patients with mantle cell lymphoma (MCL). Patients in most of studies, however, have been treated with relatively traditional chemotherapy regimens. At the authors' institution, patients with MCL received an aggressive chemotherapy regimen: rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with rituximab plus high‐dose methotrexate and cytarabine (R‐hyper‐CVAD).

METHODS:

The authors assessed the proliferation rate of MCL using immunohistochemistry and an antibody specific for Ki‐67 in 71 untreated patients who subsequently received R‐hyper‐CVAD. The study group included 59 patients who had classic MCL and 12 patients who had the blastoid variant of MCL.

RESULTS:

For the entire study group and for the group of patients with classic MCL, a proliferation index of >20% Ki‐67‐positive cells was correlated significantly with shorter failure‐free survival. There was no correlation between the proliferation index and overall survival.

CONCLUSIONS:

The current results indicated that the proliferation index in patients with MCL predicted prognosis in those who uniformly received the R‐hyper‐CVAD chemotherapy regimen. Cancer 2009. © 2009 American Cancer Society.     

Sirtuin 6 regulates the proliferation and survival of clear cell renal cell carcinoma cells via B-cell lymphoma 2

Sirtuin 6 (SIRT6) is a member of the third family of longevity proteins (SIRTs) that is involved in the development of different types of cancer. However, the potential role of SIRT6 in clear cell renal cell carcinoma (ccRCC) and its molecular mechanism have not yet been fully elucidated. Therefore, the present study aimed to investigate the association between SIRT6 and ccRCC, and to further examine the underlying mechanism of its effect on ccRCC proliferation, using bioinformatics analysis, and in vitro and in vivo experiments. The results of the present study demonstrated that SIRT6 was upregulated in ccRCC tissues. In addition, bioinformatics analysis revealed that high SIRT6 expression was closely associated with poor prognosis of patients with ccRCC. In vitro experiments demonstrated that silencing SIRT6 expression in ccRCC-derived 769-P and 786-O cells significantly inhibited their proliferation, migration and invasion. Consistent with these results, in vivo assays demonstrated that SIRT6 knockdown markedly attenuated tumor growth arising from 769-P cells. Furthermore, depletion of SIRT6 enhanced the sensitivity of ccRCC cells to cisplatin. Notably, silencing SIRT6 expression decreased B-cell lymphoma 2 (Bcl-2) expression and increased Bax expression, respectively. Taken together, these results suggest that SIRT6 acts as a proto-oncogene in ccRCC through the augmentation of the Bcl-2-dependent pro-survival pathway, and may be used as a therapeutic target for patients with ccRCC.     

Evaluation of ER and Ki-67 proliferation index as prognostic factors for survival following neoadjuvant chemotherapy with doxorubicin/docetaxel for locally advanced breast cancer

Background The aim of the study was to identify reliable predictive biological markers for treatment outcome following neoadjuvant adriamycin/docetaxel (AT) chemotherapy in locally advanced breast cancer patients. Materials and methods This study was a phase II study on AT neoadjuvant chemotherapy in locally advanced breast cancer patients. Patients received 50 mg/m² of doxorubicin intravenously (IV) over 15 min followed by docetaxel 75 mg/m² infused over 1 h, repeated every 3 weeks for three cycles. Surgery was performed within 3–4 weeks following the last cycle of chemotherapy. We analyzed the pre-treatment and post-treatment expression levels of ER, PgR, HER-2, Ki-67 proliferation index, and p53 and examined the correlation between the markers and clinical parameters with treatment response, overall survival and relapse-free survival following neoadjuvant treatment. Results From July 2001 to September 2004, 61 patients were enrolled. The meaningful parameters adversely influencing survival were post-treatment ER(−) status (P = 0.013) and post-treatment Ki-67 index above 1.0% (P = 0.013). At the multivariate level, the post-treatment Ki-67 proliferation index ≤ 1.0 was the only meaningful prognostic factor for better survival (P = 0.033). Notably, tumors with Ki-67 index ≤ 1.0 were more likely to express ER with statistical significance (P = 0.002). Tumors with ER(+) and Ki-67 index ≤ 1.0 showed the highest survival rate, followed by ER(+) and Ki-67 index > 1.0%, ER(−) and Ki-67 ≤ 1.0%, and ER(−) and Ki-67 > 1.0% with the worst survival (P = 0.033). Conclusion Collectively, post-treatment ER status and Ki-67 proliferation index were prognostic of overall survival following neoadjuvant AT chemotherapy.     

Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study.

BACKGROUND: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. RESULTS: Hematological toxicities (grade > or =3) occurred more frequently in females (P <0.05), and thrombocytopenia and leukopenia were more frequent in patients with high lactate dehydrogenase (LDH) levels (P <0.05). Non-hematological toxicities (grade > or =2) were more frequent in patients with extranodal disease or bone marrow involvement. The overall response rate (ORR) in patients receiving one prior chemotherapy regimen was higher than those receiving two or more regimens (P <0.05). The median PFS was shorter in MCL patients, in those with extranodal disease, or in those receiving two or more prior chemotherapy regimens (P <0.01). The PFS intervals of patients with higher serum rituximab levels (> or =70 microg/ml) immediately before the third infusion were longer than in other patients (P <0.01). CONCLUSIONS: Several prognostic factors and serum rituximab levels are useful for predicting the toxicity and efficacy of rituximab monotherapy.