Proliferative Activity as Measured by MIB-1 Labeling Index and Long-term Outcome of Cerebellar Juvenile Pilocytic Astrocytomas

Proliferative activity of cerebellar juvenile pilocytic astrocytomas (CJPA) and its significance for prognosis was retrospectively investigated.Forty-four consecutive children operated between 1981 and 1997 with a mean age of 8.3 years (3 months to 20 years) were reviewed. Clinical and radiological follow-up was available for 38 patients ranging from 0 to 18yrs (mean 6.3 years). Proliferative activity was determined by MIB-1 immunohistochemistry on sections of resected tumor specimen.Total resection was achieved in 35 children (79.5%), subtotal in 9 (20.5%). Currently, 31 are tumor-free, 6 have stable remnants, one developed spinal seeding and one died. Radiology revealed a cystic mural node type tumor in 27 patients (61.4%), a solid lesion with a small cyst in 5 patients (11.4%), and a solid tumor in 12 patients (27.3%). Mean MIB-1 labeling index (LI) of all tumors was 4.4% (range 0.6–12%, SD = 2.7) and did not correlate with age, gender, localization, amount of resection, follow-up status, histological appearence or grade of neovascularization, but showed a significant correlation to radiological types: 6.9% in solid tumors versus 3.7% in the cystic mural node type (p = 0.0037). Five year progression-free survival (PFS) of all patients was 84.4%, differences between subgroups of MIB-1<5% (27 patients, PFS = 87.4%) and MIB-1>5% (13 patients, PFS = 76.3%) were not significant.CJPA showed a remarkable high MIB-1 LI, but no significant correlation to PFS in this series. Nevertheless, radiologically solid tumors demonstrated a significantly higher MIB-1 LI and thus may need further investigation for possible increased ability of regrowth.     

Prognostic Significance of Endothelial Surface Score and MIB-1 Labeling Index in Glioblastoma

The aim of this study is to investigate the usefulness of a vascular endothelial surface score (VESS) and MIB-1 labeling index (MIB-1 LI), in a defined series of glioblastomas, as biological markers with prognostic significance of survival. Tumor tissue and survival were studied in a series of 38 patients with glioblastoma, previously treated by surgical resection and radiotherapy. For each tumor, immunohistochemical and morphornetric studies were performed in order to study MIB-1 LI, and VESS, expressed as the CD-34 immunostained endothelial surface per 1000 tumor cells. The survival for the entire patient population of the series was 48.1 ± 14.1 weeks, and the mean VESS for the tumors of the series ranged from 16.7 to 107µm² per 1000 tumor cells (mean: 38.7 ± 18.2). Factors such as age or MIB-1 LI were not significatively associated with survival, but the median survival for the 18 patients with a VESS less than 35 was 50.7 ± 3.7 weeks, versus 45.9 ± 2.8 weeks for the 20 patients showing a VESS higher than 36 (p < 0.05). Our present results suggest that tumor VESS, expressed as the CD-34 immunostained endothelial surface per each 1000 tumor cells, may have usefulness, as angiogenic-related factor influencing survival, in patients with glioblastoma.     

Prognostic and therapeutic implications of the MIB-1 labeling index in breast cancer

Background  Assessment of tumor proliferative activity is considered to be the most powerful prognostic factor aside from axillary lymph node status. The purpose of this study is to assess the clinical value of measurement of proliferative activity using the MIB-1 labeling index in patients with breast cancer. Methods  Surgical specimens from 36 patients with benign breast disorders and 146 patients with breast cancer were investigated. The MIB-1 labeling index was determined on the specimens stained by immunohistochemical methods as much as possible. Clinical factors associated with the MIB-1 labeling index were reviewed. Results  The MIB-1 labeling index for non-proliferative disorders, proliferative disorders, and breast cancer was 3.4±1.9%, 8.9±6.2% and 20±12%, respectively. The MIB-1 labeling index and tumor size, lymph node metastasis status, and clinical stage according to the TNM classification correlated significantly. Survival rate was inversely correlated with the MIB-1 labeling index. No patient with an MIB-1 labeling index of less than 10% had lymph node metastases, and all are alive without recurrence. Patients with an MIB-1 labeling index of over 30% had an extremely poor prognosis. Conclusions  The MIB-1 labeling index is very useful for predicting both either extremely good or extremely poor prognosis, and axillary lymph node metastasis.     

Alterations in p53, p21, and MIB-1 Labeling Index in Primary Human Astrocytomas Following Radiation Therapy

Summary Little is known about the cellular and genetic changes that occur in human astrocytomas following radiation therapy (RT). Experimental studies would suggest that early effects include induction of p53 and p21 expression, cell cycle arrest, and selection of tumor cells with molecular changes that correlate with radiation resistance. Unfortunately, tissue sampling of primary human astrocytomas closely following radiation therapy is uncommon, hindering comparative assessment of primary human tumors. Through local databases, we were able to collect eight cases in which tissue was resected within 8 weeks of RT because of bulky residual disease: two patients with grade II diffuse astrocytomas (LGA) and 6 patients with high-grade astrocytomas (HGA; 1 anaplastic astrocytoma, 5 glioblastomas). Routine histopathologic sections, MIB-1 labeling index (LI), p53 and p21 expression, and EGFR expression were compared between the pre- and post-RT samples. Only one tumor (52d post-RT) showed prominent radiation-induced histopathologic changes. p53 expression was detected in two tumors pre-RT and in six tumors post-RT. In the four tumors in which p53 expression was induced, the post-RT LI was lower in each case, and p21 expression had increased in 3/4 of these cases. No change in LI was detected in tumors in which p53 expression was unchanged. EGFR expression was not altered following RT. The results of this unique series document that some primary human astrocytomas increase expression of p53 and p21 and decrease proliferation in response to RT. However, the small size of the series argues for further studies of radiation induced molecular changes in primary human astrocytoma tissue.     

Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index

Summary Objective: Survivin has been identified as a protein expressed in cancer cells and a member of the inhibitor-of-apoptosis protein family. Recent studies suggest that the expression of survivin increases during the G2/M phase of the cell cycle, and may be used in clinical prognosis. We examined whether survivin expression in human gliomas would be a correlative of prognosis. Methods: We prepared polyclonal anti-survivin serum to establish a survivin index for stained sections, using an immunohistochemical procedure, according to the method used for scoring MIB-1 index, and then stained 29 paraffin-embedded sections from surgical specimens of 29 patients who were classified into three grades of World Health Organization with the mean age of low grade astocytoma (grade II) being 34.7; anaplastic astrocytoma (grade III), 48.8; and glioblastoma multiform (grade IV), 58.4. Results: On staining with the anti-survivin antiserum, all specimens contained positive cells, but the survivin index was heterogeneous among grades. The mean percentage of immunoreactive cells in each specimen was 70.0 (SD 18.2) in grade II, 81.3 (16.5) in grade III, and 85.0 (13.6) in grade IV. Then we compared the survivin index to the MIB-1 index and found that in low-grade gliomas (grade II and III), the difference in survival times between the high and low survivin indexes was significant (P=0.007), whereas that between the high and low MIB-1 indexes was not significant (P=0.092).Conclusion: Survivin is more sensitive marker than MIB-1 for the evaluation of low-grade gliomas in that it helps to predict patient survival. Much larger glioma patient series are needed to validate the findings of our limited study.     

Clinicopathological features, MIB-1 labeling index and apoptotic index in recurrent astrocytic tumors

This is a study of 64 cases of recurrent astrocytic tumors of all four WHO grades wherein a comparative evaluation of initial vs. recurrent tumor was done with respect to histological grading, MIB-1 labeling index (LI) and apoptotic index (AI). The aim was to identify factor/s that could influence interval to recurrence and/or malignant progression. Recurrence was noted in all grades and upon recurrence, 93.3% of grade II (low grade diffuse) astrocytomas and 63.6% of grade III anaplastic astrocytomas underwent malignant progression. However, none of the Grade I tumors showed evidence of malignant progression. Though interval to recurrence varied considerably, there was a correlation with histological grade of the initial tumor in that grade I and II tumors had a significantly longer mean interval to recurrence (43 months and 54.8 months respectively) as compared to grade III and IV (glioblastoma multiforme) tumors (17.6 and 12.8 months respectively). The interval to recurrence was also longer for grade II and III tumors which showed progression on recurrence (55.3 months for Grade II->Grade III; 54 months for Grade II->Grade IV and 20.6 months for Grade III->IV) as compared to tumors which recurred to the same grade (12.5 months for Grade III->Grade III and 12.8 months for Grade IV->Grade IV). A statistically significant inverse correlation of MIB-1 LI with interval to recurrence was noted. Higher the MIB-1 LI, shorter was the interval to recurrence. Further a cut off MIB-1 LI value of 2.8% could be proposed in predicting recurrence free survival. Interestingly, MIB-1 LI of grade II tumors, which had progressed to grade IV was significantly higher than MIB-1 LI of grade II tumors which had progressed to grade III. Thus, this study establishes the potential role of MIB-1 LI of the initial tumor in determining interval to recurrence. However, apoptotic index has no role in predicting either interval to recurrence or malignant progression.     

Increased MIB-1 Labeling Index Is Associated with Abducens Nerve Morbidity in Primary Sporadic Petroclival Meningioma Surgery: Beyond Location and Approach

Abducens nerve palsy is a severe dysfunction after petroclival meningioma (PC MNG) surgery. The objective of this investigation was to analyze abducens nerve outcomes in patients who underwent the retrosigmoid approach in relation to the MIB-1 index. Thirty-two patients with primary sporadic PC MNG were retrospectively analyzed. Mean follow-up was 28.0 months. Analysis of the MIB-1 index was performed to evaluate the abducens nerve outcome. An optimal MIB-1 index cut-off value (<4/≥4) in the association with postoperative CN VI palsy was determined by ROC analysis (AUC: 0.74, 95% CI: 0.57–0.92). A new-onset CN VI palsy was present in 7 cases (21.88%) and was significantly associated with an increased MIB-1 index (≥4%, p = 0.025) and a peritumoral edema in the brachium pontis (p = 0.047) which might be caused by the increased growth rate. Tumor volume, cavernous sinus infiltration, auditory canal invasion, and Simpson grading were not associated with new CN VI deficits. Six (85.7%) of the 7 patients with both an increased MIB-1 index (≥4%) and new abducens nerve palsy still had a CN VI deficit at the 12-month follow-up. A peritumoral edema caused by a highly proliferative PC MNG with an elevated MIB-1 index (≥4%) is associated with postoperative abducens nerve deficits.     

Proliferative activity of central neurocytoma: Measurement of tumor volume doubling time,MIB-1 staining index and bromodeoxyuridine labeling index

Central neurocytoma is considered to be a benign intracranial neoplasm, but little is known about the biological behavior of this type of tumor.Proliferative activity of central neurocytoma was measured in 10 cases using MIB-1 staining for Ki-67 antigen.The MIB-1 staining value varied from < 0.1% to 5.6%, to indicating that some of these tumors have proliferative potential similar to that of anaplastic astrocytoma or malignant meningioma. Thebromodeoxyuridine labeling index (BUdR LI, BrdU LI) was measured in 2 cases and the results correlated well with those of the MIB-1 analysis. Tumor volume doubling time (Td) measured in one case was 358 days which is similar to that of malignant meningioma.In one case, the MIB-1 value taken beforeand after 58 Gy of radiation treatment decreased markedly from 5.6%to 0.2%. The other 9 cases were also treated by radiation therapy (50—60 Gy) and no tumor recurrence was observed during follow-up periods ranging from 23 to 160 months. Another two patients with partially removed and 3 with subtotallyremoved tumors showing relatively high MIB-1 values might also have benefited from radiation therapy.     

Proliferative Activity of Microvascular Cells in Glioblastomas does not Correlate with Time to Recurrence

The time to recurrence operation (TR) is a good growth parameter, in particular for glioblastomas. Recently, we have shown that Ki-67 labeling index (LI) of tumor cells has a high inverse correlation with this time interval. In the current study, the LI of microvascular cells (MVC) was examined in the same glioblastoma cases. The LI of MVC of primary and recurrent tumors had no relationship and did not show any correlation to TR. The growth fraction of MVC was significantly lower than that of tumor cells. The MVC in glioblastomas seems to have chaotical proliferation properties without any link to the tumor growth potential. This observation may have implications for anti-angiogenic therapy.     

Immune Dysfunction as Measured by the Systemic Immune-Inflammation Index is Associated with the Sub-Type of Minimal Residual Disease and Outcome in Stage II Colon Cancer Treated with Surgery alone

Objective: Within 5 years after curative surgery for stage II colon cancer 25% of patients will relapse due to minimal residual disease (MRD). MRD is the net result of the biological properties of subpopulations of primary tumour cells which enable them to disseminate, implant in distant tissues and survive and the immune system’s ability to eliminate them. We hypothesize that markers of immune dysfunction such as the systemic inflammation index (SII) are associated with the sub-type of MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). A higher immune dysfunction being associated with a more aggressive MRD and worse prognosis. Methods and Patients: Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-CEA one month after surgery. The SII, absolute neutrophil, platelet and lymphocyte counts (ANC, APC, ALC) were determined immediately pre-surgery and one month post-surgery. These were compared with the sub-types of MRD; Group I MRD (-); Group II mM positive and Group III CTC positive; cut-off values of SII of >700 and >900 were used. Follow-up was for up to 5 years or relapse and survival curves using Kaplan-Meier (KM) were calculated. Results: One hundred and eighty one patients (99 women) participated, mean age 68 years, median follow up 4.04 years; I: = 105 patients, II: N= 36 patients, III: N=40 patients. The SII significantly decreased post-surgery only in Group I patients. The frequency of SII >700 and >900 was significantly higher in Group III, between Groups I and II there was no significant difference.  The SII was significantly associated with the number of CTCs detected. The 5-year KM was 98% Group I, 68% Group II and 7% Group III. Conclusions: The results of the study suggest that the severity of immune dysfunction as determined by the SII is associated with differing sub-types of MRD and a worse prognosis; increasing immune dysfunction is associated with a more aggressive CTC positive MRD sub-type; a more severe immune dysfunction is associated with a higher number of CTCs detected.