scholarly journals Metaphase cytogenetics and plasma cell proliferation index for risk stratification in newly diagnosed multiple myeloma

2020 ◽  
Vol 4 (10) ◽  
pp. 2236-2244
Author(s):  
Patrick W. Mellors ◽  
Moritz Binder ◽  
Rhett P. Ketterling ◽  
Patricia T. Greipp ◽  
Linda B. Baughn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Risk Stratification ◽  
Proliferation Index ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
Improve Risk Stratification ◽  
Risk Scoring ◽  
Risk Scoring System ◽  
Cell Proliferation Index

Abstract Metaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

scholarly journals Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4396-4396
Author(s):  
Patrick Mellors ◽  
Moritz Binder ◽  
Rhett P. Ketterling ◽  
Patricia Griepp ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Risk Modeling ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals A Multi-Center Epidemiological and Prognostic Analysis of Cytogenetic Abnormalities in a Cohort of 1015 Chinese Patients with Newly-Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3094-3094
Author(s):  
Fengyan Jin ◽  
Guangxun Gao ◽  
Yujun Dong ◽  
Chunrui Li ◽  
Wenrong Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Research Funding ◽  
Asian Population ◽  
Response To Therapy ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
Western Countries ◽  
1Q Gain

Introduction: Emerging evidence supports that cytogenetic abnormalities (CAs) drive myelomagenesis and heterogeneity (e.g., clinical presentation, response to therapy, and prognosis) of multiple myeloma (MM). Diversity of CAs, including primary (IgH translocations and trisomies) and secondary CAs (copy number abnormalities) argues that MM is not a "single disease". Thus, identification of CAs at diagnosis is essential for risk stratification, guiding treatment, and prognostic estimation in daily practice. However, although frequency, configuration, and significance of CAs have been well documented in the Western countries, this information is lacking in the Asian population. To this end, a multi-center retrospective analysis was carried out to examine epidemiology and prognostic significance of CAs alone or in combination in a cohort of Chinese patients with newly-diagnosed MM (NDMM). Materials and Methods: A total of 1015 NDMM patients who had the baseline information of CAs detected by FISH at four institutes nationwide were included. According to the IMWG consensus updated in 2016, 1q gain, del(17p), t[4;14], and t[14;16] were defined as high-risk CAs (HRCAs), while another HRCA t[14;20] was not tested routinely in a majority of these patients. In addition, del(1p) and del(13q14) were considered as an adverse CA. According to the mSMART3.0 proposed by Mayo Clinic in 2018, double-hit (DHMM) and triple-hit MM (THMM) were defined as co-occurrence of 2 or >= 3 HRCAs, respectively. The Kaplan-Meier approach was used to estimate progression-free survival (PFS) and overall survival (OS). Results: In this cohort, the median age of 1015 patients was 61 years; 63.5% were male. The type of IgG, light chain, IgA, IgD, non/oligosecretory, IgM, or IgE accounted for 42.9%, 26.2%, 24.5%, 3.4%, 2.5%, 0.4%, and 0.1%, respectively. Del(13q) (46.4%) and 1q gain (46.1%; 3 copies = 73.8%, >= 4 copies = 26.2%) represented the most common CAs, followed by t(4;14) (14.0%), t(11;14) (11.8%), del(1p) (11.5%), del(17p) (9.9%; 20-50% cells = 35.6%, > 50% cells = 64.4%), and t(14;16) (5.1%). While none of these CAs was detected in 23.8% of cases, the frequency of patients who carried 1 - 5 CAs was 31.9%, 28.0%, 13.4%, 2.0%, and 0.9%, respectively. In the 1q+ cases, 36.4% patients carried second CA(s), including del(13q) (61.1%), t(4;14) (20.3%), del(1p) (14.8%), del(17p) (10.7%), t(11;14) (10.4%), and t(14;16) (8.1%). In the del(17p) cases, 57.5% patients had additional CA(s), including del(13q) (75.2%), 1q gain (49.5%), del(1p) (21.6%), t(4;14) (19.6%), t(14;16) (8.7%), and t(11;14) (2.2%). In the cases bearing IgH translocations, 26.0% patients also carried other CA(s), including del(13q) and 1q gain (61.9% for each), and del(17p) (9.3%). In the cases harboring HRCAs, the percentage of patients who carried 1 - 4 HRCAs was 70.2%, 24.8%, 3.7%, and 1.1%, respectively. Overall, 14.3% and 2.9% patients had DHMM or THMM, of whom 65.0%, 18.0%, 12.0%, and 5.0% had 2 - 5 HRCAs, respectively. While there was no significant difference in PFS between the cases carrying 1 and 2 CAs (P = 0.209), the patients who had 3 or more CAs displayed a sharp reduction in median PFS (P = 0.022 and P = 0.003 for 3 vs 1 or 2 CAs). Although multiple CAs was associated with shorter median OS, no statistical significance was observed for each comparison (P > 0.05). However, patients who carried >= 2 HRCAs had significantly shorter median PFS (12.1 months; P = 0.0004) and OS (29.3 months; P = 0.027) than those who had one single HRCA (32.2 and 65.6 months for median PFS and OS). Conclusion: In comparison with the Western countries, the incidence of secondary HRCAs (e.g., 1q gain and del(17p)) is relatively higher in Chinese patients at diagnosis, while the standard-risk CA such as t(11;14) is clearly less frequent. The proportion of Chinese patients who carry multiple CAs (up to 5) or HRCAs appear to be greater as well. In this context, patients carrying two or more HRCAs, so called DHMM or THMM, exhibit significantly worse outcome than those carrying only one HRCA. Together, this study builds up an up-to-date profile of CAs for Chinese patients, which might lay a foundation for revising the criteria for risk stratification and the guideline for treatment that is more feasible and practicable in China. It also provides the information about frequency and configuration of MM-driven CAs, which might be more relevant to the Asian population. Disclosures Kumar: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals The Prognostic Impact of Dynamic Changes of Genetic Risk Stratification in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-3
Author(s):  
Huishou Fan ◽  
Jiahui Liu ◽  
Chenglu Yuan ◽  
Xue-Han Mao ◽  
Xiaoqing LI ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Genetic Risk ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Dynamic Changes ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Aberrations

Purpose: Most data on the prognostic impact of cytogenetic abnormalities come from the setting of newly diagnosed multiple myeloma, it remains unclear whether the dynamic changes of cytogenetic aberrations affect the prognostic evaluation in multiple myeloma. Methods: We analyzed the prognostic impact of dynamic changes of cytogenetic abnormalities with a cohort consisting of 80 paired patients with consecutive cytogenetic data both at diagnosis and recurrence among 568 patients with newly diagnosed multiple myeloma. Results : Three patterns of recurrence were established from 80 paired patients: Pattern A (40%) consisted of 32 patients without new cytogenetic abnormalities at the time of progression. Pattern B (15%) consisted of 12 patients harboring new standard risk (SR) cytogenetic aberrations. Pattern C (45%) consisted of 36 patients with new high-risk (HR) cytogenetic abnormalities. The median overall survival (mOS; P &lt;0.001) and median progression-free survival (mPFS; P =0.013) differed significantly among three patterns. Four groups including 60 paired patients were further established according to genetic risk stratification changes. There were 15 patients who kept SR in group 1 (25%); 12 SR patients who evolved into HR group in group 2 (20%); 17 HR patients without new HR cytogenetic abnormalities in group 3 (28%); and 16 HR patients harboring new HR cytogenetic aberrations in group 4 (27%). The mOS (P=0.001) also differed significantly among these four groups. Conclusions: Dynamic cytogenetic changes significantly affected prognostic evaluation in multiple myeloma. Patients harboring new HR cytogenetic abnormalities and escalated genetic risk stratification at relapse had worse outcomes. Figure 1 Disclosures Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Risk Scoring System for Prognosis of Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4748-4748
Author(s):  
Yachun Jia ◽  
Guangyao Kong ◽  
Aili He
Keyword(s):  
Multiple Myeloma ◽  
Risk Score ◽  
Scoring System ◽  
Clinical Characteristics ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
The Cancer Genome Atlas ◽  
Newly Diagnosed ◽  
Risk Scoring ◽  
Risk Scoring System

Abstract A Risk Scoring System for Prognosis of Multiple Myeloma Background: Multiple myeloma (MM) is the second most frequently-occurring hematologic malignancy characterized by anemia, renal damage, osteolytic lesions and hypercalcemia (Kumar, et al. 2017), without specific prognostic indicators. Protein arginine methyltransferases 3 (PRMT3) is an enzyme which participates in the progression of some malignant diseases (Xiao, et al. 2017). However, the prognostic value of PRMT3 in MM remains unclear. In this study, we developed a risk scoring system based on the expression of PRMT3 to distinguish MM cohorts with different clinical characteristics. Methods: we integrated 4 datasets from The Cancer Genome Atlas (TCGA) or gene expression omnibus (GEO) and analyzed the correlation between PRMT3 expression and R-ISS stage, diseases progression, clinical characteristics or prognosis. Furthermore, we collected a cohort of newly diagnosed MM and healthy donor samples and then performed qRT-PCR to verify the expression of PRMT3. A risk scoring system was established to point out the prognostic indicator for clinical outcome of MM. The predictive power was evaluated by using Receiver Operating Characteristic (ROC) and Kaplan-Meier survival curve. Results: By extensive data analysis, we found the expression of PRMT3 was upregulated during the progression of myeloma (Figure 1 A p=0.573, 0.028, 0.02, respectively). The expression level of PRMT3 in relapsed MM patients was higher than that in newly diagnosed MM patients (Figure 1 B p=0.02, 0.016, 0.002, respectively). Meanwhile, the expression of PRMT3 was also increased in MM patients with advanced R-ISS stage (Figure 1 C p=0.001, 0.042, respectively). Moreover, the validation in a new cohort of MM samples showed the expression of PRMT3 was higher in MM patients compared to normal controls (Figure 1 D p=0.012). MM patients with high expression of PRMT3 showed prolonged Event Free Survival (EFS) and Overall Survival (OS) (Figure 2 A&B EFS: p=0.008, OS: p=0.001). Furthermore, we found the expression of PRMT3 had a positive correlation with B2M(p=0.018), HGB (p=0.001), aspirate plasma cells (p=0.002) and bone marrow biopsy plasma cells (p=0.001 Table not shown). Meanwhile, univariate and multivariate analysis showed that B2M, LDH, ALB, MRI and PRMT3 were independent adverse prognostic factors for OS in MM patients (p&lt;0.001, p&lt;0.001, p=0.0044, 0.0403, 0.0312, Table not shown). Finally, we established a risk scoring system which performed remarkable predicting effectiveness among MM patients. The ROC curve showed that the risk model performed well in 3-year OS (Figure 2 C AUC=0.749). A threshold score 1.26897 was recommended to distinguish the high and low risk score groups. Patients with higher risk score had a shorter OS than those with lower risk score (median 27.45 months vs. 50.13 months, p&lt;0.001 Figure 2 D). Conclusion: Our study identified that PRMT3 was upregulated in MM patients and that increased PRMT3 was an independent adverse prognostic factor for OS in MM. The risk scoring system based on the expression of PRMT3 provided distinct insights into the prognosis of MM patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Molecular Indicators of High-Risk Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-6-sci-6
Author(s):  
John D. Shaughnessy ◽  
Bart Barlogie
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
High Risk ◽  
Risk Stratification ◽  
Staging System ◽  
Low Risk ◽  
Proliferation Index ◽  
Newly Diagnosed ◽  
Gene Model ◽  
Staging Systems

Abstract High-risk multiple myeloma (HRMM) is routinely defined by laboratory parameters alone or in combination in the Durie-Salmon and, more recently, the ISS staging systems. The Bartl grade, a cell morphology-based staging system, has seen limited use. The presence of abnormal cytogenetics, high BrdU labeling index, interphase FISH abnormalities, and flow cytometric measures have also been used. A molecular-based classification and risk stratification of MM may improve the definition of HRMM. Global gene expression profiling (GEP) with of CD138-selected plasma cells followed by unsupervised hierarchical cluster analysis revealed that MM comprises a spectrum of seven distinct reproducible subtypes. A validated molecular classification schema has been defined as follows: (MS = t(4;14); MF = t(14;16) or t(14;20); CD-1 = t(11;14) or t(6;14) and CD-2 = t(11;14) or t(6;14) with high CD20 and/or VPREB3), hyperdiploidy (HY = high DKK1, FRZB, NCAM1, TNFSF10), low bone disease (LB = NF-kB signature, high CCND2, CST6, and IL6R) and proliferation (PR = high MIK67, CCNB1, CCNB2, TOP2A, and TYMS). Correlating GEP with outcome in two independent cohorts permitted the identification of a high-risk signature (UAMS 17-gene model), present in approximately 13% of newly diagnosed disease. GEP and high-resolution comparative genomic hybridization in 92 cases confirmed that the altered expression of the 17 genes in the model is driven by 1q gains and 1p losses. This high-risk signature is evident in a subset of all 7 molecular subtypes and negatively influences outcome. For example, low-risk MS disease fares much better than high-risk MS disease. We recently reported that the addition of bortezomib to TT3 has significantly improved outcome in low-risk MS disease, thereby demonstrating the value of GEP in evaluating benefits of new treatments that might be otherwise masked. When subjected to multivariate analysis including the International Staging System (ISS) and a gene expression-based proliferation index (GEP PI), the UAMS 17-gene model remained a significant predictor of outcome. Mulligan and colleagues developed outcome classifiers for relapsed disease treated with single agent bortezomib or high dose dexamethasone improved upon the risk stratification provided by the ISS. These predictive models showed some specificity for bortezomib. Using U133A data from newly diagnosed disease treated with ASCT, the Mayo clinic group validated the UAMS 17-gene model, but also showed that the t(4;14) translocation remained a significant adverse variable. The IFM recently reported on a 15-gene model of high-risk (IFM 15-gene model) related to cell proliferation. Multivariate showed that the UAMS 17-gene model was significant in all datasets, while the IFM 15-model was significant in a limited number. This difference might be attributed to the dependence of the IFM model to cell proliferation. GEP on 71 paired diagnostic and relapse samples indicate that the UAMS 17-gene model score increases in 80% of the cases and a low-risk to high-risk conversion in 14 of 24 (58%) severely impacted post-relapse survival. Expression of TP53 is a surrogate for 17p13 deletion, and TP53 expression below a specific threshold (seen in approximately 10% of newly diagnosed disease) imparts a poor prognosis in low-risk – but not high-risk – MM, defined by the UAMS 17-gene model. In conclusion, while the majority of patients with MM can anticipate long-term disease control, approximately 25% of patients with molecularly defined HRMM do not benefit from current approaches.

Noninvasive Carcinoma of the Breast: Angiogenesis and Cell Proliferation

2004 ◽  
Vol 128 (8) ◽  
pp. 893-896 ◽  
Author(s):  
Ying Cao ◽  
Gladell P. Paner ◽  
Leonard B. Kahn ◽  
Prabha B. Rajan
Keyword(s):  
Cell Proliferation ◽  
Microvessel Density ◽  
Carcinoma In Situ ◽  
Nuclear Grade ◽  
Proliferation Index ◽  
Carcinoma Of The Breast ◽  
Cell Proliferation Index ◽  
Noninvasive Carcinoma ◽  
Mib 1

Abstract Context.—Angiogenesis and the cell proliferation index can predict the prognosis of invasive breast carcinoma; however, little is known of their roles in noninvasive tumor. Objective.—To investigate the correlation of microvessel density and cell proliferation index with other histologic parameters (histologic type, nuclear grade, and mitotic count) in 65 cases of noninvasive carcinoma of the breast. Design.—Formalin-fixed, paraffin-embedded tissues from 65 cases of carcinoma in situ of the breast were immunostained with antibody against factor VIII antigen and proliferation-associated nuclear antigen MIB-1. The microvessel density was measured by counting the total number of microvessels around the carcinoma in situ per 10 low-power microscopic fields. The cell proliferation index was calculated by counting MIB-1–positive nuclei in 100 tumor cells. A χ2 test and Spearman rank correlation test were used for statistical analysis. Results.—The microvessel density and cell proliferation index of comedo-type, high-nuclear-grade ductal carcinomas in situ are significantly higher than those of either noncomedo type ductal carcinomas in situ or lobular carcinoma in situ (P &lt; .001). Conclusions.—Angiogenesis and the cell proliferation index are active biological processes and may be considered as markers to separate low- and high-risk patients with noninvasive breast carcinomas.

scholarly journals Current Paradigm of Treatment for Pancreatic Neuroendocrine Tumor

2021 ◽  
Vol 26 (1) ◽  
pp. 24-32
Author(s):  
Min Je Sung ◽  
Moon Jae Chung
Keyword(s):  
Cell Proliferation ◽  
Medical Treatment ◽  
Neuroendocrine Tumor ◽  
Standard Treatment ◽  
Pancreatic Neuroendocrine Tumor ◽  
Somatostatin Analogues ◽  
Proliferation Index ◽  
Ki 67 ◽  
Grade 3 ◽  
Cell Proliferation Index

Pancreatic neuroendocrine tumor (PNET) refer to tumors originating from the islet of Langerhans and shows various prognosis based on the presence or absence of symptoms due to hormone secretion, the Ki-67 cell proliferation index, and the histologic grade, and according to the degree of disease progression defined by the tumor-node-metastasis (TNM) stage classification. The purpose of medical treatment for PNET is to control symptoms or inhibit tumor growth. Somatostatin analogues can be administered for the purpose of controlling symptoms caused by the secretion of specific hormones, and are accepted as effective drugs for inhibiting the progression of G1/G2 tumors based on World Health Organization (WHO) classification with a Ki-67 cell proliferation index less than 20%. Among the molecularly targeted agents, everolimus and sunitinib can be considered in patients with WHO G1/G2 PNET showing progression after somatostatin analog therapy. Cytotoxic chemotherapy is generally administered to patients with large tumor volume and rapidly progressing metastatic NET, and etoposide/cisplatin combination therapy has been considered as a standard treatment. For the patient group of Grade 3 PNET (well differentiated) newly classified by the WHO 2017 classification, guidelines for standard treatment have not yet been established. As it has been reported, studies are needed to evaluate the treatment response rate of somatostatin analogues or molecularly targeted therapies for the patient with Grade 3 PNET. It is important to consider a multidisciplinary approach with all possible treatment options including medical treatment, radical resection of primary or metastatic lesions, liver-directed therapies, and peptide receptor radionuclide therapy for the patients with PNET.

scholarly journals Prognostic Implications of Metabolic Total Volume and Total Lesion Glycolysis Assessed By PET/CT Combined with High Levels of Bone Marrow Plasma Cells Percentages As a Potential Risk Model in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3193-3193
Author(s):  
Toshiki Terao ◽  
Yoichi Machida ◽  
Takafumi Tsushima ◽  
Akihiro Kitadate ◽  
Daisuke Miura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Risk Stratification ◽  
Tumor Volume ◽  
Mononuclear Cells ◽  
Total Lesion Glycolysis ◽  
Whole Body ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Pet Ct

Introduction: Multiple myeloma (MM) is a heterogeneous malignant plasma cell (PC) disorder and the survival ranges from several months to > 10-years. Several risk stratification systems such as the Revised International Staging System (R-ISS) have been developed. PET/CT allows the direct assessment of metabolic tumor burden in various malignancies. Therefore, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), which are volumetric parameters applicable to PET/CT, are emerging tools for MM prognostication. This study was aimed to determine the value of MTV and TLG using PET/CT in the prognostication and in combination with various hematologic parameters such as bone marrow PC (BMPC) percentages and circulating tumorous PCs (CPCs) to identify the patients with high-risk features. Methods: A total of 196 consecutive patients with newly diagnosed MM (NDMM) who underwent baseline whole-body PET/CT between January 2009 and June 2019 at Kameda Medical Center, Kamogawa-shi, Japan, were retrospectively analyzed. PET/CT was performed using dedicated PET/CT scanners (Discovery ST Elite Performance; GE Healthcare, Milwaukee, USA). The standard uptake value (SUV) was normalized according to the injected dose and lean body mass. The baseline SUVmax of all lesions was recorded, and the highest value was considered as the SUVmax of the patient. MTV was defined as the myeloma lesions volume visualized on PET/CT scans with SUV greater than or equal to the fixed absolute threshold of SUV = 2.5. TLG was calculated as the sum of the product of average SUV (SUVmean) and MTV of all lesions. Computer‐aided analysis of PET-CT images for MTV and TLG calculations was performed using an open-source software application of Metavol (Hokkaido University, Sapporo, Japan). The CPCs were measured using an 8-color flowcytometry and reported as the percentage per total mononuclear cells using the monoclonal antibodies of CD19, 38, 45, 56, 117, 200, κ, λ, and CD138. The BMPC was calculated by counting the percentages of CD138-stained PCs among the all nucleated cells on bone marrow biopsy samples. Eleven patients (13.8%) were excluded because the MTV data could not be retrieved. Ultimately, 185 patients were included in our analysis. Written informed consent was obtained from all patients. Results: Among the 185 patients, 28 patients (15.1%) were negative for avid lesion on PET/CT. Whole-body MTV and TLG ranged from 0 to 2440.7 mL, with a median of 34.2 mL and from 0 to 12582.4 g, with a median of 97.0 g, respectively. The best cut-off values of MTV and TLG that discriminate the survival using a receiver-operating-characteristic curve analysis were 56.4 mL and 166.4 g, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with a lower cut-off value of MTV (≤56.4 mL) had better survival with not reached (NR) and 37.3 months as compared to those with a higher cut-off value (>56.4 mL) that reached 52.9 and 23.8 months, respectively (p=0.003 and 0.019). Similarly, the OS and PFS of patients with a lower cut-off value of TLG (≤166.4 g) showed better survivals with NR and 37.3 months as compared to those with a higher cut-off value (>166.4 g) that reached 54.3 and 28.8 months, respectively (p=0.0047 and 0.012). Next, we explored the prognostic impact of the clinical variables including MTV or TLG, CPCs, and BMPC. High levels of CPCs and BMPCs levels were defined as ≥0.018% of the total mononuclear cells and BMPCs of ≥57%, respectively. Univariate analysis showed that age≥70, serum creatinine≥2.0 mg/dL, R-ISS stage 3, higher cut-off value of MTV, and higher cut-off value of TLG were the associated with shorter OS. To measure the tumor volume with accuracy, we combined BMPC or CPCs and MTV or TLG. On multivariate analysis, age≥70 and the combination of higher cut-off value of MTV or TLG and high level of BMPC percentage were significantly associated with shorter OS [Hazard Ratio (HR) 2.12, p=0.038, HR 2.66, p=0.027 and HR 2.57, p=0.029, respectively] and PFS (Not assessed, HR 2.52, p=0.018 and HR 2.7, p= 0.011, respectively) (Figure 1). Conclusion: Our findings demonstrated that MTV and TLG calculated from pretreatment PET/CT were useful for risk stratification in patients with NDMM when combined with BMPC. The prognostic performance of the combined high-burden of TLG or MTV and high levels of BMPC were independent of the established risk factors. Disclosures Matsue: Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria.

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