High Proliferation Index Research Articles

Preoperative prediction of gastrointestinal stromal tumors with high Ki-67 proliferation index based on CT features.

BackgroundTo determine whether preoperative computed tomography (CT) features can be used for the prediction of gastrointestinal stromal tumors (GISTs) with a high Ki-67 proliferation index (Ki-67 PI).MethodsA total of 198 patients with surgically and pathologically proven GISTs were retrospectively included. All GISTs were divided into a low Ki-67 PI group (<10%) and a high Ki-67 PI group (≥10%). All imaging features were blindly interpreted by two radiologists. Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the predictive performance of the imaging features.ResultsImaging features were found to be significantly different between the low and the high Ki-67 PI groups (P<0.05). Wall thickness of necrosis showed the highest predictive ability, with an area under the curve (AUC) of 0.838 [95% confidence interval (CI): 0.627–0.957], followed by necrosis, necrosis degree, hyperenhancement of the overlying mucosa (HYOM), and long diameter (LD) (AUC >0.7, P<0.05). HYOM was the strongest predictive feature for the high Ki-67 PI GISTs group, with an odds ratio (OR) value of 30.037 (95% CI: 5.707–158.106).ConclusionsImaging features, including the presence of necrosis, high necrosis degree, thick wall of necrosis, and HYOM were significant predictive indicators for the high Ki-67 PI GISTs group.

S1911 Primary Colon Burkitt’s Lymphoma Presenting as Colonic Obstruction

Introduction: Primary colon lymphomas are very rare colon malignancies and Burkitt´s lymphoma (BL) variant is usually diagnosed in children and immunocompromised patients. BL is a highly aggressive malignancy and is the fastest growing human cancer. Primary colon BL (PCBL) is very rare in adults with few reported cases located around ileocecal valve region. There are only two published cases of PCBL causing colonic obstruction due to ileocecal valve region involvement. We present a unique PCBL case located in splenic flexure of colon causing colonic obstruction. Case description/methods: A 56-year-old female presented with 10-day history of worsening diffuse abdominal pain, nausea, vomiting & inability to pass gas. She had diffuse abdominal tenderness & hyperactive bowel sounds. Labs were unremarkable. Abdominal CT scan revealed complete colonic obstruction from splenic flexure exophytic colonic mass measuring 14 x 10 x 10 cm with small mesenteric & hepatic lesions. Emergent laparoscopic transverse colon diverting loop colostomy performed due to high tumor burden that appeared to be unresectable. Subsequent colonoscopy showed large obstructing colon mass at splenic flexure of colon & proximal colon segments were dilated with decompressed distal colon. Biopsies from colon mass were indicative for diffuse large B-cell lymphoma with extensive necrosis, high proliferation index, Ki-67 80% positive. Ultrasound guided liver biopsy revealed high grade B-cell lymphoma. FISH analysis revealed findings of MYC/IGH fusion in approximately 100% of nuclei without rearrangement of BCL2 or BCL6, consistent with PCBL. Chemotherapy initiated (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) with an excellent response. Surveillance colonoscopy at 5-year post-treatment showed no concerns for disease recurrence. Discussion: PCBL is not only very rare in adults but also rare outside of ileocecal area, where concentration of lymphoid tissue is relatively increased. In english literature there are only 2 published cases of PCBL at ileocecal valve location causing colonic obstruction. To the best of our knowledge, our PCBL case is unique as being the first case of PCBL atypically located in distal colon & causing colonic obstruction. Older age or atypical GI locations cannot exclude the possibility of PCBL & should be considered as part of differential diagnosis for high-grade GI lymphomas. With advances in chemotherapy, PCBL may respond well to therapy even in disseminated stage with colonic obstruction.Figure 1.: A: Nuclear medicine PET CT scan showing multiple FDG avid mesenteric masses consistent with lymphoma and evidence of hepatic metastasis. Figure B: CT scan abdomen revealing large splenic flexure exophytic colonic mass causing colonic obstruction. Figure C: Large obstructing colon mass seen at the splenic flexure of colon during colonoscopy. Figure D: Colon mass biopsy with hematoxylin & eosin stain at 200x magnification showing extensive necrosis with crush artifact and rare clusters of viable large neoplastic cells.

Relation of FDG uptake of breast cancer and the histologic and the biologic characteristics of the tumor

Abstract Background Breast cancer is considered the most common type of cancer and the second leading cause of cancer-related death among women. The prognostic factors including histological type, tumor nuclear grade, tumor size, and preoperative tumor-nodes-metastasis (TNM), hormone receptor and immunohistochemical molecular markers in the specimens, define the prognosis and survival rate. Early diagnosis and accurate follow-up of these patients affect the management. 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) has proved to be an effective and accurate imaging technique for a variety of diagnostic oncology tasks in breast cancer, lymph node staging, staging and restaging of recurrent and metastatic disease, and treatment follow up. Sufficient knowledge of the initial characteristics of breast tumors that may affect 18F-FDG uptake is essential for optimal use and interpretation of 18FFDG PET/CT imaging. Several pioneering studies have investigated the correlation between the affinity to 18F-FDG uptake and some of the histological and biological characteristics such as tumor type, grade, hormonal receptor status and HER2 status. Objective To correlate the relation of 18F-fluoro-2-deoxy-D-gIucose (18F-FDG) positron emission tomography/ computed tomography (PET/CT) uptake in breast cancer to histopathological and biological characteristics. Methods A prospective descriptive study over the course of 6 months from August 2019 till February 2020. It included twenty five patients with pathologically proven breast carcinoma referred to the Radiology department, Ain Shams University Hospitals/ Private centers for a preoperative 18FDG PET/CT scan. Results For the tumors in 25 women, the mean SUVmax was 4.75±2.55. Primary tumor 18FFDG uptake ratio was correlated with patients' age (P = 0.032), tumor size (P = 0.034), histological grade (P=O.OI 8), estrogen and progesterone negativity (P = 0.012), Her2/neu positivity (P = 0.012), high Ki-67 level (&amp;gt;10%) (P = 0.024), axillary lymph node involvement (P = 0.038) and distant metastasis (P = 0.039). High Ki-67 level (Pearson Correlation Coefficient= 0.457; 95% confidence interval; P = 0.037) and tumor size (Pearson Correlation Coefficient =0.458; 95% confidence interval, P = 0.021) were determining factors for high 18F-FDG uptake values. The histological type (P = 0.525) was not significantly correlated with 18F-FDG uptake. Conclusion FDG PET imaging was used to estimate tumor biologic behavior of breast cancer such as histopathologic grading, immunohistochemistry, axillary lymph node status and distant metastasis. SUVmax correlated with several of pathological prognostic factors may have potential for predicting the prognosis of breast cancer. 18F-FDG PET/CT could be a useful tool to pretherapeutically predict biological characteristics and baseline risk of breast cancer Increased 18FFDG uptake on PET/CT was correlated with a high Ki-67 proliferation index and larger tumor size. These results suggest a potential role of 18F-FDG PET/CT in identifying tumor aggressiveness.

Features of Post-Resection Regeneration of Hepatocytes under the Influence of Intrahepatic Administration of Cyanocobalamin

Liver resection in most cases remains the only way to achieve an increase in life expectancy and cure of patients with large liver formations. In clinical practice, hepatoprotectors are used to improve metabolic processes of the liver, many of them include vitamin B12, the active form of which is able to stimulate reparative regeneration.The aim of the study was to identify morphological features of hepatocytes and the stroma of the resected liver during intra-organ intraoperative administration of cyanocobalamin to study the effect of vitamin B12 on the proliferative activity of hepatocytes.Material and methods. The experiment was conducted on 36 male Wistar rats. In 3 experimental groups of animals, a typical resection was performed in the volume of 70% of the initial liver mass, in the 1st experimental group, prevention of post-resection liver failure was not carried out, in the 2nd experimental group, 0.9% sodium chloride solution was injected into the preserved liver lobes after resection, in the 3rd-vitamin B12. In the animals of the 1st control group liver resection was not performed. The animals were removed from the experiment in 1, 7 and 14 days after the operation and liver material was selected for morphological examination.Results. A significant increase in the number of binuclear hepatocytes was noted in the animals of the 3rd experimental group in 14 days. When studying liver sections stained with silver impregnation after 14 days of the study, the number of reticular fibers in the animals of the 3rd experimental group was 90% higher than similar parameters in animals of the 1st control group, in the animals of the 1st and 2nd experimental groups it was less than 80%. In the immunohistochemical study, an increase in the proliferative activity of mononuclear and binuclear hepatocytes was observed in all experimental groups by the 14th day of the experiment compared with the 1st day. On the 14th day after the operation, the highest proliferation index was observed in the animals of the 3rd experimental group.Conclusion. The proposed method of intra-organ intraoperative administration of cyanocobalamin increases the proliferative activity of hepatocytes, increases the number of cells entering the mitotic cycle, and restores the structural organization of the liver, its anatomical and functional integrity.

Ki67 as Proliferative Marker in Patients with Early Breast Cancer and Its Association with Clinicopathological Factors

Introduction: Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist. Material and Methods: Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (n = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors. Results: 595 (64.9%) patients had a Ki67 <20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1–90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2−) disease (n = 717), 20% for HR+/HER2+ (n = 76), 30% for HR−/HER2+ (n = 45), and 60% for HR−/HER2− (n = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (<20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%). Conclusion: This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.

Germline BAP1 Mutation in a Family With Multi-Generational Meningioma With Rhabdoid Features: A Case Series and Literature Review.

Meningioma is the most common primary brain tumor, and recurrence risk increases with increasing WHO Grade from I to III. Rhabdoid meningiomas are a subset of WHO Grade III tumors with rhabdoid cells, a high proliferation index, and other malignant features that follow an aggressive clinical course. Some meningiomas with rhabdoid features either only focally or without other malignant features are classified as lower grade yet still recur early. Recently, inactivating mutations in the tumor suppressor gene BAP1 have been associated with poorer prognosis in rhabdoid meningioma and meningioma with rhabdoid features, and germline mutations have been linked to a hereditary tumor predisposition syndrome (TPDS) predisposing patients primarily to melanoma and mesothelioma. We present the first report of a familial BAP1 inactivating mutation identified after multiple generations of a family presented with meningiomas with rhabdoid features instead of with previously described BAP1 loss-associated malignancies. A 24-year-old female presented with a Grade II meningioma with rhabdoid and papillary features treated with subtotal resection, adjuvant external beam radiation therapy, and salvage gamma knife radiosurgery six years later. Around that time, her mother presented with a meningioma with rhabdoid and papillary features managed with resection and adjuvant radiation therapy. Germline testing was positive for a pathogenic BAP1 mutation in both patients. Sequencing of both tumors demonstrated biallelic BAP1 inactivation via the combination of germline BAP1 mutation and either loss of heterozygosity or somatic mutation. No additional mutations implicated in oncogenesis were noted from either patient’s germline or tumor sequencing, suggesting that the inactivation of BAP1 was responsible for pathogenesis. These cases demonstrate the importance of routine BAP1 tumor testing in meningioma with rhabdoid features regardless of grade, germline testing for patients with BAP1 inactivated tumors, and tailored cancer screening in this population.

Bioengineered endometrial hydrogels with growth factors promote tissue regeneration and restore fertility in murine models

Extracellular matrix (ECM) hydrogels obtained from decellularized tissues are promising biocompatible materials for tissue regeneration. These biomaterials may provide important options for endometrial pathologies such as Asherman's syndrome and endometrial atrophy, which lack effective therapies thus far. First, we performed a proteomic analysis of a decellularized endometrial porcine hydrogel (EndoECM) to describe the specific role of ECM proteins related to regenerative processes. Furthermore, we investigated the ability of a bioengineered system—EndoECM alone or supplemented with growth factors (GFs)—to repair the endometrium in a murine model of endometrial damage. For this model, the uterine horns of female C57BL/6 mice were first injected with 70% ethanol, then four days later, they were treated with: saline (negative control); biotin-labeled EndoECM; or biotin-labeled EndoECM plus platelet-derived GF, basic fibroblast GF, and insulin-like GF 1 (EndoECM+GF). Endometrial regeneration and fertility restoration were evaluated by assessing the number of glands, endometrial area, cell proliferation, neaoangiogenesis, reduction of collagen deposition, and fertility restoration. Interestingly, regenerative effects such as an increased number of endometrial glands, increased area, high cell proliferative index, development of new blood vessels, reduction of collagen deposition, and higher pregnancy rate occurred in mice treated with EndoECM+GF. Thus, a bioengineered system based on EndoECM hydrogel supplemented with GFs may be promising for the clinical treatment of endometrial conditions such as Asherman's syndrome and endometrial atrophy. Statement of significanceIn the last years, the bioengineering field has developed new and promising approaches to regenerate tissues or replace damaged and diseased tissues. Bioengineered hydrogels offer an ideal option because these materials can be used not only as treatments but also as carriers of drugs and other therapeutics. The present work demonstrates for the first time how hydrogels derived from pig endometrium loaded with growth factors could treat uterine pathologies in a mouse model of endometrial damage. These findings provide scientific evidence about bioengineered hydrogels based on tissue-specific extracellular matrix offering new options to treat human infertility from endometrial causes such as Asherman's syndrome or endometrial atrophy.

PROGNOSIS IN IDH-MUTANT AND IDH-WILD TYPE GLIOBLASTOMA

Glioblastoma (GBM) is the most common brain tumor in adults with a poor prognosis and predominantly astrocytic differentiation. GBM is classified according to the isocitrate dehydrogenase (IDH) mutation according to the World Health Organization (WHO) Brain Tumors 2016 classification. IDH-1 gene mutations are evaluated immunohistochemically (IHC) and molecular methods in current pathology laboratory practice. The aim of this study was to determine the overall survival in GBM cases according to IDH-1 mutation status and Ki-67 proliferation index. Total of 53 patients diagnosed as GBM between 2007-2020 in Sivas Cumhuriyet University Faculty of Medicine, Department of Pathology were evaluated. Disease-free median survival of 7 (13%) GBM patients with IDH mutation was 2 months (2-year survival 14%), disease-free median survival 9 months (2-year survival 24 %) in GBM IDH-wild type cases. In cases with a higher Ki-67 proliferation index, the median disease-free survival were shorter. In conclusion statistically significant results could not be obtained between disease-free survival in GBM IDH-mutant type and GBM IDH-wild type. However, the mean Ki-67 proliferation index of GBM IDH-wild type cases was found to be much higher than GBM IDH-mutant cases. High Ki-67 proliferation index was found to be associated with a significantly shorter survival.

The Correlation of the Neutrophil-Lymphocyte Ratio and the Platelet-Lymphocyte Ratio With Pathological Findings in Neuroendocrine Tumors.

IntroductionThe relationship between clinical prognostic factors and blood neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in some tumors has been investigated. In this study, we examined whether there is a relationship between pathological prognostic factors and NLR as well as PLR only in neuroendocrine tumors (NETs).MethodsA total of 115 patients with a NET diagnosis between 2014-2020 were included in the study. The efficiency of NLR and PLR in predicting distant metastases was determined by analyzing the receiver operating characteristic (ROC) curve. The relationship between histopathological parameters was also compared.ResultsThe cut-off value of NLR was 3.01 for predicting distant metastasis. At this value, the specificity was 73.7%, the sensitivity was 70.7%, and the likelihood ratio was 2.51. There was a significant relationship between NLR and tumor localization, histological grade, mitosis, Ki-67, distant metastasis, and lymphovascular invasion (all p<0.001). The cut-off value of the PLR in predicting distant metastasis was 134.4. At this value, the specificity was 59.6%, the sensitivity was 58.6%, and the likelihood ratio was 1.44. There was no significant relationship between PLR and the histopathological findings (all p>0.05).ConclusionsIn our study, a high histological grade, high mitosis, a high Ki-67 proliferation index, distant metastasis, and lymphovascular invasion were found in patients with NLR at a cut-off value above 3.01. However, we could not attain the same results for PLR. For trucut and endoscopic biopsies in particular, follow-up of patients with grades 1 and 2 NETs along with histopathological findings and evaluation of NLR in peripheral blood may be useful. NLR, which is an easily accessible inflammatory marker, can be used as an independent predictive factor in NETs.

Effects of Epidermal Growth Factor Receptor Signal Pathway on Proliferation, Invasion and E-Cadherin/Vimentin Protein Expression in Laryngeal Carcinoma Hep-2 Cells

Epidermal growth factor receptor (EGFR) is one transmembrane receptor with a high expression in more than 90% of head-neck squamous carcinoma cells. This study investigated the role of EGFR signal pathway on proliferation, invasion and expression of related proteins E-cadherin/Vimentin expression in laryngeal carcinoma cells. Laryngeal carcinoma Hep-2 cells were treated with EGFR agonist EGF or inhibitor Gefitinib followed by measuring cell cycle, proliferation index (PI) and apoptosis by flow cytometry. Transwell assay was employed for cell invasion and migration. Western blotting was further employed to test E-cadherin and Vimentin level. Compared to blank control group, EGF-treated cells had significantly lower S percentage of cell cycle at 6 h, 12 h and 24 h, plus higher PI. With prolonged incubation time, S ratio and PI were further significantly elevated, with more potent cell invasion and migration abilities, lower E-cadherin and Vimentin protein levels (p &lt; 0.05). Gefitnib significantly elevated S ratio at 6 h, 12 h and 24 h cell cycle, reduced PI, invasion or migration ability, as upregulated E-cadherin and downregulated Vimentin protein (p &lt; 0.05). Suppressing EGFR signal pathway could inhibit proliferation of laryngeal carcinoma cells, decrease cell invasion or migration, upregulate E-cadherin and downregulate Vimentin.

Tumor Budding is a reliable predictor for death and metastasis in invasive ductal breast cancer and correlates with other prognostic clinicopathological parameters

Background and objectiveBreast cancers are the most common type of cancer and the most common cause of mortality in women worldwide. Different prognostic factors are the subject of research to differentiate the prognosis even between cases at a similar stage and identify risky patients earlier and create individual treatment approaches.Tumor budding (TB) has been identified as a poor prognostic factor in many types of cancer, especially colorectal carcinomas. In our study, we aimed to determine the prognostic significance of the TB by evaluating the TB in line with clinicopathological parameters in breast invasive ductal carcinoma cases. Materials and methods311 breast carcinoma cases operated in our hospital between January 2010 and April 2020 were included in the study. In hematoxylin-eosin (H&E) sections of the cases, TB was evaluated in a single high-power field (HPF). ROC analysis was performed with overall survival data, and low, and high TB cutoffs were obtained. The relationship of the high TB with clinicopathological parameters was evaluated, and survival analysis was performed. ResultsWe determined that high TB in breast invasive ductal carcinoma cases was associated with low survival time, metastasis, axillary lymph node metastasis, angiolymphatic invasion, advanced stage (pT3), high Ki-67 proliferation index, progesterone receptor (PR) loss, and advanced age. Tumor budding was identified as an independent risk factor in overall and disease-free survival analysis. ConclusionTumor budding is a prognostic parameter that can be easily evaluated in all centers since it does not cause additional cost to routine pathological examinations. We think it may be helpful to establish a standard methodology in evaluating tumor bud in breast carcinomas and including it in regular pathology reporting.

OTME-16. Polio virotherapy of murine brain tumors causes microglia/macrophage proliferation and inflammation that is potentiated by immune checkpoint blockade

PVSRIPO is a novel viral immunotherapy that has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in 21% survival rate at 36 months following treatment. To improve clinical response rate, it is critical to resolve the mechanisms of action and therapy resistance in vivo, thereby designing effective combination therapy strategies.We used immunocompetent mouse models of glioma (CT2A) and metastatic melanoma (B16) to dissect early and late events following virotherapy with PVSRIPO. A blinded systematic review of the pathology from 62 intracranial tumors, collected on different days following PVSRIPO (or control) treatment, was performed. An overall treatment effect, measured by tumor shrinkage, dis-cohesive growth pattern, microglia enrichment, was present in 88% of tumors on day 8, but the tissue response rate fell to 42% on days 10 & 12, and 14% on day 15. The control group showed no treatment effect throughout. RNAseq from the same set of samples showed acute induction of type-I interferon-related inflammation that faded with time in Gene Set Enrichment Analysis. This suggests that sustaining adaptive antitumor immunity elicited by immediate intratumor type-I IFN-dominant inflammation is critical to long term remission. Careful review of the post treatment pathology revealed an early enrichment of both T cells and microglia in the tumor microenvironment with a high Ki-67 proliferation index. We propose that the PVSRIPO therapy effect is dependent on macrophage/microglia mediated cellular immune response, likely in response to direct viral infection. This suggests potential therapeutic interventions, including blockade of the PD1:PD-L1 immune checkpoint, to potentiate antitumor CD8+T cells in response to PVSRIPO therapy. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed higher long term remission (37%, n=11), compared to either monotherapy; this effect is CD8+T cell- and macrophage-dependent, demonstrated by depletion studies in vivo.

Abstract 3186: Differential expression of PD-L1 between primary and metastatic Middle-Eastern epithelial ovarian carcinoma and its clinico-pathological correlation

Abstract Ovarian cancer (OC) is one of the most common gynecologic cancer, which has the worst prognosis and highest mortality rate. The lack of curative treatment and the high relapse rate, especially in advanced OC, continues to present a clinical challenge, highlighting the need for new therapeutic strategies. This study was conducted to compare the expression of PD-L1 in Middle-Eastern primary epithelial ovarian carcinoma to that in peritoneal metastases and its correlation with clinico-pathological parameters. In total, 194 treatment naïve paired EOC and peritoneal metastases were analyzed by immunohistochemistry for PD-L1 expression. Clinico-pathological information was available for all patients. Significant differences in PD-L1 expression were found between primary EOC and peritoneal metastasis (p &amp;lt; 0.0001). We found discordant tumor cell PD-L1 expression between primary tumors and corresponding peritoneal metastasis in 34% (66/194) of cases. Furthermore, PD-L1 expression in peritoneal metastasis samples was significantly associated with adverse prognostic factors, such as high proliferative index (Ki67) (p = 0.0039) and high histologic grade (p = 0.0330). In conclusion, the heterogeneity of PD-L1 expression in EOC suggests its assessment as a potential biomarker for PD-L1 blockade may require analysis of metastatic lesions. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Felisa De Vera, Yan Kong, Zeeshan Qadri, Saeeda O. Ahmed, Hassan AlDossari, Khawla S. Al-Kuraya. Differential expression of PD-L1 between primary and metastatic Middle-Eastern epithelial ovarian carcinoma and its clinico-pathological correlation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3186.

Correlation between ER, PR, HER-2, and Ki-67 with the risk of bone metastases detected by bone scintigraphy in breast cancer patients: A cross sectional study

BackgroundBreast cancer is one of the most common cancers in women. About 30%–85% of breast cancers will metastasize to the bone during the course of the illness. Many studies have shown that molecular marker/subtypes can be useful in determining incidence of different and inconsistent bone metastases. This study aimed to determine the correlation of the risk of bone metastases in breast cancer based on the expression of molecular markers. MethodsThe research was conducted retrospectively by searching patients' medical record data. The target population of this study was all patients diagnosed with breast cancer who came to our tertiary hospital in the Nuclear Medicine and Molecular Imaging Department from January 2012 to December 2016. ResultsOne hundred and thirty patients (n = 130) were enrolled during the study period with characteristics of sex, age, and immunohistochemical/molecular subtype examination that underwent bone scintigraphy. Mean of age was 50.2 (23–79) years. There were no significant correlations between ER, PR, and HER-2 expressions with bone metastases in breast cancer patients. Ki-67 was showed to be correlated with bone metastases in breast cancer patients in our bivariate analysis. Molecular subtype/markers had no statistically significant correlation with bone metastases in patients with breast cancer. ConclusionKi-67 with high proliferation index was the most powerful molecular marker to determine the risk of bone metastases. The prevalence of bone metastases in the group with Ki-67 expression with high proliferation (≥20) was 1.8 times greater than the prevalence of bone metastases in the weakest HER-2 group.

Application of mid‐infrared microscopic imaging for the diagnosis and classification of human lymphomas

Mid-infrared (MIR) microscopic imaging of indolent and aggressive lymphomas was performed including formalin-fixed and paraffin-embedded samples of six follicular lymphomas and 12 diffuse large B-cell-lymphomas as well as reactive lymph nodes to investigate benefits and challenges for lymphoma diagnosis. MIR images were compared to defined pathological characteristics such as indolent versus aggressive versus reactive, germinal centre versus activated cell-of-origin (COO) subtypes, or a low versus a high proliferative index and level of PD-L1 expression. We demonstrated that MIR microscopic imaging can differentiate between reactive lymph nodes, indolent and aggressive lymphoma samples. Also, it has potential to be used in the subtyping of lymphomas, as shown with the differentiation between COO subtypes, the level of proliferation and PD-L1 expression. MIR microscopic imaging is a promising tool for diagnosis and subtyping of lymphoma and further evaluation is needed to fully explore the advantages and disadvantages of this method for pathological diagnosis.

Clinical Significance of Low Grade Follicular Lymphoma with High Proliferative Index

Introduction: Follicular lymphoma (FL) accounts for about 20% of lymphomas. The time to treatment, time to progression and overall survival are widely variable and additional prognostic factors are needed to identify patients who might benefit from upfront therapy. The association of high Ki67 proliferative index in FL with recurrence, progression, and decreased survival in unclear. Furthermore, the contribution of Ki67 proliferative index score in follicular versus interfollicular area for prognosis has not been reported.Methods: We performed a retrospective observational analysis of newly diagnosed patients with FL evaluated at University of Minnesota, from 2003 to April 2016. All cases were graded using WHO Classification histologic grading criteria. We excluded patients with no follow-up and grade 3B. We examined medical records and performed Ki67 immunohistochemical nuclear stains. Two pathologists reviewed Ki67 staining in follicular and interfollicular area and selected areas with maximum staining. Ten consecutive follicular and interfollicular areas were scored separately for Ki67 nuclear staining. Association of Ki67 with overall survival (OS) and progression-free survival (PFS) from date of diagnosis was analyzed using Cox regression. We defined PFS as time from diagnosis to initiation of first treatment or death, whichever occurred first.Results: We examined 69 cases, 63 were grade 1 and 2 follicular lymphoma and 6 were grade 3A. Median age at diagnosis was 59 years. Gender was distributed equally. At time of diagnosis FLIPI score was 0 in 9 patients (13%), 1 in 15 patients (21.7%), 2 in 19 patients (27.5%), 3 in 15 patients (21.7%), 4 in 3 patients (4.3%), and unknown in 8 patients (11.6%). 27.5% patients (27 cases) showed bone marrow involvement at the time of diagnosis. Median (interquartile range) Ki67 was 25% (15%, 40%) in follicular area and 5% (5%, 15%) in interfollicular area.Median follow-up time was 4.0 years (range 0.1 to 11.7 years). 37.7% underwent upfront observation, 14.5% were treated with RCHOP as first line of therapy, 23.2% received rituximab as maintenance therapy, few (13%) cases transformed into diffuse large B-cell lymphoma, and 20% of the patients died. OS at 5-years was 86% (95% CI: 76%, 97%), and PFS at 5-years was 25% (95% CI: 16%, 40%). Median PFS was 1.6 months. In univariate analysis, follicular Ki67 was not associated with PFS (p > 0.40) or OS. Interfollicular Ki67 was highly associated with shorter PFS with hazard ratio 1.32 per 10 units of Ki67 (95% CI: 1.08, 1.63). Results were similar adjusting for FLIPI score.Conclusions: Our data suggests that interfollicular area Ki67 score at diagnosis is prognostic to predict PFS in patients with FL. The relationship appears to be linear and doesn't change when adjusting for FLIPI score. Follicular area Ki67 has no impact on clinical outcomes. We propose that the Ki67 proliferative index should be scored in the interfollicular areas to assess the prognosis in FL. DisclosuresBachanova:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

Treatment of High Risk DLBCL with DA-R-EPOCH in Those Unable to Tolerate Intensive Chemotherapy: Well-Tolerated and Effective, but Inadequate in Double/Triple Hit or Expressing DLBCL

Treatment of High Risk DLBCL with DA-R-EPOCH in Those Unable to Tolerate Intensive Chemotherapy: Well-Tolerated and Effective, but Inadequate in Double/Triple Hit or Expressing DLBCL

Comprehensive Sequencing Analysis in Subcutaneous Panniculitis-like T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare subtype of peripheral T-cell lymphomas predominantly affecting younger individuals. Typically, SPTL presents with multifocal subcutaneous nodules, and nearly 20% of the patients have autoimmune disorders, including systemic lupus erythematosus, juvenile rheumatoid arthritis and Sjögren disease. Unlike other lymphomas, which usually require chemotherapy for long-term survival, immunosuppressive therapy alone yields favorable outcomes in SPTL. A previous study showed allelic NAV3 gene aberrations (LOH or deletion by FISH) in 44% of the SPTL samples and comparative genomic hybridization (CGH) revealed numerous DNA copy number changes. In another study, recurrent mutations were identified in various epigenetic modifiers (72%) and components of the PI3K/AKT/mTOR signaling pathway (44%). However, molecular pathogenesis of this disease has not been clearly understood.To elucidate the causative genetic lesions of SPTL, we collected 13 patients from Thailand (n=12) and Japan (n=1). Histopathology was reviewed by hematopathologists showing karyorrhexis of tumor cells infiltrating fat lobules. In all cases, lymphoma cells expressed CD3, CD5, CD8 and TIA1 but no CD56 suggesting the cytotoxic T-cells in origin. Tumor cells expressed T-cell receptor alpha/beta. The monoclonality was confirmed by southern blot (n=12). The mean percentage of SPTL cells in tissue blocks was 38% (range 20-80%). The majority of cases (75%) showed a high proliferative index (Ki-67 expression > 70%).Regarding the clinical data, 10 of 13 patients (80%) were female. The median age at diagnosis was 30 years old. Five cases (38.5%) showed systemic symptoms and 2 cases (20%) were associated with hemophagocytic syndromes. Seven cases received cyclosporine and prednisolone. All showed complete response but 2 cases relapsed. Six cases received anthracycline-based chemotherapy but 3 cases relapsed. All relapses responded to immunosuppressive therapy.We collected paired samples from each of cases (n=13). Tumor samples were collected from Formaldehyde Fixed-Paraffin Embedded (FFPE) tissues whereas germline samples were collected from either bone marrow FFPE or blood which showed no tumor involvement. We performed whole-exome and targeted-capture sequencing in those paired tumor/germline DNA samples by SureSelect v5 kit and custom kit, respectively. To identify somatic mutations and structural variations, sequencing data was analyzed using Genomon (ver. 2.3.0) and Genomon-SV. Copy number was analyzed based on sequencing data as described previously (ASH 2016 abstract by Saeki, et al.).By whole exome sequencing, 149 mutation calls were identified in 8 samples. The somatic mutations and copy number variations were grouped into 4 biological pathways which are commonly affected in cancer.1. Apoptotic associated pathway (FADD , ACIN1 , and PPM1L) : Interestingly, a nonsense mutation of FADD was found and validated. FADD protein is critical for promoting apoptosis of T-cell progenitors at the pre-TCR checkpoint.2. Epigenetic modifier pathway (GFIB , SAB130 and CHD9) : Notably, GFI1B mutation was found to be frameshift deletion causing protein truncation. Gfi1b repressed the Gata3, a transcription factor required for survival of T-lymphocyte progenitors.3. Translation initiation pathway (DHX29 and CTIF) : Missense mutation of DHX29 was identified whereas copy number analysis revealed one case possessed focal amplification of CTIF , a component of the CBP80/CBP20 translation initiation complex and associated with nonsense-mediated decay of mRNA.4. Transcription factors (MEF2B and MGA ): Targeted sequence detected mutations in MEF2B, MGA and PMS2 , which are associated with regulation of BCL6, MYC-MAX pathway and DNA mismatch repair, respectively.At least one mutation involved in either of such 4 pathways was identified in 5/8cases (62.5%). In addition, Sequence based T-cell receptor repertoire analysis proved monoclonal expansion in 5 cases.In conclusion, the identifications of novel genetic alterations provide an insight into the lymphomagenesis of SPTL. Heterogeneous mutations in different candidate pathways suggest complexpathogenesis of this rare tumor. DisclosuresMakishima:Yasuda Medical Foundation: Research Funding.

Prognostic Significance of Plasmablastic Plasma Cells in the Era of Novel Agents in Multiple Myeloma

Background:Plasmablastic (PB) feature has long been identified as poor prognosis in multiple myeloma (MM), although most data was reported in the era of conventional therapy. Furthermore, PB feature does not belong to the R-ISS scoring system in part due to lack of data since the emergence of novel therapy based regimens.Methods: We have performeda retrospective multicenter analysisof all MMdiagnosed in the network area of the Poitiers academic hospital since 2005 to identify MM with PB features. PB was defined as presence of immature cells, any percentage, characterized with high proliferative index rate, centrally reviewed in Poitiers hematology laboratory by 3 hematologists.Results: 65 MM with PB were identified, of which 53,8% were in first-line therapy. Adverse cytogenetic (IMWG) was reported in 6 patients, del17p x3, t(4;14) x2, and one with both. However, 33,8% were ISS 3, and 23,1% R-ISS 3. Presence of extramedullary disease (EMD) was reported in 40%. As a whole, ORR with any triplet-based treatment containing always a proteasome inhibitor and IMiDs or alkylator was 49,2%, with 29,2% VGPR and 4,6% CR. The median PFS and OS were 6,9 and 14,9 months as a whole, respectively, and independently of diagnosis or relapse settings. We noticed that one regimen appeared to fare much better than the other, namely VRd (bortezomib, lenalidomide and dexamethasone), with a median PFS at 36,1 months [CI95%: 0-99] vs 5,5 [0,59-10,4] otherwise; p=0,014. Similarly, ASCT was associated with longer PFS and OS, 21,4 months [12,8-30,1] vs 2,83 [0-5,7], p=0,003; and 50,4 months ([29,9-70,7] vs 6,27 [1,1-11,4] p=0,001 respectively. We were not able to demonstrate that use of anthracyclines was able to control the PB clone, although it was one of our initial hypothesis. Univariate and multivariate analysis for poor OS identified acute renal failure at disease entry, presence of EMD, of del(17p), and high LDH, markers strongly associated to PB presence. We found that the % of PB correlated to poor prognosis on a linear fashion.Conclusion: This study confirms the poor prognosis of PB feature in MM even in the era of novel agents. A triplet-based association PI + IMId + dex is warranted possibly consolidated by ASCT when possible. The role of the new anti CD38 monoclonal antibody has yet to be confirmed in this population. DisclosuresSonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding. Leleu:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

IDENTIFICATION AND STUDY OF PROGNOSTIC BIOMARKERS IN A COHORT OF EARLY-STAGE ORAL SQUAMOUS CELL CARCINOMA PATIENTS FROM ARMENIA

<h3>Background</h3> Oral squamous cell carcinoma (OSCC) is the sixth leading malignancy worldwide. The incidence of OSCC has increased in recent years. Tumor-associated macrophages have been shown to promote tumor progression by influencing tumor invasion, migration, and angiogenesis. So far, no study investigating different biomarkers in cohorts of patients with OSCC from Armenia has been published. <h3>Objective</h3> The aim of this study was to evaluate the role of tumor-associated macrophages in the prognosis of OSCC and investigate the association between the expression of Ki67 and p53 biomarkers and its relation with clinicopathologic parameters (tumor stage and grade) in a cohort of patients with OSCC from Armenia. <h3>Methods</h3> Available samples from patients diagnosed with OSCC in 2017/2018 were collected from Armenian hospitals after ethics approval (n = 13). Immunohistochemistry was performed using Visualization System and EnVision Double stain System (DAKO) for Ki67, p53, and CD163/CD68 biomarkers. Stained tissues were scanned and quantified using Image Scope software (Aperio Technologies Inc.) and QuPath v0.2.0-m9 (OSS for DPI analysis). Data were analyzed using SPSS 25.0. <h3>Results</h3> Intense nuclear expression of p53 was identified in 69.2% cases but not strongly correlated with a high proliferation index (>50% Ki67 positive cells; <i>P</i> = .125) and M2 type macrophages expression (<i>P</i> = .308). In contrast, M2 type macrophages count was correlated with tumor stage (<i>P</i> = .026). <h3>Conclusions</h3> This preliminary study identified a positive correlation between increased expression of M2 type macrophages and OSCC stage. This should be further investigated in a larger cohort of patients.