Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer.

Patient-derived organoids (PDOs) may facilitate treatment selection. This retrospective cohort study evaluated the feasibility and clinical benefit of using PDOs to guide personalized treatment in metastatic breast cancer (MBC). Patients diagnosed with MBC were recruited between January 2019 and August 2022. PDOs were established and the efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving organoid-guided treatment (OGT) were matched 1:2 by nearest neighbor propensity scores with patients receiving treatment of physician's choice (TPC). The primary outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Forty-six PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 78.4% (95% CI 64.9%-91.9%) in predicting clinical responses. Thirty-six OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs. 5.0 months; hazard ratio 0.53 [95% CI 0.33-0.85]; p = .01) and improved disease control (88.9% vs. 63.8%; odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis in hormone receptor-positive, human epidermal growth factor receptor 2-negative patients demonstrated differentially modulated pathways implicated in DNA repair and transcriptional regulation in those with reduced response to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in those with reduced response to palbociclib. Our study shows that PDO-based functional precision medicine is a feasible and effective strategy for MBC treatment optimization and customization.

Pathological Responses of the Primary Tumor and Locoregional Lymph Nodes After Neoadjuvant Immunochemotherapy in Esophageal Squamous Cell Cancer.

Background: The current study attempted to describe the specific patterns of pathological tumor response and locoregional node metastases from surgically resected esophageal squamous cell carcinoma after neoadjuvant immunochemotherapy (NAIC), as well as to explore the association between clinicopathological characteristics and such oncological patterns. Methods: Fifty-one patients with cT3 or deeper esophageal squamous cell cancer underwent subtotal esophagectomy after NAIC. The NAIC regimen included intravenous administration of platinum-based and docetaxel- and taxane-based chemotherapeutics along with a 200 mg fixed dose of one programmed death 1 (PD-1) inhibitor, given every 3 weeks. We divided patients into tumor/nodal good-responders and poor-responders based on the pathological observation of the tumor or nodal responses. We also examined the association between clinicopathological factors and tumor/nodal responses. Further, significant baseline predictors for tumor and nodal good-responders were identified using multivariate binary logistic regression. Results: Of the 51 patients, 68.6% achieved marked primary tumor response. Notably, 21.6% of patients achieved complete pathological response. Significant differences in treatment cycles between tumor good-responders and tumor poor-responders (P = 0.019) were observed. For locoregional nodal responses, only 33.3% of patients achieved down-staged nodal disease. Of the investigated variables, neoadjuvant cycles (odds ratio (OR): 5.271, 95% confidence interval (CI): 1.278 - 21.740, P = 0.022) and pretreatment platelets (OR: 0.979, 95% CI: 0.962 - 0.996, P = 0.017) were identified as independent predictors for good tumor and nodal responses. Conclusions: We conclusively noted that most patients receiving NAIC were tumor good-responders, whereas only one-third of patients were nodal good-responders. Furthermore, we identified that treatment cycle number and baseline platelet counts were independent predictors of combined tumor and nodal responses.

The correlation analysis of TERT promoter mutations with IDH1/2 mutations and 1p/19q detected in human gliomas.

BACKGROUND: To investigate the correlations between mutations in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase (IDH) 1 and 2 mutations or 1p/19q deletion in human gliomas. METHODS: TERT promoter gene and IDH gene mutations in 110 glioma specimens were evaluated using first generation Sanger sequencing. The 1p/19q status was determined with fluorescence in situ hybridization. The relationship between TERT promoter mutations and IDH gene mutations as well as 1p/19q deletion was analyzed using the χ2 test and Spearman rank correlation test. RESULTS: The TERT promoter mutation rate in 110 glioma specimens was 39.09% (43/110), with a rate of 32.56% (14/43) for C228T mutation and 67.44% (29/43) for C250T mutation. The IDH gene mutation rate in all specimens was 31.82% (35/110), with a rate of 52.78% (19/36) in low-grade gliomas and 21.62% (16/74) in high grade gliomas. The 1p/19q deletion rate was 28.18% (31/110) in all specimens. Correlation analysis revealed that TERT promoter mutation was positively correlated with 1p/19q deletion (relative precision (rp) = 0.244, P = .015). In lower-grade glioma with IDH mutation, TERT promoter mutation was positively correlated with 1p/19q deletion (rp = 0.856, P = .000). The prognosis for gliomas with IDH mutation/TERT mutation/1p/19qdeletion was good. Mutation of the TERT promoter was negatively correlated with IDH gene mutation (rp = -0.290, P = .004), except in 10 cases of oligodendroglioma and 1 case of anaplastic oligodendroglioma. CONCLUSION: There may be a complex inter-regulatory relationship between the mutations of the TERT promoter and IDH gene as well as 1p/19q abnormalities in human gliomas.

High SHP2 expression determines the efficacy of PD-1/PD-L1 inhibitors in advanced KRAS mutant non-small cell lung cancer.

BACKGROUND: Src homology region 2 domain-containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME). METHODS: Sixty-one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next-generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME. RESULTS: SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H-score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s-SHP2) was higher in tumors with PD-L1 ≥50% versus PD-L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s-SHP2 had positive correlation with CD8, CD4, CD68, and PD-L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression-free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD-L1 had longer PFS (p < 0.001). CONCLUSION: High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME.

Timing and Origins of Local and Distant Metastases in Lung Cancer.

INTRODUCTION: Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive. METHODS: We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models. RESULTS: There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than the earlier colonized lymph node metastases. CONCLUSIONS: Our results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporospatial pattern of disease progression revealed that lung cancer was susceptible to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.

Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma.

BACKGROUND: Understanding the genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma may provide critical insight and facilitate development of novel strategies for early detection and intervention. METHODS: A total of 80 tumor tissue samples and 30 paired histologically normal lung tissue samples from 30 patients with adenocarcinoma in situ (AIS) (n = 8), minimally invasive adenocarcinoma (MIA) (n = 8), and invasive adenocarcinoma (IAC) (n = 14) were subjected to multiregion whole exome sequencing and immunohistochemistry staining for CD8 and programmed death ligand 1 (PD-L1). RESULTS: All tumors, including AIS, exhibited evidence of genomic intratumor heterogeneity. Canonical cancer gene mutations in EGFR, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), NRAS, and BRAF were exclusively trunk mutations detected in all regions within each tumor, whereas genes associated with cell mobility, gap junction, and metastasis were all subclonal mutations. EGFR mutation represented the most common driver alterations across AIS, MIA, and IAC, whereas tumor protein p53 gene (TP53) was identified in MIA and IAC but not in AIS. There was no difference in PD-L1 expression among AIS, MIA, and IAC, but the CD8 positivity rate was higher in IAC. Tumors positive for both PD-L1 and CD8 had a larger proportion of subclonal mutations. CONCLUSIONS: Mutations in EGFR, ERBB2, NRAS, and BRAF are early clonal genomic events during carcinogenesis of lung adenocarcinoma, whereas TP53 and cell mobility, gap junction, and metastasis-related genes may be late events associated with subclonal diversification and neoplastic progression. Genomic intratumor heterogeneity and immunoediting are common and early phenomena that may have occurred before the acquisition of invasion.

Impact of the updated 2018 ASCO/CAP guidelines on HER2 FISH testing in invasive breast cancer: a retrospective study of HER2 fish results of 2233 cases.

OBJECTIVES: Human epidermal growth factor receptor 2 (HER2, ERBB2) is a valuable prognostic and predictive biomarker in breast cancer. Accurate assessment of HER2 status is essential in selecting the patients with invasive breast cancer who will likely response to HER2-targeted therapies. Some major modifications in the diagnostic recommendation for fluorescence in situ hybridization (FISH) have been made in the updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologist (CAP) guideline. According to the revised guideline, concomitant IHC assays are required to arrive at the most accurate HER2 status designation after HER2 FISH equivocal results; however, little is known about its influence on the clinical practice of pathologist. The purpose of this study was to evaluate the impact of the revised 2018 ASCO/CAP guidelines on the HER2 status designation. METHODS: We retrospectively reviewed the HER2 FISH testing results from 2233 cases of invasive breast cancer between January 2014 and December 2017. Concomitant immunohistochemistry (IHC) were performed on the same tissue blocks that were used for the FISH testing. RESULTS: Compared to the 2013 guidelines, the HER2 status in 183 (8.2%) cases were re-defined when reassessed by the 2018 guidelines. Among these 183 cases, 175 equivocal cases according to the 2013 guideline were re-defined as HER2 negative (n = 173) or HER2 positive (n = 2). Eight previously classified as HER2 positive cases were converted to negative in the 2018 scheme, all of which were with HER2 IHC scores of 1+ or 2+. The number of cases in the negative category was 1705 according to the 2018 guidelines as opposed to 1524 by the 2013 guidelines. CONCLUSIONS: The updated 2018 ASCO/CAP guidelines eliminated the FISH equivocal category, which can be attributed to reflex HER2 IHC, and partly ease the dilemma for clinical practice. Reflex IHC for FISH equivocal cases is of prime importance; furthermore, HER2 FISH results were converted from positivity to negativity based on the concomitant IHC results in a small percentage of cases. In all, implementation of the 2018 ASCO/CAP guidelines provides much clearer instructions and recommendations for the HER2 status designation, and thus reduces the risk of misdiagnosis.

Impact of repeat HER2 testing after initial equivocal HER2 FISH results using 2013 ASCO/CAP guidelines.

PURPOSE: The updated 2013 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing have made some major changes in HER2 fluorescence in situ hybridization (FISH) interpretation criteria with additional FISH equivocal cases. Repeat HER2 testing is recommended after initial HER2 FISH equivocal results; however, little is known about its impact on final HER2 status. The aim of this study is to investigate whether reflex test clarifies HER2 status, and to characterize clinicopathological features of the newly defined HER2 equivocal group. METHODS: A total of 886 consecutive cases of primary invasive breast cancer conducted with dual-probe HER2 FISH testing between November 2013 and December 2015 were reviewed. HER2 immunohistochemistry (IHC) and FISH testing were performed on a different tissue block or a new specimen after initial HER2 FISH equivocal results. RESULTS: Compared to 2007 guideline, 85 (9.6%) cases changed their category by using 2013 guideline. The major change of the 85 cases is that 57 (6.4%) cases in HER2 FISH-negative category changed to equivocal, and the equivocal category cases increased from 36 to 67. HER2 FISH equivocal was significantly associated with HER2 IHC equivocal (2+) and chromosome 17 polysomy (P < 0.01). Repeat testing by IHC and FISH clarified HER2 status in 33 and 42% of HER2 equivocal cases, respectively. Overall 32 (48%) initial HER2 equivocal cases stayed HER2 equivocal after repeat FISH and or IHC testing. These tumors were ER/PR+, with high KI-67 index. CONCLUSION: New guidelines classify more HER2 FISH equivocal cases. Repeat HER2 testing clarifies HER2 status in about 50% of initial HER2 FISH equivocal cases. In addition, HER2 equivocal cases merit further study as there is limited information about prognosis and optimal treatment strategy for this population.

Overexpression of SRC-3 promotes esophageal squamous cell carcinoma aggressiveness by enhancing cell growth and invasiveness.

Steroid receptor coactivator-3 (SRC-3), a transcriptional coactivator for nuclear receptors and other transcription factors, plays an important role in the genesis and progression of several cancers. However, studies investigated the role of SRC-3 in esophageal squamous cell carcinomas (ESCCs) are limited, and the role of SRC-3 in tumor progression remains unclear. We examined the expression of SRC-3 in 8 ESCC cell lines and 302 human ESCC tissues by qPCR, Western blot, and immunohistochemistry. In addition, ESCC cell lines were subjected to proliferation and invasion assays, tumorigenicity assay, flow cytometry assay, qPCR, Western blot, and Chromatin Immunoprecipitation assay to investigate the role of SRC-3 in cancer progression. SRC-3 was overexpressed in 48% of cases and correlated with poor overall (P = 0.0076) and progression-free (P = 0.0069) survival of surgically resected ESCC patient. Cox regression analysis revealed that SRC-3 is an independent prognostic marker. Furthermore, we found that activation of insulin-like growth factor (IGF)/AKT) was involved in the SRC-3 on the cell growth and invasiveness in two ESCC cell lines, Eca109 and EC18 cells. SRC-3 overexpression is clinically and functionally relevant to the progression of human ESCC, and might be a useful molecular target for ESCC prognosis and treatment.

PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer.

We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR­21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS, which may require more aggressive treatment.

Rare discrepancies in a driver gene alteration within histologically heterogeneous primary lung cancers.

OBJECTIVES: Most lung adenocarcinomas consist of mixtures of histological subtypes harboring different frequencies of driver gene mutations. However, little is known about intratumoral heterogeneity(ITH) within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to personalized treatment. METHODS: Morphologically different areas within the same surgically resected adenocarcinomas were extracted from tissues to analyze gene status in each growth pattern. Driver genes, epidermal growth factor receptor (EGFR), KRAS and EML4-ALK, were assessed by assays with different sensitivities. RESULTS: Seventy-nine consecutive eligible patients harboring a driver gene (EGFR=65; KRAS=10; EML4-ALK=4) were enrolled. For EGFR mutations, ITH occurred in 13.3% (8/60) by direct sequencing (DS) and 1.7% (1/60) by amplification refractory mutation system (ARMS) (P=0.016) among adenocarcinomas, but consistent within five adeno-squamous cell carcinomas by both methods. ITH among KRAS mutations were detected in 20% (2/10) by DS, whereas consistent (10/10) by high resolution melting. No discrepancies in EML4-ALK rearrangements existed according to fluorescence in situ hybridization. CONCLUSION: Rare ITHs of EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas existed by methods with higher sensitivity. Discrepancies might be due to abundance of mutant tumor cells and detection assays.

[B-cell lymphomas with concurrent myc and bcl-2/IgH or bcl-6 translocations].

OBJECTIVE: To identify and investigate clinicopathological features of B cell lymphomas with concurrent myc and bcl-2/IgH or bcl-6 translocations ("double-hit" lymphoma). METHODS: Tissue microarray was constructed from formalin-fixed and paraffin-embedded tissue samples of aggressive B cell lymphomas diagnosed between 2009 and 2012, including 129 cases of diffuse large B cell lymphoma (DLBCL), 5 cases of B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLU), 7 cases of Burkitt lymphoma and 4 cases of high-grade follicular lymphoma with diffuse large B cell lymphoma component. Interphase fluorescence in-situ hybridization (FISH) was performed with a panel of probes including myc, bcl-2/IgH and bcl-6 to document related gene translocation and copy number changes. Medical record review was performed and follow-up data was recorded. RESULTS: Among 145 cases, 5 cases (3.4%) of B cell lymphomas with concurrent myc and bcl-2/IgH or bcl-6 rearrangements (double-hit lymphomas) were identified, including 2 cases involving myc and bcl-2 translocations (1 DLBCL and 1 BCLU), and 3 cases involving myc and bcl-6 translocations (all DLBCLs). Three cases with concurrent bcl-2/IgH and bcl-6 translocations were found. Single gene translocations or increase of copy numbers were found in 66 cases, representing 51.2% (66/129) of all de novo DLBCLs. Ki-67 index of the 5 "double-hit" lymphomas ranged from 60% to 100%. Clinical follow-up data were available in 4 of the 5 "double-hit" lymphoma patients, three of whom died within 2 years and 1 patient was alive after 36 months of follow-up. CONCLUSIONS: "Double-hit" B-cell lymphomas are rare and can only be identified by molecular detection. They should not be considered synonymous with BCLU morphologically, and may present entities within other morphological spectra. Most of the patients have a poor prognosis. Further in-depth studies of larger case numbers are required to determine the pathologic and genetic variables of the lesion.

Immunophenotypic features and t(14;18) (q32;q21) translocation of Chinese follicular lymphomas helps to distinguish subgroups.

BACKGROUND: The revised 2008 World Health Organization classification maintains a histological grading system (grades 1-3) for follicular lymphoma (FL). The value of grading FL has been debated. This study will yield deeper insights into the morphologic, immunophenotypic characterization and t(14;18) translocation in FL and explore their significance of diagnosis of Chinese FL subgroups. METHODS: We retrospectively reviewed the FL diagnoses according to the 2008 WHO classification in all diagnostic specimens from a multicentric cohort of 122 Chinese patients. Upon review, 115 cases proved to be truly FL. CD10, BCL6, MUM1, BCL2 and t(14;18) (q32;q21) translocation were detected by Envision immunostaining technique and fluorescence in situ hybridization. RESULTS: FL1 has larger proportion of follicular pattern (93.0%) than that of FL2 (73.7%, P = 0.036), FL3B (63.6%, P = 0.003) and FL3A (77.4%, P = 0.053), although the last P value was more than 0.05 (Pearson's chi-squared test). Areas of DLBCL were present in 25.8% (8/31) of FL3A and more frequent in FL3B (59.1%, 13/22; P = 0.015). The positivity of CD10 and BCL2 in FL1-2 were significantly higher than those in FL3 (P < 0.001, P = 0.043, respectively). The positivity of MUM1 in FL1-2 was significantly lower than that in FL3 (10.2% vs. 51.0%; P < 0.001). Furthermore the positivity of MUM1 in FL3A was significantly lower than that in FL3B (37.9% vs. 68.2%; P = 0.032). The positivity of t(14;18) was higher in FL1-2 than in FL3 (73.5% vs. 35.6%, P < 0.001), and was higher in FL3A than in FL3B (51.9% vs. 11.1%, P = 0.005). t(14;18) was significantly correlated with CD10+ (R = 0.453, P < 0.001) and MUM1+ (R = -0.482, P < 0.001). CONCLUSIONS: FL1 and FL2 were immunophenotypically and genomically similar, while FL3A and FL3B were partly immunophenotypically similar but morphologically, genomically distinct. FL3A was genomically closer to FL1-2, whereas FL3A was genomically closer DLBCL. Thus we hypothesize that FL may in fact be a heterogeneous indolent lymphoma encompassing entities with distinct molecular pathogenesis and genetic characteristics. Immunohistochemical and genetic characterization helps to distinguish subgroups of FLs. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1334018129864616.

Tau expression correlated with breast cancer sensitivity to taxanes-based neoadjuvant chemotherapy.

The purpose of this study was to investigate the correlation between tau expression in primary breast cancer and sensitivity to taxanes during neoadjuvant chemotherapy in patients with breast cancer. We used immunohistochemistry to examine tau expression in breast cancer biopsies from 113 primary breast cancer patients and evaluated the correlation between tau expression and taxane sensitivity. Twenty-eight (24.78 %, 28/113) patients were positive for tau expression. After taxanes-based neoadjuvant chemotherapy, 40 patients achieved pathological complete response (pCR) (35.4 %). Among the 40 patients with pCR, five (12.5 %) were positive for tau expression. In univariate analysis, estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2 (HER2), and tau were found to be significantly predictive of a pCR (P = 0.001, 0.030, 0.002, and 0.025, respectively). Tau, ER, and HER2 status were significant for pCR on multivariate analysis (P = 0.025, 0.005, and 0.043, respectively). Tau expression was positively related to ER (P = 0.007) and progestin receptor (P = 0.008). In conclusion, tau protein expression correlated with breast cancer sensitivity to taxanes-based neoadjuvant chemotherapy; patients negative for tau expression were more likely to achieve pCR.

[Clinicopathological features of Epstein-Barr virus-positive diffuse large B-cell lymphoma in elderly].

OBJECTIVE: To investigate the clinicopathological features of EB virus positive diffuse large B-cell lymphomas (EBV + DLBCL) of the elderly. METHODS: Four hundred and ninety-six cases of DLBCLs were retrospectively studied by in situ hybridization (ISH) to detect the EBV in tumor cells, and by immunohistochemistry to evaluate the expression of CD10, CD20, CD30, CD79a, bcl-6, bcl-2, MUM-1, CD5, CD3, TIA-1 and Ki-67 protein. Their clinicopathological correlations were analyzed. RESULTS: Of the 59 cases of EBV + DLBCL, 48 cases were EBV positive. The median age of these EBV + DLBCLs was 73 years with male predominance (1.4:1). There were 11 cases with nodal presentation only, 18 cases with extra-nodal presentation and 19 cases with both lymph nodal and extra-nodal involvements, whereas about one third cases with more than one extra-nodal involvement. Thirty-five patients presented with advanced disease (Ann Arbor stage III/IV). A performance status was available in 36 cases and 5 cases had performance status of more than 1. Seven of 30 patients were found with high lactate dehydrogenase value (more than twice of the normal). An IPI-score was calculated in 30 cases and 18 cases had an intermediate/high IPI-score (3-5). The median survival for these patients was 35 months. Morphologically, EBV + DLBCLs of the elderly generally showed a diffuse and polymorphic proliferation of large lymphoid cells with varying degrees of reactive components including small lymphocytes, plasma cells, histiocytes, and epithelioid cells. These tumor cells were frequently characterized by a broad range of B-cell maturation, containing centroblasts, immunoblasts, and Hodgkin- and Reed-Sternberg (HRS)-like giant cells. The study cohort was further morphologically divided into large cell lymphoma subtypes (n = 33) and polymorphic lymphoma subtypes (n = 14) and one case with mixed subtype. Immunohistochemical studies showed that tumor cells were positive for CD20 (47/48) and/or CD79a (45/45) in almost cases. Tumor cells were MUM-1-positive in the majority of the cases (44/47) and were stained for CD10 or bcl-6 in a few cases. Expression of bcl-2 and CD30 was observed in 80.0% (28/35) and 28.9% (11/38) cases, respectively, and most of the cases (33/39) had a high proliferative index (by Ki-67 with a 50% cut-off point). Compared with other EBV + DLBCLs, except the older age and low frequency of bcl-6 staining, no other significant differences were observed in EBV + DLBCLs of the elderly. CONCLUSIONS: EBV + DLBCLs of the elderly constitute a distinct clinicopathologic subtype of DLBCL, although many clinical and histological features with EBV + lymphomas are similar with that of younger ages. Differential diagnosis from other types of lymphomas should also be considered.

[Association of HER2 protein expression with clinicopathologic features and prognosis in Chinese patients with gastric carcinoma].

OBJECTIVE: To evaluate the epidemiological status of HER2 protein expression in Chinese patients with gastric carcinoma, and to study its clinical and prognostic significance and the association with the clinicopathological features. METHODS: The clinical data were reviewed in 860 patients with gastric carcinoma admitted to Guangdong General Hospital from 2003 to 2010. The HER2 status was evaluated using immunohistochemistry (IHC). The modified HercepTest scoring criterion was used to assess HER2 protein expression. The association between HER2 expression and clinicopathological features was analyzed by χ(2) test. Kaplan-Meier analysis, log-rank test and Cox regression model were used for the survival analysis. RESULTS: The median age of the patients was 59 years, and the male-to-female ratio was 2.06:1. Positive expression of HER2 protein (3+) was found in 77 (9.0%) cases of gastric carcinoma, and in 69 (8.9%) advanced gastric cancers. There was significantly positive association between HER2 over-expression and tumor differentiation, Lauren classification and WHO classification. No significant association was observed between HER2 protein expression and patients' age, gender, tumor location and clinical stage. There was no statistically significant difference in survival rate between patients with positive HER2 expression and negative ones. CONCLUSION: Though there was significantly positive association between HER2 expression status and tumor differentiation, histological type, it may be of limited prognostic value in gastric cancer patients.

[Immunophenotypes and prognosis of diffuse large B-cell lymphoma: a study of 500 cases].

OBJECTIVE: To study the immunophenotype and overall survival of diffuse large B-cell lymphoma (DLBCL) classified according to the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. METHODS: Five hundred cases of DLBCL were retrospectively analyzed with histologic review, immunohistochemistry, gene rearrangement study, in situ hybridization and fluorescence in situ hybridization. Follow-up data were collected. The overall survival rates of germinal center B-cell (GCB) and non-germinal center B-cell (non-GCB) subtypes, as well as those of DLBCL, not otherwise specified (NOS) and Epstein-Barr virus (EBV)-positive DLBCL of the elderly, were compared. RESULTS: DLBCL-NOS was the commonest subtype which accounted for 77.2% (386/500) of the cases. EBV-positive DLBCL of the elderly, primary DLBCL of central nervous system, primary mediastinal (thymic) large B-cell lymphoma and T cell/histiocyte-rich large B-cell lymphoma accounted for 9.4% (47/500), 4.4% (22/500), 2.8% (14/500) and 2.6% (13/500), respectively. 68.5% (219/320) of DLBCL-NOS belonged to non-GCB subtype. The percentage of GCB subtype and CD5-positive subtype were 28.4% (91/320) and 3.1% (10/320), respectively. Comparison of the overall survival, GCB and non-GCB immunophenotypic groups have no significant difference (P = 0.93). And the same result in which of the EBV-positive DLBCL of the elderly and DLBCL-NOS group, before and after age matched (P = 0.13 and 0.28, respectively). A double-hit lymphoma was found by FISH detection, which presenting as gray zone lymphoma in morphology. CONCLUSIONS: By using Hans algorithm, GCB and non-GCB subtypes show no significant difference in overall survival. EBV-positive DLBCL of the elderly and DLBCL-NOS also do not have significant difference in overall survival. Fluorescence in situ hybridization technique is helpful in identification of DLBCL with rare phenotypes.