Distinct Prognostic Significance Research Articles

Local Invasion Patterns Characterized by SARIFA and Tumor Budding Differ and Have Distinct Prognostic Significance in Esophageal Adenocarcinoma and Squamous Cell Carcinoma.

Both esophageal squamous cell carcinoma (ESQCC) and adenocarcinoma (EAC) are known to have poor prognosis. We aimed to investigate the invasion front areas of 57 ESQCC and 43 EAC cases to find histological signs of metastatic progression. Tumor cell clusters with different cell counts, including tumor buds (TBs) and poorly differentiated clusters (PDCs), were assessed. The presence of the recently described Stroma AReactive Invasion Front Area (SARIFA) phenomenon, which defines a direct contact between tumor cells and adipocytes, was more frequently observed in EAC than in ESQCC (p = 0.004). In adenocarcinomas, a higher prevalence of SARIFA was observed in tumors with a higher number of small clusters (TBs and small PDCs; p < 0.001); furthermore, both the high number of TBs (p = 0.016) and the presence of SARIFA (p = 0.001) correlated with a higher pT stage. SARIFA positivity in EAC (p = 0.011) and high TB in ESQCC (p = 0.0006) were found to be independent prognostic factors for lymph node metastases. Moreover, in ESQCC, the higher absolute number of both TBs and PDCs was associated with shorter overall survival (p = 0.0269 and p = 0.0377, respectively). Our results suggest that the histological subtypes of esophageal cancer behave differently, namely, that different features of the invasion front are of prognostic significance.

Clinical impact of ampulla of Vater cancer subtype classification based on immunohistochemical staining

BackgroundThe histological subtype is an important prognostic factor for ampulla of Vater (AoV) cancer. This study proposes a classification system for the histological subtyping of AoV cancer based on immunohistochemical (IHC) staining and its prognostic significance.MethodsSeventy-five AoV cancers were analyzed for cytokeratin 7 (CK7), CK20, and causal-type homeobox transcription factor 2 (CDX2) expression by IHC staining. We differentiated the subtypes (INT, intestinal; PB, pancreatobiliary; MIX, mixed; NOS, not otherwise specified) into classification I: CK7/CK20, classification II: CK7/CK20 or CDX2, classification III: CK7/CDX2 and examined their associations with clinicopathological factors.ResultsClassifications I, II, and III subtypes were INT (7, 10, and 10 cases), PB (43, 37, and 38 cases), MIX (13, 19, and 18 cases), and NOS (12, 9, and 9 cases). Significant differences in disease-free survival among the subtypes were observed in classifications II and III using CDX2; the PB and NOS subtype exhibited shorter survival time compared with INT subtype. In classification III, an association was revealed between advanced T/N stage, poor differentiation, lymphovascular invasion (LVI), the PB and NOS subtypes, and recurrence risk. In classification III, the subtypes differed significantly in T/N stage and LVI. Patients with the PB subtype had advanced T and N stages and a higher incidence of LVI.ConclusionsClassification using CDX2 revealed subtypes with distinct prognostic significance. Combining CK7 and CDX2 or adding CDX2 to CK7/CK20 is useful for distinguishing subtypes, predicting disease outcomes, and impacting the clinical management of patients with AoV cancer.

Major pathologic response exhibited distinct prognostic significance for lung adenocarcinoma post different modalities of neoadjuvant therapy.

For non-small cell lung cancer (NSCLC) patients receiving neoadjuvant therapy, the major pathologic response (MPR) is defined as the percentage of residual viable tumor cells (%RVT) in the tumor bed of no more than 10%. It has been proposed as a predictor of survival in neoadjuvant therapy-treated cohorts. Nonetheless, the significance of %RVT in the pathological assessment of lung adenocarcinoma cohorts remains undetermined. Overall, 152 lung adenocarcinoma patients were included in this retrospective study, among whom 67 received neoadjuvant targeted therapy and 85 received neoadjuvant chemotherapy. Clinicopathological characteristics, neoadjuvant treatment response, and survival status were investigated. The routinely adopted standard for MPR (%RVT ≤10%) failed to differentiate prognosis in the lung adenocarcinoma population. For the neoadjuvant chemotherapy cohort, the optimal %RVT cutoff value of RFS was 60%. However, this cutoff value was clinically insignificant in the neoadjuvant targeted therapy cohort. Hence, for these patients, we built a nomogram model including high-grade patterns and ypN stage to predict disease recurrence, demonstrating a high efficacy (a bootstrap-corrected C-index of 0.731). %RVT served as a strong indicator of the prognosis of lung adenocarcinoma in patients receiving neoadjuvant chemotherapy but not neoadjuvant targeted therapy. Residual high-grade pathological patterns might substitute MPR in prognostic evaluation of lung adenocarcinoma post-targeted therapy.

Association of endocrine therapy with overall survival in women with hormone receptor-positive, HER2-negative, node-negative breast cancer of favorable histology.

Breast carcinomas are histologically diverse and have distinct prognostic significance. Early-stage breast cancers with favorable histopathologic features are managed comprehensively including adjuvant endocrine therapy at the discretion of clinicians. Using a de-identified large national cancer registry, we evaluated the overall survival benefit of endocrine therapy in patients diagnosed with HR-positive, HER2-negative, pT1-2N0 (tumor size<3cm), non-high-grade breast cancer with favorable histologies including tubular, mucinous, and cribriform types. On propensity score matching of 2482 matched pairs, the addition of adjuvant endocrine therapy was associated with improved OS (hazard ratio: 0.81; 95% CI: 0.67-0.98, P=.03). Our findings suggest a role for endocrine therapy in future risk mitigation for favorable histologies but should be balanced with the implications of prolonged utilization.

Characteristic and prognostic significance of leukemia stem cells associated antigens expressions in t (8;21) acute myeloid leukemia

目的研究白血病干细胞（LSC）相关抗原CD34、CD38、CD123、CD96和TIM-3在t（8；21）急性髓系白血病（AML）中的表达及预后意义。方法采集2015年10月至2018年4月北京大学人民医院收治的47例初诊t（8；21）AML患者的骨髓标本，采用流式细胞术检测LSC相关膜表面抗原CD34、CD38、CD123、CD96和TIM-3的表达，分析其与复发的关系。结果47例t（8；21）AML患者中，CD34+CD38−、CD34+CD38−CD123+、CD34+CD38−CD96+、CD34+CD38−TIM-3+细胞在有核细胞中比例的中位数分别为2.37%、0.24%、0.27%、0.06%；CD34+CD38−、CD34+CD38−CD123+、CD34+CD38−CD96+和CD34+CD38−TIM-3+细胞比例与诱导治疗1个疗程缓解率无明显相关性（P值均>0.05）；CD34+CD38−、CD34+CD38−CD123+和CD34+CD38−CD96+细胞比例高的患者较比例低的患者具有更高的2年累积复发（CIR）率（P值分别为0.049、0.030、0.045），而CD34+CD38−TIM-3+细胞的比例对CIR无明显影响（P>0.05）；CD34+CD38−细胞比例及微小残留病（MRD）水平是影响患者CIR的独立预后因素（HR=6.9，95%CI 1.3~37.4，P=0.025；HR=11.1，95%CI 1.2~99.2，P=0.031）。结论不同的LSC相关抗原在t（8；21）AML中的预后意义不同，初诊骨髓有核细胞中高比例的CD34+CD38−以及CD34+CD38−CD123+和CD34+CD38−CD96+细胞可能与t（8；21）AML患者的复发有关。

Proliferative, pro-inflammatory, and angiogenesis regulator gene expression profile defines prognosis in different histopathological subtypes of nodal peripheral T-cell lymphoma.

Nodal peripheral T-cell lymphoma (PTCL) is an aggressive and heterogeneous malignancy with poor prognosis. We studied the prognostic impact of the expression profile of genes related to cell proliferation (CCNA2, TOP2A, and CHEK1), pro-inflammatory activity (NFkB1 and IKBkB), and angiogenesis (VEGF1) in nodal PTCL outcomes, as well as the ability of this genomic panel to discriminate different histological subtypes. We investigated the relative expression of regulator genes in 63 nodal PTCL patients. CCNA2, TOP2A, CHEK1, and NF-kB1 proteins were also assessed by immunohistochemistry. The median patient age was 47 years, 57.1% were male, 34.9% were diagnosed with PTCL-NOS, 28.6% with ALK-/ALCL, 22.2% with ALK+/ALCL, and 14.3% with AITL. The proliferative genes were associated with worse 3-year OS and PFS in PTCL-NOS and better 3-year PFS in ALK-/ALCL. Expression of CCNA2≥median and overexpression of CHEK1 protein (HR 3.793; p = 0.007) were associated with worse OS for all the cohort of nodal PTCL (HR 1.418; p = 0.001). The genomic expression profile tested in this study was not able to discriminate the different subtypes of nodal PTCL, although it showed a distinct prognostic significance between PTCL-NOS and ALCL-ALK. Overexpression of the CCNA2 gene and CHEK1 protein were associated with poor prognosis in the total nodal PTCL cohort.

Genomic Profiling of Biliary Tract Cancers and Implications for Clinical Practice.

Biliary tract cancers are relatively uncommon, have an aggressive disease course and a dismal clinical outcome. Until recently, there have been very few clinical advances in the management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy. The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease. Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice. Mutation profiling has highlighted the genomic differences between the intra, extrahepatic cholangiocarcinoma, and gallbladder cancer. The mutational spectrum of intrahepatic cholangiocarcinoma differs according to geographic location and ethnicity. There is a higher incidence of chromatin modulating gene mutations in Western patients as compared with Asian patients with liver fluke-associated cholangiocarcinoma. KRAS and p53 mutations are associated with an aggressive disease prognosis while FGFR mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma. FGFR and IDH mutations have promising agents in clinical trials at this time. An estimated 15% of gallbladder cancers have Her2/neu amplification and can be targeted by trastuzumab. On the other hand, an estimated 10-15% of cholangiocarcinomas have DNA repair mutations and maybe candidates for immune therapies with checkpoint inhibitors. The promise of targeted therapies for biliary tract cancers can be fulfilled with well-designed, prospective, and multi-center clinical trials.

Does Response to Bortezomib-Based Therapies Correlate to Beta-2 Microglobulin in Multiple Myeloma?

Introduction. Multiple Myeloma (MM) is a heterogeneous, incurable disease. Several prognostic scores have been developed to estimate response to treatment, progression free survival (PFS) and overall survival (OS). The International Staging System defines 3 stages with distinct prognostic significance, using serum beta 2 microglobulin (b2M) and serum albumin. However, due to a higher power of risk discrimination, current guidelines recommend to stratify patients according to cytogenetics (CG) and treat high-risk patients with Bortezomib (BZ)-based therapies.In Uruguay, BZ is financed and regulated by a National Funding Board and is approved for high-risk MM or renal impairment at diagnosis or at relapse. As a consequence, the patients included in this study are a selected high risk MM subgroup.Even though proteasome inhibitors have improved outcomes for many high-risk MM patients, some still present short response duration and poor survival. Identifying simple factors that can predict response to BZ would be useful in order to better select the most appropriate therapeutic choice.Patients and Methods. We conducted a retrospective study to evaluate MM response to BZ-based therapy according to b2M, serum creatinin (Cr) and CG. Forty-seven MM patients [median age 59 years (38-77), females 25 (53%)] from two public centers treated with BZ-based combinations were included. According to local regulatory policies, only patients with renal failure and/or high risk CG features received BZ as first line therapy (n=31). Other 16 individuals received BZ combinations for relapsed/refractory disease. Patients received a median of 5 cycles of BZ (3-6). Nineteen individuals (40%) received high dose melphalan and autologous stem cell transplantation after BZ-based induction. At diagnosis, 28 (59%) had an ISS 3, 24 (51%) patients had serum Cr higher than 2 mg/dL and 14 (30%) exhibited high risk CG. Responses to BZ therapy were evaluated according with International Myeloma Working Group criteria as complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progressive disease (PD). Responses were analyzed depending on b2M level, serum Cr and CG. Comparison between groups was made by chi-square test. PFS and OS were calculated by the Kaplan-Meier method. Survival was compared between groups by log-rank test.Results. No differences in responses to BZ-based therapies were found when comparing patients with low (lower than 5,5 mg/L) versus high b2M levels (CR/VGPR 44,4 vs 44% respectively, p=0.97), low versus high serum Cr (CR/VGPR 34 vs 55% respectively, p=0.18) and standard versus high risk CG (CR/VGPR 46,7 vs 38,5% respectively, p=0.62). Patients with renal failure (serum Cr 2 mg/dL or higher at diagnosis, n=23) had a median of 53% (0 - 88%) reduction in Cr levels after receiving at least three cycles of BZ therapy. Eleven of them (47,8%) had normal renal function after completing BZ treatment. From 9 patients requiring dyalisis at diagnosis, 4 were out of dyalisis after BZ treatment. No significant differences in PFS and OS were observed when patients with low versus high b2M levels and standard versus high risk CG were compared. Patients with low Cr levels at diagnosis show a significantly better OS compared with those with Cr higher than 2 mg/dL (median OS not reached versus 42 months respectively, p=0.004), with no differences in PFS.Conclusion. In a selected high risk MM patients group treated with BZ-based therapies, similar response rates were obtained in individuals with high or low b2M levels, Cr levels, and standard or high risk CG. Although individuals with renal failure at diagnosis exhibit similar quality of responses than standard patients, long term OS of this group is still impaired and further improvements in therapy are needed.Note: GB and ER have contributed in equal parts to this work. DisclosuresNo relevant conflicts of interest to declare.

Prognostic stratification of colorectal cancer patients: current perspectives.

Tumor staging according to the American Joint Committee on Cancer/Union for International Cancer Control tumor, node, metastasis (TNM) system is currently regarded as the standard for staging of patients with colorectal cancer. This system provides the strongest prognostic information for patients with early stage disease and those with advanced disease. For patients with intermediate levels of disease, it is less able to predict disease outcome. Therefore, additional prognostic markers are needed to improve the management of affected patients. Ideal markers are readily assessable on hematoxylin and eosin-stained tumor slides, and in this way are easily applicable worldwide. This review summarizes the histological features of colorectal cancer that can be used for prognostic stratification. Specifically, we refer to the different histological variants of colorectal cancer that have been identified, each of these variants carrying distinct prognostic significance. Established markers of adverse outcomes are lymphatic and venous invasion, as well as perineural invasion, but underreporting still occurs in the routine setting. Tumor budding and tumor necrosis are recent advances that may help to identify patients at high risk for recurrence. The prognostic significance of the antitumor inflammatory response has been known for quite a long time, but a lack of standardization prevented its application in routine pathology. However, scales to assess intra- and peritumoral inflammation have recently emerged, and can be expected to strengthen the prognostic significance of the pathology report.

Claudin-3 and Claudin-4

To investigate the immunohistochemical expression of claudin-1, claudin-3, and claudin-4 in triple-negative breast carcinomas and compare it with several clinicopathologic parameters as well as their expression in luminal cancers. A total of 128 cases of breast carcinoma were included in the study. For all these cases, immunohistochemistry for estrogen and progesterone receptors, Ki-67, and Her2 had already been performed, whereas Her2 2+ cases had been further characterized as positive or negative for Her2 amplification with the chromogenic in situ hybridization technique. Seventy-six tumors were triple negative. The remaining 52 were luminal cancers. All tumors were evaluated for the expression of claudin-1, claudin-3, and claudin-4. In the triple-negative group, the positive expression of claudin-3 and claudin-4 was related to unfavorable and favorable prognostic factors, respectively. Claudin-1 was not related to any parameter under evaluation. In the luminal cancer group, claudin-4 positivity was related to a shorter disease-free survival, whereas the inverse was observed for claudin-3. Moreover, all 3 claudins increased with increase of the grade and Ki-67 value in the luminal cancers. A distinct prognostic significance in the expression of claudin-3 and mostly of claudin-4 between triple-negative and luminal breast carcinomas was identified. Specifically, in triple-negative carcinomas, claudin-4 positivity could probably be considered as a biomarker of favorable prognosis, whereas in luminal cancers with claudin-4-positive expression, the administration of targeted therapy should eventually be part of the patients' management in the near future.

Rapid detection of IDH2 (R140Q and R172K) mutations in acute myeloid leukemia

NADP-dependent enzyme isocitrate dehydrogenase (IDH) mutations, IDH1 and IDH2, have been described in acute myeloid leukemia (AML) using next generation sequencing approaches. IDH2 mutations are heterozygous; they alter a single arginine residue at position 140 or 172 and have distinct prognostic significance. The current detection methods of IDH2 mutations are laborious and time consuming as they require DNA sequencing. Herein, we report a new allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) method to detect the IDH2 mutations. Analysis of leukemic DNA samples from 120 AML patients enabled to identify IDH2 mutations in 22 cases which were confirmed by direct DNA sequencing. Of these, 17 harbored IDH2 (R140Q) and 5 IDH2 (R172K) mutations. Serial dilution experiments showed that the assay enable to detect mutations in 10⁻³ dilutions. Our ASO-PCR method appears useful for routine diagnostic screening of these prognostically relevant alterations in AML and may be conveniently included in the diagnostic workup.

FOXA1 as a therapeutic target for breast cancer

Gene expression profiling studies have classified breast cancer into five intrinsic subtypes with distinct prognostic significance: luminal type A, luminal type B, normal-like, HER-2-positive and basal type. These studies have also uncovered novel diagnostic markers and molecular targets. FOXA1, a winged-helix transcription factor belonging to the forkhead family, is one among them as it is expressed predominantly in luminal type A breast cancer, which is characterized by the presence of estrogen receptor-α (ERα) with favorable prognosis. FOXA1 is a ‘pioneer’ factor that binds to chromatinized DNA, opens the chromatin and enhances binding of ERα to its target genes. It is essential for the expression of ∼ 50% of ERα:estrogen-regulated genes. Thus, a network comprising FOXA1, ERα and estrogen constitutes a major proliferation and survival signal for luminal type A breast cancer. However, by controlling differentiation and by regulating the expression of cell cycle inhibitor p27kip1 and the cell adhesion molecule E-cadherin, FOXA1 may prevent metastatic progression of luminal type A breast cancer. This article reviews possible roles of FOXA family transcription factors in breast cancer initiation, hormone dependency and speculates on the potential of FOXA1 as a therapeutic target.

The expression of MAGE and GAGE genes in uterine cervical carcinoma of Korea by RT-PCR with common primers

Background Melanoma antigen genes (MAGE) and GAGE genes are encoded by genes that are silent in virtually all normal adult tissues but are expressed in tumors from various tissues. These gene products are targets for specific immunotherapy as they are presented by HLA I molecules and recognized by autologous cytotoxic T-lymphocytes. However, the characteristics of these genes, especially in uterine cervical cancer are relatively unknown. Purpose This study evaluated the prevalence of MAGE and GAGE by reverse transcription-polymerase chain reaction (RT-PCR) with common primers and discusses clinical implications in cervical carcinoma. Materials and methods Fresh tissue from 37 cases of primary squamous cell carcinoma and normal cervical mucosa were evaluated for clinicopathologic parameters including Human Papilloma Virus (HPV)-16,18 infection by PCR, tumor stage by FIGO classification and lymph node involvement. RT-nested PCR for the MAGE and GAGE genes was performed with common primers and DNA sequencing after subcloning was used for identification of PCR products of MAGE. Formalin-fixed paraffin embedded material from the same specimen was analyzed by in situ RT-PCR for MAGE. Results Expression of MAGE and GAGE was not observed in normal tissues. Eleven out of 37 cases expressed MAGE mRNA (29.7%): analysis of subtypes identified one case of MAGE-1, two cases of MAGE-4b, six cases of MAGE-3, and two unknown subtypes. Thirteen out of 37 cases (35.1%) expressed GAGE mRNA. No significant relationships between expression of these genes and FIGO staging, lymph node metastasis or HPV infection were found. Conclusion Expression of MAGE and GAGE may be involved in the development of uterine cervical carcinoma from intraepithelial neoplasia, although without distinct prognostic significance. MAGE and GAGE genes have the potential to be used as targets for the treatment of uterine cervical carcinoma.

Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c-myc expression.

Medulloblastomas (MB) are the most common central nervous system malignancies in children. Numerous publications describe certain efforts to identify predictive value of various patterns of MB pathology and immunohistochemistry but received data appear to be controversial. In the present study, the apoptotic index (AI) and immunoexpression of TrkC, and c-myc proteins were investigated in biopsy samples from 68 MB with an average clinical risk to determine their prognostic utility in this tumor category. The number of cases with AI > 1.5% was significantly greater in the group of tumors in patients with recurrent MB and the mean AI was significantly higher in this group -4.7% vs. 1.1%. Furthermore, the number of tumors with AI > 1.5% was greater in the group of tumors in deceased patients and the mean Al was also higher in this group -4.6% vs. 1.2%. Immunoreactivity of the c-myc and TrkC did not show any differences between groups of patients with various clinical outcomes. A close association between Al as a continuous variable and the progression-free and overall survival was found. We found no any differences in survival times for c-myc and TrkC immunoreactivity. Multivariate revealed analysis that AI is a single significant prognostic factor for MB survival. Perhaps, investigations of c-myc and TrkC mRNA levels should be useful for clinical purposes, but in order to introduce these biomolecular markers in clinical protocols its distinct prognostic significance needs to be proved by prospective studies.

Childhood Minimal Change Disease and Focal Segmental Glomerulosclerosis: A Continuous Spectrum of Disease?

Thirty-three children with idiopathic nephrotic syndrome who underwent kidney needle biopsy were reevaluated. The male to female ratio was 2:1, and a preponderance of North-African Jewish and Arab origin over Ashkenazi Jewish origin was noted. There was a positive correlation between the severity of glomerular changes and prognosis among the 10 cases with minimal change disease (MCD) and the 23 with focal segmental glomerulosclerosis (FSGS). On long-term follow-up (mean over 11 years) chronic renal failure developed in none of 10 MCD patients, 1 of 12 FSGS patients with mild glomerular sclerosis, 1 of 7 FSGS patients with moderate glomerular sclerosis and 3 of 4 FSGS patients with severe glomerular sclerosis. Prognosis of patients with mild glomerular sclerotic lesion on light microscopy was substantially not worse than the prognosis of patients with mild glomerular alterations only on the electron microscopic study (MCD-B). Thus, both pathologically and prognostically, there was a continuous spectrum from 'pure' MCD (MCD-A) to FSGS with severe glomerular sclerosis. Glomerular changes confined to the origin of the proximal tubule ('tip' changes) were seen only in 4 patients and did not have a distinct prognostic significance. No case of peripheral location of the sclerotic segment within the glomerulus was found in our series of FSGS, and therefore no correlation between location of segmental sclerosis and prognosis was feasible.

Intrapartum fetal heart rate monitoring: II. Multifactorial analysis of intrapartum fetal heart rate tracings

The first 30 minutes and the last 30 minutes of 1,996 intrapartum FHR tracings were analyzed for baseline FHR, variability (amplitude and frequency of oscillations), accelerations, and decelerations. A modified FHR scoring system incorporating these FHR features was employed. According to the association between various FHR scores and the incidence of low Apgar scores, FHR patterns were grouped into three basic categories with distinct prognostic significance: (1) normal FHR patterns, (2) compensated distress patterns, and (3) decompensated distress patterns. It is concluded that the prognostic significance of FHR tracings is increased by incorporating several FHR monitoring criteria in the analysis.

RECOGNITION OF TYPES OF ARTERIOSCLEROSIS BY OSCILLOMETRY

The importance of the concept of cardiovascular disease as a clinical entity is fully understood today. Emphasis has been placed, and properly so, on the recognition of cardiac abnormalities of various types. Recently the necessity of obtaining information as to the condition of the vascular tree has begun to be stressed. It is not believed today that arteriosclerosis is merely an expression of aging of the arteries. As Aschoff1has said, Arteriosclerosis is not merely a change or transformation attending the process of aging; it is not a mere infirmity of old age, but rather a disease of the vessels manifesting itself mainly during senescence. The clinical recognition of arteriosclerosis thus becomes a matter of import, because the type and the degree of arteriosclerosis present in a given individual have distinct prognostic significance. Any method of clinical examination that gives reliable information as to the condition of the vascular