Axillary lymph node calcification due to metastatic papillary carcinoma

A case is presented in which calcification in an axillary lymph node seen on a screening mammogram was the presenting feature of metastatic papillary carcinoma, presumed to be of thyroid origin. The differential diagnosis of axillary lymph node calcification seen on mammography is reviewed.     

Spontaneous intracranial hypotension: A study of six cases with MR findings and literature review

Spontaneous intracranial hypotension is clinically characterized by orthostatic headache and other symptoms caused by low cerebrospinal fluid pressure due to leakage of cerebrospinal fluid from dural punctures or other medical causes. The other symptoms are mainly due to traction of the cranial and spinal nerves owing to descent of the brain caused by low cerebrospinal fluid pressure. Magnetic resonance imaging is very useful in the diagnosis because of its characteristic findings. We describe the MRI findings in six cases that had variable clinical presentation.     

Bilateral optic pathway glioma with intracranial calcification: Magnetic resonance imaging and magnetic resonance spectroscopy findings

Optic nerve glioma is the most common primary neoplasm of the optic nerve in childhood. It can extend intracranially along the optic pathway (optic pathway glioma). The lesion tends to present with decreased visual acuity in the affected eye, but can cause additional symptoms when it is large. Local involvement within the orbit can be characterized using CT, but MRI is superior in showing the intracranial extent of the lesion. Intracranial calcification in optic pathway glioma is rare. We present a rare case of optic pathway glioma with calcification in the intracranial component. Also, we describe MR spectroscopy (MRS) findings in this case.     

17P deleted multiple myeloma presenting with intracranial disease: durable remission after tailored management

In multiple myeloma (MM), del(17p) is associated with a poor outcome if present in greater than half the tumour cells. Similarly, intracranial involvement, often seen in the context of advanced disease, also heralds short survival. We present a rare case of MM presenting with intracranial disease and carrying del(17p) in 100% of tumour cells. This patient was successfully treated with combination chemotherapy employing central nervous system directed agents and bortezomib, followed by autologous stem cell transplant and consolidation with radiotherapy, bortezomib and thalidomide. We also present the outcomes of our single‐centre experience of MM patients presenting with del(17p) disease. Copyright © 2015 John Wiley & Sons, Ltd.     

利用光学投影无接触性、简易、快速定位颅内病变、重要血管及功能区的临床研究

目的:探讨利用高清数码投影仪的光学投影功能,定位颅内病变、颅内重要血管及功能区的临床可行性.方法:利用简易索尼HDR-PJ410 高清数码摄像机(内含投影仪及照相机)的光学投影功能,将普通MRI片或CT片上颅内病变、颅内重要血管及功能区三维定位信息直接投射转变为颅脑表面空间位置信息,为临床无接触性、简易、快速定位颅内病变、颅内重要血管及功能区提供帮助.结果:开颅后直视下表浅的颅内病变、重要血管、功能区位置均符合真实位置(100%).深部颅内病变经多层面投影引导后亦顺利找到并切除.术后头颅CT复查手术区域、范围切除满意,随访患者术后恢复良好.结论:利用光学投影可以无接触性、简易、快速定位颅内病变、重要血管及功能区.该方法利用光学投影,无创,可以重复、随时使用,且无直接接触病人,保证了无菌性,对于手术中辅助定位极为有利,简易、低廉,病人零费用,而且快速、高效,定位准确,适合于基层及急诊时的快速应用,有极广的应用价值.但对颅脑深部肿瘤的引导应用例数尚少,应用的病人随访时间尚短,有待进一步探讨.     

Preoperative dynamic contrast-enhanced MRI correlates with molecular markers of hypoxia and vascularity in specific areas of intratumoral microenvironment and is predictive of patient outcome

Background

Measures of tumor vascularity and hypoxia have been correlated with glioma grade and outcome. Dynamic contrast-enhanced (DCE) MRI can noninvasively map tumor blood flow, vascularity, and permeability. In this prospective observational cohort pilot study, preoperative imaging was correlated with molecular markers of hypoxia, vascularity, proliferation, and progression-free and overall patient survival.

Methods

Pharmacokinetic modeling methods were used to generate maps of tumor blood flow, extraction fraction, permeability-surface area product, transfer constant, washout rate, interstitial volume, blood volume, capillary transit time, and capillary heterogeneity from preoperative DCE-MRI data in human glioma patients. Tissue was obtained from areas of peritumoral edema, active tumor, hypoxic penumbra, and necrotic core and evaluated for vascularity, proliferation, and expression of hypoxia-regulated molecules. DCE-MRI parameter values were correlated with hypoxia-regulated protein expression at tissue sample sites.

Results

Patient survival correlated with DCE parameters in 2 cases: capillary heterogeneity in active tumor and interstitial volume in areas of peritumoral edema. Statistically significant correlations were observed between several DCE parameters and tissue markers. In addition, MIB-1 index was predictive of overall survival (P = .044) and correlated with vascular endothelial growth factor expression in hypoxic penumbra (r = 0.7933, P = .0071) and peritumoral edema (r = 0.4546). Increased microvessel density correlated with worse patient outcome (P = .026).

Conclusions

Our findings suggest that DCE-MRI may facilitate noninvasive preoperative predictions of areas of tumor with increased hypoxia and proliferation. Both imaging and hypoxia biomarkers are predictive of patient outcome. This has the potential to allow unprecedented prognostic decisions and to guide therapies to specific tumor areas.     

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1α, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1α, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.     

Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia,angiogenesis and inflammation responses

Aims

Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions.

Methods and Results

By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB.

Conclusions

Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.     

The p53 codon 72 proline allele is endowed with enhanced cell-death inducing potential in cancer cells exposed to hypoxia

The preferential retention of the arginine allele at the p53 codon 72 locus is commonly observed in tumours from arginine/proline heterozygotes. Considering that cancer cells are harboured in a hypoxic environment in vivo, we here tested the hypothesis that the p53 codon 72 proline allele confers a survival disadvantage in presence of hypoxia. Here, we show that the transient transfection of the proline allele in p53 null cancer cells exposed to low oxygen tension or to the hypoxia-mimetic drug Desferoxamine induces a higher amount of cell death than the arginine allele. Accordingly, proline allele transiently transfected cell lines express lower levels of hypoxia pro-survival genes (HIF-1alpha, carbonic anhydrase IX, vascular endothelial growth factor, heme oxygenase-I, hepatocyte growth factor receptor, vascular endothelial growth factor receptor 2), compared to those transiently transfected with the arginine allele. Further, we report that the exposure of the arginine/proline heterozygote MCF-7 breast cancer cell line to cytotoxic concentration of Desferoxamine for several weeks, gives raise to hypoxia-resistant clones, carrying the arginine, but not the proline allele. These data indicate that the p53 codon 72 proline allele is less permissive for the growth of cancer cells in a hypoxic environment, and suggest that the preferential retention of the arginine allele in the tumour tissues of arginine/proline heterozygous patients may depend upon its lowered capacity to induce cell death in a hypoxic tumour environment.     

Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma

Carbonic anhydrase 9 (CA9) is a protein to be upregulated under exposure to hypoxic conditions. Hypoxic conditions are known to be associated with resistance to chemotherapy and radiotherapy, and with poor cancer prognosis. We examined CA9 expression in surgical specimens from oesophageal squamous cell carcinoma (ESCC) patients (n=127) using immunohistochemistry and real-time RT-PCR. We also examined CA9 expression and cell proliferation in ESCC cell lines (TE-2, TE-8 and TE-15) and an immortalised human oesophageal cell line (CHEK-1) using real-time RT-PCR, Western blotting, ELISA and MTT assay. Immunohistochemistry, high expression of CA9 was found in 63 of the 127 primary tumour specimens and was correlated with poor outcome (P=0.0003) and more aggressive/less favourable clinicopathological parameters (tumour size (P=0.0235), tumour depth (P<0.0001), regional lymph node metastasis (P=0.0031), distant lymph node metastasis (P=0.0077), stage (P<0.0001) and blood vessel invasion (P=0.006)). In vitro, CA9 expression in cultured cells and culture medium was also induced by hypoxia (P<0.01). CA9 is correlated with poor prognosis and malignant phenotype in patients with ESCC, and was upregulated by hypoxia. It is suggested that control of CA9 expression might improve the effectiveness of chemotherapy and radiotherapy in ESCC.     

卵巢癌细胞株SKOV-3ipl对缺氧的适应及其与VEGF、Bcl-2蛋白表达的关系

目的 :研究卵巢癌细胞株SKOV 3ipl在缺氧条件下的适应力及其与VEGF、Bcl 2蛋白表达的关系。方法 :贴壁培养卵巢癌细胞株SKOV 3ipl在缺氧条件下培养 (85 %N2 ,5 %CO2 ,1 0 %H2 ,极低氧浓度 :<1 0 0×1 0 - 6 ) ,在不同缺氧时相收集细胞 ,应用免疫细胞化学PARP标记检测细胞凋亡、免疫细胞化学检测VEGF的表达 ,Westernblot检测PCNA及Bcl 2蛋白表达的改变。结果 :缺氧培养 8至 1 6小时后 ,凋亡细胞增加 (与缺氧 0小时相比 ,P <0 .0 1 ) ,PCNA表达下降 (与缺氧 0小时相比 ,P <0 .0 1 )、VEGF无表达 ;缺氧 2 4小时后细胞凋亡与 0小时相比 ,差异无显著性 ,PCNA表达回升 ,Bcl 2蛋白及VEGF表达明显升高 (与缺氧 0小时相比 ,P <0 .0 1 )。结论 :卵巢癌细胞株SKOV 3ipl在缺氧培养 8至 1 6小时内发生凋亡、细胞增殖抑制 ,2 4小时后对缺氧耐受 ,细胞增殖 ;细胞对缺氧的适应可能与VEGF及Bcl 2蛋白表达增加有关     

原发性乳腺癌恶性钙化乳腺钼靶摄片征象特征与TWIST蛋白、VEGF及E-cadherin的表达相关性研究

背景与目的：现阶段国内女性群体中原发性乳腺癌发生率呈逐渐提升趋势,对女性身心健康造成极大影响。因此对原发性乳腺癌恶性钙化钼靶摄片征象特征及与血管内皮生长因子（vascular endothelial growth factor,VEGF）以及上皮钙黏蛋白（E-cadherin,E-Cad）表达相关性进行系统分析,以便于为临床诊治提供针对性指导。方法：运用回顾性分析法对常州市第二人民医院2015年3月—2019年4月收治的经手术后病理学检查证实的243例原发性乳腺癌患者的资料进行研究,均于术前接受乳腺钼靶摄片检查,并在术后接受了病理、免疫组织化学检测,以手术后病理学检查结果为金标准,分析本组诊断结果。结果： 本组243例患者中,恶性钙化118例,无恶性钙化125例;通过分析,Twist蛋白和乳腺癌恶性钙化的发生、形态以及数量存在显著相关性,且乳腺癌组织内Twist蛋白阳性表现与VEGF阳性表达呈正相关（P＜0.05）,Twist蛋白阳性表现与E-Cad阳性表达呈负相关（P＜0.05）。结论：Twist蛋白、VEGF、E-Cad表达可为乳腺癌恶性钙化钼钯摄片诊断提供生物学基础,有着重要临床意义。     

Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia

Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage.     

模拟深埋条件下挤压复合伤大鼠生命耐受力及心电图变化

目的探讨模拟深埋条件下持续挤压伤复合低氧缺水缺食大鼠的生命耐受力及其心电变化规律与特点。方法 Wistar清洁级雄性大鼠42只,经钳夹法作用于双后肢（压力为4.5±0.3 kg）,置入常压低氧舱内（氧浓度为10±0.1%）,禁食水。其中18只于持续挤压后1、3、5、6.5 d4个时间点行心电图检查,并均与挤压前做自身对照。25只大鼠用作生命耐受时间观察（其中一只大鼠既做心电图检查,又做生命耐受观察）。结果 25只大鼠于持续挤压后4.2～6.8 d内全部死亡（平均活存时间5.3±0.7 d）,挤压后,13/18只大鼠（72.2%）心电图发生明显变化,包括：ST段下移、T波高尖、P波低平或消失、QRS波群增宽、QT间期延长和异常J波。其中挤压后1 d见ST段下移,3 d见ST段下移、T波高尖、P波消失或低平,5 d见ST段下移、T波高尖、QT间期延长,6.5 d见QRS波群增宽、QT间期延长及异常J波。结论模拟深埋挤压伤复合低氧缺水缺食条件下,大鼠死亡时间为4.2～6.8 d,大鼠心电图发生明显的异常,如：ST-T改变、P波低平或消失、QT间期延长和异常J波等,具有高发性、速发性、进行性和多样性特点。     

SIOP CNS GCT 96: final report of outcome of a prospective,multinational nonrandomized trial for children and adults with intracranial germinoma,comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease

Background

We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s).

Methods

Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy.

Results

Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival.

Conclusions

Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.     

Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX,an intrinsic marker of hypoxia,in nude mice xenografted with human colorectal carcinoma

Carbonic anhydrase IX (CA IX) is frequently expressed in human carcinomas and absent from the corresponding normal tissues. Strong induction by tumor hypoxia predisposes CA IX to serve as a target for cancer diagnostics and therapy. Here we evaluated targeting properties and pharmacokinetics of CA IX-specific monoclonal antibody (MAb) M75. Binding parameters of (125)I-labeled M75, including equilibrium dissociation constant, hypoxia-related binding to various cell lines and internalization, were analyzed in vitro. Biodistribution of (125)I-M75 in nude mice bearing HT-29 human colorectal carcinoma xenografts with hypoxic pattern of CA IX expression was studied by measurements of radioactivity in dissected tissues and macroautoradiography of tissue sections. Pharmacokinetics of intravenously administered (125)I-M75 was described using a 2-compartment model. Blood clearance showed a distribution phase t(1/2)(alpha) = 3.4 hr and an elimination phase t(1/2)(beta) = 55.3 hr postinjection. Despite predominant CA IX localization in less accessible perinecrotic regions, (125)I-M75 exhibited specific accumulation in xenograft, with a mean uptake of 15.3 +/- 3.6% of injected dose per gram of tumor tissue at 48 hr postadministration. Specificity of M75 localization was confirmed by low tumor uptake of control antibody. Altogether, our data demonstrate that M75 MAb is a promising tool for selective immunotargeting of hypoxic human tumors that express CA IX.     

The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia

The Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) is a hypoxia-inducible proapoptotic member of the Bcl-2 family that induces cell death by associating with the mitochondria. Under normal conditions, BNIP3 is expressed in skeletal muscle and in the brain at low levels. In many human solid tumors, BNIP3 is upregulated in hypoxic regions but paradoxically, this BNIP3 expression fails to induce cell death. Herein, we have determined that BNIP3 is primarily localized to the nucleus of glial cells of the normal human brain, as well as in the malignant glioma cell line U251. Upon exposure of U251 cells to hypoxia, BNIP3 expression in the cytoplasm increases and localizes with the mitochondria, contributing to induction of cell death. In contrast, when BNIP3 is forcibly over expressed in the nucleus, it fails to induce cell death. Expression of N-terminal BNIP3 (lacking the transmembrane and conserved domains) in U251 cells blocks hypoxia-induced cell death acting as a dominant negative protein by binding to wild-type BNIP3 and blocking its association with the mitochondria. In glioblastoma multiforme (GBM) tumors, BNIP3 expression is increased in hypoxic regions of the tumor and is primarily localized to the nucleus in approximately 80% of tumors. Hence, BNIP3 is sequestered in the nucleus within the brain but under hypoxic conditions, BNIP3 becomes primarily cytoplasmic, promoting cell death. In GBMs, BNIP3 expression is increased but it remains sequestered in the nucleus in hypoxic regions, thereby blocking BNIP3's ability to associate with the mitochondria, providing tumor cells with a possible survival advantage.