Contribution of CSF cytology in the diagnostic work-up of breast cancer patients with neurological symptoms: a retrospective analysis over two decades

The aim of this study was to evaluate the contribution of cytological analysis of cerebrospinal fluid (CSF) in the diagnostic work-up of breast cancer patients who present with neurological symptoms suspected for central nervous system (CNS) metastases. In the period 1989–2009, a total of 81 patients with breast cancer underwent CSF cytological examination. Relevant tumour characteristics, clinical presentation and radiological findings were scored. The CSF cytological diagnosis was classified according to the 1996 NCI-sponsored conference approach as malignant, suspicious for malignancy, atypical, benign or inadequate. During the course of 20 years, 145 CSF cytological examinations were performed. Relatively common neurological symptoms resulting in cytological CSF examination were headache (n = 25), nausea and vomiting (n = 19), sensory disturbances (n = 16), and cranial nerve dysfunction (n = 16). Of these, headache and nausea/vomiting were most often associated with malignant cells in the CSF (CSF⁺) (in 48 and 53% of the cases, respectively). The 4 patients with both headache and confusion/altered mental status all had CSF⁺. In 10 patients, CSF⁺ was found despite the absence of radiological evidence for metastasis in/around the CNS. In our series, repeated CSF analysis appeared to have limited additional value, and CSF⁺ was strongly correlated with shorter survival. A substantial number of patients with neurological symptoms but without radiological abnormalities can have CSF⁺. In our series, the additional value of repeated cytological examination of CSF was limited. Our study underscores the value of CSF cytology as a tool for the unequivocal diagnosis of metastatic spread of breast cancer to the CNS, and confirms that CSF⁺ is a strong predictor of poor survival.     

Detection of central nervous system metastasis with cerebrospinal fluid beta-2-microglobulin

Beta-2-microglobulin determinations in cerebrospinal fluid (CSF) of patients with leukemia, lymphoma, and oat cell carcinoma were performed to evaluate the utility of this test in early detection of metastasis to the central nervous system (CNS). In the presence of CNS disease, significantly higher levels (P less than 0.001) were found than in normals or patients without CNS disease. Serial measurements were performed on two patients, and in all cases beta-2-microglobulin became elevated coincident with CNS relapse, and returned to normal as remission was achieved. Serial testing of CSF beta-2-microglobulin, in patients with cancers known to invade the CNS, should facilitate prompt treatment of CNS metastasis.     

A novel glycobiomarker,Wisteria floribunda agglutinin macrophage colony‐stimulating factor receptor,for predicting carcinogenesis of liver cirrhosis

Recently, we identified a novel liver fibrosis glycobiomarker, Wisteria floribunda agglutinin (WFA)‐reactive colony stimulating factor 1 receptor (WFA⁺‐CSF1R), using a glycoproteomics‐based strategy. The aim of this study was to assess the value of measuring WFA⁺‐CSF1R levels for the prognosis of carcinogenesis and outcome in liver cirrhosis (LC) patients with hepatitis C virus (HCV). WFA⁺‐CSF1R and Total‐CSF1R levels were measured in serum samples from 214 consecutive HCV‐infected patients to evaluate their impact on carcinogenesis and the survival of LC patients. Serum WFA⁺‐CSF1R levels were significantly higher in LC patients than chronic hepatitis (CH) patients (p < 0.001). The AUC of WFA⁺‐CSF1R for predicting overall survival, calculated by time‐dependent ROC analysis, was 0.691 and the HR (per 1‐SD increase) was 1.80 (95% CI, 1.23–2.62, p < 0.001). Furthermore, the survival rate of LC patients with high WFA⁺‐CSF1R levels (≥310 ng/ml) was significantly worse than those with lower levels (p < 0.01). The AUC of WFA⁺/total‐CSF1R percentage (WFA⁺‐CSF1R%) for predicting the cumulative carcinogenesis rate was 0.760, with an HR of 1.66 (95% CI 1.26–2.20, p < 0.001). In fact, the carcinogenesis rate was significantly higher in LC patients with a high WFA⁺‐CSF1R% (≥ 35%, p = 0.006). Assessing serum levels of WFA⁺‐CSF1R has diagnostic value for predicting carcinogenesis and the survival of LC patients.     

Pulsatile Erlotinib in EGFR-Positive Non–Small-Cell Lung Cancer Patients With Leptomeningeal and Brain Metastases: Review of the Literature

Patients with epidermal growth factor receptor (EGFR)-positive (EGFR⁺) non–small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients. Experience with “pulsatile” dosing, however, is limited. We review the literature on the pharmacology and clinical outcomes of pulsatile erlotinib in the treatment of EGFR⁺ NSCLC with brain and leptomeningeal metastases, and include available data on the use of next-generation TKIs in CNS progression. We also provide our institution's experience with patients treated with pulsatile erlotinib for CNS metastasis, and propose clinical criteria for its use. Pulsatile erlotinib is a reasonable alternative in EGFR⁺ patients with new or worsening CNS disease, without evidence of systemic progression, and without confirmed T790M resistance mutations within the CNS.     

An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis in lung adenocarcinoma cancer patients

Leptomeningeal carcinomatosis (LC) is a metastatic cancer invading the central nervous system (CNS). We previously reported a metabolomic diagnostic approach as tested on an animal model and compared with current modalities. Here, we provide a proof of concept by applying it to human LC originating from lung cancer, the most common cause of CNS metastasis. Cerebrospinal fluid from LC (n = 26) and normal groups (n = 41) were obtained, and the diagnosis was established with clinical signs, cytology, MRI and biochemical tests. The cytology on the CSF, the current gold standard, exhibited 69% sensitivity (～100% specificity) from the first round of CSF tapping. In comparison, the nuclear magnetic resonance spectra on the CSF showed a clear difference in the metabolic profile between the LC and normal groups. Multivariate analysis and cross‐validation yielded the diagnostic sensitivity of 92%, the specificity of 96% and the area under the curve (AUC) of 0.991. Further spectral and statistical analysis identified myo‐inositol (p < 5 × 10^?14), creatine (p < 7 × 10^?8), lactate (p < 9 × 10^?4), alanine (p < 7.9 × 10^?3) and citrate (p < 3 × 10^?4) as the most contributory metabolites, whose combination exhibited an receiver–operating characteristic diagnostic AUC of 0.996. In addition, the metabolic profile could be correlated with the grading of radiological leptomeningeal enhancement (R² = 0.3881 and p = 6.66 × 10^?4), suggesting its potential utility in grading LC. Overall, we propose that the metabolomic approach might augment current diagnostic modalities for LC, the accurate diagnosis of which remains a challenge.     

Proton beam therapy with concurrent chemotherapy for glioblastoma multiforme: comparison of nimustine hydrochloride and temozolomide

Central nervous system lymphoma (CNSL) is diagnostically challenging. The identification of reliable and easy to measure biomarkers is desirable to facilitate diagnosis. Here, we evaluated the value of cerebrospinal fluid (CSF) osteopontin (OPN) as a diagnostic biomarker for CNSL. OPN concentrations in CSF from 37 patients with CNSL (29 with primary CNSL and 8 with secondary CNS involvement of systemic lymphoma) and 36 controls [6 patients with inflammatory CNS disease other than multiple sclerosis (MS), 8 with MS, 9 with glioblastoma (GBM) and 13 healthy controls] were determined using an enzyme-linked immunosorbent assay. Non-parametric tests and receiver operating characteristic (ROC) curves were performed for determination of diagnostic accuracy. Median CSF OPN level in all CNSL patients was 620 ng/mL and higher than in patients with inflammatory CNS disease (356 ng/mL); P?P?P?P?P?=?.009) and overall survival (HR 1.52, 95?% CI 1.04–2.21; P?=?.029). CSF OPN is a potential biomarker in CNSL.     

Clinical relevance of flow cytometric immunophenotyping of the cerebrospinal fluid in patients with diffuse large B-cell lymphoma

BackgroundCentral nervous system (CNS) relapse is an uncommon but dramatic complication of diffuse large B-cell lymphoma (DLBCL). Several studies have demonstrated the superiority of cerebrospinal fluid (CSF) flow cytometry (FCM), as compared with conventional cytology (CC), in detecting occult leptomeningeal disease. The clinical relevance of a positive FCM still has to be clarified.Patients and methodsWe analyzed CSF from 114 DLBCL patients at diagnosis (n = 95) or at relapse (n = 19) by FCM and CC. Most patients received meningeal prophylaxis. FCM results did not influence treatment strategies.ResultsFourteen samples were FCM+, versus one CC+ (also FCM+). Within all patients without neurological symptoms (n = 101), four (4%) relapsed in the CNS, with a median time to relapse of 5.2 months. Only one-fourth (25%) was FCM+ before relapse. More than one extranodal disease site and elevated lactate dehydrogenase levels were associated with an increased risk of CNS relapse.ConclusionsFCM gives far more positive results than CC. However, a positive FCM result did not translate into a significant increase in CNS relapse rate in this histologically uniform population receiving CNS prophylaxis.     

Clearance of Hepatitis C Virus (HCV) Is Associated With Improved Outcomes in HCV-Associated Lymphoma

BackgroundImproved hepatitis C virus (HCV) clearance due to directly acting antiviral agents has led to remarkably improved outcomes of indolent HCV-associated non-Hodgkin lymphoma (NHL). The impact of directly acting antivirals on the outcomes of aggressive NHL is still under investigation. Characteristics of HCV-associated NHL in black patients are not well characterized. We report outcomes of HCV-associated NHL compared to their HCV-negative counterparts in a predominantly black population.Patients and MethodsPatients with lymphoma between January 2007 and December 2017 were retrospectively studied. Depending on presence or absence of HCV RNA, patients were grouped into HCV positive (HCV⁺) and HCV negative (HCV^?) cohorts. Depending on virologic clearance (VC), HCV⁺ were classified into HCV⁺ with VC and HCV⁺ without VC. Overall response rate (ORR), complete response, overall survival (OS), and progression-free survival (PFS) of HCV⁺ patients with and without VC were compared to HCV^? patients.ResultsOf 397 patients with lymphoma, 40 had HCV. Black comprised 90% of HCV⁺ patients. Diffuse large B-cell lymphoma was most frequent (47%) in the HCV⁺ group. HCV⁺ patients without VC had significantly worse OS and PFS compared to HCV^? patients. There were no differences in ORR, complete response, PFS, and OS of HCV⁺ patients with VC and HCV^? patients. These results were consistent in subgroups of diffuse large B-cell lymphoma and aggressive lymphoma.ConclusionHCV clearance is positively associated with lymphoma outcomes in black patients. Patients who clear HCV have noninferior outcomes to HCV^? patients, while those who fail to clear HCV have significantly worse outcomes.     

Understanding of the immunological heterogeneity of canine mammary carcinomas to provide immunophenotypic features of circulating leukocytes as clinically relevant prognostic biomarkers

We have evaluated the phenotypic features of peripheral blood leukocytes as putative novel biomarkers with prognostic values to monitor canine mammary carcinomas. Female dogs were categorized into distinct groups, referred as mammary carcinoma in benign mixed tumor-MC-BMT and mammary carcinoma-MC. Our findings demonstrate that decreased percentage of B-cells along with increased frequency of NK-cells, CD8⁺T-cells, and CD8⁺CD5^Low+T-cells beside higher T/B-cells and lower CD4⁺/CD8⁺ ratio were the hallmarks of MC-BMT. Despite the lower expression of MHCI and MHCII, the lymphocytes from MC-BMT and MC displayed higher migration potential as suggested by enhanced frequency of CD18⁺ events. Although increased levels of macrophage-like cells/(CD14⁺CD16⁺) and decreased levels of MHCII expression were a common phenotypic feature in mammary carcinoma, down-regulation of MHCI was selectively observed in MC. Decreased frequency of CD4⁺ T-cells with increased levels of CD8⁺ T-cells and lower CD4⁺/CD8⁺ T-cell ratio were relevant biomarkers of MC-BTM(−). Although decreased expression of MHCI by monocytes was observed in MC-BTM regardless of the presence of lymph node metastasis, this phenotypic feature was restricted to MC free of metastasis. The CD4⁺/CD8⁺ T-cells ratio lower than 1.8 was elected as a valid parameter with outstanding performance to predict survival in MC-BMT. On the other hand, the MHCI expression by monocytes higher than 10² MFI showed good value to estimate worse outcome in MC. These results should help to improve our understanding of the immunological heterogeneity of canine mammary carcinomas and provide tools for the determination of cut-off scores of clinically relevant immonophenotypic prognostic biomarkers.     

Beclin 1 expression is an independent prognostic factor for gastric carcinomas

Beclin 1, an important autophagy-related protein in human cells, is involved in autophagy, differentiation, anti-apoptosis, and cancer progression, which is increased during periods of cell stress and extinguished during the cell cycle. In order to clarify the role of Beclin 1 in gastric carcinogenesis and subsequent progression, its expression was examined by immunohistochemistry and in situ hybridization (ISH) on tissue microarrays containing gastric carcinomas, adjacent non-neoplastic mucosa, and metastatic lymph node. Gastric carcinoma tissue and cell lines were studied for Beclin 1 expression by Western blot or RT-PCR, respectively. The results demonstrated that Beclin 1 was distinctively expressed in GES-1, AGS, BGC-823, GT-3 TKB, HGC-27, KATO-III, MGC-803, MKN28, MKN45, SCH, SGC-7901, or STKM-2 at both mRNA and protein levels. However, Beclin 1 mRNA was highly expressed in gastric carcinoma than matched mucosa by real-time PCR and ISH (P?<?0.05). Beclin 1 expression was negatively related to distant metastasis and poor prognosis of gastric carcinoma (P?<?0.05). Beclin 1 was highly expressed in male than female patients with gastric carcinoma (P?<?0.05). The 65-year-elder patients with gastric carcinoma had higher Beclin 1 expression than the younger ones (P?<?0.05). The diffuse-type carcinomas showed less Beclin 1 expression than intestinal- and mixed-type ones (P?<?0.05). In intestinal-type gastric carcinoma, Beclin 1 expression was inversely associated with venous invasion, lymph node metastasis, and tumor–node–metastasis (TNM) staging (P?<?0.05). Kaplan–Meier analysis indicated that Beclin 1 expression was positively linked to favorable prognosis of the patients with overall and intestinal-type carcinoma (P?<?0.05). Cox’s proportional hazard model indicated that venous invasion, lymph node metastasis, distant metastasis, TNM staging, and Beclin 1 expression were independent prognostic factors for gastric carcinomas (P?<?0.05). It was suggested that aberrant Beclin 1 expression is closely linked to pathogenesis, metastasis, and differentiation of gastric carcinoma. Beclin 1 expression might be employed to indicate the favorable prognosis of gastric carcinomas as an independent factor.     

Local Intracerebral Administration of Paclitaxel with the Paclimer® Delivery System: Toxicity Study in a Canine Model

Summary Introduction: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer^?), and the efficacy of Paclimer^? was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer^? in a canine dose escalation toxicity study to prepare its translation into clinical scenarios. Methods: Twelve normal beagle dogs underwent a right parieto-occipital craniectomy and were randomized to receive either Paclimer^? at 2-mg/kg (n = 5), empty microspheres at 2-mg/kg (n = 1), Paclimer^? at 20-mg/kg (n = 5), or empty microspheres at 20-mg/kg (n = 1). Post-operatively, dogs were observed daily for signs of neurotoxicity. Complete blood counts and plasma levels of paclitaxel were obtained weekly. CSF levels and MRI scans were obtained on days14–120. Paclitaxel concentrations were quantified by LC-MS. Results: Animals treated with 20-mg/kg Paclimer^? had minimal paclitaxel levels in plasma (range 0–7.84 ng/ml) and CSF (range 0–1.16 ng/ml). Animals treated with 2mg/kg Paclimer^? had undetectable levels of paclitaxel in plasma, CSF was not obtained to minimize animal suffering. All animals exhibited normal behavior and weight gain, and were alive post-operatively through the last day of the study (day 60–120) without signs of neurological toxicity. There was no evidence of systemic toxicity or myelosuppression. MR imaging was comparable between Paclimer^? animals and controls. Adverse effects included wound infections and a brain abscess, all of which responded to antibiotic therapy, and one ventriculomegaly due to communicating hydrocephalus. Conclusions: Paclimer^?-based delivery of paclitaxel is safe for intraparenchymal delivery at the tested doses in normal dogs.     

Central nervous system pharmacokinetics of high-dose cytosine arabinoside

Summary The cerebrospinal fluid (CSF) pharmacokinetics of cytosine arabinoside (Ara-C) was determined in 8 patients with metastatic cancer in the central nervous system. High dose (3 gm/M²) one-hour intravenous infusions of Ara-C were given with serial CSF sampling obtained from indwelling Ommaya reservoirs. CSF was analyzed by high pressure liquid chromatography. Mean Ara-C elimination half life of 140 minutes in CSF was eight times longer than that in plasma. The peak mean CSF concentration of Ara-C (2.l ug/ml) was about 7% of the plasma concentration (30 ug/ml).A total of 28 treatment courses were administered with minimal hematopoietic, gastrointestinal and neurological toxicities. A schedule of administration of 2 high-dose treatments 12 hours apart repeated every two weeks should maintain cytotoxic CSF concentrations which could prove useful in the management of CNS leukemia and lymphoma.     

Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value

This study examined the diagnostic and prognostic value of vascular endothelial growth factor (VEGF) levels in the cerebrospinal fluid (CSF) of 39 patients with leptomeningeal metastasis (LM). Vascular endothelial growth factor levels at diagnosis were significantly higher in patients with LM (median 359 pg ml(-1)) than in patients with other neurological diseases (median <25 pg ml(-1)). The specificity of VEGF levels above 250 pg ml(-1) for LM was high (98.3%), while the sensitivity was low (51.4%; 73% for VEGF values above 100 pg ml(-1)). In 49% of the LM patients, particularly with lymphoma or medulloblastoma, VEGF levels were below 250 pg ml(-1) and thus in the range of VEGF levels in other neurological diseases. Vascular endothelial growth factor levels correlated significantly with CSF lactate and albumin. Vascular endothelial growth factor levels mirrored the clinical course with a marked reduction in response to therapy and an increase at relapse in some patients who had serial CSF samples available. Multivariate Cox regression analysis showed VEGF below 100 pg ml(-1) (relative risk (RR)=4.24, P=0.0002) and age below 60 years (RR=2.5, P=0.004) to be associated with longer survival in LM. In conclusion, CSF VEGF levels in LM vary considerably. High VEGF levels have a very high specificity for LM and may help to establish the diagnosis. The role of VEGF as a predictor of outcome should be substantiated in prospective studies.     

EBV+ lymphoepithelial carcinoma of the parotid gland in Mexican mestizo patients with chronic autoimmune diseases

Lymphoepitheliai carcinomas of the salivary gland are rare tumors constantly associated with EpsteinBarr virus (EBV) and mainly identified in Asiatic and Greenlander population. Four cases have been described in Caucasians, only two with EBV infection. We describe two cases of parotid gland lymphoepithelial carcinomas in Mexican mestizo women in which chronic latent EBV infection was documented by immunohistochemistry andin situ hybridization. One patient had primary Sjögren’s syndrome and the other systemic lupus erythematosus of six and three years of evolution, respectively. Epithelial neoplastic cells showed latency pattern II (LMP1⁺, EBNA-2^?, EBER⁺) with a dense inflammatory infiltrate composed mainly by CD8⁺ T lymphocytes. Follow-up excluded nasopharyngeal involvement in both patients. This report expands the ethnic groups in which salivary lymphoepithelial carcinomas associated with chronic latent EBV infection have been described, and illustrates for the first time its association with autoimmune diseases in two women living in a region non-endemic for this unusual neoplasm.     

Prognostic value of arginase‐II expression and regulatory T‐cell infiltration in head and neck squamous cell carcinoma

Tumor‐infiltrating lymphocytes are present in a variety of tumors and play a central role in antitumor immune responses. Nevertheless, most cancers progress probably because tumors are only weakly immunogenic and develop multiple immunosuppressive mechanisms. In the present study, on head and neck squamous cell carcinoma, we found high intraepithelial infiltration of regulatory FOXP3⁺ T cells, and relatively high levels of BDCA2⁺ and FOXP3⁺ cells in stromal (peripheral) regions of the tumors. Tumor‐infiltrating (intraepithelial) FOXP3⁺ T cells were significantly more frequent in patients with oropharynx and oral cavity squamous cell carcinoma and in patients without lymph node metastasis. Furthermore, arginase‐II (ARG2) was expressed by 60%, inducible nitric oxide synthetase by 9%, cyclooxygenase‐2 by 43%, and B‐cell lymphoma 2 (BCL2) by 26% of tumors. Interestingly, the absence of ARG2 expression, enhanced stromal infiltration of CD11c⁺ myeloid dendritic cells, and high numbers of FOXP3⁺ T cells were each significantly associated with prolonged overall survival, and the latter two parameters were also confirmed by multivariate analysis. For disease‐free survival, multivariate analysis revealed significant negative correlations with BCL2 and ARG2 expression by tumor cells. These findings shed new light on mechanisms of cancer progression, and provide rationales for therapeutic inhibition of immunosuppressive mechanisms in head and neck squamous cell carcinoma.     

Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors

Summary The pharmacokinetics of carboplatin in cerebrospinal fluid (CSF) and plasma was studied in five children with brain tumors (four medulloblastomas and one ependimoblastoma) who underwent preirradiation treatment with carboplatin. Carboplatin pharmacokinetics was studied following the administration of 600 mg/m² as a 1-h infusion. Four children were treated a few weeks after surgery, whereas one child with an unresectable tumor was treated prior to surgery. All patients had a ventricular-peritoneal CSF shunt connected to a subcutaneous reservoir. Total platinum and free carboplatin were measured. The mean AUC values for free carboplatin in CSF and plasma were 2.29±1.20 and 8.18±1.27 mg ml^–1 min, respectively. The mean ratio of CSF AUC to plasma AUC was 0.28 (range, 0.17–0.46). Both plasma peak levels and AUC values showed limited interpatient variability. On the other hand, carboplatin levels in CSF showed substantial interpatient variability, with a>5-fold difference in peak levels and a 3-fold difference in AUC values being recorded. The interpatient difference in CSF pharmacokinetics may have been related at least in part to the different anatomical alterations induced by the surgical procedures or by the presence of a large tumor mass. In the four evaluable patients exhibiting macroscopic residual tumor, we observed one complete remission (CR) and two partial remissions (PR) following two cycles that consisted of two doses of 600 mg/m² carboplatin given on 2 consecutive days (total dose, 1200 mg/m²) and were separated by a l-month interval. These results may give some indication as to the optimal dose and schedule for carboplatin administration in the treatment of primitive neuroectodermic tumors (PNET).This work was partially supported by the AIRC     

ER+/HER2+ Breast Cancer Has Different Metastatic Patterns and Better Survival Than ER−/HER2+ Breast Cancer

BackgroundHuman epidermal growth factor receptor 2–positive (HER2⁺) breast cancer is generally treated with HER2-targeted therapy combined with chemotherapy. Patients with HER2⁺ and estrogen receptor–positive (ER⁺) cancer are additionally treated with long-term hormone therapy. This study examined the metastatic pattern and prognosis of both ER⁺/HER2⁺ and ER^?/HER2⁺ breast cancer.Patients and MethodsA total of 54,147 patients with HER2⁺ breast cancer from the National Cancer Data Base (NCDB, 2010-2013) and 31,946 patients with HER2⁺ breast cancer from the Surveillance, Epidemiology, and End Results Program (SEER, 2010-2014) were examined. Sites of metastasis and overall survival (OS) were examined in the NCDB, while OS and breast cancer–specific survival were examined in the SEER database.ResultsCompared to ER^?/HER2⁺ breast cancer, ER⁺/HER2⁺ breast cancer was more likely to metastasize to bone but less likely to brain, liver, and lung and less likely to result in multiple metastases. In univariate analysis based on the NCDB, patients with ER^?/HER2⁺ breast cancer had worse OS in all metastasis subsets, including patients who received HER2-targeted therapy. This poor survival for ER^?/HER2⁺ persisted in patients with metastasis to bone and lung, and multiple metastases. In multivariate analysis adjusting for age, tumor grade, surgery, chemotherapy, HER2-targeted therapy, and hormone therapy, ER^?/HER2⁺ patients with bone metastasis still had worse OS. In the SEER, ER^?/HER2⁺ patients had both worse OS and breast cancer–specific survival in univariate analysis.ConclusionThis large study showed patients with ER⁺/HER2⁺ and ER^?/HER2⁺ breast cancers had different metastatic patterns. Patients with ER^?/HER2⁺ breast cancer may require more aggressive treatment.     

DPC4蛋白在胆道恶性肿瘤中的缺失表达

Objective To clarify the relationship between loss of expression of DPC4 proteins and pathogenesis of biliary tract carcinoma. Methods 71 primary biliary tract carcinomas (BTCa), including 38 common bile duct (CBD) carcinomas, 18 gallbladder carcinomas, and 15 hilar bile ducts (HBD) carcinomas were examined by immunohistochemical staining. In addition, the CBD carcinomas were divided into two groups, a tumor group with metastasis (M+ group, 27 cases) and a tumor group without metastasis (M− group, 11 cases). Results The frequency of loss expression of DPC4 protein was 32.8% in BTCa, 47.3% in CBD carcinoma, 11% in gallbladder carcinoma and 13% in HBD carcinoma. A comparison of the frequency of loss expression of DPC4 showed significantly statistical difference in the CBD carcinoma versus gallbladder carcinoma and HBD carcinoma (P<0.01). The frequency of loss expression of DPC4 was 48.1% in the M⁺ group and 45.4% in the M⁻ group. There was no significantly statistical difference between them (P>0.05). Conclusion There is a close relationship between the pathogenesis of BTCa and inactivation of DPC4 with different frequencies of DPC4 gene alteration in various locations of the biliary tract, but inactivation of DPC4 is not related with tumor metastasis in BTCa.     

Serum levels of osteopontin as a prognostic factor in patients with oral squamous cell carcinoma

Osteopontin (OPN) is a multifunctional glycophosphoprotein that was detected in many carcinomas, and it may have a prognostic role. The aim of this study was to determine osteopontin serum levels in patients with oral squamous cell carcinoma (OSCC) and investigated its correlation with clinicopathological features of tumor. Using an ELISA kit, we assessed and compared the circulating levels of OPN in blood serum of 45 oral squamous cell carcinoma patients with 45 healthy control samples. The serum osteopontin level in patients with OSCC was significantly higher (145.8?±?14.6 ng/ml, n?=?45) compared with the healthy controls (53.9?±?9.6 ng/ml, n?=?45, p?<?0.001). Mean serum osteopontin level was significantly higher in patients with nodal metastasis (p?=?0.03) and higher stage (p?=?0.02). Findings of the present study suggest that OPN may have a potential role in pathogenesis of OSCC and it may be used as a tool for monitoring tumor progression.     

恶性淋巴瘤患者脑脊液可溶性白细胞介素2受体水平的动态观察及其临床意义

用双抗体夹心ＥＬＩＳＡ方法动态监测４６例恶性淋巴瘤（ＭＬ）患者脑脊液（ＣＳＦ）中可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）水平变化。发现ＭＬ患者脑脊液中ｓＩＬ－２Ｒ比正常人显著升高（Ｐ＜０．００１），且６例有中枢神经系统（ＣＮＳ）浸润者ｓＩＬ－２Ｒ与无ＣＮＳ浸润者相比有显著性差异（Ｐ＜０．０１）；而治疗达ＣＲ或ＰＲ后ｓＩＬ－２Ｒ显著降低（Ｐ＜０．０５），与正常人者相比Ｐ＞０．０５，脑脊液ｓＩＬ－２Ｒ水平与血清中ｓＩＬ－２Ｒ水平无显著相关性。认为动态监测ＭＬ患者脑脊液ｓＩＬ－２Ｒ水平有助于估价病变严重程度、ＣＮＳ有无浸润及疗效评定