Tumor Marker Studies Research Articles

Dynamic study of immunoregulatory factors and tumor markers in patients with advanced gastric cancer before and after chemotherapy

Objective To analyze the dynamic changes of immunoregulatory factors and tumor markers before and after chemotherapy in patients with advanced gastric cancer. Methods From October 2015 to February 2018, 58 patients with chemotherapy AGC in our hospital were selected as gastric cancer group.According to the efficacy of chemotherapy they were divided into effective group, stable group and ineffective group.Meanwhile, 30 healthy persons were selected as normal group.The immunoglobulins (IgA, IgG, IgM), T lymphocyte subsets (CD3+ , CD4+ , CD8+ , CD4+ /CD8+ ) and related tumor markers (CEA, CA199, CA242) were compared before and after chemotherapy. Results The levels of IgA((2.11±0.89) g/L), IgM((10.65±4.61) g/L), IgG((1.25±0.45) g/L), CD8+ ((28.12±3.56)%), CEA((40.33±16.24) μg/L), CA199((76.34±21.56) kU/L) and CA242((29.34±9.57)k U/L) in the gastric cancer group were significantly higher than those in the normal group IgA((0.93±0.36) g/L), IgM((6.46±3.59) g/L), IgG((0.65±0.32) g/L), CD8+ ((25.02±4.78)%), CEA((1.81±0.55) μg/L), CA199((7.51±2.67) kU/L), CA242((3.35±1.21) kU/L)(t=6.958, 3.600, 6.495, 3.435, 12.952, 17.370, 14.773, P<0.05), while CD3+ ((64.12±5.12)%), CD4+ ((34.12±4.10)%), CD4+ /CD8+ (1.09±0.28) were lower than the normal group (CD3+ (71.23±7.14)%, CD4+ (39.78±5.20)%, CD4+ /CD8+ (1.47±0.40))(t=5.376, 5.592, 5.192, P<0.05). The total effective rate of AGC patients in gastric cancer group was 79.31 % (46/58), and the ineffective rate was 20.69 % (12/58). IgA, IgG, IgM, and CD8+ in the effective group were significantly lower than those before chemotherapy (t=3.925, 3.745, 4.036, 2.661, P<0.05), while CD3+ , CD4+ , CD4+ /CD8+ were significantly higher than before chemotherapy (t=3.520, 3.077, 3.218, P<0.05). The subcellular level of protein and T lymphocytes was significantly better than that of stable group and ineffective group (P<0.05). The levels of tumor markers CEA, CA199 and CA242 in the effective group and stable group were significantly lower than those before chemotherapy (P<0.05), and significantly lower than the ineffective group (P<0.05). Conclusion The levels of immunoglobulins, T lymphocyte subsets and tumor markers in patients with AGC have significant changes after chemotherapy, and their levels can guide the efficacy of chemotherapy. Key words: Advanced gastric cancer; Chemotherapy; Immunoglobulin; T lymphocyte subsets; Tumor markers

Hyperglycosylated hCG and Its Free ß-Subunit Drives Malignancy

Tumor marker studies were conducted measuring 2,277 malignancies using a cut-off of 3 fmol/ml. As found 110 of 110 trophoblastic malignancies or 100% were positive for ß-core fragment an hCG serum degradation product. Just 949 of 2167 (44%) of non-trophoblastic or other cancers were positive using this 3 fmol/ml cut-off. When the cut-off of the assay was lowered to 0.1 fmol/ml, or lowered by 30-fold 100% of non-trophoblastic or other cancers were detected, or all cancers were detected. What do cancers secrete. Cancer were tested with three immunoassays, Immulite total hCG, B152 hyperglycosylated hCG and FBT11 free ß-subunit, serum of 34 trophoblastic cancers and 32 non-trophoblastic cancers were tested. A total of 34 of 34 trophoblastic cancer produced primarily hyperglycosylated hCG (B152 hyperglycosylated assay 96%±12% of Immulite), and 32 of 32 non-trophoblastic cancers produced primarily hyperglycosylated hCG free ß-subunit (B152 hyperglycosylated assay 102%±6.2% of Immulite, FBT11 free ß-subunit assay 128%±10% of Immulite). Seven independent laboratories each showed with a wide mixture of cancers (patient tissue and cancer cell lines) that ß-subunit promoted malignancy (cell growth, cell invasion and blockage of apoptosis) in cancer cells. I then showed that hyperglycosylated hCG and its ß-subunit promoted malignancy in 10 different cancer cell lines. I then tied my data and the seven independent laboratory data together and concluded that hyperglycosylated hCG and its ß-subunit drove malignancy in all or most cancers.

Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): An Abridged Explanation and Elaboration.

The Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) were developed to address widespread deficiencies in the reporting of such studies. The REMARK checklist consists of 20 items to report for published tumor marker prognostic studies. A detailed paper was published explaining the rationale behind checklist items, providing positive examples and giving empirical evidence of the quality of reporting. REMARK provides a comprehensive overview to educate on good reporting and provide a valuable reference for the many issues to consider when designing, conducting, and analyzing tumor marker studies and prognostic studies in medicine in general. Despite support for REMARK from major cancer journals, prognostic factor research studies remain poorly reported. To encourage dissemination and uptake of REMARK, we have produced this considerably abridged version of the detailed explanatory manuscript, which may also serve as a brief guide to key issues for investigators planning tumor marker prognostic studies. To summarize the current situation, more recent papers investigating the quality of reporting and related reporting guidelines are cited, but otherwise the literature is not updated. Another important impetus for this paper is that it serves as a basis for literal translations into other languages. Translations will help to bring key information to a larger audience world-wide. Many more details can be found in the original paper.

Research progress of tumor markers in pancreatic cancer tissue

Pancreatic cancer is a hidden disease, rapid progress, treatment and poor prognosis of the digestive tract malignant tumor, in recent years, the incidence rate has increased significantly. At present, surgical resection is the only effective way to long－term survival of pancreatic cancer patients, however, once the clinical diagnosis of the disease patients mostly in late or distant metastases occur, often lost the best chance of operation. The development of modern biomedical science and technology provides a new technique for the study of high sensitivity pancreatic cancer markers, which can improve the early diagnosis rate of pancreatic cancer, thus improving the surgical resection rate and improving the prognosis of patients. The study of tumor markers in pancreatic cancer tissues has always been a hot topic in the early diagnosis of pancreatic cancer. This paper reviews the progress of pancreatic cancer tumor markers in pancreatic cancer tissues. Key words: Pancreatic neoplasms; Early diagnosis; Neoplasms by histologic type; Tumor markers

Abstract 3776: Examination of ERCC1 status in circulating tumor cells as a prognostic tool for patients with nasopharyngeal carcinoma

Abstract Investigation of the expression pattern of DNA-repair protein excision repair cross-complementation group 1 (ERCC1) has been reported to allow selection of patients with non-small cell lung cancer who are likely to benefit from cisplatin-based therapy. Recent evidence suggests that ERCC1 expression may also find prognostic use in patients with nasopharyngeal carcinoma (NPC). We evaluated ERCC1 expression and genotype from NPC tissues and peripheral blood mononuclear cells of patients with NPC. ERCC1 expression was detected in 61/77 cases (79.2%) with varying intensities, where high ERCC1 expression significantly associated with worse relapse-free survival (RFS) (HR 2.34, 1.06-5.16, p=0.036). In addition, the presence of ERCC1 C118T genotype was significantly associated with favorable RFS and overall survival (OS) in a subgroup of patients with undetectable post-treatment plasma EBV DNA. These findings support a prognostic role for ERCC1 examination in NPC. However, the invasive nature of obtaining biopsy samples for tumor marker studies is a major hindrance of this approach. To facilitate the investigation of ERCC1 expression in a noninvasive manner, we have developed a negative selection immunomagnetic method for isolating circulating tumor cells from patient blood. Cell line spike-in experiments reveal a mean recovery rate of 66% for NPC cells with greater than 99% removal of non-targeted blood cells. Specificity of CTC identification was confirmed by detection of the expression of the Epstein-Barr virus encoded small RNA (EBER) in the CTCs. This method also allowed the simultaneous analysis of the expression of multiple protein markers including CD45, cytokeratin and ERCC1. It is expected that the development of noninvasive methodologies for tumor marker studies will facilitate their clinical application for improved patient care and monitoring in the future. Note: This abstract was not presented at the meeting. Citation Format: Edwin P. Hui, Brigette BY Ma, KC Allen Chan, Charles ML Chan, SC Cesar Wong, Ka Fai To, Herbert HF Loong, Frankie KF Mo, Roger KC Ngan, Anthony TC Chan. Examination of ERCC1 status in circulating tumor cells as a prognostic tool for patients with nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3776. doi:10.1158/1538-7445.AM2017-3776

BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses

Background:The co-chaperone protein Bcl-2-associated athanogene-1 (BAG-1) is overexpressed in breast cancer and has been incorporated in the oncotype DX and PAM50 breast cancer prognostic assays. Bcl-2-associated athanogene-1 exists as multiple protein isoforms that interact with diverse partners, including chaperones Hsc70/Hsp70, Ser/Thr kinase Raf-1 and Bcl-2, to promote cancer cell survival. The BAG-1L isoform specifically binds to and increases the transcriptional activity of oestrogen receptor in cells, and in some, but not all studies, BAG-1 expression is predictive of clinical outcome in breast cancer.Methods:A systematic review of published studies reporting BAG-1 (mRNA and/or protein) expression and clinical outcome in early breast cancer. The REporting Recommendations for Tumour MARKer and Prognostic Studies (REMARK) criteria were used as a template against which data were assessed. Meta-analyses were performed for studies that provided a hazard ratio and 95% confidence intervals for clinical outcomes including disease-free survival or breast cancer-specific survival from univariate analysis.Results:Eighteen studies used differing methodologies and reported on differing outcomes. Meta-analyses were only possible on results from a subset of reported studies. Meta-analyses suggested improved outcome with high BAG-1 mRNA and high BAG-1 nuclear expression by immunohistochemisty.Conclusions:Increased levels of BAG-1 are associated with better breast cancer outcomes.

Laparoscopic approach to adnexal mass in adolescents: A retrospective analysis

Background: Adnexal masses result from benign or malignant lesions of ovarian, tubal and paratubal origin as well as pregnancy related causes such as mullerian anomalies, infectious causes and ectopic pregnancy. The current study aimed to evaluate the preoperative diagnosis, surgical procedure and histopathological findings of adolescent girls who underwent laparoscopic surgery for adnexal mass in our hospital. Materials and Methods: A retrospective chart review of patients with adnexal mass was conducted over a period of one year from Jan 2014-2015. Overall 96 patients were included in the study after reviewing clinical records. In all the patients' malignancy was excluded by preoperative imaging with sonography, CT or MRI and tumor marker study. Results: Laparoscopy was the operative approach for all 96 patients. None resulted in malignant histology. Majority of the adnexal masses were simple cyst (28%), 11.4% were dermoid cyst, 2% were endometriotic cyst. One patient had tubal ectopic, 3 patients had Koch's abdomen and pelvis. Among them one 13 year old girl underwent rudimentary horn excision who presented as a para tubal mass with acute abdomen. Almost half of the patients (68.7%) presented with acute abdomen of which 41.6% were adnexal torsion. All adnexal masses were resected laparoscopically and the outcome was uneventful in all the patients. Conclusion: Laparoscopy is regarded as an appropriate surgical method for benign adnexal masses which was safe and effective even for giant ovarian cyst in well selected cases as most of the pelvic adnexal masses seen in adolescents and young girls are of benign nature.

Diagnosis and management options in malignant pleural effusions.

Malignant pleural effusion (MPE) denotes an advanced malignant disease process. Most of the MPE are metastatic involvement of the pleura from primary malignancy at lung, breast, and other body sites apart from lymphomas. The diagnosis of MPE has been traditionally made on cytological examination of pleural fluid and/or histological examination of pleural biopsy tissue that still remains the initial approach in these cases. There has been tremendous advancement in the diagnosis of MPE now a day with techniques i.e. characteristic Ultrasound and computed tomography features, image guided biopsies, fluorodeoxyglucose-positron emission tomography imaging, thoracoscopy with direct biopsy under vision, tumor marker studies and immunocytochemical analysis etc., that have made possible an early diagnosis of MPE. The management of MPE still remains a challenge to pulmonologist and oncologist. Despite having various modalities with better tolerance such as pleurodesis and indwelling pleural catheters etc., for long-term control, all the management approaches remain palliative to improve the quality of life and reduce symptoms. While choosing an appropriate management intervention, one should consider the clinical status of the patient, life expectancy, overall cost, availability and comparative institutional outcomes, etc.

Safety and Outcome Measures of First-in-Human Intraperitoneal α Radioimmunotherapy With 212Pb-TCMC-Trastuzumab.

Purpose:One-year monitoring of patients receiving intraperitoneal (IP) 212Pb-TCMC-trastuzumab to provide long-term safety and outcome data. A secondary objective was to study 7 tumor markers for correlation with outcome.Methods:Eighteen patients with relapsed intra-abdominal human epidermal growth factor receptor-2 expressing peritoneal metastases were treated with a single IP infusion of 212Pb-TCMC-trastuzumab, delivered <4 h after 4 mg/kg IV trastuzumab. Seven tumor markers were studied for correlation with outcome.Results:Six dose levels (7.4, 9.6, 12.6, 16.3, 21.1, 27.4 MBq/m2) were well tolerated with early possibly agent-related adverse events being mild, transient, and not dose dependent. These included asymptomatic, abnormal laboratory values. No late renal, liver, cardiac, or other toxicity was noted up to 1 year. There were no clinical signs or symptoms of an immune response to 212Pb-TCMC-trastuzumab, and assays to detect an immune response to this conjugate were negative for all tested. Tumor marker studies in ovarian cancer patients showed a trend of decreasing Cancer antigen 72-4 (CA 72-4) aka tumor-associated glycoprotein 72 (TAG-72) and tumor growth with increasing administered radioactivity. Other tumor markers, including carbohydrate antigen (CA125), human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and carcinoembryonic antigen (CEA) did not correlate with imaging outcome.Conclusions:IP 212Pb-TCMC-trastuzumab up to 27 MBq/m2 seems safe for patients with peritoneal carcinomatosis who have failed standard therapies. Serum TAG-72 levels better correlated to imaging changes in ovarian cancer patients than the more common tumor marker, CA125.

A preliminary study of screening bile tumor markers for extrahepatic cholangiocarcinoma with proteomics technology

Objective To analyze differentially expressed proteins in bile of extrahepatic cholangiocarcinoma (EHCC)by proteomics technology, and to detect the potential tumor markers for diagnosis of bile duct malignancy. Methods Bile samples from 16 patients with EHCC and 16 patients with sphincter of oddi dysfunction (control) were collected for proteomic analysis by isobaric tags for relative and absolute quantitation (iTRAQ). The differentially expressed proteins were identified by mass spectrometry and retrieved by protein database. Results Protein maps of both EHCC group and control group were established successfully by iTRAQ. Analysis software identified an average of 275 proteins in EHCC group and 218 proteins in control group. Statistical filter screened 12 proteins of more than double difference, 4 of which were of diagnostic value, identified by mass spectrometry, which were MUC3a, Annexin A3, REG3A and Tumor-associated trypsin inhibitor (TATI). Functional analysis revealed that these proteins were associated with cancer cellular oncogenesis, proliferation, differentiation and metastasis. Conclusion Proteomic analysis by iTRAQ can identify the protein variance in bile of patients with EHCC, and identify four new potential biomarkers correlated with biological behavior of cholangiocarcinoma. Key words: Cholangiocarcinoma; Bile ducts, extrahepatic; Proteomics; Bile; Tumor markers

Lymphoepithelial cyst of pancreas: spectrum of radiological findings with pathologic correlation.

The purpose of the study was to investigate imaging features as well as pathologic and clinical findings of lymphoepithelial cyst (LEC) of pancreas. Ten patients with surgically resected and pathologically proven LEC, found in a single institution database between 2000 and 2015, were evaluated in a retrospective fashion. Patients' demographics, clinical presentation, co-morbidities, imaging features, cytology and histopathology results, and serum/aspirate biomarkers levels were recorded. Eighty percent of patients were male with median age of 59. All lesions were exophytic, with median size of 36mm. 80% were classified as complex cystic lesions, showing enhancing septa or enhancing rim without measurable enhancing solid component. 80% were located in tail or body. In one patient with MRI, the lesion was mildly T1 hyperintense and markedly T2 hyperintense. All cases were anechoic or hypoechoic on EUS, and majority of them showed posterior acoustic enhancement. Of patients with available fluid aspirate analysis, 3 out of 4 had CEA level>192ng/mL and 1 out of 3 had elevated (>250IU/ml) amylase level. Four out of 7 patients had elevated serum CA 19-9 levels (>37 U/mL); one patient with a value of 361 U/mL had co-existing pancreatic adenocarcinoma. Round shape, mild complexity, and exophytic location in pancreatic body and tail can be suggestive of LECs. These features however are not specific and may be seen with other cystic pancreatic lesions. CT findings should be used in conjunction with EUS, cytology, and tumor marker studies to secure the diagnosis of LEC.

Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients

IntroductionColorectal cancer (CRC) diagnosed before age 30 years is a fatal disease whose biology remains poorly understood. To understand its pathogenesis, we compared molecular and clinical data in surgically treated early-age onset and adult onset patients. Materials and MethodsClinical data and tumor tissue were collected retrospectively for 94 patients with early-age onset CRC (age ≤30 years) and compared to 275 adult CRC patients (age ≥50 years). Tumor morphology, microsatellite instability (MSI) and stability (MSS), KRAS and BRAF mutations, and mismatch repair (MMR) expression (MSH2, MLH1, MSH6, PMS2) were assessed. ResultsEarly-age CRC was distinguished from adult CRC by advanced stage presentation (P<0.001), frequent high grade cancers (P<0.001), and poor prognosis (P<0.001). MSI was associated with favorable survival and MMR loss in both groups. Compared to adults, MSI in early-onset CRC was more prevalent (P<0.01), not tightly linked to MLH1/PMS2 loss, and never associated with BRAFV600E mutations (P<0.01). MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC (9% vs. 3%). DiscussionSpecific genetic subtypes are found at different frequencies in early-age onset and adult onset CRC. Complete absence of the indolent MSI/BRAFV600E genotype and enrichment in the unfavorable MSS/BRAFV600E genotype help explain the poor prognosis of early onset CRC.

A Systematic Review of Diagnostic Biomarkers of COPD Exacerbation.

The aims of this systematic review were to determine which blood-based molecules have been evaluated as possible biomarkers to diagnose chronic obstructive pulmonary disease (COPD) exacerbations (AECOPD) and to ascertain the quality of these biomarker publications. Patients of interest were those that have been diagnosed with COPD. MEDLINE, EMBASE, and CINAHL databases were searched systematically through February 2015 for publications relating to AECOPD diagnostic biomarkers. We used a modified guideline for the REporting of tumor MARKer Studies (mREMARK) to assess study quality. Additional components of quality included the reporting of findings in a replication cohort and the use of receiver-operating characteristics area-under-the curve statistics in evaluating performance. 59 studies were included, in which the most studied biomarkers were C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). CRP showed consistent elevations in AECOPD compared to control subjects, while IL-6 and TNF-α had variable statistical significance and results. mREMARK scores ranged from 6 to 18 (median score of 13). 12 articles reported ROC analyses and only one study employed a replication cohort to confirm biomarker performance. Studies of AECOPD diagnostic biomarkers remain inconsistent in their reporting, with few studies employing ROC analyses and even fewer demonstrating replication in independent cohorts.

Quick regression of brain metastases from lung adenocarcinoma with epidermal growth factor receptor-tyrosine kinase inhibitor treatment: A case report and literature review.

Brain metastasis (BM) commonly occurs in patients with advanced lung cancer, and is associated with poor prognosis and limited treatment options, particularly for end-stage patients who are in poor physical and mental state. We herein present a case of lung adenocarcinoma with BM, as revealed by tumor marker and imaging studies. The patient was a 74-year-old woman who was diagnosed with lung adenocarcinoma with several metastatic lesions in the mediastinal lymph nodes, bone and brain. The patient underwent two cycles of chemotherapy, but the cancer recurred with enlarged BM, resulting in confusion and body dysfunction. The patient then received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy with icotinib. After approximately 12 h of treatment the symptoms disappeared, and the metastatic lesions in the brain largely regressed in the following months. Our case indicates that the EGFR-TKI icotinib may provide a rapid and safe approach for emergency situations with BM from lung adenocarcinoma.

Comparative study of tumor markers in patients with colorectal carcinoma before and after chemotherapy.

Colorectal carcinoma (CRC), the second leading cause of cancer-related deaths in US, has a rising time-trend in India. Tumour markers in CRC are extensively researched, and there's still debate on their diagnostic and prognostic values. In this hospital-based longitudinal study in north India, 51 male diagnosed CRC cases (pre-chemotherapy) were contrasted against 50 age and sex matched controls. Nine biomarkers: carcinoembryonic antigen (CEA), prolactin (PRL), alfa feto protein (AFP), total human chorionic gonadotropin (hCG), cancer antigen-125 (CA-125), serum testosterone, prostate specific antigen (PSA) and ferritin were measured by direct chemiluminescence technique. Further, follow-up was done on 47 cases after treatment with six cycles of 5-flurouracil (5-FU) and oxaliplatin. Mean serum CEA (case: 5.94±8.27 ng/mL, control: 2.5±0.79 ng/mL, P<0.05), PRL (case: 28.12±13.39 ng/mL, control: 14.24±13.13 ng/mL, P<0.0001), AFP (case: 10.9±6.65 ng/mL, control: 4.02±1.26 ng/mL, P<0.0001) levels were significantly raised in CRC cases compared to controls. On the contrary, mean testosterone level (P<0.05) was lower among the cases. After chemotherapy, the mean serum CEA (P<0.05), AFP (P<0.0001) and CA-125 (P<0.05) levels among the cases decreased significantly compared to their pretreatment levels. The present study strongly indicates the role of CEA, PRL, AFP, CA-125 and testosterone as important biomarkers in male CRC patients from north India. Further, AFP, CA-125 and CEA may be used to assess the effectiveness of chemotherapy in such patients.

OP28PRELIMINARY RESULTS OF THE PROSPECTIVE FEASIBILITY CNS GCT-4 CONSORTIUM TRIAL FOR PATIENTS WITH REFRACTORY/RECURRENT CNS GERM CELL TUMORS (GCT)

INTRODUCTION: We present updated findings on the response rate, toxicity and early outcomes of a re-induction regimen of gemcitabine, oxaliplatin and paclitaxel (GemPOx) administered, in responsive patients, prior to myeloablative chemotherapy and autologous hematopoietic cell rescue (HDCx + AuHCR). METHOD: Since December 2004, 14 recurrent or refractory patients (12 MMGCT, 2 germinoma; 12 males; mean age 16.5 years, range 7-34 years) have been treated with up to 4 cycles of gemcitabine (800mg/m2), oxaliplatin (100mg/m2) and paclitaxel (170 mg/m2), administered on one day at 14 days intervals. RESULTS: Of 14 patients, five were treated on a preceding feasibility pilot with 1-3 cycles of GemPOx, and nine have been formally enrolled on an ongoing prospective multi-center trial. Seven patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions and two developed progressive disease (PD) while on GemPOx. Twelve of the 14 patents subsequently underwent HDCx + AuHCR; 6 subsequently received irradiation. Transient hepatotoxicity and pancytopenia were the most prevalent toxicities. Five patients continue alive and disease-free for 9 + , 20 + , 22 + , 26+ and 28+ months since end of therapy. CONCLUSION: GemPOx appears to be an effective re-induction regimen for patients with recurrent CNS MMGCT, with acceptable toxicities. The ongoing multi-center, international trial should confirm this and demonstrate the contribution of GemPOx towards improved survival when followed by HDCx + AuHCR with or without further irradiation, in the setting of minimal residual disease.

Neurological Involvement in Erdheim-Chester Disease.

Dear Editor, We present a clinical case of a 74-year-old man with a personal record of nasal polyps and sinusitis. The patient was first admitted to our Department of Neurology with symptoms of instability and dizziness of 6 months of evolution, which subsided spontaneously. Physical examination revealed amaurosis with an afferent pupillary defect in the left eye associated with conjunctival injection, with a slightly hyperemic optic nerve head and mild proptosis in that same eye, as well as paresthesia of the first branch of the trigeminal nerve on the left side of his face. The patient was hospitalized, and several analysis and diagnostic test was performed, together with a study of autoimmunity and tumor markers, CSF analysis, and brain MRI. The analysis revealed the following abnormal findings: erythrocyte sedimentation rate, 67 mm; antinuclear antibody inconclusive (1/80); positive for anti-DNA (37 UI/mL), perinuclear antineutrophil cytoplasmic antibody and antimyeloperoxidase-IgG (45 U/mL); and negative for antiproteinase 3 IgG. All other studies yielded normal findings. Brain MRI revealed a lesion with signs of aggressiveness in the bilateral nasoethmoid region, with an epidural component in that area, and meningeal thickening and hyperenhancement (Fig. 1). Immunohistochemical studies of a biopsy sample taken from the lesion revealed histiocytosis with foamy histiocytes (positive for CD68, and negative for S100 and CD1a), as well as intense lymphoid infiltration and eosinophils (Supplementary Figs. 1 and 2 in the online-only Data Supplement). These data confirmed the diagnosis of Erdheim-Chester disease (ECD). Fig. 1 Brain MRI. A: An axial, T1-weighted cranial MRI image obtained after administering intravenous contrast medium, the arrow point the epidural enhancement on the frontal lobe. B: A coronal, T1-weighted cranial MRI image showing an infiltrating-like lesion ... Tc-99 scintigraphy was performed, but no lesions compatible with ECD were observed. A body CT scan revealed emphysematous air spaces with paraseptal and centrilobular distributions in both upper lobes. These data, together with the results of aspirometry study, confirmed an interstitial pattern. Prednisolone was added to the treatment, which resulted in a progressive improvement of the neurological symptoms. The patient was discharged after 10 days of treatment. The patient experienced no recurrence of the symptoms during a follow-up period of 4 years. EDC is a rare form of non-Langerhans cell histiocytosis, for which there are approximately 400 cases described in the medical literature.1 It is a systemic disease that affects mainly adults between their fifth and seventh decades of life; the prevalence is slightly higher in men.2 ECD is diagnosed through the assessment of clinical symptoms and radiological and histological criteria. The main diagnostic criteria are histological, and are usally sufficient to confirm the disease.2 The histology of ECD is characterized by histiocytic infiltration with special histiocyte that do not contain Birbeck granules, and an immunohistochemical profile that is characterized by positivity to CD68 and negativity to CD1a and S100.3 The cardinal sign of ECD is bone involvement, which is observed in 96% of patients.1 CNS involvement occurs in 51% of the patients with ECD, and is responsible for 29% of all deaths due to the disease.1 The neurological clinical symptoms, in lowering order of frequency, are diabetes insipidus, exophthalmos, cerebellar ataxia, panhypopituitarism, and papilledema.2 Brain MRI describes two patterns: infiltrating and nodular thickening of the dura mater; the former is the most frequently observed.4 The low prevalence of this disease means that no standardized treatment has yet been established.4 However, there are now some first-line drugs, such as interferon-α, which exert positive effect on survival.1 However, the beneficial effects of interferon-α have yet to be clarified.4 Corticoids are used to control the symptoms of ECD.2 Vemurafenib (a BRAF inhibitor) induces a fast clinical improvement in patients who are positive for the BRAF V600E mutation, which is found in 54% of ECD patients.3 The average 1- and 5-year survival rates of the disease are 95% and 68%, respectively.2 Involvement of the CNS has recently been proposed as the only independent clinical prognostic factor for a poor survival.1 The patient described herein presented with neurological symptoms and lung involvement. Only an anatomopathological analysis of biopsy samples allowed a definitive diagnosis, since the patient did not present any other symptoms.

Reporting in studies of protein biomarkers of prognosis in colorectal cancer in relation to the REMARK guidelines.

The REMARK guidelines give authors comprehensive and specific advice on the complete and transparent reporting of studies of prognostic tumor markers. The aim of this study was to use the REMARK guidelines to evaluate the quality of reporting in a sample of studies assessing tissue-based protein markers for survival after resection of colorectal cancer. Eighty pertinent articles were scored according to their conformity to 26 items derived from the REMARK criteria. Overall, on a scale of adequacy of reporting that potentially ranged from 26 to 78, the median for these studies was 60 (interquartile range 54-64) and several criteria were adequately covered in a large proportion of studies. However, others were either not dealt with or inadequately covered, including description of the study design (35%), definition of survival endpoints (48%), adjuvant therapy (54%), follow-up procedures and time (59%), neoadjuvant therapy (63%), inclusion/exclusion criteria (73%), multivariable modeling methods and results (74%), and discussion of study limitations (85%). Inadequacies in presentation militate against comparability among protein marker studies and undermine the generalizability of their findings. The quality of reporting could be improved if journal editors were to require authors to ensure that their work satisfied the REMARK criteria.

A cross-sectional study of tumor markers during normal and high-risk pregnancies

ObjectiveTo determine tumor marker concentrations during normal and high-risk pregnancies. MethodsThe present cross-sectional study included women attending the gynecology outpatient department at All India Institute of Medical Sciences, New Delhi, India, between November 1, 2012 and March 31, 2013. Their serum was assayed for carcinoembryonic antigen (CEA), cancer antigen 19–9 (CA19-9), and cancer antigen 15–3 (CA15-3). ResultsA total of 251 pregnant women and 31 nonpregnant women were included. Median CEA value was lower among pregnant women than among nonpregnant women (1.2μg/L vs 1.4μg/L; P=0.006), whereas that of CA15-3 was higher (16.7U/mL vs 12.3U/mL; P=0.03). CA19-9 concentration was higher among pregnant women aged 25–29years (7.0U/mL) or 30–34years (7.2U/mL) than among those aged 20–24years (4.2U/mL; P=0.01 for both). The CA15-3 level was increased during the second (13.0U/mL) and third (60.5U/mL) trimesters compared with the first trimester (9.5U/mL) (P≤0.01 for both comparisons). It was also raised in high-risk pregnancies (33.7U/mL), specifically pregnancies complicated by gestational diabetes mellitus (39.7U/mL), intrahepatic cholestasis of pregnancy (64.3U/mL), or heart disease (54.0U/mL) (P<0.05 for all). ConclusionCA15-3 concentrations rise during pregnancy, but whether this increase can be attributed to physiological changes in breast tissue needs to be investigated further.

PRELIMINARY RESULTS OF A PROSPECTIVE FEASIBILITY PILOT STUDY OF "GEMPOX" (GEMCITABINE, OXALIPLATIN, AND PACLITAXEL) IN PEDIATRIC AND ADULT PATIENTS WITH REFRACTORY OR RECURRENT CENTRAL NERVOUS SYSTEM (CNS) GERM CELL TUMORS (GCT): THE INTERNATIONAL CNS GCT CONSORTIUM TRIAL, CNS GCT-4

BACKGROUND: The optimal management of patients with recurrent CNS GCT, especially those with non-germinomatous (mixed malignant) GCT (MMGCT), remains unclear. Preliminary results are presented on the response rate, toxicity and early outcomes of a re-induction regimen of gemcitabine, oxaliplatin and paclitaxel (GEMPOX) administered, in responsive patients, prior to myeloablative chemotherapy and autologous hematopoietic cell rescue (HDCx + AuHCR). METHODS: Since December 2004, 13 recurrent or refractory patients (12 MMGCT, 1 germinoma; 12 males; mean age 16.5 years, range 7-34 years) have been treated with up to 4 cycles of gemcitabine (800 mg/m2), oxaliplatin (100 mg/m2) and paclitaxel (170 mg/m2), administered on one day at 14 days intervals. RESULTS: Of 13 patients, five were treated on a preceding feasibility pilot with 1-3 cycles of GEMPOX, and seven have been formally enrolled on an ongoing prospective multi-center trial. Six patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions and two developed progressive disease (PD) while on GEMPOX; one patient with PD after 1 cycle had pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma.; the second patient, with pure pineal choriocarcinoma, progressed following the second cycle of GEMPOX. Eleven of the 13 patents subsequently underwent HDCx + AuHCR. Six of them subsequently received irradiation. Transient hepatotoxicity and pancytopenia were the most commonly observed toxicities. Other toxicities included: paclitaxel anaphylaxis (1), transient encephalopathy (1), peripheral neuropathy (1), hyperesthesia (4), mucositis (2) and electrolyte imbalances (3). Four of the 12 patients with MMGCT continue alive and disease-free for 8+ , 10+ , 14+ and 16+ months since discontinuation of all therapy. One patient (with pure yolk sac tumor) relapsed in a loco-regional extra-CNS location (cavernous and ethmoid/sphenoid sinuses) and remains alive with progressive disease on therapy now 12+ months post-HDCx + AuHCR. CONCLUSIONS: GEMPOX appears to be an effective re-induction regimen for patients with recurrent CNS MMGCT, with acceptable toxicities. The ongoing multi-center, international trial should confirm this and demonstrate the contribution of GEMPOX towards improved survival when followed by HDCx + AuHCR with or without further irradiation, in the setting of minimal residual disease. SECONDARY CATEGORY: Pediatrics.