Small Cell Tumor Research Articles

Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome

Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ T-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well-characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC-I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5-year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach.

Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.

277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.

Primary natural killer/T cell lymphoma of the cervix: Case report and clinicopathological analysis

ObjectiveTo present pathological and molecular characterizations of a rare case that was diagnosed as nasal-type natural killer (NK)/T cell lymphoma primarily arising in the cervix. Case reportAn Asian woman was admitted to hospital with a hysteromyoma, and laparotomy was performed. A large tumor of the uterus was found, which was limited to the cervix. Pathological examination showed NK/T cell lymphoma, which was supported by histological and immunohistochemical studies and was confirmed by evidence of Epstein–Barr virus infection. Less commonly, this case concerned a cytotoxic T cell phenotype, as molecular studies showed evidence of a clonal T cell receptor γ chain gene rearrangement. Microscopically, prominent and extensive necrosis was the distinctive feature of this case, which reminded us of considering it as a tumor. ConclusionPrimary NK/T lymphoma of the cervix is rare. Our experience in this case provided variable information on both pathological and molecular studies. This case may be of value in the differential diagnosis of lymphoid lesions and other small cell tumors of the cervix.

Desmoplastic Small Round Cell Tumor, a "Floating Island" Pattern in Pleural Fluid Cytology: A Case Report and Review of the Literature.

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive sarcoma with characteristic clinical and pathologic features. It typically involves pelvic and abdominal organs of young male patients, and patients usually present at advanced stage with poor prognosis. A few reports are available describing the cytopathologic features of DSRCT in serous effusions, with the majority of published cases depicting undifferentiated small blue cells that need to be distinguished from other small blue cell tumors. We report an interesting case of DSRCT involving a pleural effusion with a “floating island” pattern that has been described in hepatocellular carcinoma, renal cell carcinoma, and adrenal cortical carcinoma. In our case, the epithelioid tumor cells form cohesive aggregates surrounded by a single layer of spindle cells, mimicking the “endothelial wrapping” in other tumors with “floating island” patterns. We demonstrate, by ancillary testing, that these peripheral spindle cells are tapered/flattened DSRCT cells, in contrast to endothelial wrapping cells, as seen in other tumors with this unique cytomorphology. To our knowledge, this is the first case report describing DSRCT showing a “floating island” pattern that needs to be differentiated from metastatic hepatocellular carcinoma, renal cell carcinoma, and adrenal cortical carcinoma in effusion cytology.

Primary Endometrial High Grade Neuroendocrine Carcinoma: A Case Report with Cytological, Histopathological and Immunohistochemical Features

An 84-year-old woman suffered from post-menopausal genital bleeding for 3 months. Based on the endometrial cytological findings (suggestive of high grade neuroendocrine carcinoma) showing that there were rosette-like and cord-like structures consisting of small rounded tumor cells with oval nuclei and scanty cytoplasm, radical hysterectomy was performed. Histopathological and immunohistochemical examinations on the operated specimens revealed primary high grade neuroendocrine carcinoma of the endometrium. Despite the extensive treatment against the malignancy, the patient died due to widespread metastases after 5 months after the surgery and autopsied.

Neuroendocrine tumors of the vagina

The paper covers the most important topographic-anatomic and histological characteristics of the vagina, gives general information on the epidemiology of primary vaginal cancer (VC), on the rules of its staging, describes the frequently encountered morphological types of this tumor, and indicates the properties and features of the course of neuroendocrine tumors (NETs), including the most common manifestations of carcinoid syndrome and the symptoms of tumor hypersecretion of a number of biologically active substances. It also indicates the most common sites of NETs, the rules of their classification according to the grade and mitotic activity of tumor cells, as well as major methods for biochemical and radiological diagnosis. The immunohistochemical NET markers that can diagnose VC, their physiological role, sensitivity, and specificity, as well as the possibility of determining them in the body’s biological environments in order to increase physicians’ awareness are described in detail and the main aspects of tumor immunohistochemical staining are denoted. The role of circulating tumor cells as a promising method to specify the extent of NETs is defined. The paper gives epidemiological information on the development of vaginal NET and summarizes the available data by their clinical course and treatment results. It provides current guidelines on the required treatment volume and specifies the role of surgical intervention and the necessary volume if the intervention is expedient. It sets forth the up-to-date guidelines for chemotherapy for small cell tumors, as well as VC, which includes the specific features of managing patients with tumor recurrences depending on the time of their development.

Ewing′s sarcoma arising from base of nasal cavity and extending to nasopharynx and oral cavity

Ewing's sarcoma (ES) is a malignant, small cell tumor of skeletal system seen in young adults and children. The prognosis is very poor in this type of tumor, which has a metastasis potential at an early stage. It is rarely seen in head and neck region; mandible is involved relatively frequent while paranasal involvement is very rare. Furthermore, ES arising from base of nasal cavity and hard palate is extremely rare. The aim of this report was to discuss a 14-year-old girl with ES arising from base of nasal cavity and extending to nasopharynx in the light of literature.

Ewing's Sarcoma of Maxilla: A Rare Presentation

ABSTRACT Ewing's sarcoma is a rare malignant small cell tumor occurring in the first and second decades of life and usually involving the long bones of the limb. Literature shows that less than 3% of the tumor originates in the maxillofacial region of which 1% occurs in jaw bones with higher predilection for mandible. Mean age of presentation of this tumor in bones of head and neck region is 10.9 years. Surgery is the first line of treatment and considering the aggressive behavior of the tumor multimodality treatment is preferred to reduce recurrence rate. Due to small number of cases affecting the jaws, there are no definite protocols in treatment of Ewing's sarcoma of maxilla. We are presenting a case of Ewing's sarcoma of maxilla in a 60 years old patient, as it is involving a rare site and has occurred in an uncommon age group. How to cite this article Mohiyuddin SMA, Deo RP, Jyothi DN, Kumar HML, Sagayaraj A. Ewing's Sarcoma of Maxilla: A Rare Presentation. Int J Head Neck Surg 2015;6(2):96-98.

Gallbladder: A rare primary site for small cell carcinoma

Neuroendocrine tumors (NETs) are an extremely rare entity in gallbladder (GB), occurring in approximately 0.5% cases of NETs from all sites. In the present case report, a 42-year-old male presented with recurrent right upper quadrant pain for 2 months. Abdominal ultrasound revealed a small nodular swelling in the GB. On aspiration cytology that appeared as individual small tumor cells mostly in dispersed population and frequent nuclear molding within cell aggregates in a necrotic background. The patient was diagnosed as NET of GB. Histopathology revealed; uniform small rounded cells arranged in peritheliomatous pattern with intervening areas of massive necrosis. Nuclear molding, salt-pepper nuclear chromatin and frequent mitoses were also evident. Immunohistochemistry with chromogranin confirmed the diagnosis of small cell carcinoma.

Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast.

Although rare, neuroendocrine carcinoma of the breast (NECB) is becoming an increasingly recognized entity. The current literature is limited to case reports and small series and therefore a comprehensive population-based analysis was conducted to investigate the clinicopathologic features and long-term outcomes associated with NECB. We included all patients in the SEER Database from 2003 to 2010 with a diagnosis of NECB. The 2012 WHO classification system was used to categorize patients based on histopathologic diagnosis: well-differentiated neuroendocrine tumors, small/oat cell or poorly differentiated neuroendocrine tumors, adenocarcinoma with neuroendocrine features (ANF), large cell neuroendocrine and carcinoid tumors. Survival analysis was performed for disease specific (DSS) and overall (OS) survival. Of the 284 cases identified, 52.1% were classified as well-differentiated, 25.7% small cell, 14.8% ANF, 4.9% large cell, and 2.5% carcinoid. In general, patients presented with advanced disease: 36.2% had positive lymph node metastases and 20.4% presented with systemic metastases. Five-year DSS rates for stage I-IV NECB were 88.1, 67.8, 60.5, and 12.4%, respectively, while five-year OS rates were 77.9, 57.3, 52.9, and 8.9%, respectively. DSS and OS were significantly different for well-differentiated neuroendocrine tumors and ANFs compared to small cell and carcinoid tumors. On univariate Cox proportional hazards regression, small cell carcinoma was significantly associated with worse DSS (OR 1.97, 95% CI 1.05-3.67) and OS (OR 2.66, 95% CI 1.49-4.72) compared to other neuroendocrine tumors. NECB is associated with advanced stage disease at presentation and an unfavorable prognosis for stage II-IV disease and small cell, large cell, and carcinoid histologic subtypes.

EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma.

Soft tissue sarcomas (STS) are heterogeneous malignant tumors of mesenchymal origin. Due to low incidence and high number of different histological subtypes, their pathogenesis and thus potential targets for their therapy remain barely investigated. Several studies revealed significant higher EPHB4 expression in malignancies such as prostate and colorectal cancer showing survival advantages for these tumor cells. Therefore we studied the expression of EPHB4 in a total of 46 clinical human specimens of different STS and human fibroblasts. EPHB4 mRNA and protein expression were significantly increased in synovial sarcoma. After targeting EPHB4 in fibrosarcoma, synovial sarcoma, liposarcoma and MFH sarcoma cell lines by siRNA or by inhibition of autophosphorylation using the specific EPHB4 kinase inhibitor NVP-BHG712 a decreased proliferation rate/vitality of synovial- and fibrosarcoma cells was observed. Silencing of EPHB4 significantly reduced the transmigration of synovial sarcoma cells towards fibroblasts and endothelial cells. In addition, we assessed the anti-metastatic effect of EPHB4 inhibition in vivo by intraperitoneal administration of the EPHB4 inhibitor in an appropriate sarcoma lung metastasis xenograft model. As result 43% of NVP-BHG712 treated mice (n = 3/7) developed pulmonary metastases whereas all control mice (n = 5) revealed lung metastases. The residual 57% of mice (n = 4/7) showed only small local tumor cell spots. Size measurements of the Vimentin positive area explained significant decrease in lung metastasis formation (p < 0.05) after EPHB4 kinase inhibition. In summary, these data provide first evidence of the importance of EPHB4 in the tumorigenesis of synovial sarcoma and present EPHB4 as a potential target in the therapy of this malignancy.

Medulloblastoma metastatic to the pancreas: a case report

We present a case of medulloblastoma metastatic to the pancreas in a 41-year-old woman with recurrent cerebellar medulloblastoma. On presentation, computed tomography of the abdomen and pelvis showed a 2.2 cm × 2.6 cm hypodense pancreatic head mass associated with obstruction of the pancreatic duct. Endosonography with fine needle aspiration (EUS-FNA) was performed. Cytology showed a malignant small cell neoplasm that was consistent with medulloblastoma and was morphologically identical to the primary cerebellar medulloblastoma. Metastatic medulloblastoma to the pancreas is an extremely rare form of a secondary pancreatic tumor and very few case reports exist in the literature. The diagnosis rests on comparing cytological features when primary and secondary tumors are both available.

Abstract 2180: Serum 25-hydroxyvitamin D, vitamin D binding protein, and lung cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

Abstract Background: Vitamin D may inhibit tumor progression by suppressing metastasis, proliferation, and angiogenesis. The vitamin D binding protein (DBP) is the primary carrier of circulating vitamin D compounds and functions in actin scavengering, macrophage activation, and neutrophil chemotaxis. Little is known about the association between vitamin D, DBP, and lung cancer survival. We investigated the association between serum concentrations of 25-hydroxyvitamin D (25(OH)D), DBP, and lung cancer mortality in 500 lung cancer cases from the ATBC Study. Methods: Serum concentrations of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free circulating vitamin D, were measured in fasting blood samples collected at baseline. Hazards ratios (HR) and 95% confidence intervals (CI) were used to estimate survival by quartiles of 25(OH)D, DBP, and the 25(OH)D:DBP molar ratio. Results: Median survival time was 0.5 years (IQR: 0.1 - 1.1) for 428 cases that died from lung cancer and 1.7 years (IQR: 0.1 - 7.8) for 72 lung cancer survivors. Median serum concentrations (nmol/L) of 25(OH)D and DBP were 33 (IQR: 20-50) and 5951 (IQR: 4725-7196), respectively, for lung cancer deaths and 37 (IQR: 22-52) and 5431 (IQR: 4600-7151), respectively, for lung cancer survivors. In multivariable adjusted models, higher concentrations of serum 25(OH)D were associated with a small but not statistically significant increase in lung cancer mortality (Q4 vs. Q1 HR = 1.20; 95% CI: 0.90, 1.60). Survival was not associated with higher serum concentrations of DBP (Q4 vs. Q1 HR = 1.01; 95% CI: 0.76, 1.34). A higher 25(OH)D:DBP molar ratio was associated with a slightly reduced risk of mortality, although not significant (Q4 vs. Q1 HR = 0.87; 95% CI: 0.65, 1.18). DBP concentration did not modify the association between 25(OH)D or the 25(OH)D:DBP molar ratio and lung cancer survival. In histology-specific analyses, elevated concentrations of 25(OH)D was associated with higher mortality in squamous cell carcinomas (HR = 1.47; 95% CI: 0.82, 2.65) and adenocarcinomas (HR = 1.42; 95% CI: 0.33, 6.05), but reduced mortality in small cell carcinomas (HR = 0.62; 95% CI: 0.18, 2.10). A higher 25(OH)D:DBP molar ratio was associated with higher mortality for squamous cell tumors (HR = 1.28; 95% CI: 0.68, 2.40), and lower mortality for adenocarcinomas (HR = 0.10; 95% CI: 0.02, 0.57) and small cell tumors (HR = 0.52; 95% CI: 0.12, 2.18). Associations between serum DBP and mortality were similar across histologic types. Conclusion: Higher vitamin D status was weakly associated with lung cancer survival and DBP was unrelated to survival; however, a higher 25(OH)D:DBP molar ratio indicative of unbound or “free” vitamin D may be related to increased adenocarcinoma and possibly small cell carcinoma survival. The findings should be evaluated in other longitudinal studies. Citation Format: Gabriella M. Anic, Stephanie J. Weinstein, Satu Männistö, Demetrius Albanes. Serum 25-hydroxyvitamin D, vitamin D binding protein, and lung cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2180. doi:10.1158/1538-7445.AM2014-2180

Abstract LB-316: The landscape of actionable genomic lesions in small cell bladder cancer

Abstract Small cell cancers are aggressive tumors with unfavorable prognosis. Small cell bladder carcinomas are a particularly troublesome and poorly differentiated tumor where little is known and in which few targeted therapeutic options exist for molecularly defined patients. We therefore sought to characterize both common and actionable aberrant pathways in small cell bladder tumors to serve as a guide for therapeutic development. Utilizing a combination of deep targeted capture and whole-genome sequencing approaches, we characterized the mutational and DNA copy number alteration spectrum of twenty patients with small-cell bladder cancer including multi-region profiling of a subset of cases with mixed small cell and urothelial histologies. Integrating molecular, clinical, and pathway data along with comparative genomic analyses of 371 urothelial bladder and small cell lung cancers, we identified histology- and lineage-specific lesions and significant differences in the prevalence of specific pathway aberrations. Whole-genome sequencing revealed structurally complex tumors and, in some cases, somatic hypermutation, including one sample harboring more than 150,000 clonal mutations. Aberrations in G1/S cell cycle progression appear to be pathognomonic in small cell tumors. Furthermore, additional lesions affecting both pro/anti apoptotic as well as metabolic pathways occurred in patterns that are distinct from other small-cell and bladder cancers. In total, 85% of small cell bladder cancer samples contain at least one potentially clinically actionable lesion. These results indicate that integrative genomic analyses of small-cell bladder cancer facilitates therapeutic development and pathway targeting in a complex mutational landscape. Citation Format: Matthew T. Chang, Saurabh Asthana, Gopakumar Iyer, Neil Desai, Hikmat Al-Ahmadie, Jocelyn Chapman, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, David B. Solit, Barry S. Taylor. The landscape of actionable genomic lesions in small cell bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-316. doi:10.1158/1538-7445.AM2014-LB-316

Abstract 3980: Pre-clinical evaluation of a novel DNA crosslinking agent, Ureidomustin (BO-1055) in pediatric sarcomas

Abstract DNA crosslinking agents continue to be an important part of chemotherapy for pediatric sarcomas. We tested potent analogues of phenyl N-mustard-benzene conjugates in several tumor models. In this work, we compared the efficacy of a novel water-soluble DNA alkylating agent, Ureidomustin (BO-1055) in Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, desmoplastic small round cell tumor (DSRCT) cell lines and early cultures derived from primary patient samples. We tested its toxicity in normal human cells in vitro including the proliferation of mesenchymal stromal cells, bone marrow-derived endothelial cells and purified cord blood CD34+ cells in colony-forming assay (for hematopoietic progenitor cells) and in cobblestone area forming assay (for hematopoietic stem cells). We performed cell viability, cytotoxicity and caspase activation assays in a dose-dependent and time-dependent manner. We also performed apoptosis, cell cycle analyses using flow cytometry, immunoblot analysis and in vivo experiments in nude mice using Ewing sarcoma (A673) cell line transduced with GFP/luciferase for bioimaging. We evaluated cardiotoxicity in the HL-1 cardiomyocyte line in vitro and noted a 227 fold less cytotoxicity using BO-1055 compared to Doxorubicin. Based on MTD testing in nude mice, we used 30mg/kg q2d for 5 doses after tumors reached 75-100mm3 and were detected on luciferase bioimaging. Our results indicated that BO-1055 has a significant therapeutic window in its activity (mean IC50±SD μM) for rhabdomyosarcoma (0.16±0.11), Ewing sarcoma (0.48±0.29) and DSRCT (3.07±0.94) but not for osteosarcoma (IC50&amp;gt;10μM). The mean IC50 in benign cells was &amp;gt;10μM. Treatment with BO-1055 resulted in G2 arrest and activation of caspases 3 and 7 in a dose dependent manner. A673 xenografts were significantly inhibited by BO-1055 compared to the control mice injected with vehicle, based on mean fluorescence intensity and size of the tumors. Our results suggest that BO-1055 has potent activity against Ewing sarcoma and rhabdomyosarcoma and presents a strong rationale for further development as a therapeutic agent. Citation Format: Srikanth R. Ambati, Elissa WP Wong, Benet Pera, Elizabeth Peguero, Eloisi Caldas Lopes, Jin-Jer Chen, Jae-Hung Shieh, Tsann-Long Su, Malcolm AS Moore. Pre-clinical evaluation of a novel DNA crosslinking agent, Ureidomustin (BO-1055) in pediatric sarcomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3980. doi:10.1158/1538-7445.AM2014-3980

Case Report: Hyponatremia of malignancy – An alternative mechanism? Syndrome of inappropriate atrial natriuretic peptide (SIANP)

Euvolemic hyponatremia in the setting of lung cancer is most commonly due to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, a subset of patients with small cell carcinoma and hyponatremia also have elevated levels of atrial natriuretic peptide (ANP), which is produced by some small cell tumors. We report the case of a 64-year-old man with a limited-stage small cell carcinoma of the lung undergoing chemoradiation therapy, who was admitted to hospital with a pulmonary embolism. Two months earlier, at the time of diagnosis with lung cancer, he had a hypotonic, euvolemic hyponatremia, presumed to be caused by SIADH. At that time, his serum sodium readily normalized with fluid restriction and ADH-antagonist therapy with demeclocycline. However, during his second admission, the hyponatremia was refractory to treatment: his sodium level slowly declined from 138 mmol/L to a nadir of 118 mmol/L, despite early initiation of fluid restriction and maximal doses of demeclocycline. Laboratory values revealed a low but inappropriately non-zero level of ADH but also an inappropriately low level of aldosterone and an elevated level of ANP, suggesting that SIADH might not be the only contributor to the hyponatremia. While a causal link between ectopic ANP production and hyponatremia has never been established, an inappropriately high level of ANP can directly decrease sodium re-absorption in the proximal convoluted tubule of the kidney and increase glomerular filtration rate (GFR), resulting in greater excretion of sodium and water. In addition, high circulating levels of ANP can inhibit aldosterone secretion, potentially resulting in further sodium wasting. Here, the elevated ANP and inappropriately low aldosterone suggested the possibility that the refractory hyponatremia, although initiated by SIADH, was further worsened by an ANP-mediated natriuresis and suppression of aldosterone response.

Open tubular lab-on-column/mass spectrometry for targeted proteomics of nanogram sample amounts.

A novel open tubular nanoproteomic platform featuring accelerated on-line protein digestion and high-resolution nano liquid chromatography mass spectrometry (LC-MS) has been developed. The platform features very narrow open tubular columns, and is hence particularly suited for limited sample amounts. For enzymatic digestion of proteins, samples are passed through a 20 µm inner diameter (ID) trypsin + endoproteinase Lys-C immobilized open tubular enzyme reactor (OTER). Resulting peptides are subsequently trapped on a monolithic pre-column and transferred on-line to a 10 µm ID porous layer open tubular (PLOT) liquid chromatography LC separation column. Wnt/ß-catenein signaling pathway (Wnt-pathway) proteins of potentially diagnostic value were digested+detected in targeted-MS/MS mode in small cell samples and tumor tissues within 120 minutes. For example, a potential biomarker Axin1 was identifiable in just 10 ng of sample (protein extract of ∼1,000 HCT15 colon cancer cells). In comprehensive mode, the current OTER-PLOT set-up could be used to identify approximately 1500 proteins in HCT15 cells using a relatively short digestion+detection cycle (240 minutes), outperforming previously reported on-line digestion/separation systems. The platform is fully automated utilizing common commercial instrumentation and parts, while the reactor and columns are simple to produce and have low carry-over. These initial results point to automated solutions for fast and very sensitive MS based proteomics, especially for samples of limited size.

Ovarian tumor-initiating cells display a flexible metabolism

An altered metabolism during ovarian cancer progression allows for increased macromolecular synthesis and unrestrained growth. However, the metabolic phenotype of cancer stem or tumor-initiating cells, small tumor cell populations that are able to recapitulate the original tumor, has not been well characterized. In the present study, we compared the metabolic phenotype of the stem cell enriched cell variant, MOSE-LFFLv (TIC), derived from mouse ovarian surface epithelial (MOSE) cells, to their parental (MOSE-L) and benign precursor (MOSE-E) cells. TICs exhibit a decrease in glucose and fatty acid oxidation with a concomitant increase in lactate secretion. In contrast to MOSE-L cells, TICs can increase their rate of glycolysis to overcome the inhibition of ATP synthase by oligomycin and can increase their oxygen consumption rate to maintain proton motive force when uncoupled, similar to the benign MOSE-E cells. TICs have an increased survival rate under limiting conditions as well as an increased survival rate when treated with AICAR, but exhibit a higher sensitivity to metformin than MOSE-E and MOSE-L cells. Together, our data show that TICs have a distinct metabolic profile that may render them flexible to adapt to the specific conditions of their microenvironment. By better understanding their metabolic phenotype and external environmental conditions that support their survival, treatment interventions can be designed to extend current therapy regimens to eradicate TICs.

Case Report: Hyponatremia of malignancy – An alternative mechanism? Syndrome of inappropriate atrial natriuretic peptide (SIANP)

Euvolemic hyponatremia in the setting of lung cancer is most commonly due to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). However, some patients with small cell carcinoma and hyponatremia have low levels of ADH but elevated levels of atrial natriuretic peptide (ANP), which is produced by some small cell tumors. We report the case of a 64-year-old man with a limited-stage small cell carcinoma of the lung undergoing chemoradiation therapy, who was admitted to hospital with a pulmonary embolism. Two months earlier, at the time of diagnosis with lung cancer, he had a hypotonic, euvolemic hyponatremia, presumed to be caused by SIADH. At that time, his serum sodium readily normalized with water restriction and ADH-antagonist therapy with demeclocycline. However, during his second admission, his sodium level slowly declined from 138 mmol/L to a nadir of 118 mmol/L, despite early initiation of water restriction and maximal doses of demeclocycline. Laboratory values revealed a very low level of ADH, an inappropriately low level of aldosterone and an elevated ANP suggesting that SIADH could not explain his hyponatremia. While a causal link between ectopic ANP production and hyponatremia has never been established, an inappropriately high level of ANP can directly decrease sodium re-absorption in the proximal convoluted tubule of the kidney and increase glomerular filtration rate (GFR), resulting in greater excretion of sodium and water. In addition, high circulating levels of ANP can inhibit aldosterone secretion, potentially resulting in further sodium wasting. Here, the low levels of ADH, elevated ANP, and inappropriately low aldosterone suggested the possibility of an ANP-mediated hyponatremia through the suppression of aldosterone response.

A prognostic analysis of pediatrics central nervous system small cell tumors: evaluation of EGFR family gene amplification and overexpression.

BackgroundCentral nervous system (CNS) tumors are the most common solid tumors that occur in children, however there were few big-data follow-up analysis published in China. Overexpression of epidermal growth factor receptor (EGFR) family members was reported on glioblastoma (GBM) and medulloblastoma (MB) before. However, the correlation between EGFR family members expression with prognosis of MB, supratentorial primitive neuroectodermal tumor (PNET) and small cell GBM is unclear in Chinese children.MethodsA retrospective and survival analysis was performed on children (age ≤ 16 years) diagnosed as CNS primary small cell tumors in the Affiliated Provincial Hospital, Shandong University from 2000 to 2012, including MB (n = 44), PNET (n = 8) and small cell GBM (n = 19). The expression of EGFR, ERBB-2, ERBB-3 and ERBB-4 were detected by immunohistochemistry (IHC). The fluorescence in situ hybridization (FISH) was used to observe the amplification of EGFR and ERBB-2 gene.ResultsMedian survival times of MBs, small GBMs and PNETs were 23 ± 6.7 months, 8 ± 4.7 months and 10 ± 1.4 months. Expression and amplification of ERBB-2, ERBB-3 and ERBB-4 were not observed in all tumor samples. The multiply Cox regression suggested the overexpression and amplification of EGFR were negative prognostic factors for MB. Radiotherapy had the positive function for all pediatric patients.ConclusionOverexpression of EGFR predicts poor outcomes of MBs, small cell GBMs and PNETs, suggesting those three CNS tumor subtypes can be considered as one group for the potential common mechanism. The current individual treatment and big data analysis of pediatric CNS embryonal tumors and GBM continues to be very challenging in China.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7649640001237474