Predicting resection margin status of pancreatic neuroendocrine tumors on CT: performance of NCCN resectability criteria.

OBJECTIVE: To test the performance of the National Comprehensive Cancer Network (NCCN) CT resectability criteria for predicting the surgical margin status of pancreatic neuroendocrine tumor (PNET) and to identify factors associated with margin-positive resection. METHODS: Eighty patients with pre-operative CT and upfront surgery were retrospectively enrolled. Two radiologists assessed the CT resectability (resectable [R], borderline resectable [BR], unresectable [UR]) of the PNET according to NCCN criteria. Logistic regression was used to identify factors associated with resection margin status. κ statistics were used to evaluate interreader agreements. Kaplan-Meier method with log-rank test was used to estimate and compare recurrence-free survival (RFS). RESULTS: Forty-five patients (56.2%) received R0 resection and 35 (43.8%) received R1 or R2 resection. R0 resection rates were 63.6-64.2%, 20.0-33.3%, and 0% for R, BR, and UR diseases, respectively (all p ≤ 0.002), with a good interreader agreement (κ, 0.74). Tumor size (<2 cm, 2-4 cm, and >4 cm; odds ratio (OR), 9.042-18.110; all p ≤ 0.007) and NCCN BR/UR diseases (OR, 5.918; p = 0.032) were predictors for R1 or R2 resection. The R0 resection rate was 91.7% for R disease <2 cm and decreased for larger R disease. R0 resection and smaller tumor size in R disease improved RFS. CONCLUSION: NCCN resectability criteria can stratify patients with PNET into distinct groups of R0 resectability. Adding tumor size to R disease substantially improves the prediction of R0 resection, especially for PNETs <2 cm. ADVANCES IN KNOWLEDGE: Tumor size and radiologic resectability independently predicted margin status of PNETs.

Resection Versus Observation for Small (≤2 cm) Pancreatic Neuroendocrine Tumors.

BACKGROUND: We hypothesized that those patients with pancreatic neuroendocrine tumors (pNETs) ≤2 cm managed nonoperatively would have comparable disease progression to individuals undergoing an operation. METHODS: Patients diagnosed with nonfunctional pNETs ≤ 2 cm who were evaluated at a single comprehensive cancer center from 2010 to 2017 were selected from a cancer registry database. Clinicopathologic variables were obtained via retrospective chart review. Primary outcomes were overall and disease specific survival. Variables were compared between the 2 groups using chi-square and independent t-test. RESULTS: Fifty-two individuals had tumors ≤2 cm, of whom 75% had an operation, while 25% were observed. Each treatment arm had similar distributions of gender, race, and tumor location. The most common operation was distal pancreatectomy (n = 29) followed by pancreatoduodenectomy (n = 6). Nine patients had grade III postoperative complications and 4 had grade IV under Clavien-Dindo classification. The observation group was noted to have a mean disease progression interval of 80.9 months, while those who underwent an operation had a mean disease progression interval of 94.6 months (P = .246). CONCLUSIONS: Overall disease progression in patients with pNETs ≤ 2 cm without evidence of metastasis at the time of presentation is not different between those who underwent operation compared to those observed.

(-)-Oleocanthal and (-)-oleocanthal-rich olive oils induce lysosomal membrane permeabilization in cancer cells.

(-)-Oleocanthal (oleocanthal) is a phenolic compound found in varying concentrations in extra virgin olive oil oleocanthal has been shown to be active physiologically, benefiting several diseased states by conferring anti-inflammatory and neuroprotective benefits. Recently, we and other groups have demonstrated its specific and selective toxicity toward cancer cells; however, the mechanism leading to cancer cell death is still disputed. The current study demonstrates that oleocanthal, as well as naturally oleocanthal-rich extra virgin olive oils, induced damage to cancer cells' lysosomes leading to cellular toxicity in vitro and in vivo. Lysosomal membrane permeabilization following oleocanthal treatment in various cell lines was assayed via three complementary methods. Additionally, we found oleocanthal treatment reduced tumor burden and extended lifespan of mice engineered to develop pancreatic neuroendocrine tumors. Finally, following-up on numerous correlative studies demonstrating consumption of olive oil reduces cancer incidence and morbidity, we observed that extra virgin olive oils naturally rich in oleocanthal sharply reduced cancer cell viability and induced lysosomal membrane permeabilization while oleocanthal-poor oils did not. Our results are especially encouraging since tumor cells often have larger and more numerous lysosomes, making them especially vulnerable to lysosomotropic agents such as oleocanthal.

Pediatric Ewing's Sarcoma/Primitive Neuroectodermal Tumor (ES/PNET) Developed in the Small Intestine: A Case Report / 임상소아혈액종양

Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) are a group of malignant tumors with varying degrees of neuroectodermal differentiation. Although it may develop in any organs, ES/PNET originating from small intestine is exceedingly rare. We experienced a 9-year-old girl presenting with abdominal pain, melena, and iron deficiency anemia. Imaging work-up showed multiple masses in the small bowel and omentum with disseminated peritoneal seeding nodules, indicating lymphoma as the most likely diagnosis. Pathological reports from explorative diagnostic laparoscopic biopsy showed tumors comprising small round cells with CD99 expression and EWS-FLI1 translocation leading to the diagnosis of ES/PNET. Tumor burden decreased gradually during five consecutive cycles of systemic chemotherapy. The patient received segmental resection of jejunum, followed by adjuvant chemotherapy. This is the first pediatric case of ES/PNET found in small intestine in Korea.

Pediatric Ewing's Sarcoma/Primitive Neuroectodermal Tumor (ES/PNET) Developed in the Small Intestine: A Case Report / 임상소아혈액종양

Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) are a group of malignant tumors with varying degrees of neuroectodermal differentiation. Although it may develop in any organs, ES/PNET originating from small intestine is exceedingly rare. We experienced a 9-year-old girl presenting with abdominal pain, melena, and iron deficiency anemia. Imaging work-up showed multiple masses in the small bowel and omentum with disseminated peritoneal seeding nodules, indicating lymphoma as the most likely diagnosis. Pathological reports from explorative diagnostic laparoscopic biopsy showed tumors comprising small round cells with CD99 expression and EWS-FLI1 translocation leading to the diagnosis of ES/PNET. Tumor burden decreased gradually during five consecutive cycles of systemic chemotherapy. The patient received segmental resection of jejunum, followed by adjuvant chemotherapy. This is the first pediatric case of ES/PNET found in small intestine in Korea.

MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells.

Malignant brain tumors are the leading cause of cancer-related deaths in children. Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are particularly aggressive embryonal tumors of unknown cellular origin. Recent genomic studies have classified CNS-PNETs into molecularly distinct subgroups that promise to improve diagnosis and treatment; however, the lack of cell- or animal-based models for these subgroups prevents testing of rationally designed therapies. Here, we show that a subset of CNS-PNETs co-express oligoneural precursor cell (OPC) markers OLIG2 and SOX10 with coincident activation of the RAS/MAPK (mitogen-activated protein kinase) pathway. Modeling NRAS activation in embryonic OPCs generated malignant brain tumors in zebrafish that closely mimic the human oligoneural/NB-FOXR2 CNS-PNET subgroup by histology and comparative oncogenomics. The zebrafish CNS-PNET model was used to show that MEK inhibitors selectively eliminate Olig2+/Sox10+ CNS-PNET tumors in vivo without impacting normal brain development. Thus, MEK inhibitors represent a promising rationally designed therapy for children afflicted with oligoneural/NB-FOXR2 CNS-PNETs.

[Malignant medulloepithelioma mimicking retinoblastoma - clinical and morphological case analysis and cell culture experience]. / . Zlokachestvennaya medulloepitelioma, simuliruyushchaya retinoblastomu ­ kliniko-gistologicheskii analiz sluchaya i opyt polucheniya kletochnoi kul'tury.

The paper presents clinical and morphological case analysis of primary intraocular malignant medulloepitelioma (medulloblastoma) of rare localization (central part of the retina with optic nerve involvement) that simulated retinoblastoma in a 2-year-old child. Histological features of the tumor are given in details (tubular and mesh structures of the tumor, rosettes, ribbons, cells with hyperchromic nuclei, and cellular polymorphism). An experience of creating a primary intraocular malignant medulloepitelioma cell culture, as yet exclusive in the Russian Federation, is described. Culture sensitivity for particular drugs (oxaliplatin, irinotecan, ifosfamide, and ascorbic acid at different concentrations) was evaluated by MTT-assay. Of the four products, IC50 (3.3 mg/ml) was obtained only for ascorbic acid. Despite the relative rarity of primary intraocular malignant medulloepitelioma, its differential diagnosis should be carried out, with retinoblastoma in mind in the first place. The obtained data on the effectiveness of ascorbic acid against intraocular malignant medulloepitelioma cells can be used to supplement the existing chemotherapeutic protocols in pediatric ocular and neuro-oncology.

Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors.

Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue.

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.

Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses.

Certain risk groups among tumors of the central nervous system (CNS) in children take an almost inevitably fatal course. The elucidation of molecular mechanisms offers hope for improved therapy. Aberrant methylation is common in malignant brain tumors of childhood and may have implications for stratification and therapy. Methylation of p16 (INK4A), p14 (ARF), TIMP3, CDH1, p15 (INK4B )and DAPK1 in medulloblastoma (MB) and ependymoma has been discussed controversially in the literature. DUTT1 and SOCS1 have not previously been analyzed. We examined methylation in MB, sPNET and ependymoma using methylation-specific PCR (MSP), quantitative Combined Bisulfite Restriction Analysis (COBRA) and direct and clone sequencing of bisulfite PCR products. We detected methylation of p16 (INK4A) (17/43), p14 (ARF) (11/42) and TIMP3 (9/44) in MB and others by MSP. CDH1 was not only methylated in MB (31/41), but also in normal controls. Evaluation of MSP results by quantitative COBRA and sequencing yielded methylation between the detection limits of COBRA (1%) and MSP (0.1%). Only p16 (INK4A )and TIMP3 were methylated consistently in medulloblastomas (p16 (INK4A ) 14%, TIMP3 11%) and p16 (INK4A) also in anaplastic ependymomas (1/4 tumors). Methylation ranged from 1-5%. Evaluation of methylation using MSP has thus to be supplemented by quantitative methods. Our analyses raise the issue of the functional significance of low level methylation, which may disturb the delicate growth factor equilibrium within the cell. Therapeutic and diagnostic implications urge into depth analyses of methylation as a mechanism, which might fill some of the gaps of our understanding of brain tumor origin.

Long-term survival of high-risk pediatric patients with primitive neuroectodermal tumors treated with antineoplastons A10 and AS2-1.

Primitive neuroectodermal tumors (PNETs) are usually successfully treated with craniospinal radiation and chemotherapy; however, difficulties with standard treatment can be encountered in very young children, in adult patients at high risk of complication from standard treatment, and in patients with recurrent tumors. Thirteen children, either with recurrent disease or high risk, were treated in phase II studies with antineoplastons (ANP). The median age of patients was 5 years, 7 months (range, 1-11). Medulloblastoma was diagnosed in 8 patients, pineoblastoma in 3 patients, and other PNET in 2 patients. Previous treatments included surgery in 12 patients (1 had biopsy only, suboccipital craniotomy), chemotherapy in 6 patients, and radiation therapy in 6 patients. Six patients had not received prior chemotherapy or radiation. The treatment consisted of intravenous infusions of 2 formulations of ANP, A10 and AS2-1, and was administered for an average of 20 months. The average dosage of A10 was 10.3 g/kg/d and of AS2-1 was 0.38 g/kg/d. Complete response was accomplished in 23%, partial response in 8%, stable disease in 31%, and progressive disease in 38% of cases. Six patients (46%) survived more than 5 years from initiation of ANP; 5 were not treated earlier with radiation therapy or chemotherapy. The serious side effects included single occurrences of fever, granulocytopenia, and anemia. The study is ongoing and accruing additional patients. The percentage of patients' response is lower than for standard treatment of favorable PNET, but long-term survival in poor-risk cases and reduced toxicity makes ANP promising for very young children, patients at high risk of complication of standard therapy, and patients with recurrent tumors.

Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts.

Irofulven is a novel, small molecular weight semisynthetic compound, derived from a family of mushroom toxins known as illudins. This DNA alkylating agent has a chemical structure unlike any other chemotherapeutic agent in clinical use. The molecule is currently being studied in several Phase I, II, and III trials. The objectives of this study were to evaluate the antitumor activity of Irofulven in a panel of 20 pediatric solid tumor xenografts and to relate the Irofulven systemic exposure, defined as area under the concentration time curve, to the antitumor dose associated with tumor regression in the tumor models. Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three cycles. The minimum effective dose of Irofulven causing objective regression (> or =50% volume regression) of advanced tumors was determined for each of 19 of 20 independently derived tumor models (12 brain tumors, 4 neuroblastomas, and 4 rhabdomyosarcomas). At the maximum tolerated dose for three cycles of treatment (4.6 mg/kg/day) objective regressions were determined in 14 of 18 tumor lines (78%). However, the dose-response relationship was acute. At 2 mg/kg only 3 of 15 tumors tested demonstrated objective regressions, and in 3 additional tumors volume regressions were not achieved at a higher dose level (3 mg/kg), hence were not additionally tested. After administering the maximum tolerated dose (tolerated for one or two cycles of treatment) of Irofulven, 7 mg/kg, to mice bearing sensitive and resistant human tumors plasma concentration-time profiles were determined. Tumors were highly sensitive to Irofulven, but the systemic exposure required for a significant rate of objective response in this panel of tumors is in excess of that achievable in patients at tolerable doses, using this schedule of drug administration.

Basal ganglia and thalamic tumours: an imaging approximation.

INTRODUCTION: Among brain tumours, those arising from the deep brain are rare. In many cases they are low-grade astrocytomas. But primitive neuroectodermal tumours, ganglion cell tumours, oligodendrogliomas, lymphomas, and germinal neoplasms can also grow up from the basal ganglia and thalamic region. In other occasions peripheral neoplasms developing in neighbouring structures like the cerebral lobes, the ventricular walls, choroidal plexus, pineal gland and the hypothalamic-chiasmatic-suprasellar region can spread to the deep brain. IMAGING: Imaging cannot reliably indicate that a histological picture for a tumour of this kind should be suspected. Although the macro- and microscopical characteristics of brain tumours are often the basis of the imaging findings, these data usually overlap and are only useful as an approximation tool. CONCLUSIONS: Nonetheless, whilst radiologists and clinicians must always be cautious when evaluating the macroscopic peculiarities of a brain tumour, the value of imaging cannot be overestimated when any sort of pathology is encountered. Moreover, besides the classic CT and MRI findings, new MRI-related techniques, such as magnetic resonance spectroscopy (MRS), are able to extract a different kind of information from cerebral neoplasms, and they could be important widespread diagnostic alternatives in the very near future.

Oral contraceptives: a cause of hyperbilirubinemia in stem cell transplant patients.

Conjugated hyperbilirubinemia in the clinical setting of hematopoietic stem cell transplantation can have multiple etiologies that may prompt various therapeutic interventions. Two patients who received short courses of a high-dose estrogen-progesterone combination to treat breakthrough menstrual bleeding during transplant are reported. Conjugated hyperbilirubinemia developed in both patients within days of beginning therapy and resolved after the ethinyl estradiol and norgestrel (Ovral; Pharmacia and Upjohn, Kalamazoo, MI, U.S.A.) was discontinued. In one of the patients, this occurred on three separate occasions during the course of transplantation. Recognizing the cholestatic effect of estrogens during transplantation may prevent unnecessary alterations in therapy beyond the simple discontinuation of these medications.

Maternal diet and risk of astrocytic glioma in children: a report from the Childrens Cancer Group (United States and Canada)

N-nitroso compounds and their precursors, nitrites and nitrates, have been hypothesized as risk factors, and vitamins C and E, which inhibit N-nitroso formation, as protective factors for brain tumors. A case-control study of maternal diet during pregnancy and risk of astrocytoma, the most common childhood brain tumor, was conducted by the Childrens Cancer Group. The study included 155 cases under age six at diagnosis and the same number of matched controls selected by random-digit dialing. A trend was observed for consumption of cured meats, which contain preformed nitrosamines (a class of N-nitroso compounds) and their precursors (adjusted odds ratio [OR] for highest quartile of intake relative to lowest = 1.7, P trend = 0.10). However, no strong trends were observed for nitrosamine (OR = 0.8, P = 0.60); nitrite (OR = 1.3, P = 0.54); nitrate (OR = 0.7, P = 0.43); vitamin C (OR = 0.7, P = 0.37); or vitamin E (OR = 0.7, P = 0.48). Iron supplements were associated with a significant decrease in risk (OR = 0.5, 95 percent confidence interval = 0.3-0.8). The effect of several dietary factors differed by income level, making interpretation of the results difficult. Future research should investigate the effect of dietary components not assessed in this study, as these may explain the disparate effects by income level. The results of this study provide limited support for the nitrosamine hypothesis.