Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

[Gastro-intestinal neuroectodermal tumor (GNET): A case report of a small intestine tumor with hepatic metastases]. / Tumeur neuroectodermique gastro-intestinale (GNET) : à propos d'un cas de tumeur du grêle avec métastases hépatiques.

The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET.

GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors.

GATA3 is a transcription factor important in the differentiation of breast epithelia, urothelia, and subsets of T lymphocytes. It has been suggested to be useful in the evaluation of carcinomas of mammary or urothelial origin or metastatic carcinomas, but its distribution in normal and neoplastic tissues is incompletely mapped. In this study, we examined normal developing and adult tissues and 2040 epithelial and 460 mesenchymal or neuroectodermal neoplasms for GATA3 expression to explore its diagnostic value in surgical pathology, using monoclonal antibody (clone L50-823) and Leica Bond automated immunohistochemistry. GATA3 was expressed in trophoblast, fetal and adult epidermis, adult mammary and some salivary gland and sweat gland ductal epithelia, urothelia, distal nephron in developing and adult tissues, some prostatic basal cells, and subsets of T lymphocytes. It was expressed stronger in fetal than in adult mesothelia and was absent in respiratory and gastrointestinal epithelia. In epithelial neoplasms, GATA3 was expressed in >90% of primary and metastatic ductal and lobular carcinomas of the breast, urothelial, and cutaneous basal cell carcinomas and trophoblastic and endodermal sinus tumors. In metastatic breast carcinomas, it was more sensitive than GCDFP. Among squamous cell carcinomas, the expression was highest in the skin (81%) and lower in cervical (33%), laryngeal (16%), and pulmonary tumors (12%). Common positivity was found in skin adnexal tumors (100%), mesothelioma (58%), salivary gland (43%), and pancreatic (37%) ductal carcinomas, whereas frequency of expression in adenocarcinomas of lung, stomach, colon, endometrium, ovary, and prostate was <10%. Chromophobe renal cell carcinoma was a unique renal tumor with frequent positivity (51%), whereas oncocytomas were positive in 17% of cases but other types only rarely. Among mesenchymal and neuroectodermal tumors, paragangliomas were usually positive, which sets these tumors apart from epithelial neuroendocrine tumors. Mesenchymal tumors were only sporadically positive, except epithelia of biphasic synovial sarcomas. GATA3 is a useful marker in the characterization of not only mammary and urothelial but also renal and germ cell tumors, mesotheliomas, and paragangliomas. The multiple specificities of GATA3 should be taken into account when using this marker to detect metastatic mammary or urothelial carcinomas.

Primitive neuroectodermal tumors of adrenal gland.

OBJECTIVES: To analyze the clinical and pathological characteristics of adrenal primitive neuroectodermal tumors for a better understanding of the disease. METHODS: A retrospective analysis of four cases of adrenal primitive neuroectodermal tumors (two male, two female; age 21-30, average 24) was made. All patients went through necessary endocrinological exams, computer tomography scans (for site-specific diagnoses) and pathological tests. RESULTS: No positive result was reported in routine laboratory tests and endocrinological exams. Computer tomography scans showed bulk soft tissue masses with rough borders. The masses were 8-17 cm in diameter with solid-cystic changes. Among the four patients, one refused to receive treatment after definitiver diagnosis through needle biopsy, three received surgical treatments and their post-operative pathological exams all confirmed the diagnoses of primitive neuroectodermal tumors. During the follow-ups, the untreated patient died 6 months afterwards, one patient died 8 months after palliative treatment; one patient showed distant metastasis 13 months after surgery and did not respond well to both radio- and chemotherapy; one patient had local recurrence 1 month after surgery and is presently undergoing chemotherapy. CONCLUSIONS: Adrenal primitive neuroectodermal tumor is a very rare tumor. It originates in primitive neuroectoderma and is found mainly in 20-30-year-old young populations. It has non-specific clinical or imaging manifestation and its diagnosis is mostly based on pathological examinations. The tumor is fast-developing, highly malignant with poor prognosis.

Comprehensive epidermal growth factor receptor gene analysis from cytological specimens of non-small-cell lung cancers.

Epidermal growth factor receptor (EGFR) gene mutations and increased copy numbers are considered as predictors of response to EGFR tyrosine kinase inhibitors (EGFR-TKI) in non-small-cell lung cancer (NSCLC). Lung cancer diagnosis is often based on cytology alone. However, almost all published data on EGFR gene analyses were obtained from biopsies. This study tested the feasibility of EGFR gene analyses on cytological specimens. Eighty-four cytological specimens from NSCLCs were prospectively analysed for EGFR gene mutation in exons 18-21 and EGFR gene copy numbers were evaluated by fluorescence in situ hybridisation (FISH). A FISH-positive result was defined according to the criteria by Cappuzzo et al established for biopsies of NSCLCs. Fluorescence in situ hybridisation results of cytological specimens were compared to the FISH results on matching biopsies (n=33). Initial diagnosis of NSCLC was solely based on cytology in 37 out of 84 (44.0%) patients. Out of 80 NSCLCs, 6 (7.5%) showed EGFR gene mutations. Out of 67 cancers, 45 (67.2%) were FISH positive on cytological specimens. Comparison of FISH showed a FISH-positive result in 21 out of 33 (63.6%) cytological specimens but in only 8 out of 33 (24.2%) matched biopsies. Epidermal growth factor receptor gene analyses are well applicable to cytological specimens. The high FISH-positive rate of NSCLC on cytological specimens contrasts with the low rate on biopsies when previously suggested criteria are used. New criteria for a positive EGFR FISH status to predict response to therapy with EGFR-TKI need to be defined for cytological specimens.

Isolated hepatic perfusion for the treatment of patients with advanced liver metastases from pancreatic and gastrointestinal neuroendocrine neoplasms.

BACKGROUND: We report results of using isolated hepatic perfusion (IHP) in patients with advanced progressive liver metastases (LM) from pancreatic and gastrointestinal neuroendocrine neoplasms (NENs). METHODS: Thirteen patients with LM from NENs (mean percent hepatic replacement, 30; range, 10-60) were treated with a 1-hour hyperthermic IHP via a laparotomy with the use of 1.5 or 2.0 mg/kg melphalan and/or 1 mg tumor necrosis factor. An oxygenated extracorporeal circuit with inflow through the gastroduodenal artery and common hepatic artery, and outflow to a segment of the inferior vena cava was used. Portal flow and inferior vena cava flow were shunted to the axillary vein. Radiographic response, recurrence pattern, and survival were assessed. RESULTS: Mean operative time was 9 hours (8-11 hours), and a median hospital stay was 10 days (6-64 days). Fifty percent of evaluable patients had a radiographic partial response in the liver (mean duration, 15 months; range, 6-26 months; 2 ongoing). Four had a marginal response (25%-49% reduction in the neoplasm). The median, hepatic, progression-free survival was 7 months (range, 3-27 months). The median actuarial survival was 48 months including 1 treatment mortality (median follow-up, 23 months). CONCLUSIONS: For patients with advanced LM from NENs, IHP provides a reasonable response rate and duration with acceptable morbidity; continued clinical evaluation is important.

MR imaging of hepatic metastases caused by neuroendocrine tumors: comparing four techniques.

OBJECTIVE: The aim of our prospective study was to assess the MR imaging characteristics of hepatic metastases of neuroendocrine tumors and to determine the optimal MR sequence for their detection. SUBJECTS AND METHODS: Thirty-seven consecutive patients with liver metastases from neuroendocrine tumors underwent 1.5-T MR imaging of the liver comprising T2-weighted fast spin-echo with respiratory monitoring, breath-hold T2-weighted single-shot fast spin-echo, and T1-weighted gradient-recalled echo sequences before and after the injection of gadoterate dimeglumine. Images were reviewed independently by three observers for the number, location, and pattern of signal and enhancement of metastases. RESULTS: A total of 359 metastases were detected, 279 on T2-weighed fast spin-echo, 231 on T2-weighed single-shot fast spin-echo, 272 on unenhanced T1-weighted, 322 on hepatic arterial phase, and 228 on portal venous phase images. Hepatic arterial phase images revealed the greatest number of metastases in 70% of patients, including 35 metastases seen only on this sequence, and was significantly superior to the unenhanced T1-weighted and portal venous phase sequences (p < 0.01). The lesion-to-liver contrast was significantly greatest with T2-weighed fast spin-echo sequences. The enhancement patterns of metastases were predominantly hypervascular, hypovascular, peripheral with progressive fill-in, and delayed in, respectively, 27, four, four, and two patients. Most metastases with peripheral enhancement and progressive fill-in were heterogeneous on T2-weighted images and were without globular peripheral enhancement. CONCLUSION: Hepatic metastases of neuroendocrine tumors had a typical hypervascular pattern in 73% of patients. Hepatic arterial phase and fast spin-echo T2-weighed sequences are the most sensitive.

Metastatic Ewing sarcoma/PNET of bone at diagnosis: prognostic factors--a report from Saudi Arabia.

BACKGROUND: To evaluate outcome and prognostic factors in Saudi Arabian patients with metastatic Ewing sarcoma and PNET of bone (PMES) at diagnosis. PROCEDURE: Ninety-nine of 304 (33%) consecutive patients with Ewing sarcoma and PNET of bone registered at our centre from 1975 to 1998, had metastatic disease at registration and 93 were available for analysis. The maximum x-axis diameter of the primary tumor was used as the measure of primary tumor size. Usually a trial of systemic treatment was undertaken before a decision was made on local treatment. Standard chemotherapy regimens were used in all treated patients. Forty-one (44%) patients did not receive radical local treatment due to an inadequate response to chemotherapy, or a decision not to undertake more than palliative treatment. Radical treatment of the primary site was radiation alone 41 (79%), resection alone 7 (13%), and resection and radiation 4 (8%). RESULTS: The 5-year survival rates were 9% for all 93 evaluable patients, 16% for 52 patients who received chemotherapy and radical local treatment, 0% for 41 patients who received lesser treatment, 19% for 43 patients with lung metastases alone, and 0% (P = 0.002) for 50 patients with other sites involved. For 60 patients with imaging data, 5-year survivals were 34 and 0% when the maximum transverse diameter of the primary tumor was < 10 cm (N = 20) and > or = 10 cm (N = 40), respectively. CONCLUSIONS: Small primary tumor size and the presence of lung metastases alone were the only significant favorable prognostic factors. Earlier diagnosis will be the basis for better results.

Distant metastases from sinonasal cancer.

Distant metastases from sinonasal malignancy are generally a rare event except in the terminal stages of the diseases and many patients die from recurrence before the secondaries become clinically manifest. Sinonasal neoplasia covers a diverse range of pathologies, some of which have a greater tendency to spread than others, in particular adenoid cystic carcinoma, malignant melanoma and some of the sarcomas. Notwithstanding this, the frequency with which systemic metastases occurs is such that screening at presentation could not be regarded as cost-effective and is consequently only instituted in the presence of specific symptoms.

Teratoid carcinosarcoma of the ovary with prominent neuroectodermal differentiation.

We present what we believe to be only the second report of ovarian teratoid carcinosarcoma. The patient, a 59-year-old woman, was admitted to hospital complaining of a pelvic mass and of abdominal fullness. Advanced ovarian cancer was diagnosed, and a tumorectomy was done. The tumor occupied the pelvis, and metastasis was found in the liver and spleen. The solid tumor was composed of chondrosarcoma, squamous cell carcinoma, adenocarcinoma and malignant neuroectodermal components, which contained ganglioneuroblastoma-like and medulloepithelioma-like areas. Immunohistochemically, the neuroectodermal cells were positive for both neural and epithelial markers. This ovarian tumor consisted of frankly malignant components, with prominent neuroectodermal elements mixed with epithelial and mesenchymal elements in an organoid fashion; a quite rare tumor.

[Surgical resection of recurrent pulmonary metastases]. / Resección quirúrgica de metástasis pulmonares de repetición.

The lung is a common site of metastasis. Resectability seems to be the only prognostic factor acknowledged in the literature. Other variables, such as time until tumoral reproduction, duration of the disease-free period, number of metastases and ganglia involvement are not grounds for ruling out surgery. Between February 1996 and January 1998 we operated on 45 patients with pulmonary metastasis, 16 of whom underwent surgery for the same reason more than once. The total number of chest operations in the study group was 42. Retrospectively, we studied all patients undergoing chest surgery more than once, with histologically confirmed resection of pulmonary metastases. One hundred twenty-five metastases (7.8 metastases/patient) were resected. We recorded 3 cases of persistent air leaks that stopped after aspiration through chest tubes was continued. No postoperative (1 to 30 days) mortality was observed. Repetition of pulmonary metastasis should not by itself be considered a reason for ruling out surgery.

Ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosou rea hydrochloride.

We report on the toxicity, intrathecal pharmacokinetics, and therapeutic effect of the ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea hydrochloride (ACNU) against the subarachnoid dissemination of primary central nervous system tumors. Fifteen patients received ventriculolumbar perfusion of ACNU. One was treated with ventriculolumbar perfusion of ACNU alone, and the others underwent concomitant systemic chemotherapy; three of these patients received irradiation as well. ACNU was administered at an initial dose of 0.5 and was increased to 1.5 to 10.0 mg in six patients. Because of a lack of Level 2 or greater toxicity, the subsequent seven patients received 8.7 to 10.0 mg of ACNU dissolved in artificial cerebrospinal fluid (CSF) at a concentration of 0.1 mg/ml, from the start of the treatment. During ACNU administration, the lumbar CSF was drained at approximately the same rate as that of the infusion. Twelve patients received from 3 to 42 courses (average, 14 courses). The cumulative dose of ACNU ranged from 5 to 330.4 mg (average, 82.9 mg). One patient had a convulsion; two patients experienced transient headache, nausea, and vomiting; two others reported transient headache, nausea, vomiting, and fecal incontinence; and one experienced transient nausea, vomiting, and fecal incontinence. No side effects were noted in the other nine patients. When 9.0 to 9.5 mg of ACNU, dissolved in 90 to 95 ml of artificial CSF, was administered for 37 to 52 min, the maximum concentration of ACNU in the lumbar CSF was 9.86 to 12.79 micrograms/ml and the area under the drug concentration-time curve was 260.8 to 502.5 micrograms.min/ml.(ABSTRACT TRUNCATED AT 250 WORDS)