Concept: Neuroendocrine tumor
PURPOSE: Pasireotide (SOM230), a novel multireceptor ligand somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst1-3, 5). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics profiles of pasireotide long-acting release (LAR) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor (GEP NET) refractory to other SSAs. METHODS: In this randomized, multicenter, open-label, phase II study, patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were randomly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20, 40, or 60 mg once every 28 days for 3 months. RESULTS: Forty-two patients received pasireotide LAR. Adverse events were reported by 34 (81 %) patients, with the most frequently reported including diarrhea, fatigue, abdominal pain, and nausea. Mean fasting glucose levels were increased compared with baseline at all points throughout the study. After the third injection of pasireotide LAR, the median trough plasma concentrations on day 84 were 4.82, 12.0, and 19.7 ng/mL in the 20-, 40-, and 60-mg treatment groups, respectively. Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections (accumulation ratios were approximately 1 from all dose levels). CONCLUSIONS: This study demonstrated that a new, once-monthly, intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET. Steady state levels of plasma pasireotide were achieved after three injections.
Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ((177)Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either (177)Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ((177)Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the (177)Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the (177)Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the (177)Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the (177)Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with (177)Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the (177)Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
Takotsubo cardiomyopathy is seen, though rarely, in anaphylaxis treated with epinephrine. Stress cardiomyopathy is most likely to occur in middle-aged women. The underlying etiology is believed to be related to catecholamine release in periods of intense stress. Catecholamines administered exogenously, and those secreted by neuroendocrine tumors (e.g., pheochromocytoma) or during anaphylaxis have been reported to cause apical ballooning syndrome, or takotsubo syndrome. However, reverse takotsubo stress cardiomyopathy is rarely seen or reported in anaphylaxis treated with epinephrine.
Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET.
Aim: The aim of this study is to ascertain the high somatostatin receptor (SSTR) uptake in spleen and to compare the uptake in spleen and splenosis using SSTR PET/CT using( 68)Ga-DOTATOC. Materials and Methods: SUV(max) of spleen on (68)Ga-DOTATOC SSTR PET/CT (acquired for initial staging) in 10 patients with known neuroendocrine neoplasm of pancreatic tail was analyzed. All patients underwent left pancreatectomy and splenectomy. Diagnosis of splenosis was confirmed on CT, and SUV(max) was noted on follow-up SSTR PET/CT. Results: SUV(max)was 28.8 ± 12.5 in normal spleen and 10.5 ± 4.3 in splenosis. Conclusion: The high uptake of( 68)Ga-DOTATOC (which has a high affinity to SSTR 2) in the spleen as compared to splenosis, which has a different histology, suggests white pulp as the probable site of high SSTR 2 expression.
BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine cancer of the skin. The utility of CD99 (MIC-2) in the diagnosis of MCC has been previously studied, with reported rates of expression ranging from 13 to 55%. When specified, a membranous or cytoplasmic staining pattern was considered significant. Recent studies of CD99 have identified a paranuclear dot-like expression pattern in certain non-neuroendocrine pancreatic and colonic lesions. We recently noted paranuclear dot-like staining in several cases of MCC, including cases lacking cytokeratin 20 (CK20) expression. METHODS: Fourteen cases of MCC were stained with CK20 and CD99 antibody, and the pattern and intensity of staining were recorded. Seven cases of pulmonary small cell carcinoma (PSCC) and one case of primitive neuroectodermal tumor (PNET) were used for comparison. RESULTS: All 14 cases of MCC showed at least focal CD99 staining, with both membranous and paranuclear dot-like staining patterns identified. CK20 staining was present in 12/14 cases, with the characteristic dot-like pattern identified. Four of seven cases of PSCC showed CD99 staining, with two showing a finely granular dot-like staining pattern. CONCLUSIONS: We report an unusual pattern of paranuclear dot-like expression of CD99 in 14 cases of MCC, two of which did not express CK20. This previously unrecognized expression pattern may be of use in differentiating MCC from other cutaneous malignancies, especially when CK20 expression is limited or absent.
Octreotide and everolimus have demonstrated efficacy in neuroendocrine tumors. Pasireotide is a somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate the safety and feasibility of combining pasireotide with everolimus in patients with advanced neuroendocrine tumors. Cohorts of patients with advanced neuroendocrine tumors were treated with escalating doses of pasireotide (600-1200 μg s.c. b.i.d., followed by pasireotide LAR 40-60 mg i.m. monthly) and everolimus (5-10 mg daily). Twenty-one patients were treated. Dose-limiting toxicities consisting of grade 3 rash and grade 3 diarrhea were observed. Twelve patients were safely treated at the maximum protocol-defined dose level of pasireotide LAR 60 mg i.m. monthly and everolimus 10 mg daily. Hyperglycemia was common; other observed toxicities were consistent with the known toxicities of either agent alone. Partial tumor response was observed in one patient; 17 (81%) patients experienced at least some tumor regression as their best response to therapy. In conclusion, pasireotide LAR 60 mg i.m. monthly in combination with everolimus 10 mg daily is feasible and associated with preliminary evidence of antitumor activity in patients with advanced neuroendocrine tumors. Further studies evaluating this combination are warranted.
Primary ovarian carcinoids and metastatic tumors share similar morphologic features. Metastatic carcinoids must be excluded from primary ones for prognostic and therapeutic reasons. Gastrointestinal neuroendocrine (carcinoid) tumors are much more common with the majority arising from small intestine and appendix. The aim of this study is to evaluate the role of immunohistochemistry for CDX2 in differentiating primary ovarian from metastatic carcinoids of primary gastrointestinal origin. Thirty primary pure ovarian carcinoids, 16 primary ovarian carcinoids arising in association with benign teratomas, 10 ovarian carcinoids metastatic from primary gastrointestinal tract and 70 gastrointestinal neuroendocrine tumors were studied for the expression of CDX2 by immunohistochemistry. CDX2 expression revealed that 40 (57.1%) of 70 cases of gastrointestinal carcinoids and 9 (90%) of 10 ovarian metastatic carcinoids showed positive nuclear staining (diffuse or focal). On the other hand, 3 (18.8%) of 16 primary carcinoids with teratomatous elements showed weak positivity. Among the 70 gastrointestinal carcinoids, CDX2 was positive in 38 (90.5%) of 42 cases in the duodenum, small intestine, appendix, and only in 2 (11.8%) of 17 cases of colorectal carcinoids and none of the 11 cases in the stomach. It is concluded that CDX2 may be a useful marker to distinguish primary ovarian carcinoid from metastasis from small intestinal and appendiceal neuroendocrine tumors.
Appendiceal neuroendocrine neoplasms (NENs) are rare and usually incidentally discovered. Most cases are clinically indolent, although the rare aggressive ones are poorly predictable. The aim of this study was to test the applicability and prognostic significance of the new World Health Organization (WHO) classification and to test the several pathologic features and TNM staging systems (American Joint Committee on Cancer and European Neuroendocrine Tumor Society) in these tumors. A multi-institutional retrospective series of 138 appendiceal NENs was selected on the basis of the availability of both pathologic material and clinical information, including follow-up data. All cases were reviewed to record pathologic features and to apply year 2000 and 2010 WHO classifications, as well as European Neuroendocrine Tumor Society and American Joint Committee on Cancer TNM stages. Clinical and pathologic characteristics were compared with disease outcome by contingency, univariate, and multivariate survival analyses. Although up to one third of cases presented several malignancy-associated pathologic features, only 4 patients died of the disease. Adverse outcome was significantly associated with extramural extension (including mesoappendix), well-differentiated carcinoma diagnosis (2000 WHO classification), pT3-4 stage, older age, and presence of positive resection margins, but not with tumor size, mitotic or proliferative indexes, and, consequently, 2010 WHO grading. In the appendix, at variance with midgut/hindgut NENs, the 2000 WHO classification performs better than the grading-based 2010 WHO scheme and, together with tumor stage, is the most relevant parameter associated with clinical aggressiveness.
Neuroendocrine tumors (NET) encompass a heterogeneous group of tumors demonstrating varied clinical behavior. The field has recently witnessed several important developments stemming from improvements in histopathological classification schemes, advanced imaging techniques, and a deeper understanding of the molecular mechanisms underlying tumor progression (in both sporadic and hereditary cancers). Platinum-based chemotherapy remains the mainstay of therapy for high grade carcinomas. In contrast, the treatment of advanced well-differentiated NET depends on site of origin, underlying tumor biology, and whether or not the patient is symptomatic. Somatostatin analogs continue to play a key role in controlling hormone-mediated symptoms. In addition, octreotide has demonstrated anti-tumor activity in midgut carcinoids. Novel somatostatin analogs (for use alone or in the context of peptide receptor radiotherapy or imaging) are on the horizon. Agents targeting VEGF- and mTOR-pathway signaling have been approved for pancreatic neuroendocrine tumors. In addition, two RET inhibitors have been approved for medullary thyroid cancer, evidence for a fundamentally new treatment paradigm (based on the use of targeted agents). Despite the advances, there remains a serious unmet need for additional treatment options for refractory high-grade neuroendocrine carcinomas, paragangliomas/pheochromocytomas, adrenocortical carcinomas, and progressive carcinoid tumors. Furthermore, the role of liver-directed therapy in the context of available systemic approaches needs clarification. Steady progress is anticipated, however, given the unprecedented number of ongoing clinical trials related to NET (including studies focused on symptom control, genetics, imaging, and novel therapies).