Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC.

All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded.

253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS>> 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72).

We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.

Chromogranin A (CgA) is a well-established marker for diagnosis and follow up of patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Recently, it has been shown that plasma levels of CgA correlate with tumor load and predict survival of patients with NEN of the small bowel. It is assumed that this is as well valid for NEN of the colon and rectum, however, this is not supported by data. To evaluate this assumption, we analyzed 62 patients with NEN of the colon and rectum listed in the Marburg GEP-NEN registry for clinicopathological characteristics, expression and plasma levels of CgA. The present study demonstrates that immunohistochemical CgA and synaptophysin are good markers for histological diagnosis in patients with NEN of the colon and rectum. However, plasma CgA is a poor marker to follow-up these patients because only a minority exhibited increased levels which did not increase significantly during tumor progression. In contrast to NEN of the small bowel, there is no correlation of CgA plasma levels with tumor burden or survival. Patients with NEN of the colon and rectum displayed a relatively good prognosis resulting in a median survival of 8.5 years. However, a subset of patients affected by G3 neoplasms, exhibited a poorer prognosis with a median survival of 2.5 years. Taken together, CgA is a valuable marker for immunohistochemical diagnosis, but CgA plasma concentration is not suitable to mirror tumor burden or prognosis in patients with NEN of the colon and rectum.

We review the imaging findings of pediatric gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using contemporary anatomic and molecular imaging techniques. A low index of suspicion can result in significant delays in diagnosis of pediatric GEP-NETs. A multimodality imaging approach, using both anatomic and functional imaging, is essential in the diagnosis, staging, and surveillance of these potentially malignant tumors.

Gastroenteropancreatic (GEP) neuroendocrine neoplasms can be broadly separated into well- and poorly differentiated categories. Tumours within each category have similarities in morphology and immunophenotype, but vary in grade, behaviour, molecular signature and responses to therapy. The aetiology of these differences is multifactorial. Site of origin, mucosal milieu and hereditary influences are some of the currently known factors. Given these differences, staging and grading systems continue to evolve, and the most recent World Health Organization classification of pancreatic neuroendocrine neoplasms reflects this by introducing a grade 3 neuroendocrine tumour category for morphologically well-differentiated tumours with an elevated Ki-67 proliferation index and/or mitotic count. This review aims to highlight current classification guidelines with discussion of unique site-specific features of selected GEP neuroendocrine neoplasms and an emphasis on practical issues related to daily reporting.

Histone deacetylase inhibitors (HDACi) are novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with multiple myeloma (MM). Although HDACi have demonstrable synergy when combined with proteasome inhibitors (PIs), recent evidence indicates that combination of HDACi and PI is beneficial only in a subset of patients with advanced MM, clearly indicating that other rational combinations should be explored. In this context we hypothesized that understanding the molecular signature associated with inherent resistance to HDACi would provide a basis for the identification of therapeutic combinations with improved clinical efficacy. Using human myeloma cell lines (HMCL) categorized as sensitive, intermediate or resistant to HDACi, gene expression profiling (GEP) and gene ontology enrichment analyses were performed to determine if a genetic signature associated with inherent resistance to HDACi-resistance could be identified. Correlation of GEP to increasing or decreasing sensitivity to HDACi indicated a unique 35-gene signature that was significantly enriched for two pathways - regulation of actin cytoskeleton and protein processing in endoplasmic reticulum. When HMCL and primary MM samples were treated with a combination of HDACi and agents targeting the signaling pathways integral to the actin cytoskeleton, synergistic cell death was observed in all instances, thus providing a rationale for combining these agents with HDACi for the treatment of MM to overcome resistance. This report validates a molecular approach for the identification of HDACi partner drugs and provides an experimental framework for the identification of novel therapeutic combinations for anti-MM treatment.

In the 2010 WHO classification, a Ki-67 proliferation index of 20% is the cut-off between intermediate-grade and high-grade gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN). However, in clinical practice, tumours with a Ki-67 index of >15% are often considered high grade and treated with chemotherapy. In 40-70% of high-grade NENs, somatostatin receptors are overexpressed, enabling peptide receptor radionuclide therapy (PRRT) to be performed. We investigated the role of PRRT with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index.

A total of 33 patients with advanced GEP-NENs, positive somatostatin receptor imaging (SRI+) and a Ki-67 proliferation index ranging from 15% to 70% were treated with Lu-PRRT. A cumulative activity of 18.5 GBq or 27.8 GBq of 177Lu-DOTATATE was administered in four or five cycles. Receiver operating characteristic (ROC) curve analysis was used to determine the best threshold of Ki-67 expression to predict disease progression.

All patients completed the intended treatment. The median follow-up was 43 months (range 3-69 months). Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%. The median progression-free survival (PFS) was 23 months (95% CI 14.9-31.0 months) and the median overall survival was 52.9 months (95% CI 17.1-68.9 months). ROC curve analysis at 23 months revealed that the best Ki-67 index cut-off was 35%. In 23 patients (70%) the Ki-67 index was ≤35% and in 10 patients (30%) the Ki-67 index was in the range 36-70%. The DCR in the former group was 87% and 30% in the latter. The median PFS was 26.3 months (95% CI 18.4-37.7 months) and 6.8 months (95% CI 2.1-27 months), respectively (p = 0.005).

Lu-PRRT showed antitumour activity in SRI+ GEP-NENs of intermediate and high-grade. DCR and PFS were significantly better in patients with a Ki-67 index of ≤35% than in those with a Ki-67 index of >35%. On the basis of these results, PRRT should be considered as a therapeutic option in patients with high-grade SRI+ GEP-NENs, in particular those with a Ki-67 proliferation index of ≤35%.

BACKGROUND

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common type of neuroendocrine tumors, accounting for more than half of neuroendocrine neoplasms (NENs). We performed a retrospective study in our center to investigate the clinicopathological features, risk factors of metastasis, and prognosis of GEP-NENs in a Chinese population.

METHODS

Four hundred forty patients with GEP-NENs treated at the First Affiliated Hospital of Zhengzhou University between January 2011 and March 2016 were analyzed retrospectively. Multivariate logistic regression was performed to identify independent risk factors for metastasis of the tumors. The Kaplan-Meier method was used for survival analysis, and log-rank tests for comparisons among groups.

RESULTS

Primary sites were the stomach (24.3%), rectum (24.1%), pancreas (20.5%), esophagus (12.3%), unknown primary origin (UPO-NEN) (8.0%), duodenum (6.1%). Three hundred eighty-nine of the 440 GEP-NENs cases (88.4%) were non-functional tumors, and patients had non-specific symptoms, which could have led to delay in diagnosis and treatment. Neuroendocrine tumor, neuroendocrine carcinoma, and mixed adenoendocrine carcinoma were 56.8%, 33.2% and 3.2%, respectively, of the cases. One hundred thirty (29.5%) of the tumors were G1, 120 (27.3%) G2, and 190 (43.2%) G3. The immunohistochemical positive rate of synaptophysin was 97.7% and of chromogranin 48.7%. Logistic regression analysis revealed that the diameter and pathological classification of tumors were the most important predictors for metastasis. The median survival time was 34 months for patients with well-differentiated neuroendocrine tumors grade G3 and 11 months for poorly differentiated neuroendocrine carcinoma. The median survival time of patients with localized disease, regional disease, and distant disease was 36 months, 15 month, and 6 months, respectively.

CONCLUSIONS

This study constitutes a comprehensive analysis of the clinicopathological features of GEP-NENs in a Chinese population. GEP-NENs may occur at any part of the digestive system. The diameter and pathological classification of tumor are the most important predictors for metastasis. The prognosis is poor for patients with poorly differentiated neuroendocrine cancers and distant metastases.

BACKGROUND

The combination of radiopeptide therapy [peptide receptor radionuclide therapy (PRRT)] with radiosensitizing chemotherapy of gastroenteropancreatic neuroendocrine tumors (GEP NETs) may improve efficacy, but has the potential to increase myelotoxicity. In a prospective clinical study of GEP NET patients treated with (177)Lu-octreotate PRRT in combination with capecitabine and temozolomide, as a prelude to a planned Australasian Gastro-Intestinal Trials Group (AGITG) international randomized controlled trial, we characterized the incidence and degree of hematological toxicity.

METHODS

Well-differentiated progressive metastatic GEP NETs in 65 patients were treated with 4 cycles of 7.8 GBq (177)Lu-octreotate, 1,650 mg/m(2) capecitabine (n = 28) and 1,500 mg/m(2) capecitabine with 200 mg/m(2) temozolomide (n = 37), and monitored for hematological toxicity over a 5-year period.

RESULTS

Short-term, self-limited hematological toxicity grade 3/4 comprised anemia in 1 patient (3.5%) in the 28 patient-cohort of patients treated with (177)Lu-octreotate and capecitabine. One of these patients (3.5%) later developed significant anemia and one developed thrombocytopenia (3.5%) over a median follow-up of 60 months (SD 20). The incidence of short-term grade 3/4 reversible myelosuppression in 37 patients after (177)Lu-octreotate/capecitabine/temozolomide was zero. Long- term follow-up for a median of 36 months (SD 11) showed significant thrombocytopenia in 2.7% and neutropenia in 2.7% of the patients and anemia in 10.8% of the patients (n = 4). The 3-year median hemoglobin and platelet and neutrophil counts trended downwards, but remained within normal ranges. Two patients in this cohort developed myelodysplastic syndrome.

CONCLUSIONS

The modest reversible hematological toxicity of PRRT of GEP NETs is not significantly increased by the addition of radiosensitizing chemotherapy with capecitabine and temozolomide in combination with (177)Lu-octreotate, which has the potential to enhance the efficacy of radiopeptide therapy.

BACKGROUND

Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive tumors. Their molecular pathogenesis is still largely unknown, and consequently, the best therapeutic management also remains to be determined. We conducted a systematic review on molecular alterations found in gastroenteropancreatic NECs (GEP-NECs) and discuss potential applications of targeted therapies in setting.

METHODS

Systematic review of studies about molecular features in tumor tissues of patients with GEP-NECs. The Medline, Lilacs, Embase, Cochrane, Scopus and Opengrey databases were sought, without time, study design or language restrictions.

RESULTS

Of the 1.564 studies retrieved, 41 were eligible: 33 were retrospective studies and eight were case reports. The studies spanned the years 1997-2017 and involved mostly colorectal, stomach and pancreas primary tumors. Molecular alterations in the TP53 gene and the p53 protein expression were the most commonly observed, regardless of the primary site. Other consistently found molecular alterations were microsatellite instability (MSI) in approximately 10% of gastric and colorectal NEC, and altered signaling cascades of p16/Rb/cyclin D1, Hedgehog and Notch pathways, and somatic mutations in KRAS, BRAF, RB1 and Bcl2. In studies of mixed adeno-neuroendocrine carcinomas (MANECs) the molecular features of GEP-NEC largely resemble their carcinoma/adenocarcinomas tumor counterparts.

CONCLUSIONS

Despite the paucity of data about the molecular drivers associated with GEP-NEC, some alterations may be potentially targeted with new cancer-directed therapies. Collaborative clinical trials for patients with advanced GEP-NEC are urgently needed.

The purpose of this study was to assess the value of the spatial heterogeneity of somatostatin receptor (SSR) volume, quantified as asphericity (ASP), and to predict response to peptide receptor radionuclide therapy (PRRT) in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN).

From June 2011 to May 2013, patients suffering from GEP-NEN who underwent pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®) prior to [177Lu-DOTA0-Tyr3]octreotate ([177Lu]DOTATATE)-PRRT were enrolled in this retrospective evaluation. SSR expression in 20 NEN patients was qualitatively and quantitatively assessed using the Krenning score, the metastasis to liver uptake ratio (M/L ratio), and ASP at baseline. Response to PRRT was evaluated based on lesions, which were classified as responding lesions (RL) and non-responding lesions (NRL) after 4- and 12-month follow-ups. The values of the Krenning score, M/L ratio, and ASP for response prediction were compared by using the Mann-Whitney U test, Kruskal-Wallis test, and receiver operating characteristic (ROC) curves.

Seventy-seven metastases (liver, n = 40; lymph node, n = 24; bone, n = 11; pancreas, n = 2) showed SSR expression. A higher ASP level was significantly associated with poorer response at both time points. ROC analyses revealed the highest area under the curve (AUC) for discrimination between RL and NRL for ASP after 4 months (AUC 0.97; p = 0.019) and after 12 months (AUC 0.96; p < 0.001), followed by the Krenning score (AUC 0.74; p = 0.082 and AUC 0.85; p < 0.001, respectively) and M/L ratio (AUC 0.77; p = 0.107 and AUC 0.82; p < 0.001). The optimal cutoff value for ASP was 5.12 % (sensitivity, 90 %; specificity, 93 %).

Asphericity of SSR-expressing lesions in pretherapeutic single-photon emission computed tomography with integrated computed tomography (SPECT/CT) is a promising parameter for predicting response to PRRT in gastroenteropancreatic neuroendocrine neoplasms.

Transforming growth factor-beta1 (TGFbeta1) plays a role in neoplastic transformation and transdifferentiation. Galpha(12) and Galpha(13), referred to as the gep oncogenes, stimulate mitogenic pathways. Nonetheless, no information is available regarding their roles in the regulation of the TGFbeta1 gene and the molecules linking them to gene transcription. Knockdown or knockout experiments using murine embryonic fibroblasts and hepatic stellate cells indicated that a Galpha(12) and Galpha(13) deficiency reduced constitutive, auto-stimulatory or thrombin-inducible TGFbeta1 gene expression. In contrast, transfection of activated mutants of Galpha(12) and Galpha(13) enabled the knockout cells to promote TGFbeta1 induction. A promoter deletion analysis suggested that activating protein 1 (AP-1) plays a role in TGFbeta1 gene transactivation, which was corroborated by the observation that a deficiency of the G-proteins decreased the AP-1 activity, whereas their activation enhanced it. Moreover, mutation of the AP-1-binding site abrogated the ability of Galpha(12) and Galpha(13) to induce the TGFbeta1 gene. Transfection of a dominant-negative mutant of Rho or Rac, but not Cdc42, prevented gene transactivation and decreased AP-1 activity downstream of Galpha(12) and Galpha(13). In summary, Galpha(12) and Galpha(13) regulate the expression of the TGFbeta1 gene through an increase in Rho/Rac-dependent AP-1 activity, implying that the G-protein-coupled receptor (GPCR)-Galpha(12) pathway is involved in the TGFbeta1-mediated transdifferentiation process.

Lysophosphatidic acid (LPA) plays a critical role in the pathophysiology of ovarian cancers. Previous studies have shown that LPA stimulates the proliferation of ovarian cancer cells via Gα12. The present study utilizing Protein/DNA array analyses of LPA-stimulated HeyA8 cells in which the expression of Gα12 was silenced, demonstrates for the first time that Gα12-dependent mitogenic signaling by LPA involves the atypical activation cAMP-response element binding protein (CREB). Results indicate that the robust activation of CREB by LPA is an early event that can be monitored by the phosphorylation of SER133 of CREB as early as 3min. The findings that the expression of the constitutively activated mutant of Gα12 stimulates CREB even in the absence of LPA in multiple ovarian cancer cell lines confirm the direct role of Gα12 in the activation of CREB. This is further substantiated by the observation that the silencing of Gα12 drastically attenuates LPA-stimulated phosphorylation of CREB. Our results also establish that LPA-Gα12-dependent activation of CREB is through a cAMP-independent, but Ras-ERK-dependent mechanism. More significantly, our findings indicate that the expression of the dominant negative S133A mutant of CREB leads to a reduction in LPA-stimulated proliferation of HeyA8 ovarian cancer cells. Thus, results presented here demonstrate for the first time that CREB is a critical signaling node in LPA-LPAR and Gα12/gep proto-oncogene stimulated oncogenic signaling in ovarian cancer cells.

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

The INK4a/ARF locus on chromosome 9p21 is one of the important defenses against tumor development and engages both the Rb and the p53 tumor suppressor pathways through its capacity to encode two distinct proteins, p16(INK4a) and p14(ARF). Despite controversial reports, the body of present data suggests that tumor suppressors p16(INK4a) and p14(ARF) are targets of in-activation in GEP-NETs. Moreover, tumor type-specific aberrant p16(INK4a) silencing appears to be associated with advanced tumor stage and may function as a predictor of patients' outcome after surgical resection. Since conventional histological and biochemical assessment are limited with respect to predicting GEP-NET behavior or outcome, methylation profiles including INK4a/ARF might offer a tool to refine future diagnosis and therapeutic management of GEP-NET patients.

Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.

Purpose: Although somatostatin analogues (SSA) and peptide receptor radionuclide therapy (PRRT) are validated therapies in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET), it remains unclear whether SSA combined with PRRT or as maintenance therapy can provide prolonged survival compared with patients treated with PRRT alone. In this retrospective study, we aimed to investigate whether there is a survival benefit to adding SSA to PRRT as a combination therapy and/or maintenance therapy.Patients and Methods: The investigation included 168 patients with unresectable GEP-NETs treated at the University Hospital Bonn, Bonn, Germany. The patients were divided into two main groups: PRRT monotherapy (N = 81, group 1) and PRRT plus SSA (N = 87, group 2) as combined therapy with PRRT and/or as maintenance therapy after PRRT.Results: Data for overall survival (OS) were available from 168 patients, of whom 160 had data for progression-free survival (PFS). The median PFS was 27 months in group 1 versus 48 months in group 2 (P = 0.012). The median OS rates were 47 months in group 1 and 91 months in group 2 (P < 0.001). The death-event rates were lower in group 2 (26%) than in group 1 (63%). SSA as a combination therapy with PRRT and/or as a maintenance therapy showed a clinical benefit rate (objective response or stable disease) of 95%, which was significantly higher than group 1 (79%).Conclusions: SSA as a combination therapy and/or maintenance therapy may play a significant role in tumor control in patients with GEP-NET who underwent a PRRT. Clin Cancer Res; 24(19); 4672-9. ©2018 AACR.

Neuroendocrine neoplasms of the digestive system (GEP-NEN) represent a heterogeneous group of malignancies with various clinical presentation and prognosis. GEP-NENs can potentially affect all organs of the gastrointestinal tract; characteristically they share the biological property to produce and secrete peptides and neuroamines. About 30% of GEP-NENs are hormonally active and can cause specific clinical syndromes. The clinical presentation mainly depends on the primary site of the tumor and its functionality. Because of the wide spectrum of clinical symptoms and their misperceived rarity, diagnosis of GEP-NENs is often delayed for years and tumors are detected first in an advanced stage. Early identification of a specific hormonal syndrome can significantly impact tumor diagnosis and treatment, moreover the preoperative management of NEN hormonal release avoids potential life threatening hormonal crisis. However, GEP-NEN diagnostic work-up is challenging, it requires a multidisciplinary team and needs particular experience; standardized protocols and clinical experience are essential for a proper endocrine diagnostic work-up. In addition to the biochemical diagnostic, further radiologic and endoscopic imaging modalities are required moreover, somatostatin-receptor based functional imaging, using either Octreotide-scintigraphy or novel PET-based techniques with specific isotopes like Ga68-DOTA-octreotate, plays an important role for the detection of the primary tumor as well as for the evaluation of the tumor extent.

The aim of this study was to explore the possible involvement of the angiopoietin (Ang)-1, -2/Tie-2 system in the development, growth, and metastases evolution of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs). We prospectively examined the serum levels of Tie-2, Ang-1, and Ang-2 by ELISA in 42 patients with proven GEP-NETs and 27 controls. We also determined the expression of the Ang/Tie-2 system in freshly isolated peripheral blood monocytes and in tumor cells from malignant primary tumors and/or liver metastases samples from GEP-NET patients by flow cytometry and/or RT-PCR. Furthermore, the function of the Ang/Tie-2 system in monocytes from controls and patients was assessed by a chemotaxis assay. GEP-NET patients showed enhanced serum levels of soluble form of Tie-2 (sTie-2), Ang-1, and Ang-2 (P<0.05 in all cases), compared to controls. sTie-2 and Ang-2 levels were significantly higher in GEP-NETs with metastases compared to those with no metastases. In addition, a significant correlation was detected between Ang-2 levels and chromogranin A or sTie-2 concentrations or 5-hydroxy-indole acetic acid excretion (r=0.71, r=0.60, and r=0.81 respectively, P<0.01 in all cases). Furthermore, we observed an enhanced expression of Ang-1, Ang-2, and Tie-2 in freshly isolated tumor cells from GEP-NET both by immunohistochemistry and by RT-PCR. Interestingly, an enhanced expression and function of Tie-2 was detected in monocytes from GEP-NET patients. Our data suggest that the Ang/Tie-2 system is involved in the growth and development of metastases of GEP-NETs, and that favors the recruitment of Tie-2(+) monocytes to the tumor site, where they can promote inflammation and angiogenesis.

BACKGROUND

Carboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients.

METHODS

A tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m(2)) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy.

RESULTS

Of 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade ≥3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard.

CONCLUSIONS

Everolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens.

UNASSIGNED

NCT00936702.

Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. Since we previously demonstrated that LIG3-dependent repair is involved in the genomic instability, drug resistance and survival of MM cells, we here investigated the biological relevance of PARP1, a driver component of Alternative-Non Homologous End Joining (Alt-NHEJ) pathway, in MM. We found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by Olaparib impaired MM cells viability in vitro and was effective against in vivo xenografts of human MM. Anti-proliferative effects induced by PARP1-inhibition were correlated to increase of DNA double-strand breaks, activation of DNA Damage Response (DDR) and finally apoptosis. Importantly, by comparing a gene expression signature of PARP inhibitors (PARPi) sensitivity to our plasma cell dyscrasia (PC) gene expression profiling (GEP), we identified a subset of MM patients which could benefit from PARP inhibitors. In particular, Gene Set Enrichment Analysis (GSEA) suggested that high MYC expression correlates to PARPi sensitivity in MM. Indeed, we identified MYC as promoter of PARP1-mediated repair in MM and, consistently, we demonstrate that cytotoxic effects induced by PARP inhibition are mostly detectable on MYC-proficient MM cells. Taken together, our findings indicate that MYC-driven MM cells are addicted to PARP1 Alt-NHEJ repair, which represents therefore a druggable target in this still incurable disease.

BACKGROUND

Multiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy.

METHODS

Since HDACi and DNMTi combination have potential therapeutic value in MM, we aimed to build a GEP-based score that could be useful to design future epigenetic-targeted combination trials. In addition, we investigated the changes in GEP upon HDACi/DNMTi treatment.

RESULTS

We report a new gene expression-based score to predict MM cell sensitivity to the combination of DNMTi/HDACi. A high Combo score in MM patients identified a group with a worse overall survival but a higher sensitivity of their MM cells to DNMTi/HDACi therapy compared to a low Combo score. In addition, treatment with DNMTi/HDACi downregulated IRF4 and MYC expression and appeared to induce a mature BMPC plasma cell gene expression profile in myeloma cell lines.

CONCLUSIONS

In conclusion, we developed a score for the prediction of primary MM cell sensitivity to DNMTi/HDACi and found that this combination could be beneficial in high-risk patients by targeting proliferation and inducing maturation.

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (<em>GEP</em>)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of <em>GEP</em>70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.

EP37 family proteins are non-lens members of the betagamma-crystallin superfamily, of which expression is observed in integumental tissues of the Japanese newt, Cynops pyrrhogaster. In the present study, a gene was isolated that has high homology with ep37 and is transcribed mainly in the gastric epithelial cells and hence designated gep. The predicted amino acid sequence of the gep cDNA contains four betagamma-crystallin motifs in the N-terminal half, as is the case in the integumental EP37 proteins. Immunohistochemical analysis showed that GEP protein was mainly localized on the luminal content of the surface mucous cells of the gastric epithelium in both premetamorphic larvae and adults. In addition, GEP protein was also expressed in fundic glands after metamorphosis. Considering the fact that beta- and gamma-crystallins are evolutionarily related to stress-induced proteins, this localization suggests that GEP protein may have an evolutionarily conserved role in protection against physico-chemical stresses, such as physical abrasion and autodigestion, during assimilation.