Anja Rinke , Patrick Michl and Thomas Gress
Review: Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors
Cancers 2012, 4(1), 113-129; doi:10.3390/cancers4010113 - published online 8 February 2012
Show/Hide AbstractAbstract: Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors.

Håkan Örlefors , Anders Sundin , Barbro Eriksson , Britt Skogseid , Kjell Öberg , Göran Åkerström and Per Hellman
Article: PET-Guided Surgery — High Correlation between Positron Emission Tomography with ¹¹C-5-Hydroxytryptophane (5-HTP) and Surgical Findings in Abdominal Neuroendocrine Tumours
Cancers 2012, 4(1), 100-112; doi:10.3390/cancers4010100 - published online 8 February 2012
Show/Hide AbstractAbstract: Positron emission tomography (PET) with ¹¹C-labeled 5-hydroxytryptophane (5-HTP) is a sensitive technique to visualize neuroendocrine tumours (NETs), due to high intracellular uptake of amine-precursors like L-dihydroxyphenylalanine (L-DOPA) and 5-HTP. NETs are often small and difficult to localize in spite of overt clinical symptoms due to hormonal excess. In our study, 38 consecutive NET patients underwent ¹¹C-5-HTP-PET and morphological imaging by CT within 12 weeks prior to surgery. Surgical, histopathological and 5-HTP PET findings were correlated. ¹¹C-5-HTP-PET corresponded to the surgical findings in 31 cases, was false negative in six, and true negative in one case resulting in 83.8% sensitivity and 100% specificity. Positive predicted value was 100%. In 11 patients ¹¹C-5-HTP-PET was the only imaging method applied to localize the tumour. Thus, we could demonstrate that functional imaging by ¹¹C-5-HTP-PET in many cases adds vital preoperative diagnostic information and in more than every fourth patient was the only imaging method that will guide the surgeon in finding the NET-lesion. Although the present results demonstrates that ¹¹C-5-HTP may be used as an universal NET tracer, the sensitivity to visualize benign insulinomas and non functioning pancreatic NETs was lower.

Yoshihiro Nishida , Satoshi Tsukushi , Yoji Shido , Hiroshi Urakawa , Eisuke Arai and Naoki Ishiguro
Review: Transition of Treatment for Patients with Extra-Abdominal Desmoid Tumors: Nagoya University Modality
Cancers 2012, 4(1), 88-99; doi:10.3390/cancers4010088 - published online 7 February 2012
Show/Hide AbstractAbstract: Treatment modalities for desmoid tumors have been changed because of the high recurrence rate, even after wide resection, and some cases experience spontaneous self-regression during clinical course. The treatment modality in our institutions before 2003 was surgical resection with wide surgical margin, however, meloxicam, which is a NSAID and a selective COX-2 inhibitor has been applied consecutively since 2003. We reviewed the previously reported outcomes of surgical and conservative treatment in our institutions. Among 30 patients receiving surgical treatment, 16 (53%) recurred. Younger age ( p < 0.05) was a significant poor factor. According to RECIST for meloxicam treatment, CR was in one, PR in 10, SD in eight, PD in one evaluated at 2011. Older age ( p < 0.01) was significantly associated with good outcome for meloxicam treatment. Results of the previous study indicated that surgical treatment alone could not control desmoid tumors, even with negative surgical margin. Considering the functional impairment resulting from surgery with negative surgical margin, a conservative and effective treatment modality with fewer complications is desired. Conservative treatment with meloxicam is a promising novel modality for patients with extra-abdominal desmoid tumors.

Patrick Beauchesne
Review: Fotemustine: A Third-Generation Nitrosourea for the Treatment of Recurrent Malignant Gliomas
Cancers 2012, 4(1), 77-87; doi:10.3390/cancers4010077 - published online 1 February 2012
Show/Hide AbstractAbstract: Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas.

Tal Leibovich-Rivkin , Yosef Buganim , Hilla Solomon , Tsipi Meshel , Varda Rotter and Adit Ben-Baruch
Article: Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations
Cancers 2012, 4(1), 55-76; doi:10.3390/cancers4010055 - published online 20 January 2012
Show/Hide AbstractAbstract: Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of Ras^High/p53^Low-modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFa and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-kB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout.

Ursula Plöckinger
Review: Diagnosis and Treatment of Gastrinomas in Multiple Endocrine Neoplasia Type 1 (MEN-1)
Cancers 2012, 4(1), 39-54; doi:10.3390/cancers4010039 - published online 20 January 2012
Show/Hide AbstractAbstract: Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease. It is associated with a broad range of endocrine tumours, most frequently arising in the parathyroid glands, the pituitary and the pancreas. Most neuroendocrine tumours will be diagnosed in the pancreas as non-functioning neuroendocrine tumours or insulinomas. Forty-two percent of the patients will develop a gastrin-secreting neuroendocrine tumour, a gastrinoma. Gastrinomas in MEN-1 tend to be small, multiple and preferentially located in the duodenum. This paper will focus on the specific characteristics of gastrinomas in the setting of MEN-1 compared to sporadic gastrinomas. The developments in understanding the tumorigenesis of these tumours and the consequences for diagnosis and therapy will be discussed.