Cancers, Volume 4, Issue 1 (March 2012) – 21 articles , Pages 1-322

For many thoracic malignancies, surgery, when feasible, is the preferred upfront modality for local control. However, adjuvant radiation plays an important role in minimizing the risk of locoregional recurrence. Tumors in the thoracic category include certain subgroups of non-small cell lung cancer (NSCLC) as well as thymic malignancies. The indications, radiation doses, and treatment fields vary amongst subtypes of thoracic tumors, as does the level of data supporting the use of radiation. For example, in the setting of NSCLC, postoperative radiation is typically reserved for close/positive margins or N2/N3 disease, although such diseases as superior sulcus tumors present unique cases in which the role of neoadjuvant vs. adjuvant treatment is still being elucidated. In contrast, for thymic malignancies, postoperative radiation therapy is often used for initially resected Masaoka stage III or higher disease, with its use for stage II disease remaining controversial. This review provides an overview of postoperative radiation therapy for thoracic tumors, with a separate focus on superior sulcus tumors and thymoma, including a discussion of acceptable radiation approaches and an assessment of the current controversies involved in its use. Full article

Desmoid tumors are benign soft tissue tumors associated with locally aggressive growth and high rates of morbidity, but they do not metastasize via lymphatic or hematogenous routes. While most of the data on desmoid tumors originates in the adult literature, many of the findings have been applied to the management of pediatric patients. This article discusses the epidemiology, etiology, clinical presentation, pathology, and treatment of this rare tumor in the pediatric population and includes a literature review of the most recent large series of pediatric patients with desmoid tumors. Full article

The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro, in vivo and human tumor specimen. Expression of EMT markers was analyzed using immunohistochemistry and real-time PCR. For in vitro studies, BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail, and cell aggregation assays were performed. To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor cell proliferation and apoptosis. Snail and Twist was expressed in 61 % and 64% of PNETs. This was associated with loss of E-cadherin. RT-PCR revealed conservation of the EMT markers Slug and Snail in BON-1 cells. Transfection with siRNA against Slug was associated with upregulation of E-cadherin, enhanced cell-cell adhesion and inhibition of cell proliferation. Snail-inhibition in vivo by PEG was associated with increased apoptosis, decreased tumor cell proliferation and dramatic reduced tumor volume in Rip1Tag2 mice. The presented data show that EMT plays a key role in tumorgenesis of PNETs. The activation of Snail in a considerable subset of human PNETs and the successful effect of Snail inhibition by PEG in islet cell tumors of transgenic mice provides first evidence of Snail as a drug target in PNETs. Full article

Despite the therapeutic advances in neuro-oncology, most patients with glioblastoma ultimately experience local progression/relapse. Re-irradiation has been poorly viewed in the past, mainly due to the overestimated risk of side effects using conventional radiotherapy. To date, thanks to the improvement of several delivery techniques, together with improved imaging capabilities, re-irradiation is a viable salvage treatment option to manage such clinical scenario. A literature overview on the feasibility and efficacy of the different irradiation modalities for recurrent glioblastoma along with considerations on areas of improvement are provided. Full article

We retrospectively evaluated the usefulness of combined measurement of L-methyl-[¹¹C]methionine (MET) and 3'-deoxy-3'-[¹⁸F]fluorothymidine (FLT) positron emission tomography (PET) in the differential diagnosis between recurrent gliomas and necrotic lesions. Twenty-one patients with high-grade glioma, previously treated with surgery and radiotherapy with chemotherapy and first radiological suspicion of recurrence were enrolled. The uptake was assessed by the maximum standardized uptake value (SUVmax) and lesion-to-normal tissue count density ratio (L/N ratio). Of the 21 lesions, 15 were diagnosed recurrent gliomas and six were necrotic lesions. The average SUVmax was not significantly different between recurrent gliomas and necrotic lesions on either MET-PET or FLT-PET. The average L/N ratio of recurrent gliomas (3.36 ± 1.06) was significantly higher than that of necrotic lesions (2.18 ± 0.66) on MET-PET (p < 0.01) and the average L/N ratio of recurrent gliomas (7.01 ± 2.26) was also significantly higher than that of necrotic lesions (4.60 ± 1.23) on FLT-PET (p < 0.01). ROC curve analysis showed that the areas under the curves were high but not different between MET- and FLT-PET. PET studies using MET and FLT are useful in the differentiation of recurrent glioma from treatment-induced necrotic lesion. However, there is no complementary information in the differentiation with simultaneous measurements of MET- and FLT-PET. Full article

In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context. Full article

Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8⁺ cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4⁺ T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy. Full article

We report here a review of the current medical literature on pregnancy associated desmoids, including 10 cases of our own. The pertinent findings are that a large percentage of desmoids in females arise in and around pregnancy. Most occur in the abdominal muscles, particularly the right rectus abdominus, perhaps related to trauma from abdominal stretching and fetal movement. While these tumors may regress spontaneously after delivery most can be surgically resected with low recurrence rates even with R1 resections and this is clearly the treatment of choice. Subsequent pregnancies do not appear to result in recurrence in either FAP or non FAP patients. It is not clear from currently available data whether pregnancy associated desmoids are molecularly distinct from other desmoids. Full article

Transcatheter methods such as transcatheter arterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have an important role in the treatment for advanced hepatocellular carcinoma (HCC). Recently, sorafenib, an inhibitor of tyrosine kinases, has been found to obtain survival benefits in patients with HCC, leading to major advances in the treatment of advanced HCC. However, it is associated with a low tumor response rate, minimal survival advantage, and high rates of adverse events. On the other hand, high rates of objective treatment response with HAIC for advanced HCC have been reported, although convincing evidence of it contributing to overall survival in HAIC has been lacking. In Japan, HAIC still tends to be the preferred method for the treatment of advanced HCC, even in patients with poor liver function. However, the choice of chemotherapeutic agents in TACE/HAIC for HCC varies between institutions. In this review, based on studies reported to date in the literature, we refer to current knowledge regarding the chemotherapeutic agents used for TACE/HAIC for HCC in Japan and consider the future perspectives for HAIC for this cancer. Full article

The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis, with one interesting subgroup defined as secondary IBC where pathologically identifiable IBC appears after surgical treatment of a primary non-inflammatory breast cancer. One possible mechanism can be related to the stimulation of dormant micrometastasis through local angiogenesis occurring as part of posttraumatic healing. In this report, we review cases of secondary IBC and others where localized trauma was followed by the appearance of IBC at the traumatized site that have been identified by our IBC Registry (IBCR) and hypothesize that angiogenesis appearing as part of the healing process could act as an accelerant to an otherwise latent breast malignancy. It is therefore possible that secondary IBC can be used as a model to support local angiogenesis as an important contributor to the development of an aggressive cancer. Full article

The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio) during routine follow-up in the years 2000–2009. CgA showed a higher sensitivity for midgut (68%) than pancreatic (54%) NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs. Full article

The majority of gastrinomas causing Zollinger-Ellison syndrome (ZES) are located in the duodenum or the pancreas. Primary hepatic gastrinomas (PHG) are extremely rare and difficult to diagnose because the liver is the commonest site of metastatic disease and gastrinomas can be very small. Furthermore, gastrinomas are typically slow-growing thus a missed, occult primary tumour may not become evident for many years. The diagnosis of PHG is therefore dependent on a careful search for a primary and long-term biochemical follow-up following curative hepatic resection. We report a case of a 7 cm PHG in a 48 year old man with ZES. Preoperatively, both a basal and stimulated gastrin levels were elevated. Surgical exploration including intraoperative ultrasound and duodenotomy, failed to reveal a primary. Patient underwent a right hepatectomy. Yearly, gastrin and secretin stimulation tests remain normal 6 years following surgery. He remains symptom free off all medication. An additional 26 cases of PHG were found. Including this case, 21 had at least 1 year follow-up, however only eight had greater than 5 years (median 24 months). Post-op gastrin levels were reported in 25, however provocative testing was done in only 10. Persistence and recurrence occurred in one and four, respectively. PHG causing ZES is extremely rare. Although the current literature claims to include 26 additional cases of PHG, without a thorough search for the primary and long-term follow-up data including provocative testing, this diagnosis remains a challenge. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Advanced intra-abdominal desmoids tumors present with severe symptoms, complications or rapid growth, which lead to adverse outcomes. Our aim was to evaluate the treatment and outcome of patients with advanced intra-abdominal desmoids tumors, and develop guidelines for surgical management of these patients. We reviewed the clinical courses of 21 adult patients with advanced stage intra-abdominal desmoid tumors who presented to an intestinal rehabilitation and transplantation program. Patients with massive intestinal resection presented in two groups. The first group had a short small intestinal remnant after resection ( < 60 cm). These patients were poor rehabilitation candidates and eventually met criteria for transplant. The second had longer intestinal remnants and were more successfully rehabilitated and have not had complications that would lead to transplantation. Advanced intra-abdominal desmoid tumors have outcomes after resection that merit aggressive resection and planned intestinal rehabilitation and intestinal transplantation as indicated. Full article

The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combinations of exocrine and neuroendocrine components, ranging from adenomas or carcinomas with interspersed neuroendocrine cells at one extreme to classical neuroendocrine tumors with a focal exocrine component at the other. In addition, both exocrine and neuroendocrine components can have different morphological features ranging, for the former, from adenomas to adenocarcinomas with different degrees of differentiation and, for the latter, from well differentiated to poorly differentiated neuroendocrine tumors. However, although this range of combinations of neuroendocrine and exocrine components is frequently observed in routine practice, mixed exocrine-neuroendocrine carcinomas, now renamed as mixed adenoneuroendocrine carcinomas (MANECs), are rare; these are, by definition, neoplasms in which each component represents at least 30% of the lesion. Gastrointestinal MANECs can be stratified in different prognostic categories according to the grade of malignancy of each component. The present paper is an overview of the main clinicopathological, morphological, immunohistochemical and molecular features of this specific rare tumor type. Full article

Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21⁺ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response. Full article