Imaging diagnosis of genitourinary tract tumors

Recent advance of imaging technique have brought great advantages for management of genitourinary tract tumors. We described few examples of changes in this field from our experience. Many asymptomatic masses are discovered in the kidney and adrenal gland associated with wide clinical application of CT and US. In the kidney, the greater part of incidental masses are renal cell carcinomas (RCC) and the rate of such cases has been increasing. When small RCC is diagnosed without any clinical symptoms, better survival would be expected. Many adrenal incidental mass are also discovered by routine use of CT for abdominal workup. Since greater part of these masses are benign nonfunctioning adenomas, correct diagnosis should be made in order to avoid inappropriate surgery. Rapid development of MR also resulted in some changes in the diagnosis of urinary tract tumors. However, MR cannot be used as a screening method. For staging of RCC, intravascular or adjacent organ invasion was well determined with MR compared with CT. Differentiation of adrenal carcinomas from nonfunctioning adenomas is suggested by the difference of signal intensity on T2 weighted images. Fast spin echo scan with GD-DTPA enhancement is new MRI technique separating bladder mucosal layer from muscle layer as hyper-intensity area. Using this method, diagnostic accuracy of deep muscle invasion for bladder tumor would be improved.     

Rare and unusual tumors of the genitourinary tract.

The entity of small cell undifferentiated carcinoma of the urinary tract is clearly recognized, though treatment still poses considerable difficulties. Small cell undifferentiated carcinoma may lead to systemic symptoms by hormone production, even in patients with localized tumors. The survival rates of adults with Wilms' tumor approach only 50% of those seen in children. Cisplatin may be effective in relapsing patients. Cancer of the female urethra should be treated by combined surgery and radiotherapy. One should differentiate between urachal and nonurachal adenocarcinoma. DNA ploidy seems to be an important prognostic parameter in adenocarcinoma of the bladder. After orchiectomy, adjuvant chemotherapy is recommended even in testis-confined malignant lymphoma. Organ-preserving surgery and radiotherapy should be used in malignant lymphoma of the bladder. Patients with uncommon urologic tumors should be treated at larger cancer centers. Alternatively, the clinician should at least enter relevant information on patients seen with these malignancies into collective databases. This review summarizes the clinical aspects of rare and unusual tumors of the genitourinary tract in adults.     

Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract

Factors that determine the clinical course and outcome of patients with gastrointestinal (GI) carcinoid tumors are complex and multifaceted. These include the site of origin within the GI tract, the size of the primary tumor, and the anatomical extent of disease, whether localized, regional, or metastatic to distant sites. The new World Health Organization (WHO) histological classification of endocrine tumors, including carcinoids, represents a significant advance in terms of providing a consistent framework for histopathological interpretation that should facilitate multicenter research on treatment outcomes. Histochemical indicators of a poorer prognosis are the degree of expression of the proliferation protein Ki-67 and the p53 tumor suppressor protein. Adverse clinical indicators are the malignant carcinoid syndrome, carcinoid heart disease, and high concentrations of the tumor markers, urinary 5-HIAA and plasma chromogranin A.     

Surgical management of neuroendocrine tumors of the gastrointestinal tract

Neuroendocrine tumors of the pancreas (islet cell tumors) and of the luminal gastrointestinal tract (carcinoids) are a heterogeneous group of epithelial neoplasms that share certain common characteristics. First, they are similar histologically and are difficult to distinguish under light microscopy. Second, they can be associated with hypersecretory syndromes. Third, they are generally slow-growing and have a better prognosis than adenocarcinomas at the same site; however, they do become incurable when they progress to unresectable metastatic disease. Surgery is the only curative treatment and is recommended for most patients for whom cross-sectional imaging suggests that complete resection is possible. This article reviews the surgical management of gastrointestinal neuroendocrine tumors, including the preoperative control of hormonal symptoms, extent of resection required, postoperative outcomes, and differing management strategies as determined by whether the tumor has arisen sporadically or as part of a familial disorder, such as multiple endocrine neoplasia type 1 (MEN1).     

New strategies for advanced neuroendocrine tumors in the era of targeted therapy

Low- to intermediate-grade neuroendocrine tumor (NET) constitutes a group of indolent malignancies that share the capacity for secreting hormones and neuroamines. Until recently, there were few therapeutic options for oncologic control. The PROMID study showed that octreotide long-acting repeatable formulation can delay tumor growth in midgut NETs. And, recent phase III studies showed both everolimus and sunitinib improved progression-free survival in pancreatic NETs, validating the phosphoinositide 3-kinase/Akt/mTOR pathway and angiogenesis as important targets for further advances. Ongoing and planned pivotal studies targeting these pathways in other NET subtypes may widen their therapeutic application. Development of rational combinations may further improve therapeutic outcome. These successes and our improved understanding of the underlying molecular biology are likely to lead to further important advances on the horizon.     

Current therapeutic strategies for childhood hepatic malignant tumors

The two main malignant hepatic tumors in children are hepatoblastomas (HBLs) and hepatocellular carcinomas (HCCs). The past two decades have brought significant improvement to the outcomes of children diagnosed with malignant hepatic tumors, especially HBL, due to improvements in diagnosis and treatment. Histological diagnosis is essential for differential diagnosis of these tumors. In surgery, liver resection has become a safe and secure technique because of progress in anatomical knowledge and surgical dissection; also liver transplantation has become widely used for unresectable tumors. Moreover, the introduction of effective chemotherapeutic regimens has significantly improved the survival of children with HBL due to an increase in the number of patients ultimately undergoing tumor resection, and a reduction in the incidence of post-surgical recurrence. These improvements are the result of multicenter cooperative trials conducted by the Japanese Study Group for Pediatric Liver Tumor, the Children’s Oncology Group, and the International Childhood Liver Tumor Strategy Group, including work of the German Association of Pediatric Hematology and Oncology. This paper summarizes the results of these studies and calls on the current international collaboration study called the Children’s Hepatic Tumors International Collaboration Project to establish global clinical research on childhood hepatic malignant tumors.     

Significance of urinary neopterin in patients with malignant tumors of the genitourinary tract

The urinary neopterin excretion was measured by high-performance liquid chromatography in 417 healthy subjects and in 76 patients with clinically and pathohistologically verified neoplasias of the urinary tract (bladder tumor, carcinoma of the prostate, and renal cell carcinoma). The patients with early tumor stages both with bladder tumor and carcinoma of the prostate had normal urinary neopterin levels, except one patient with bladder tumor who had a value at the upper confidence limit. Of 40 patients with higher stages of bladder tumor and carcinoma of the prostate, 35 had elevated urinary neopterin levels. Two of 10 patients with bladder tumor in stage T3, 1 of 4 patients with carcinoma of the prostate Stage C, and 2 of 15 patients with prostatic cancer Stage D showed normal neopterin levels. The patients with renal cell carcinoma did not demonstrate any definite correlation between tumor stage and urinary neopterin excretion. The current study suggests that the neopterin assay may supplement laboratory measurements in tumors of the urinary tract, providing helpful information regarding case selection for the most convenient therapeutic management and postoperative follow-up.     

Follow-up surveillance strategies for genitourinary malignancies

BACKGROUND: Genitourinary cancers account for more than 20% of all malignancies in the United States. These cancers do not usually yield rapid mortality, thereby necessitating longer-term surveillance strategies. METHODS: A review and analysis of relevant studies were performed. Follow-up strategies are proposed to reflect effective methods to detect recurrent prostate, bladder, renal, and testicular cancers. Cost analysis was performed using Medicare reimbursement rates. RESULTS: For genitourinary tumors, follow-up tests can be planned rationally based on detection rates and patterns. Tumor grade and stage drive follow-up strategies, along with therapeutic implications of detecting a recurrence. Symptomatic recurrences often obviate the need for radiographic tests and can minimize costs. Stage- specific plans for these four urologic malignancies are outlined specifically. CONCLUSIONS: Not all surveillance approaches have been critically tested for follow-up of genitourinary tumors, but ample data are available to propose sound medical and economic strategies.     

Liver-directed therapies in liver metastases from neuroendocrine tumors of the gastrointestinal tract

Presence of liver metastases in neuroendocrine tumors is a major factor altering both quality of life and prognosis. Surgery is recognized as the sole curative treatment. When it is not possible, radiological directed therapies are crucial, particularly in liver metastases from the small bowel. Thermal ablative therapies as radiofrequency ablation and microwave are alternative treatments alone or in combination with surgery. Hepatic artery embolization or chemoembolization, as radioembolization, has been shown to have good clinical, biochemical, and morphological responses when liver burden does not permit ablative therapies. However, technical issues are multiple and there is no randomized study to compare their efficacy. The choice of management depends on liver burden and metastases pattern, but also on origin of the primary tumor, tumor differentiation, and tumor proliferative activity. These patients should benefit of a multidisciplinary management to limit morbidity and mortality.     

Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges

This paper summarizes the current understanding of the biology of somatostatin receptor (sst), role of immunotherapy in neuroendocrine tumor (NET), new agents for PPRT, and methods to assess response and clinical benefit in NET. One of the most interesting aspects of sst biology is the recent discovery of truncated variants of the sst5 receptor subtype with unique tissue distribution and response to somatostatin (SST). These truncated receptors are associated with bad patient prognosis, decreased response to SST analogs, and may be new targets for diagnoses and treatment. IFN remains a cost-effective agent, particularly in classic mid gut carcinoids, and there is interest to continue examining immunotherapy's in this disease. PRRT remains a key strategy for treatment and imaging. In addition to the classic agents, there are a series of new agents targeting other receptors such as the incretin receptors (GLP-1R; GIPR) and other G-protein coupled receptors with great potential. With regards to therapy monitoring, the most commonly used criteria are Response Criteria Evaluation in Solid Tumors (RECIST). However, for different reasons, these criteria are not very useful in NET. Incorporation of other criteria such as Choi as well as functional imaging assessment with PET would be of great interest in this area.     

Management of advanced genitourinary tumors

The management of advanced genitourinary tumors is rapidly evolving thanks to the clinical availability of several targeted drugs with different mechanisms of action. Among clinicians, in-depth knowledge of all the aspects of the disease, together with the capacity to interpret and accurately correlate clinical data and imaging findings, are strongly needed. Moreover, the optimization of treatment sequences might lead to better disease control with respect to prognostic categories, radiological monitoring and newer biomarkers. Among the genitourinary tumors, only few data are available on bladder, testicular and penile cancers. Our report is supported by scientific and clinical experience in renal cell carcinoma and prostate cancer.     

Current therapeutic strategies for childhood hepatic tumors: surgical and interventional treatments for hepatoblastoma

Surgery is the mainstay of multimodal treatment for hepatoblastomas. Among the various staging systems used, PRETEXT is currently adopted in all major study groups worldwide as a common pretreatment staging system. Although variations of treatment strategies among study groups exist, the majority of hepatoblastoma cases currently undergo preoperative chemotherapy. It is therefore critical to determine the optimal surgical treatment during the initial courses of chemotherapy. Patients with PRETEXT IV tumors, multifocal tumors and tumors invading major vessels of the liver are candidates for liver transplantation. Liver transplantation requires preparation in advance, and consultation to a liver expertise team must take place no later than after two cycles of chemotherapy. The existence of pulmonary metastasis is a predictor of poor prognosis of the patient. Surgery for pulmonary nodules should be considered for those patients remaining positive after cycles of chemotherapy. A considerable number of patients have been reported to achieve long-term survival after resecting pulmonary metastasis. The existence of pulmonary metastasis at diagnosis is no longer a contraindication for liver transplantation, provided that the pulmonary nodules are eliminated by chemotherapy or by metastasectomy. Transcatheter arterial chemoembolization (TACE) is a useful tool for the local control of hepatoblastomas, although there are very few reports statistically supporting the significant advantage of this treatment modality. Based on individual cases, TACE could be beneficial in maximizing the anti-tumor effect with less toxic side effects.     

RET and neuroendocrine tumors

Glial cell line-derived neurotrophic factor (GDNF), a ligand of RET tyrosine kinase, and its family ligands promote the survival and differentiation of a variety of neurons. Gene ablation studies have revealed that the GDNF-RET receptor system is essential for the development of kidney and peripheral neurons, including sympathetic, parasympathetic and enteric neurons. RET can activate various signaling pathways such as RAS/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. These signaling pathways are activated via binding of adaptor proteins to intracellular tyrosine residues of RET phosphorylated by its own kinase activity. The RET is profoundly involved in the development of several human neuroendocrine diseases. The constitutive activation of the RET by somatic rearrangement with other partner genes or germ-line mutations causes a considerable population of human papillary thyroid carcinomas or multiple endocrine neoplasia (MEN) type 2A and 2B, respectively, whereas the dysfunction of RET by germ-line missense and/or nonsense mutations causes Hirschsprung's disease. Biological properties of mutant RET protein determine the disease phenotype. For example, the MEN 2B mutation alters the substrate specificity of RET tyrosine kinase and RET carrying the MEN 2B mutation hereby induces the different set of genes from that carrying the MEN 2A mutation. In this review, we describe the current knowledge about the molecular mechanism of RET activation in human neuroendocrine tumors as well as the physiological roles and signal transduction of RET tyrosine kinase.     

Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies

Analysis of the recurrent genetic aberrations present in human tumors provides insight into how normal cells escape appropriate proliferation and survival cues. Commonly mutated genes encode proteins that monitor DNA damage (e.g., p53), proteins that regulate the cell cycle (such as Rb), and proteins that regulate signal transduction pathways (such as APC, PTEN and Ras). Analysis of the relevant targets and downstream events of these genes in normal and tumor cells will clearly highlight important pathways for tumorigenesis. However, more infrequent mutations are also informative in defining events critical for the process of tumorigenesis, and often delineate important pathways lying downstream of commonly mutated oncogenes and tumor suppressors. Together, these studies have led to the conclusion that deregulated protein synthesis plays an important role in human cancer. This review will discuss the evidence implicating mRNA translation as an important downstream consequence of signal transduction pathways initiated by mutated oncogenes and tumor suppressors, as well as additional genetic findings implicating the importance of global and specific translational control in human cancer. It will also discuss therapeutic strategies that take advantage of differences in translational regulation between normal and tumor cells.     

胃神经内分泌肿瘤的诊断和治疗

胃神经内分泌肿瘤（G-NETs）是指来源于胃上皮及类肠嗜铬（ECL）细胞等神经内分泌细胞相关的肿瘤,占胃原发肿瘤一小部分,故长期以来对其认识局限,诊疗缺乏统一标准。但近年来G-NETs发病率较前明显升高,对其认识逐渐加深,临床根据G-NETs分化程度、与高胃泌素血症相关与否分为4个亚型,并针对不同亚型进行治疗。本文就近年来有关G-NETs流行病学、临床表现、诊断标准、治疗方法等最新进展做一综述,以期为G-NETs的诊疗提供参考。     

Somatostatin analogs for the treatment of neuroendocrine tumors

Somatostatin is an important regulator of endocrine and exocrine secretion, affecting the release of many hormones. The effects of somatostatin are mediated through its interaction with one of five somatostatin receptors. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express multiple somatostatin receptors, making them excellent potential therapeutic targets. Many trials have shown that treatment with somatostatin analogs is associated with disease stabilization and prolonged survival. More recently, somatostatin analogs have been shown to have antiproliferative effects, thus broadening the scope of their uses. In this review, we update the current data on the treatment of GEP-NETs with somatostatin analogs, with particular emphasis on the results of the PROMID study. In addition, we discuss the current state of knowledge of novel therapies against GEP-NETs, including the use of somatostatin analogs with broader receptor binding profiles, chimeric somatostatin-dopamine molecules, combinations of somatostatin analogs with other active chemotherapy agents, and peptide receptor-targeted radionuclide therapy.     

Therapeutic strategies for neuroendocrine liver metastases

Patients who have neuroendocrine tumors frequently present with liver metastases. A wide panel of treatment options exists for these patients. Liver resection with curative intent achieves the best long‐term results. Highly selected patients may be considered for liver transplantation. Substantial recurrence rates reported after surgical approaches call for neoadjuvant and adjuvant concepts. Liver‐directed, locally ablative procedures are recommended for patients with limited, nonresectable tumor burden. Angiographic liver‐directed techniques, such as transarterial embolization, transarterial chemoembolization, and selective internal radiotherapy, offer excellent palliation for patients with liver‐predominant disease. Peptide receptor radionuclide therapy is a promising palliative procedure for patients with hepatic and/or extrahepatic metastases. The efficacy of these treatment options needs to be evaluated in randomized trials. Somatostatin analogues have demonstrated effectiveness not only for symptomatic relief in patients with secreting tumors but also for the control of proliferation in small intestinal neuroendocrine tumors and most recently also in those originating from the pancreas. Chemotherapy is an option mainly for those with pancreatic neuroendocrine tumors and high‐grade tumors irrespective of the origin. Novel drugs targeting specific pathways within the tumor cell have produced improved progression‐free survival compared with placebo in patients with pancreatic neuroendocrine tumors. Despite such a diverse armamentarium, there is uncertainty with regard to the optimal treatment regimens. Newly introduced molecular‐based markers, along with the conduction of clinical trials comparing the efficacy of treatment modalities, offer a chance to move the treatment of neuroendocrine tumor disease toward personalized patient care. In this report, the authors review the approaches for treatment of neuroendocrine liver metastases, identify shortcomings, and anticipate future perspectives. Furthermore, clinical practice recommendations are provided for currently available treatment options. Although multiple modalities are available for the treatment of neuroendocrine liver metastases, optimal management is unclear. The current knowledge pertaining to these treatment options is analyzed. Cancer 2015;121:1172–1186. © 2014 American Cancer Society.     

PDGFRα expression as a novel therapeutic marker in well-differentiated neuroendocrine tumors

Aims: To evaluate the biological significance of dense vascular networks associated with low-grade NENs, we assessed the impact of PDGFRα tissue expression in 77 GEP/NEN patients, associating PDGFRα expression with the morphological characterization in low-grade tumors.

Methods and results: Paraffin-embedded specimens of 77 GEP- NEN tissues, collected from January 2006 to March 2018, were evaluated for PDGFRα tissue expression and correlations with clinicopathological characteristics. PDGFRα tissue expression was significantly correlated with grade and the NEN growth pattern (p < 0.001) but not with gender, primary site or lymph nodes metastatic status. PDGFRα staining was mainly localized in the vascular pole of the neuroendocrine cells and in Enterochromaffin (EC) cells. In particular PDGFRα tissue expression was significantly more expressed in G2 (p < 0.001) than G1 and G3 cases (p 0.004; p < 0.0002;) and correlated with an insular growth pattern. PDGFRα tissue expression was associated with the Ki67 index and we found a significant negative trend of association with the Ki67 proliferation index (P < 0.001): thus PDGFRα expression is referred to morphological and not to proliferative data.

Conclusions: PDGFRα represents an effective target for new anti-angiogenic treatment in WD- GEP-NENs, in particular in G2 cases, and in G3 cases only when there is a mixed insular-acinar pattern. In this context, it is important to carefully delineate those tumors that might better respond to this type of treatment alone or in combination. Further investigation of the relationship between PD-L1 and PDGFRa is warranted, and may contribute to optimize the therapeutic approach in patients with GEP-NENs.