SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022).

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided.

Primary Neuroendocrine Tumor of the Parotid Gland: A Case Report and a Comprehensive Review of a Rare Entity.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies from cells derived from the neural crest with neuroendocrine differentiation. Despite the differences in the site of origin, nomenclature, biological behavior, and functional status, NETs share certain ultrastructural and immunohistochemical features. NETs are relative rare tumors with an annual incidence of 5.76 new cases per 100.000 inhabitants and they usually appear in the gastrointestinal tract or in the pulmonary system. Head and neck NETs are uncommon with limited information regarding frequency, most of them showing small cell carcinoma features. NETs that arise from the salivary glands are exceedingly rare. Regardless of their low frequency, it is imperative to accurately differentiate these tumors from the much more common squamous cell carcinomas and from metastasis from another primary tumor due to the completely different therapeutic approaches and prognosis. The diagnosis is based on the recognition of the typical neuroendocrine architecture and immunohistochemical staining and on an exhaustive work-up. Hereby, we report a case of a moderately differentiated NET of the parotid gland that was treated with a complete parotidectomy. We summarize the clues that led to the final diagnosis and major strategies that were employed to manage the patient. We also perform a comprehensive review of the scarce available literature on this topic.

Congestive heart failure in a 77-year-old woman receiving adjuvant treatment with imatinib for a large gastric gastrointestinal stromal tumour.

We report on a 77-year-old patient complaining of abdominal pain who was diagnosed with a gastric mesenchymal tumour with a poor prognosis (high mitotic index, 25% Ki-67 proliferation index and c-kit positive). During surgery, there was instrument-related rupture of the tumour. Coadjuvant therapy with imatinib was initiated. Three weeks later, the patient developed symptoms of congestive heart failure and this led to the discontinuation of imatinib treatment; diuretic treatment was initiated, which led to an improvement in the symptoms. Echocardiography study showed a left ventricle ejection fraction of 55% with an alteration in the relaxation of the ventricle. In the follow-up, there has been no evidence of disease relapse or development of new symptoms.

Vinflunine: a new vision that may translate into antiangiogenic and antimetastatic activity.

Microtubules and tubulin are major dynamic and structural cellular components that play a key role in several cell functions, including division, signalling and intracellular trafficking. Normal epithelial cells have a highly structured, rigid cytoskeletal network that is compatible with cell motility. Thus, tubulin and microtubules are compelling cellular targets for chemotherapy. In fact, among anticancer agents, those that target microtubules constitute one of the most effective classes of chemotherapeutics in cancer. The list of compounds that target either tubulin or microtubules is extensive and consists of chemically unique compounds that bind to the tubulin dimers and destabilize microtubules (Vinca alkaloids) and those that bind to the microtubule polymer and stabilize microtubules (taxanes). Tumour-induced angiogenesis, the formation of new capillaries from existing blood vessels, and epithelial-mesenchymal transition are two steps that are critical for both tumour growth and metastatic spread. Three possible mechanisms of action are described with vinflunine, the new-generation Vinca alkaloid to arrive in clinical practice are as follows: it acts against tubulin and microtubules, disrupts newly formed blood vessels and seems to be able to reduce the metastatic process as shown in preclinical studies. These findings support the hypothesis that vinflunine, by blocking microtubule functions that contribute to cell shape, polarization, migration and other processes, might be responsible not only for tumour-cytostatic but also for specific antiangiogenic or antiepithelial-mesenchymal transition effects.

Immune microenvironment in colorectal cancer: a new hallmark to change old paradigms.

Impact of immune microenvironment in prognosis of solid tumors has been extensively studied in the last few years. Specifically in colorectal carcinoma, increased knowledge of the immune events around these tumors and their relation with clinical outcomes have led to consider immune microenvironment as one of the most important prognostic factors in this disease. In this review we will summarize and update the current knowledge with respect to this intriguing and complex new hallmark of cancer, paying special attention to infiltration by T-infiltrating lymphocytes and their subtypes in colorectal cancer, as well as its eventual clinical translation in terms of long-term prognosis. Finally, we suggest some possible investigational approaches based on combinatorial strategies to trigger and boost immune reaction against tumor cells.

Sunitinib-induced asthenia: from molecular basis to clinical relief.

Asthenia-fatigue syndrome (AFS) is defined as a persistent, subjective sense of tiredness related to cancer or its treatment and greatly impacts quality of life among cancer patients. All tyrosine kinase inhibitors, but especially sunitinib, may induce AFS. The reason for sunitinib-induced AFS is not yet well understood. Adverse events caused by sunitinib associated with AFS may include anemia, hypothyroidism, nausea and vomiting. However, AFS is also reported when active treatment with sunitinib is ongoing, and no other relevant adverse event can justify it. The molecular mechanisms by which sunitinib triggers AFS remain elusive. Sunitinib displays multiple off-target tyrosine-kinase interactions and competitively inhibits multiple proteins through the blockade of their ATP-binding sites. The broad spectrum of kinases inhibited may play a key role not only in terms of activity but also in terms of toxicity induced by sunitinib. This study considered different clinical observations and current metabolic and pharmacological knowledge, leading to hypotheses regarding which molecular mechanisms may be involved in sunitinib-induced AFS in cancer patients. Deeper knowledge of the molecular mode of action of sunitinib may lead to improved optimization of its clinical use.

Potential role of sugar transporters in cancer and their relationship with anticancer therapy.

Sugars, primarily glucose and fructose, are the main energy source of cells. Because of their hydrophilic nature, cells use a number of transporter proteins to introduce sugars through their plasma membrane. Cancer cells are well known to display an enhanced sugar uptake and consumption. In fact, sugar transporters are deregulated in cancer cells so they incorporate higher amounts of sugar than normal cells. In this paper, we compile the most significant data available about biochemical and biological properties of sugar transporters in normal tissues and we review the available information about sugar carrier expression in different types of cancer. Moreover, we describe the possible pharmacological interactions between drugs currently used in anticancer therapy and the expression or function of facilitative sugar transporters. Finally, we also go into the insights about the future design of drugs targeted against sugar utilization in cancer cells.

Colorectal cancer: response to sunitinib in a heavily pretreated colorectal cancer patient.

A 64-year-old man was admitted to the emergency room in May 2000 due to pelvic pain, functional disability of the lower limb, and bleeding from a rectal fistula. The patient was diagnosed with a rectum-sigma adenocarcinoma (pT1N0M0 stage). After surgery by left hemicolectomy, the patient received adjuvant chemotherapy with tegafur for 6 months. Due to the development of subsequent recurrences (infravesical relapse, bone and lung progression) associated with CEA progression and pain worsening, the patient received treatment by every available agent for the metastatic colorectal cancer, including oxaliplatin and radiotherapy; irinotecan; FOLFOX schema; oral capecitabine; raltitrexed; irinotecan and cetuximab; cetuximab as a single agent; always in combination with zolendronic acid-based treatment for pain control. Once the patient had progressed to all the approved drugs available in the market, sunitinib (50mg/day given for 4 weeks followed by 2 weeks of rest) was proposed as compassionate use. The patient received sunitinib for a total of 6 months (four cycles). On account of the nonmeasurable disease nature of the metastatic presentation in the present case, the clinical benefit was measured in terms of reduction of painkiller intake, improvement in performance status of the patient, and CEA serum levels. In addition to all of these clinical and biological data, CT images showed an increase in necrotic area of the bone lesion without any decrease in tumor size by classical RECIST criteria. The patient is still under sunitinib treatment and has recovered his normal daily activity.

Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib.

Sunitinib is an orally available small-molecule multikinase inhibitor. This agent potently inhibits the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit in addition to other kinases in biochemical and cell-based assays. In several relevant preclinical cancer models, sunitinib exerts significant antiangiogenesis and antitumor effects. In phase I studies, using intermittent dosing schedules, oral administration of doses up to 50 mg/day were reasonably well tolerated and resulted in plasma concentrations in the range of targeted levels needed for sustained kinase inhibition. Biomarker and functional imaging studies showed modulation of circulating markers of angiogenesis as well as a reduction in tumor metabolism. Sunitinib showed clinical activity in patients with renal cell cancer and in patients with imatinib-resistant gastrointestinal stromal tumors. Definitive randomized clinical trials showed significant clinical activity in these two indications leading to regulatory approval. In addition, this drug has showed activity in a variety of other tumor types such as breast, colon, and lung cancer and is being explored in combination with standard drugs in these diseases. The observation that biological and functional imaging effects are reduced during drug-free intervals has prompted the evaluation of protracted dosing schedules. A better understanding of mechanisms involved in resistance to sunitinib provides the rationale for combination strategies that hopefully will result in better clinical effect. Ongoing studies will elucidate the overall role of this drug in cancer treatment.

Glucose transporter expression and the potential role of fructose in renal cell carcinoma: A correlation with pathological parameters.

All mammalian cells contain one or more members of the facilitative glucose transporter (GLUT) gene family. Glucose transporter membrane proteins (GLUT) regulate the movement of glucose between the extracellular and intracellular compartments, maintaining a constant supply of glucose available for metabolism. Tumor cells are highly energy-dependent, therefore GLUT overexpression is often observed. In fact, overexpression of GLUT1 has been correlated with hypoxia markers in several tumor types, including renal cell carcinoma (RCC). We retrospectively analyzed 80 paraffin-embedded RCC samples. The pattern of GLUT1-5 expression in RCC specimens was evaluated using tissue-array technology and correlated with histological tumor characteristics. Pathological parameters included tumor location, renal pelvis, vein and lymph vessel invasion, capsule breakage, histological subtype, Furhman grade, hilar invasion and tumor stage at diagnosis. The expression of five facilitative glucose transporters, GLUT1 (erythrocyte type), GLUT2 (liver type), GLUT3 (brain type), GLUT4 (muscle/fat type) and GLUT5 (small intestinal type), was semi-quantitatively analyzed. In non-parametric, Mann-Whitney U and Kruskal-Wallis tests, a significant positive correlation was consistently found between moderately differentiated RCC tissues and the expression of GLUT5 (p=0.024). Patients who had pelvic invasion and capsule breakage at diagnosis also showed increased GLUT5 expression levels (p=0.039 and p=0.019, respectively). Moreover, GLUT5 showed statistical significance in those samples identified as being of clear cell histological type (p=0.001). A high expression of GLUT5 in human RCC was observed. GLUT5 appears to be correlated with grade II differentiation, locoregional invasion and aggressiveness, and may play a role in RCC development.