Vasoactive intestinal peptide (VIP) secreting tumour (VIPoma) is a rare functional neuroendocrine tumour that typically arises from pancreatic islet cells. These present as sporadic, solitary pancreatic neoplasias with an estimated incidence of one in ten million individuals per year. Only around 5% of VIPomas are associated with multiple endocrine neoplasia type I syndrome. Excessive VIP secretion produces a clinical syndrome characterized by refractory watery diarrhoea, hypokalemia and metabolic acidosis. These coupled with elevated plasma levels of VIP are diagnostic. The majority of VIPomas are malignant and have already metastasized at the time of diagnosis (60%). Metastases occur most frequently in the liver, or regional lymph nodes, lungs, kidneys and bones. Some reports of skin metastases have been documented. Complete surgical resection continues to be the only potentially curative treatment. However, when the neoplasia cannot be excised completely, surgical debulking may provide palliative benefit. Other palliative options have included recently the peptide receptor radionuclide therapy which has shown to be effective and well-tolerated. This article will review all aspects of pancreatic VIPomas highlighting aspects such as clinical presentation, diagnosis and management.

Trastuzumab, a humanized monoclonal antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER-2) prolongs disease-free survival (DFS) and overall survival (OS) in patients with early-stage breast cancer. Although it is generally well tolerated, it has been associated with cardiotoxicity, mainly a reduction of left-ventricular ejection fraction (LVEF), especially if the patient has received anthracyclines.It is generally known that a drop in LVEF has limited diagnostic ability. Therefore, the identification of serum biomarkers of cardiotoxicity, able to detect damage at an earlier phase, has become ideal. Troponins (conventional and high sensitive), natriuretic peptides, reactive C protein (CRP), myeloperoxidase (MPO), etc are different molecular markers which have been assessed to check their role in the detection of treatment induced cardiotoxicity (CTIC) with controversial results.OBJECTIVEThis systematic review will synthesize available evidence assessing the role of different serum biomarkers in early prediction of cardiotoxicity in breast cancer patients treated with adjuvant trastuzumab.METHODS/DESIGNSystematic review conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Distinct scientific databases such as Google Scholar, Pubmed, EBSCOhost, and PsycINFO were searched to aid in the investigation of the research problem.Randomized clinical trials (RCT) and observational studies of patients with early breast cancer receiving adjuvant trastuzumab were eligible for inclusion. Two investigators have independently evaluated those studies and used standardized data extraction templates to collect data on the study and patients’ characteristics.RESULTS 11 articles were selected, one RCT and ten observational studies. The most studied biomarker was N-terminal-pro-brain natriuretic peptide (NT-proBNP) followed by troponins. Findings showed that NT-proBNP was not predictive of CTIC while conflictive results were seen with troponins.One study showed a predictive role of high sensitive (hs) CRP and another found a relationship with the levels of MPO.CONCLUSIONBiomarkers offer a unique potential to improve the effectiveness and safety of trastuzumab through timely detection of CTIC and prompt initiation of appropriate treatment. Troponins I and T have shown a predictive role in early detection of CTIC but further research would be needed to enable more insight and improve the overall patient outcome.

Journal of Unexplored Medical Data is an open access journal, which considers well-conducted medical science studies, including clinical trials, pilot studies, research reports, original articles, reviews and short communications in the field of medical science.

Gemcitabine is an antineoplastic used to treat several malignancies including pancreatic cancer. Its toxicity profile is well known with myelotoxicity, increased vascular permeability and peripheral oedema as most frequent adverse events. However, several cases of acute renal failure have been reported and haemolytic uremic syndrome (HUS) seems to be the underlying process. The cause of HUS remains unknown but its consequences can be lethal. Therefore, a high grade of suspicion is crucial to diagnose it and promptly treat it. This hopefully will reduce its morbidity. HUS is characterized by progressive renal failure associated with microangiopathic haemolytic anaemia and thrombocytopenia. The primary event is damage to endothelial cells and thrombotic microangiopathy (TMA) is the histopathological lesion. TMA affects mainly renal microvasculature. However, some cases evolve with central nervous or cardiovascular systems involvement. We present here a case of gemcitabine-induced HUS, with renal and cardiovascular system affected at the time of diagnosis which to our knowledge this is the first time of such case to be reported.

Taxanes are anti-microtubulin drugs that have a broad spectrum of antitumor activity.They are probably the most widely used cytotoxics. 1 Their common adverse effects include bone marrow suppression, hypersensitivity or skin reactions, alopecia and peripheral sensory neuropathy 1 .

Introduction: Pancreatic cancer needs to be treated by multimodality therapies. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) has shown effectiveness in the treatment of this disease by increasing response rate with an impact on median survival. Toxicity could be concerning but supportive measures can help significantly. Methods: All patients diagnosed with metastatic pancreatic cancer were discussed at a multidisciplinary team. Those consider fit enough, were treated with FOLFIRINOX.We assessed primarily the response after three months of treatment and also side-effects. Results: We evaluated 55 patients, 29 female. Median age was 61 (51-68). The most common toxicities grade 3 or higher were gastrointestinal, mainly diarrhoea and nausea/vomiting. 12 patients required admission due to diarrhoea and dehydration. Haematological toxicities such as neutropenia grade 3-4 occurred in 26 patients, 7 of them needed admission due to neutropenic sepsis. Fatigue was also a relevant side-effect present in all the patients, grade 1 in most of them but grade 3 or higher in 21 patients. Dose of chemotherapy was reduced in 37 patients. In 6 of them the reason for a reduction was peripheral neuropathy. 36 patients had a response, 11 stable disease, and the rest progression. Conclusion: FOLFIRINOX as a therapy for metastatic pancreatic adenocarcinoma is a good option providing good supportive measures are in place to reduce the side-effects.

Introduction: Capecitabine is a fluoropyrimidine widely used to treat colorectal cancer and metastatic breast cancer. It is a prodrug converted to fluorouracil (FU), which is the active form. FU metabolism is catalysed by dihydropyrimidine dehydrogenase (DPD). Patients with DPD deficiency cannot metabolize capecitabine at a normal rate and will be at risk of life-threatening side-effects. The prevalence of DPD deficiency in Caucasians is 3%-5%. Between 10-40% of patients will develop severe toxicity early during treatment with fluoropyrimidines, which leads to a discontinuation of treatment. This could be explained by clinical factors, such as age and sex but much of the variability in side-effects remains unexplained. DPD deficiency test could be done, but what is its sensitivity and specificity to detect capecitabine serious toxicity? Methods: We have studied a population of colorectal cancer patients who will start capecitabine. Screening for DPD deficiency has been carried out. If the patient is classified as poor metabolizer, capecitabine is replaced by raltitrexed. If intermediate metabolizer, capecitabine was started with 50% of the dose. Results: We have studied 25 patients. 4 of them experienced life threatening toxicities. One of them with first cycle, although he had received 5FU in the past without issues. This patient died. The other 3 started experiencing serious adverse events, mainly in the form of diarrhoea, and one of them suffered neutropenia grade 4 too, generally after cycles 3 or 4. The early cycles had been well tolerated. 1/25 patients was classified as intermediate metabolizer. None was classified as poor metabolizer. The 4 patients who experienced serious adverse events were considered normal metabolisers without any other risk factors (no comorbidities, 50-70 years old). Table below shows the sensitivity 0% and specificity 95% Conclusion: This small study does shows that those patients classified as normal metabolisers are still at risk of life-threatening toxicities. Further studies will be needed to determine what other factors are playing a significant role in prediction of toxicities.

Neuroendocrine（NE） gastroenteropancreatic tumors are a heterogeneous group of neoplasias arising from neuroendocrine cells of the embryological gut. Their incidence have increased significantly over the past 3 decades probably due to the improvements in imaging and diagnosis. The recent advances in molecular biology have translated into an expansion of therapeutic approaches to these patients. Somatostatin analogs, which initially were approved for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Several new drugs such as antiangiogenics and others targeting mammalian target of rapamycin pathways have been approved to treat progressive pancreatic neuroendocrine tumors（NETs） although their role in nonpancreatic is still controversial. The treatment of NETs requires a coordinated multidisciplinary approach. The management of localized NETs primarily involves surgical resection followed by surveillance. However, the treatment of unresectable and/or metastatic disease may involve a combination of surgical resection, systemic therapy, and liver-directed therapies with the goal of alleviating symptoms of peptide release and controlling tumor growth. This article will review the current therapeutic strategies for metastatic gastroenteropancreatic NETs and will take a glimpse into the future approaches.

Hepatocellular carcinoma (HCC) is a common neoplasia which represents the second leading cause of cancer related death.Most cases occur in developing countries, but its incidence is rising in Western countries due to hepatitis C.Although hepatitis therapies have evolved and the HCC screening has increased in several areas, 40% present with advanced disease which is only amenable for palliative systemic treatment.HCC continues posing a challenge, in part due to the inherent chemoresistance of this neoplasia, the pharmacologic challenges due to an ill liver, difficulty in assessing radiological responses accurately, etc .Traditional chemotherapy have shown some responses without clear survival benefit, however, sorafenib demonstrated advantages in survival in advanced HCC when liver function is kept and recently immunotherapy seems to be a promising approach for some patients.This article will briefly expose the most relevant systemic treatment modalities to offer a general view from the past to the future.

This supplement is intended to focus on key difficulties associated with cancer biology. The supplement is intended to address drug resistance, tumor microenvironment and metastasis, although other relevant sub-topics may be included at the discretion of the guest editors.Clinical Medicine Insights: Oncology aims to provide researchers working in this complex, quickly developing field with online, open access to highly relevant scholarly articles by leading international researchers. In a field where the literature is ever-expanding, researchers increasingly need access to up-to-date, high quality scholarly articles on areas of specific contemporary interest. This supplement aims to address this by presenting high-quality articles that allow readers to distinguish the signal from the noise. The editor in chief hopes that through this effort, practitioners and researchers will be aided in finding answers to some of the most complex and pressing issues of our time.

Introduction: Cetuximab is a monoclonal antibody against epidermal growth factor receptor which is used in metastatic colorectal cancer treatment. Mostly used in combination with chemotherapy, sometimes it is used as monotherapy and given its favourable toxicity profile it could be a good choice for elderly patients.Methods: We carried out a study to evaluate the safety and efficacy of this drug as monotherapy in an elderly population with metastatic colorectal cancer KRAS wild-type. The study evaluated only the first four months of treatment. Patients included were older than 74 and were seen once monthly with blood tests (routine haematology and a general biochemistry which included CEA) and a CT scan was done every two months.Results: We evaluated 31 patients (18 men and 13 women). Most common adverse reactions were acneiform rash (63%), hand-foot syndrome (11%), growth of eyelashes (12%), conjunctivitis (13%), paronychia (9.1%), hypomagnesemia (19%), stomatitis (17.5%) and gastrointestinal disorders (18%). Only in three cases it was necessary a reduction in the dose of the cetuximab (due to hepatic toxicity grade 3, diarrhoea grade 3 and stomatitis grade 3). Only four patients developed progressive disease while on the first four months, one of them within the first two months. 11 had stable disease and the rest had partial response.Conclusion: The results demonstrated that cetuximab monotherapy is beneficial for the treatment of elderly patients with metastatic colorectal cancer and it has a favourable toxicity profile. Introduction: Cetuximab is a monoclonal antibody against epidermal growth factor receptor which is used in metastatic colorectal cancer treatment. Mostly used in combination with chemotherapy, sometimes it is used as monotherapy and given its favourable toxicity profile it could be a good choice for elderly patients. Methods: We carried out a study to evaluate the safety and efficacy of this drug as monotherapy in an elderly population with metastatic colorectal cancer KRAS wild-type. The study evaluated only the first four months of treatment. Patients included were older than 74 and were seen once monthly with blood tests (routine haematology and a general biochemistry which included CEA) and a CT scan was done every two months. Results: We evaluated 31 patients (18 men and 13 women). Most common adverse reactions were acneiform rash (63%), hand-foot syndrome (11%), growth of eyelashes (12%), conjunctivitis (13%), paronychia (9.1%), hypomagnesemia (19%), stomatitis (17.5%) and gastrointestinal disorders (18%). Only in three cases it was necessary a reduction in the dose of the cetuximab (due to hepatic toxicity grade 3, diarrhoea grade 3 and stomatitis grade 3). Only four patients developed progressive disease while on the first four months, one of them within the first two months. 11 had stable disease and the rest had partial response. Conclusion: The results demonstrated that cetuximab monotherapy is beneficial for the treatment of elderly patients with metastatic colorectal cancer and it has a favourable toxicity profile.

Introduction: Fluoropyrimidines are the backbone of the majority of approved chemotherapy regimens for colorectal cancer (CRC). However, they are not free of toxicities which sometimes may preclude their administration or continuation. Raltitrexed is indicated for palliative treatment of advanced CRC where 5-fluorouracil (5-FU) is inappropriate or not tolerated, thus in those cases with intolerance to fluoropyrimidines we replace them by this drug. Methods: We carried out a retrospective study to identify the reasons for using raltitrexed in our CRC population and the most frequent toxicities experienced. Clinical notes from patients diagnosed with CRC were identified and those who received raltitrexed in the last year were included. Results: We evaluated 156 patients with CRC, 36 eligible (21 men, 15 women). 28 were receiving adjuvant treatment while 8 were metastatic. 30/36 were on capecitabine, 6 on 5-FU. The reasons to change for raltitrexed were: permanent palpitations (31%), ischaemic cardiopathy (39%), uncontrollable diarrhoea and stomatitis (16%), palmo-plantar dysesthesia (14%). All the patients were able to finish the therapy without any delays. In 18/28 the raltitrexed was combined with oxaliplatin as adjuvant treatment and in 5/8 in metastatic setting. The most frequent toxicities seen with raltitrexed were diarrhoea, tiredness, stomatitis and anorexia, but all of them grade 1-2. Conclusion: Raltitrexed has got a favourable safety profile compared to fluoropyrimidines and it is well tolerated when replacing those in CRC patients..

Introduction: Fluoropyrimidines are the backbone of the majority of approved chemotherapy regimens for colorectal cancer. Though generally well tolerated, however, they are not free of toxicities including cardiopathies.Methods: We carried out a retrospective review to evaluate cardiac toxicity in those patients receiving a fluoropyrimidine, either capecitabine or 5-fluorouracil for colorectal cancer. Patients who had received a fluoropyrimidine in the past 2 years were evaluated and those who had a cardiac toxicity were included in our analysis.Results: We evaluated 756 patients, 76% had colon cancer and 24% rectal cancer. 16.8% had a cardiotoxicity. Most of them (56%) had chest pain with ischaemic changes in the ECG (angina and myocardial infarction), tachyarrhythmia with palpitations (26%), symptomatic bradyarrhythmia (13%), hypotension (5%). 3 patients died of cardiac arrest after a heart attack. Most of these patients were having capecitabine (78%) and the rest were having 5-fluorouracil in a continuous infusion. 92% of those patients developing ischaemic changes had a pre-existing ischaemic condition. We have not evaluated subclinical changes in the ECG while having these treatments.Conclusion: Larger studies are necessary to evaluate cardiac toxicity with fluoropyrimidines to know risk factors predisposing to this toxicity and to prompt a correct treatment. We plan to carry out a prospective study to evaluate subclinical ECG changes with fluoropyrimidines. Introduction: Fluoropyrimidines are the backbone of the majority of approved chemotherapy regimens for colorectal cancer. Though generally well tolerated, however, they are not free of toxicities including cardiopathies. Methods: We carried out a retrospective review to evaluate cardiac toxicity in those patients receiving a fluoropyrimidine, either capecitabine or 5-fluorouracil for colorectal cancer. Patients who had received a fluoropyrimidine in the past 2 years were evaluated and those who had a cardiac toxicity were included in our analysis. Results: We evaluated 756 patients, 76% had colon cancer and 24% rectal cancer. 16.8% had a cardiotoxicity. Most of them (56%) had chest pain with ischaemic changes in the ECG (angina and myocardial infarction), tachyarrhythmia with palpitations (26%), symptomatic bradyarrhythmia (13%), hypotension (5%). 3 patients died of cardiac arrest after a heart attack. Most of these patients were having capecitabine (78%) and the rest were having 5-fluorouracil in a continuous infusion. 92% of those patients developing ischaemic changes had a pre-existing ischaemic condition. We have not evaluated subclinical changes in the ECG while having these treatments. Conclusion: Larger studies are necessary to evaluate cardiac toxicity with fluoropyrimidines to know risk factors predisposing to this toxicity and to prompt a correct treatment. We plan to carry out a prospective study to evaluate subclinical ECG changes with fluoropyrimidines.

Introduction: Oxaliplatin is a third generation platinum derivative, used mainly for gastrointestinal tumors. Ocular toxicity is uncommon but it has been reported. In fact, it may produce a variety of ocular changes, most of them being transient and reversible.Methods: We carried out a retrospective study to evaluate ocular toxicities in patients who received oxaliplatin for colorectal cancer.Results: 365 patients were evaluated and ocular toxicities were documented in 38. 61% had metastatic colorectal cancer. In 96% oxaliplatin was combined with a fluoropyrimidine. The most frequent ocular toxicities seen were tearing (52%), dry eyes (29%), conjunctivitis (15%), blurred vision (34%), vision of bright lights especially at night (14%), altered colour vision (9%), visual loss (58%) and eye pain (12%). None of these patients had a permanent damage. After stopping the chemotherapy all of the toxicities were recovered. The fluoropyrimidines may have played a role in these toxicities too though it is difficult to know exactly which.Conclusion: Unfortunately, the mechanism of this toxicity remains unknown, therefore further studies are expected to bring clarity. Introduction: Oxaliplatin is a third generation platinum derivative, used mainly for gastrointestinal tumors. Ocular toxicity is uncommon but it has been reported. In fact, it may produce a variety of ocular changes, most of them being transient and reversible. Methods: We carried out a retrospective study to evaluate ocular toxicities in patients who received oxaliplatin for colorectal cancer. Results: 365 patients were evaluated and ocular toxicities were documented in 38. 61% had metastatic colorectal cancer. In 96% oxaliplatin was combined with a fluoropyrimidine. The most frequent ocular toxicities seen were tearing (52%), dry eyes (29%), conjunctivitis (15%), blurred vision (34%), vision of bright lights especially at night (14%), altered colour vision (9%), visual loss (58%) and eye pain (12%). None of these patients had a permanent damage. After stopping the chemotherapy all of the toxicities were recovered. The fluoropyrimidines may have played a role in these toxicities too though it is difficult to know exactly which. Conclusion: Unfortunately, the mechanism of this toxicity remains unknown, therefore further studies are expected to bring clarity.

Oxaliplatin is a platinum compound mainly used in the treatment of colorectal cancer. According to its manufacturer it is not considered vesicant agent though it has been shown to cause severe tissue damage if extravasation occurs in large doses. Several cases of extravasation have been reported; most of them from incorrectly placed peripheral cannula or incorrect use of central venous access devices. To reduce these risks, peripherally inserted central catheters and midline catheters have been increasingly used and are especially helpful if poor peripheral venous access. Midlines are mainly used for patients not receiving vesicant drugs, and are generally inserted without radiological guidance. They are believed to be safe, but we present the first ever-documented oxaliplatin extravasation injury from a midline catheter.

Systemic anticancer therapies may produce several toxicities including eye adverse events. In fact, contrary to general belief, the eye is a really sensitive organ. These adverse events may vary between a simple lacrimation to a marked irreversible visual loss even at therapeutic doses. A review of the literature was conducted showing that ocular toxicity is not as uncommon as previously thought and unfortunately in most cases, the mechanism underlying this continue to be poorly understood. Dealing with this toxicity is relevant and a close collaboration between oncologists, ophthalmologists and pharmacists would be advisable to reduce the incidence of serious toxicities.

To the editor, Pemetrexed is a multitargeted antifolate approved for nonsmall cell lung cancer, non-squamous type, either as initial treatment in combination with cisplatin or as monotherapy for maintenance or second-line, and for non-resectable malignant pleural mesothelioma in combination with cisplatin (1,2). Pemetrexed is usually a well-tolerated drug, however, it has got certain side-effects. The most common adverse reactions (occurring in ≥20%) when used as single-agent are fatigue, nausea and anorexia, but it may have additional complications such as diarrhea, rash or myelosuppression (3), which is generally the dose-limiting toxicity. As expected, when combined with cisplatin some of these side-effects may be more noticeable, especially myelosuppression and stomatitis. Despite using steroids as prophylaxis, to reduce potential cutaneous toxicities (CT) or their severity, these adverse reactions have been described in up to 14% of the patients treated with pemetrexed alone, and in 22% when combined with cisplatin, being grade 3 or 4 in approximately 0.8-1.3% of cases (4,5).