Ursula Falkmer

Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms)

Neuroendocrine tumours of the gastroenteropancreatic system have generated increased attention during the last decade. The incidence of neuroendocrine tumours seems to have increased during this time period and new diagnostic and therapeutic procedures have furthermore enhanced the interest of physicians in these diseases. Although there is an increased awareness of neuroendocrine tumours among physicians, there is still both a doctor’s and patient’s delay of several years until the correct diagnosis is made. Most oncologists, endocrinologists, and gastroenterologists see only a few such patients, sometimes not every year, making them uncomfortable with the diagnosis and treatment. Therefore, a group of members of the Nordic Neuroendocrine Tumour Group wanted to compile some guidelines to facilitate the diagnosis and treatment of these patients. The members have been working in this field for 10 /30 years and have amassed vast experience in the management of these patients. Because of the rareness of the disease only a few randomized trials have been performed and, therefore, the evidence-based medicine criteria reach only grade three to four in diagnosis and treatment. However, the large number of uncontrolled studies form the basis of today’s knowledge for the management of these tumours. A general consensus has been reached by the members of this group. Our opinion is very much in agreement with that from other parts of the world including Europe, Australia, and North America.

Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms) Part I—General Overview

The incidence of neuroendocrine tumours of the gastroenteropancreatic system seems to have increased during the past decade. New diagnostic and therapeutic procedures have aroused the interest of physicians, though most see very few cases of such diseases. A group of members of the Nordic Neuroendocrine Tumour Group decided to compile some guidelines to facilitate the diagnosis and treatment of patients with these tumours. Part I of these guidelines discusses the principles of histopathology, biochemical and radiological diagnosis as well as therapeutic options.

Nutritional status, cachexia and survival in patients with advanced colorectal carcinoma. Different assessment criteria for nutritional status provide unequal results

BACKGROUND & AIMS Different nutrition assessment tools and definitions are proposed for cancer-associated malnutrition and wasting (cachexia). We studied the associations between these assessments and overall survival in stage IV colorectal carcinoma patients. METHODS Anthropometric measures, energy intake, biochemical variables, nutritional risk screening, assessment of malnutrition, cachexia and body composition from computed tomography images were analysed, in 77 patients from Norway and Canada. Results were dichotomized into presence or absence of nutritional risk, malnutrition, cachexia and sarcopenia (low muscle mass) and associated with survival. RESULTS Overall, 22% up to 55% of the patients had cachexia according to different cachexia criteria: 34% were malnourished, 42% were at nutritional risk, and 39% were sarcopenic. Forty-four percent of the patients did not meet criteria for any of these conditions. Patients with cachexia defined by Cancer Cachexia Study Group (CCSG) had shorter survival in an unadjusted analysis, [Hazard ratio (HR) = 2.43; 95% confidence interval (CI) 1.32-4.47; P = 0.005]. After adjusting for nation, age and gender, cachexia (HR = 2.26; CI 1.18-4.32; P = 0.014) and malnutrition (HR = 1.83; CI 1.06-3.13; P = 0.029) remained significant predictors of survival. CONCLUSIONS Nutritional depletion in up to 55% of the patients was found. The lack of concordance between the results obtained by different assessment criteria was obvious. CCSGs cachexia score was the best prognostic factor for overall survival.

Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part II-specific NE tumour types.

Part II of the guidelines contains a description of epidemiology, histopathology, clinical presentation, diagnostic procedure, treatment, and survival for each type of neuroendocrine tumour. We are not only including gastroenteropancreatic tumours but also bronchopulmonary and thymic neuroendocrine tumours. These guidelines essentially cover basic knowledge in the diagnosis and management of the different forms of neuroendocrine tumour. We have, however, tried to give more updated information about the epidemiology and histopathology, which is essential for the clinical management of these tumours.

Treatment with Combined Streptozotocin and Liposomal Doxorubicin in Metastatic Endocrine Pancreatic Tumors

Treatment with combined streptozotocin and liposomal doxorubicin is safe and efficient in patients with endocrine pancreatic tumors (EPTs). No cardiac toxicity was reported. Background: The combination of streptozotocin and doxorubicin has been shown to be superior to streptozotocin and fluorouracil in the treatment of metastatic EPTs. However, the risk of cardiac toxicity from anthracyclins hampers the usefulness of the drug combination. Liposomal doxorubicin has a lower frequency of cardiac adverse events compared to doxorubicin. We wanted to assess the efficacy and safety of combined streptozotocin and liposomal doxorubicin in patients with metastatic EPTs. Methods: Thirty patients with metastatic EPTs were recruited from three medical centers in Norway and Sweden during a time period of 3 years. All patients had histopathologically confirmed diagnoses and bidimensionally measurable lesions. 30 mg/m2 of liposomal doxorubicin was administered on day 1 of each cycle. During the first course, 1 g of streptozotocin was given on 5 consecutive days. Thereafter, 2 g of streptozotocin was given on day 1 only. Treatment was repeated every 3 weeks. Results: Twelve of 30 patients (40%) achieved an objective radiological response with a median duration of 9 months. Stabilization of disease was achieved in 17 of 30 patients (57%) for a median duration of 11 months. Only one patient had progressive disease as best response. The 2-year progression-free survival was 18% and the 2-year overall survival was 72%. The treatment was well tolerated. None of the patients experienced cardiac toxicity. Conclusion: We conclude that combined streptozotocin and liposomal doxorubicin is a safe and efficient treatment for EPTs. The efficacy seems to be comparable to that of combined streptozotocin and doxorubicin, whereas the cardiac toxicity clearly favors using the liposomal drug combination.

Pattern of distribution and prognostic value of angiogenesis in pancreatic duct carcinoma : A semiquantitative immunohistochemical study of 45 patients

In specimens obtained from resected pancreata, the intratumoral microvessel density (IMD), the proliferation rate of the neoplastic parenchymal cells, and their p53 protein expression were assessed. The sources of errors were great in the measurements of the IMD. This statement can be illustrated by the finding that when the IMD was calculated by manual counting in five areas of intense neovascularization (hot spot regions), using ×200 and ×400 magnifications, the numbers of microvessels per square millimeter were 65 ± 23 and 106 ± 8, respectively, which reflects a significant difference. Two patterns of microvessel distribution could be identified: one with hot spots only in the stroma (n = 19) and one in which the hot spots were located in areas of neoplastic parenchyma (including its stroma) (n = 26). The IMD was significantly greater in the latter group. There was no general correlation of neoplastic disease with the IMD. However, when a scoring system was used to assess the angiogenesis, hot spots in areas of neoplastic parenchyma were associated with a greater proliferation rate of the tumor cells, and with a short length of survival of the patients from their neoplastic disease.

Expression of chromogranins A, B, and C (secretogranin II) in human adrenal medulla and in benign and malignant pheochromocytomas An immunohistochemical study with region-specific antibodies

In a recent immunohistochemical study of pheochromocytomas, a difference was observed between benign and malignant pheochromocytomas in their expression in different parts of the chromogranin (Cg) A molecule. The purpose of the present study was to extend the investigations by including two other members of this Cg family, CgB and C. Twenty‐five patients operated on for clinicopathologically benign pheochromocytomas, and four for metastasizing pheochromocytomas, were studied. Expression of the different Cg regions was studied immunohistochemically by means of region‐specific antibodies: four raised against CgA epitopes, five against CgB, and two against CgC. Adrenal medulla parenchyma from three surgical adrenalectomy specimens was used as non‐neoplastic control. All cells of normal adrenal medulla were immunoreactive to all 11 region‐specific Cg antibodies. In the pheochromocytomas, variations in the expression pattern occurred, but no significant quantitative differences were noted between benign and malignant tumours. Nevertheless, in all four malignant pheochromocytomas, the antibodies raised against the C‐terminal regions of both CgB and CgC visualised a noticeable population of large spindle‐shaped tumour cells, characterised by elongated processes. This cell type occurred in all four malignant pheochromocytomas but only in one benign tumour. Their structure and immunoreactivity differed from those of the sustentacular cells in the pheochromocytoma parenchyma. The use of region‐specific antibodies raised against epitopes in the C‐terminal region of CgB and CgC can facilitate the diagnosis of malignant pheochromocytoma.

The established and future biomarkers of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with a median survival of 12months. The MPM incidence is 1-6/100,000 and is increasing as a result of historic asbestos exposure in industrialized countries and continued use of asbestos in developing countries. Lack of accurate biomarkers makes diagnosis, prognostication and treatment prediction of MPM challenging. The aim of this review is to identify the front line of MPM biomarkers with current or potential clinical impact. Literature search using the PubMed and PLoS One databases, the related-articles function of PubMed and the reference lists of associated publications until April 26th 2015 revealed a plethora of candidate biomarkers. The current gold standard of MPM diagnosis is a combination of two positive and two negative immunohistochemical markers in the epithelioid and biphasic type, but sarcomatous type do not have specific markers, making diagnosis more difficult. Mesothelin in serum and pleural fluid may serve as adjuvant diagnostic with high specificity but low sensitivity. Circulating proteomic and microRNA signatures, fibulin-3, tumor cell gene-ratio test, transcriptomic, lncRNA, glycopeptides, pleural fluid FISH assay, hyaluronate/N-ERC mesothelin and deformability cytometry may be important future markers. Putative predictive markers for pemetrexed-platinum are tumor TS and TYMS, for vinorelbine the ERCC1, beta-tubuline class III and BRCA1. Mutations of the BAP1 gene are potential markers of MPM susceptibility. In conclusion, the current status of MPM biomarkers is not satisfactory but encouraging as more sensitive and specific non-invasive markers are emerging. However, prospective validation is needed before clinical application.

Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma: a study of the monoclonal antibodies MIB-1 and DO-7 in formalin-fixed paraffin-embedded tumour material.

Formalin-fixed paraffin-embedded material from 57 patients in whom curative resection of pancreatic carcinoma had been attempted was analysed by an immunohistochemical procedure to estimate proliferation and p53 protein expression. Using the monoclonal antibody (MAb) MIB-1, which recognizes a Ki-67 epitope, the proliferating cell index (PCI, percentage of immunoreactive tumour nuclei) and proliferating cell area (PCA, percentage of immunoreactive tumour nuclear area) were calculated using an interactive image analysis system and were compared with semiquantitative scoring of stainability. MAb DO-7, which recognizes both wild- and mutant-type p53 protein, was used to assess p53 expression in the same material. MIB-1 stainings were of high quality in 53 tumours. The median PCI was 29.7% (range 0.5-82.1%) and the median PCA was 10.6% (range 0.0-36.5%). There was a close correlation between PCI and PCA (P < 0.0001). PCI and PCA values were in conformity with the semiquantitative scoring (P < 0.0001). The p53 immunohistochemical stainings were successful in 48 tumours and the protein was expressed in 22 (46%). High PCI values (> 45%, n = 14) correlated with shorter survival time (P < 0.01). PCA (P < 0.05) and the expression of p53 protein (P < 0.001) were independent prognostic variables.

Review on adjuvant chemotherapy for rectal cancer – why do treatment guidelines differ so much?

Abstract Background. The use of postoperative adjuvant chemotherapy is controversial for rectal adenocarcinoma. Both international and national guidelines display a great span varying from recommending no adjuvant chemotherapy at all, over single drug 5-fluororuacil (5-FU), to combinations of 5-FU/oxaliplatin. Methods. A review of the literature was made identifying 24 randomized controlled trials on adjuvant treatment of rectal cancer based on about 10 000 patients. The trials were subdivided into a number of clinically relevant subgroups. Results. As regards patients treated with preoperative (chemo) radiotherapy, four randomized studies were found where use of adjuvant chemotherapy showed no benefit in survival. Three trials were found in which a subset of patients received preoperative (chemo) radiotherapy. Two of these trials showed a statistically significant benefit of adjuvant chemotherapy. Twenty trials were identified in which the patients did not receive preoperative (chemo) radiotherapy, including five Asian studies in which a statistically significant benefit from adjuvant chemotherapy was reported. Conclusions. Most of the data found did not support the use of postoperative adjuvant chemotherapy for patients already treated with preoperative (chemo) radiotherapy. For patients not treated preoperatively, several studies support the use of single agent 5-FU chemotherapy. Treatment guidelines seem to differ according to if preoperative chemoradiation is considered of importance for use of adjuvant chemotherapy and if adjuvant colon cancer studies are considered transferrable to rectal cancer patients regardless of the molecular differences.