Mid-gut ACTH-secreting neuroendocrine tumor unmasked with (18)F-dihydroxyphenylalanine-positron emission tomography.

Ectopic ACTH Cushing's syndrome (EAS) is often caused by neuroendocrine tumors (NETs) of lungs, pancreas, thymus, and other less frequent locations. Localizing the source of ACTH can be challenging. A 64-year-old man presented with rapidly progressing fatigue, muscular weakness, and dyspnea. He was in poor condition and showed facial redness, proximal amyotrophy, and bruises. Laboratory disclosed hypokalemia, metabolic alkalosis, and markedly elevated ACTH and cortisol levels. Pituitary was normal on magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus blood sampling with corticotropin-releasing hormone stimulation showed no significant central-to-periphery gradient of ACTH. Head and neck, thoracic and abdominal computerized tomography (CT), MRI, somatostatin receptor scintigraphy (SSRS), and (18)F-deoxyglucose-positron emission tomography (FDG-PET) failed to identify the primary tumor. (18)F-dihydroxyphenylalanine (F-DOPA)-PET/CT unveiled a 20-mm nodule in the jejunum and a metastatic lymph node. Segmental jejunum resection showed two adjacent NETs, measuring 2.0 and 0.5 cm with a peritoneal metastasis. The largest tumor expressed ACTH in 30% of cells. Following surgery, after a transient adrenal insufficiency, ACTH and cortisol levels returned to normal values and remain normal over a follow-up of 26 months. Small mid-gut NETs are difficult to localize on CT or MRI, and require metabolic imaging. Owing to low mitotic activity, NETs are generally poor candidates for FDG-PET, whereas SSRS shows poor sensitivity in EAS due to intrinsically low tumor concentration of type-2 somatostatin receptors (SST2) or to receptor down regulation by excess cortisol. However, F-DOPA-PET, which is related to amine precursor uptake by NETs, has been reported to have high positive predictive value for occult EAS despite low sensitivity, and constitutes a useful alternative to more conventional methods of tumor localization. LEARNING POINTS: Uncontrolled high cortisol levels in EAS can be lethal if untreated.Surgical excision is the keystone of NETs treatment, thus tumor localization is crucial.Most cases of EAS are caused by NETs, which are located mainly in the lungs. However, small gut NETs are elusive to conventional imaging and require metabolic imaging for detection.FDG-PET, based on tumor high metabolic rate, may not detect NETs that have low mitotic activity. SSRS may also fail, due to absent or low concentration of SST2, which may be down regulated by excess cortisol.F-DOPA-PET, based on amine-precursor uptake, can be a useful method to localize the occult source of ACTH in EAS when other methods have failed.

Clear Cell Papillary Renal Cell Carcinoma and Renal Angiomyoadenomatous Tumor: Two Variants of a Morphologic, Immunohistochemical, and Genetic Distinct Entity of Renal Cell Carcinoma.

Clear cell papillary renal cell carcinoma (ccpRCC) and renal angiomyoadenomatous tumor (RAT) share morphologic similarities with clear cell (ccRCC) and papillary RCC (pRCC). It is a matter of controversy whether their morphologic, immunophenotypic, and molecular features allow the definition of a separate renal carcinoma entity. The aim of our project was to investigate specific renal immunohistochemical biomarkers involved in the hypoxia-inducible factor pathway and mutations in the VHL gene to clarify the relationship between ccpRCC and RAT. We investigated 28 ccpRCC and 9 RAT samples by immunohistochemistry using 25 markers. VHL gene mutations and allele losses were investigated by Sanger sequencing and fluorescence in situ hybridization. Clinical follow-up data were obtained for a subset of the patients. No tumor recurrence or tumor-related death was observed in any of the patients. Immunohistochemistry and molecular analyses led to the reclassification of 3 tumors as ccRCC and TFE3 translocation carcinomas. The immunohistochemical profile of ccpRCC and RAT samples was very similar but not identical, differing from both ccRCC and pRCC. Especially, the parafibromin and hKIM-1 expression exhibited differences in ccpRCC/RAT compared with ccRCC and pRCC. Genetic analysis revealed VHL mutations in 2/27 (7%) and 1/7 (14%) ccpRCC and RAT samples, respectively. Fluorescence in situ hybridization analysis disclosed a 3p loss in 2/20 (10%) ccpRCC samples. ccpRCC and RAT have a specific morphologic and immunohistochemical profile, but they share similarities with the more aggressive renal tumors. On the basis of our results, we regard ccpRCC/RAT as a distinct entity of RCCs.

Maslinic acid-enriched diet decreases intestinal tumorigenesis in ApcMin/+ mice through transcriptomic and metabolomic reprogramming

Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancerrelated death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in ApcMin/+ mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P,0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in ApcMin/+ mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the ApcMin/+ mice model, suggesting its chemopreventive potential against colorectal cancer.

EURECCA colorectal: multidisciplinary mission statement on better care for patients with colon and rectal cancer in Europe

Background: Care for patients with colon and rectal cancer has improved in the last twenty years however still considerable variation exists in cancer management and outcome between European countries. Therefore, EURECCA, which is the acronym of European Registration of cancer care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012 the first multidisciplinary consensus conference about colon and rectum was held looking for multidisciplinary consensus. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries. Methods: The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Experts commented and voted on the two web-based online voting rounds before the meeting (between 4th and 25th October and between the 20th November and 3rd December 2012) as well as one online round after the meeting (4th-20th March 2013) and were invited to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. All sentences that were voted on are available on the EURECCA website www.canceraudit.eu. The consensus document was divided in sections describing evidence based algorithms of diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and stage IV separately. Consensus was achieved using the Delphi method. Results: The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members. Conclusions: It is feasible to achieve European Consensus on key diagnostic and treatment issues using the Delphi method. This consensus embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.

Maslinic acid-enriched diet decreases intestinal tumorigenesis in ApcMin/+ mice through transcriptomic and metabolomic reprogramming

Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancerrelated death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in ApcMin/+ mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P,0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in ApcMin/+ mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the ApcMin/+ mice model, suggesting its chemopreventive potential against colorectal cancer.

Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis.

BACKGROUND: Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS: We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS: Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS: PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.

Single stage transforaminal retrojugular tumor resection: The spinal keyhole for dumbbell tumors in the cervical spine.

BACKGROUND: Dumbbell tumors are defined as having an intradural and extradural component with an intermediate component within an expanded neural foramen. Complete resection of these lesions in the subaxial cervical spine is a challenge, and it has been achieved through a combined posterior/anterior or anterolateral approach. This study describes a single stage transforaminal retrojugular (TFR) approach for dumbbell tumors resection in the cervical spine. METHODS: This is a retrospective review of a series of 17 patients treated for cervical benign tumors, 4 of which were "true" cervical dumbbell tumors operated by a simplified retrojugular approach. The TFR approach allows a single stage gross total resection of both the extraspinal and intraspinal/intradural components of the tumor, taking advantage of the expanded neural foramen. All patients were followed clinically and radiologically with magnetic resonance imaging (MRI). RESULTS: Gross total resection was confirmed in all four patients by postoperative MRI. Minimal to no bone resection was performed. No fusion procedure was performed and no delayed instability was seen. At follow up, one patient had a persistent mild hand weakness and Horners syndrome following resection of a hemangioblastoma of the C8 nerve root. The other three patients were neurologically normal. CONCLUSIONS: The TFR approach appears to be a feasible surgical option for single stage resection in selective cases of dumbbell tumors of the cervical spine.

Training primary care physicians in shared decision making for colorectal cancer screening : Insights from the first statewide colorectal cancer screening program in Switzerland

Background: The State of Vaud has launched the first population-based, organized, colorectal cancer screening program in Switzerland for the population aged 50 to 69. Each primary care physician (PCP) has been invited to participate in an interactive session preparing them to enroll patients in the screening program. We aimed at testing the impact of an interactive seminar for PCPs on their intention to discuss the options of no screening, screening with the fecal-immunological test (FIT) and colonoscopy. We measured attitude, intentions and knowledge through questionnaires filled by PCPs before and after a 2.5 hour-long interactive seminar. The main outcome was the proportion of physicians foreseeing to offer coloscopy vs FIT on an equal basis. Physicians estimated the proportion of their patients prescribed a fecal occult blood test (FOBT) vs coloscopy over the months before the seminar and after the interactive seminar. We used a clinical vignette to test for knowledge about screening indications. The interactive seminar included powerpoint presentations with quizzes and clickers, an 8-minute video presenting a shared decision making (SDM) consultation around CRC screening and distribution of educational materials such as a SDM decision aid and background epidemiological information.

Colorectal Cancer Screening in Switzerland: Cross-Sectional Trends (2007-2012) in Socioeconomic Disparities.

BACKGROUND: Despite universal health care coverage, disparities in colorectal cancer (CRC) screening by income in Switzerland have been reported. However, it is not known if these disparities have changed over time. This study examines the association between socioeconomic position and CRC screening in Switzerland between 2007 and 2012. METHODS: Data from the 2007 (n = 5,946) and 2012 (n = 7,224) population-based Swiss Health Interview Survey data (SHIS) were used to evaluate the association between monthly household income, education, and employment with CRC screening, defined as endoscopy in the past 10 years or fecal occult blood test (FOBT) in the past 2 years. Multivariable Poisson regression was used to estimate prevalence ratios (PR) and 95% Confidence Intervals (CI) adjusting for demographics, health status, and health utilization. RESULTS: CRC screening increased from 18.9% in 2007 to 22.2% in 2012 (padjusted: = 0.036). During the corresponding time period, endoscopy increased (8.2% vs. 15.0%, padjusted:<0.001) and FOBT decreased (13.0% vs. 9.8%, padjusted:0.002). CRC screening prevalence was greater in the highest income (>$6,000) vs. lowest income (≤$2,000) group in 2007 (24.5% vs. 10.5%, PR:1.37, 95%CI: 0.96-1.96) and in 2012 (28.6% vs. 16.0%, PR:1.45, 95%CI: 1.09-1.92); this disparity did not significantly change over time. CONCLUSIONS: While CRC screening prevalence in Switzerland increased from 2007 to 2012, CRC screening coverage remains low and disparities in CRC screening by income persisted over time. These findings highlight the need for increased access to CRC screening as well as enhanced awareness of the benefits of CRC screening in the Swiss population, particularly among low-income residents.

Local Salmonella immunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor.

NlmCategory="UNASSIGNED">The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cervical cancer in an animal model. Non muscle-invasive bladder cancer is another disease that is easily amenable to local therapies. In contrast to data obtained in the GM, in this study we show that intravesical (IVES) instillation of synthetic toll-like receptor (TLR) agonists only modestly induced recruitment of CD8 T cells to the bladder. However, IVES administration of Ty21a, a live bacterial vaccine against typhoid fever, was much more effective and increased the number of total and vaccine-specific CD8 T cells in the bladder approximately 10 fold. Comparison of chemokines induced in the bladder by either CpG (a TLR-9 agonist) or Ty21a highlighted the preferential increase in complement component 5a, CXCL5, CXCL2, CCL8, and CCL5 by Ty21a, suggesting their involvement in the attraction of T cells to the bladder. IVES treatment with Ty21a after vaccination also significantly increased tumor regression compared to vaccination alone, resulting in 90% survival in an orthotopic murine model of bladder cancer expressing a prototype tumor antigen. Our data demonstrate that combining vaccination with local immunostimulation may be an effective treatment strategy for different types of cancer and also highlight the great potential of the Ty21a vaccine, which is routinely used worldwide, in such combinatorial therapies.

Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR-Ligand Off-Rates Measurements on Living Cells.

The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the peptide-MHC (pMHC) on cells is a key parameter for cell-mediated immunity. Yet a fundamental feature of most tumor antigen-specific CD8(+) T cells is that this avidity is low. In this study, we addressed the need to identify and select tumor-specific CD8(+) T cells of highest avidity, which are of the greatest interest for adoptive cell therapy in patients with cancer. To identify these rare cells, we developed a peptide-MHC multimer technology, which uses reversible Ni(2+)-nitrilotriacetic acid histidine tags (NTAmers). NTAmers are highly stable but upon imidazole addition, they decay rapidly to pMHC monomers, allowing flow-cytometric-based measurements of monomeric TCR-pMHC dissociation rates of living CD8(+) T cells on a wide avidity spectrum. We documented strong correlations between NTAmer kinetic results and those obtained by surface plasmon resonance. Using NTAmers that were deficient for CD8 binding to pMHC, we found that CD8 itself stabilized the TCR-pMHC complex, prolonging the dissociation half-life several fold. Notably, our NTAmer technology accurately predicted the function of large panels of tumor-specific T cells that were isolated prospectively from patients with cancer. Overall, our results demonstrated that NTAmers are effective tools to isolate rare high-avidity cytotoxic T cells from patients for use in adoptive therapies for cancer treatment.