Curing pancreatic cancer.

The distinct biology of pancreatic cancer with aggressive and early invasive tumor cells, a tumor promoting microenvironment, late diagnosis, and high therapy resistance poses major challenges on clinicians, researchers, and patients. In current clinical practice, a curative approach for pancreatic cancer can only be offered to a minority of patients and even for those patients, the long-term outcome is grim. This bitter combination will eventually let pancreatic cancer rise to the second leading cause of cancer-related mortalities. With surgery being the only curative option, complete tumor resection still remains the center of pancreatic cancer treatment. In recent years, new developments in neoadjuvant and adjuvant treatment have emerged. Together with improved perioperative care including complication management, an increasing number of patients have become eligible for tumor resection. Basic research aims to further increase these numbers by new methods of early detection, better tumor modelling and personalized treatment options. This review aims to summarize the current knowledge on clinical and biologic features, surgical and non-surgical treatment options, and the improved collaboration of clinicians and basic researchers in pancreatic cancer that will hopefully result in more successful ways of curing pancreatic cancer.

CT-based and morphological comparison of glenoid inclination and version angles and mineralisation distribution in human body donors.

BACKGROUND: For optimal prosthetic anchoring in omarthritis surgery, a differentiated knowledge on the mineralisation distribution of the glenoid is important. However, database on the mineralisation of diseased joints and potential relations with glenoid angles is limited. METHODS: Shoulder specimens from ten female and nine male body donors with an average age of 81.5 years were investigated. Using 3D-CT-multiplanar reconstruction, glenoid inclination and retroversion angles were measured, and osteoarthritis signs graded. Computed Tomography-Osteoabsorptiometry (CT-OAM) is an established method to determine the subchondral bone plate mineralisation, which has been demonstrated to serve as marker for the long-term loading history of joints. Based on mineralisation distribution mappings of healthy shoulder specimens, physiological and different CT-OAM patterns were compared with glenoid angles. RESULTS: Osteoarthritis grades were 0-I in 52.6% of the 3D-CT-scans, grades II-III in 34.3%, and grade IV in 13.2%, with in females twice as frequently (45%) higher grades (III, IV) than in males (22%, III). The average inclination angle was 8.4°. In glenoids with inclination ≤10°, mineralisation was predominantly centrally distributed and tended to shift more cranially when the inclination raised to > 10°. The average retroversion angle was - 5.2°. A dorsally enhanced mineralisation distribution was found in glenoids with versions from - 15.9° to + 1.7°. A predominantly centrally distributed mineralisation was accompanied by a narrower range of retroversion angles between - 10° to - 0.4°. CONCLUSIONS: This study is one of the first to combine CT-based analyses of glenoid angles and mineralisation distribution in an elderly population. The data set is limited to 19 individuals, however, indicates that superior inclination between 0° and 10°-15°, and dorsal version ranging between - 9° to - 3° may be predominantly associated with anterior and central mineralisation patterns previously classified as physiological for the shoulder joint. The current basic research findings may serve as basic data set for future studies addressing the glenoid geometry for treatment planning in omarthritis.

Innervation of the clavicular part of the deltoid muscle by the lateral pectoral nerve.

INTRODUCTION: The innervation pattern of the clavicular head of the deltoid muscle and its corresponding topography was investigated via cadaveric dissection in the present study, focusing on the lateral pectoral nerve. MATERIALS AND METHODS: Fifty-eight upper extremities were dissected and the nerve supplies to the deltoid muscle and the variability of the lateral pectoral and axillary nerves, including their topographical patterns, were noted. RESULTS: The clavicular portion of the deltoid muscle received a deltoid branch from the lateral pectoral nerve in 86.2% of cases. Two topographical patterns of the lateral pectoral nerve were observed, depending on the branching level from the brachial plexus: a proximal variant, where the nerve entered the pectoral region under the clavicle, and a distal variant, where the nerve entered the pectoral region from the axillary fossa around the caudal border of the pectoralis minor. These dissection findings were supported by histological confirmation of peripheral nerve tissue entering the clavicular part of the deltoid muscle. CONCLUSIONS: The topographical variations of the lateral pectoral nerve are relevant for orthopedic and trauma surgeons and neurologists. These new data could revise the interpretation of deltoid muscle atrophy and of thoracic outlet and pectoralis minor compression syndromes. They could also explain the residual anteversion function of the arm after axillary nerve injury and deficiency, which is often thought to be related to biceps brachii muscle function.

Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer.

Colon cancer (CC) and rectal cancer (RC) are synonymously called colorectal cancer (CRC). Based on our experience in basic and clinical research as well as routine work in the field, the term CRC should be abandoned. We analyzed the available data from the literature and results from our multicenter Research Group Oncology of Gastrointestinal Tumors termed FOGT to confirm or reject this hypothesis. Anatomically, the risk of developing RC is four times higher than CC, while physical activity helps to prevent CC but not RC. Obvious differences exist in molecular carcinogenesis, pathology, surgical topography and procedures, and multimodal treatment. Therefore, we conclude that CC is not the same as RC. The term "CRC" should no longer be used as a single entity in basic and clinical research as well as other areas of classification.

Glenoid morphology in light of anatomical and reverse total shoulder arthroplasty: a dissection- and 3D-CT-based study in male and female body donors.

BACKGROUND: Placement of the glenoid baseplate is of paramount importance for the outcome of anatomical and reverse total shoulder arthroplasty. However, the database around glenoid size is poor, particularly regarding small scapulae, for example, in women and smaller individuals, and is derived from different methodological approaches. In this multimodality cadaver study, we systematically examined the glenoid using morphological and 3D-CT measurements. METHODS: Measurements of the glenoid and drill hole tunnel length for superior baseplate screw placement were recorded to define size of the glenoid and the distance to the scapular notch on cadaveric specimens. Glenoid angles were determined on both, 3D-CT-scans of the thoraxes using the Friedman method and on subsequently isolated scapulae from 18 male and female donors (average 84 years, range 60-98 years). RESULTS: Mean glenoid height was 36.6 mm ± 3.6, and width 27.8 mm ± 3.1 with a significant sex dimorphism (p ≤ 0.001): in males, glenoid height 39.5 mm ± 3.5, and width 30.3 mm ± 3.3, and in females, glenoid height 34.8 mm ± 2.2, and width 26.2 mm ± 1.6. The average distance from the superior screw entry to its exit in the scapular notch measured by calliper was 27.2 mm ± 6.0 with a sex difference: in males, 29.4 mm ± 5.7, and in females, 25.8 mm ± 5.9 mm with a minimum recorded distance of 15 mm. Measured by CT, the mean inclination angle for male and female donors combined was 13.0° ± 7.0, and the ante-/retroversion angle -1.0° ± 4.0°. CONCLUSION: This study is one of the first to combine dissection, including drill holes, with anatomical measurements and radiological data. In some women and smaller individuals, smaller baseplates should be selected. The published safe zone of 20 mm is generally feasible for superior screw placement, however, in small patients this distance may be substantially shorter than expected and start as of 13 and 15 mm, respectively. No correlation between glenoid height or width with the length of our drilling canal towards the scapular notch was found. Preoperative CT-based treatment planning to determine version and inclination angles is recommended.

[Short- and long-term results in operable pancreatic ductal adenocarcinomas from a cooperation between two departments gastroenterology-visceral surgery at non-university hospitals benchmarked to results of expert-centers]. / Kurz- und Langzeitergebnisse bei operablen duktalen Pankreasadenokarzinomen aus der Kooperation zwischen zwei Abteilungen Gastroenterologie-Viszeralchirurgie an nicht universitären Kliniken im Vergleich mit Resultaten aus Spitzenzentren.

The only curative approach in pancreatic ductal adenocarcinoma (PDAC) is resection, which is possible only in 15 - 30 % of patients. Local tumor spread or distant metastases are contraindications for resection in the majority of patients. Surgical-oncological quality with short- and long-term results are varying tremendously, so that "expertise/quality" are associated to hospital- or surgeon's volume and/or center formation. The treatment results also depend, to a great extent, on the medical diagnostic quality. With our retrospective study, we aim to compare the results-quality of cooperative pancreatic cancer treatment based on an extensive preoperative diagnostic procedure for staging and risk estimation in a specialized GI-medical department and visceral surgical-oncological expertise in pancreatic cancer surgery at a general hospital with the results-quality of expert centers. Fifty-three patients with PDAC had diagnosis and resection of their cancer between 1/2002 and 12/2009. The 30 day hospital-mortality was 3.8 % and the median survival time after demission from the hospital was 23.1 months. The 5-year-survival rate of R0-resected patients, all of whom had received adjuvant chemotherapy, was high with 31 %. The survival data and the extraordinarily high resection rate of 98.1 % in the patient group, whose primary tumor stage was pT3 in 81 %, reflects the excellent cooperation of high standards in medical diagnostic processes, visceral pancreatic surgery, and adjuvant medical chemotherapy. The results are well comparable to those of "high volume centers". The responsible heads of the two departments have been trained at university expert centers. Expertise in the treatment of pancreatic cancer patients may be successfully transferred from an expert center to a general hospital, if the team has high expertise.

Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin's lymphoma tumour and microenvironmental cells.

Hodgkin's lymphoma (HL) is among the most frequent nodal lymphomas in the Western world and is classified into two disease entities: nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) and classical Hodgkin's lymphoma (cHL, 95% of all HL). HL lesions are characterised by a minority of clonal neoplastic cells, namely Hodgkin and Reed-Sternberg (HRS) cells and their variants in cHL and lymphocyte-predominant (LP) cells in NLPHL, both occurring within a microenvironment of, for example, reactive T and B cells, macrophages and granulocytes that are assumed to support the proliferation and maintenance of neoplastic cells through cytokines, chemokines and growth factors. Insulin-like growth factor I (IGF-I) is an important growth factor involved in proliferation, differentiation, apoptosis and cell survival of numerous (including immune) tissues and probably has a role in tumour pathogenesis and maintenance. Although HL is characterised by disturbed cell differentiation and apoptosis mechanisms, with the involvement of the IGF-I receptor (IGF-1R), the distinct location of IGF-I in HL has not yet been defined. We localise IGF-I by double-immunofluorescence in frequent neoplastic cells of all cHL and NLPHL cases investigated. Additionally, IGF-I immunoreactivity is detected in high endothelial venules and various immune cells within the surrounding tissue of cHL including neutrophils and macrophages. IGF-1R immunoreactivity of variable intensity is found in HRS cells and high endothelial venules within the microenvironment in cHL. We assume that autocrine and paracrine IGF-I plays an anti-apoptotic role in tumour pathogenesis and in shaping the tumour microenvironment.

Body painting, ultrasound, clinical examination, and peer-teaching: A student-centered approach to enhance musculoskeletal anatomy learning.

The presented course, established 2016 as a compulsory elective for 22nd-year bachelor medical students, aimed to enhance deep learning of upper and lower limb anatomy from a clinical perspective by a maximum of student-centered activities combining hands-on skills training with team-learning. Three cohorts (in total 60 students) participated in this study. Students rotated through body painting, ultrasound, and clinical investigation supervised by faculty or an experienced clinician. Teams of 3-4 students prepared presentations on clinical anatomy and pathological conditions, which by teacher- and peer assessments on average achieved >85% (mean 17.8/20 points ± 1.06). After each activity session, the students reported their learning experience through a reflective diary. Fifty students (83%) evaluated the course by a voluntary anonymous questionnaire combining Likert-type scale and free-text questions to assess, predominantly, perception of course activities and their perceived influence on learning anatomy. Journal reports and questionnaires revealed that the students highly valued the course, and 92% (29 females, 17 males) rated group work satisfying or well-perceived. The highest appreciation achieved ultrasound followed by clinical examination and body painting, which one third proposed to integrate into the regular dissection course. All students recommended the course to their younger peers. This course was feasible to integrate in the pre-existing curriculum. Limiting factors to offer this elective course to more students are availability of clinical teachers, technical equipment, and education rooms. Being student-directed tasks, body painting and reflective diary-writing would be feasible to implement without additional faculty, which we recommend to educators for student engagement activation.

The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis).

Like in humans, diabetes mellitus is on the rise in cats. Feline diabetes is a suitable model for human type-2 diabetes. We investigated magnitude and timing of insulin suppression with induced hyperglycaemia and its relationship to plasma and urinary ketones and to pancreatic islet insulin. IGF-I is under discussion as a protective mechanism but little is known about its role in diabetes in general and its distinct localisation in feline pancreatic islets in particular. Thirteen healthy, adult cats were allocated to 2 groups and infused with glucose to maintain their blood glucose at a high or moderate concentration for 42 days resulting in insulin secretion suppression. After initial increase, insulin levels declined to baseline but were still detectable in the blood at a very low level after 6 weeks of glucose infusion and then increased after a 3 week recovery period. While IGF-I in healthy cats was primarily located in glucagon cells, in hyperglycaemia-challenge IGF-I was pronounced in the ß-cells 3 weeks after ceasation of infusion. Six/8 cats developing glucose toxicity became ketonuric after 3-4 weeks. Gross lipaemia occurred approx 1 week prior to ketonuria. Ketonuric cats required 1-2 weeks of insulin therapy after-infusion until ß-cell recovery. In conclusion, ketosis and hyperlipidaemia are likely to occur in diabetic cats with glucose at 30 mmol/L, especially after ≥2 weeks. Three weeks after ceasation of infusions, clinical and morphological recovery occurred. We propose a local protective effect of IGF-I to support survival and insulin production in the hyperglycaemic state and recovery period.

Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer.

PURPOSE: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease. METHODS: Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I-III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance. RESULTS: All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p = 0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival. CONCLUSIONS: Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.

Effects of seawater and freshwater challenges on the Gh/Igf system in the saline-tolerant blackchin tilapia (Sarotherodon melanotheron).

Prolactin (Prl) and growth hormone (Gh) as well as insulin-like growth factor 1 (Igf1) are involved in the physiological adaptation of fish to varying salinities. The Igfs have been also ascribed other physiological roles during development, growth, reproduction and immune regulation. However, the main emphasis in the investigation of osmoregulatory responses has been the endocrine, liver-derived Igf1 route and local regulation within the liver and osmoregulatory organs. Few studies have focused on the impact of salinity alterations on the Gh/Igf-system within the neuroendocrine and immune systems and particularly in a salinity-tolerant species, such as the blackchin tilapia Sarotherodon melanotheron. This species is tolerant to hypersalinity and saline variations, but it is confronted by severe climate changes in the Saloum inverse estuary. Here we investigated bidirectional effects of increased salinity followed by its decrease on the gene regulation of prl, gh, igf1, igf2, Gh receptor and the tumor-necrosis factor a. A mixed population of sexually mature 14-month old blackchin tilapia adapted to freshwater were first exposed to seawater for one week and then to fresh water for another week. Brain, pituitary, head kidney and spleen were excised at 4 h, 1, 2, 3 and 7 days after both exposures and revealed differential expression patterns. This investigation should give us a better understanding of the role of the Gh/Igf system within the neuroendocrine and immune organs and the impact of bidirectional saline challenges on fish osmoregulation in non-osmoregulatory organs, notably the complex orchestration of growth factors and cytokines.

Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines.

Rarely, scientific developments centered around the patient as a whole are published. Our multidisciplinary group, headed by gastrointestinal surgeons, applied this research philosophy considering the most important aspects of the diseases "colon- and rectal cancer" in the long-term developments. Good expert cooperation/knowledge at the Comprehensive Cancer Center Ulm (CCCU) were applied in several phase III trials for multimodal treatments of primary tumors (MMT) and metastatic diseases (involving nearly 2000 patients and 64 centers), for treatment individualization of MMT and of metastatic disease, for psycho-oncology/quality of life involving the patients' wishes, and for disease prevention. Most of the targets initially were heavily rejected/discussed in the scientific communities, but now have become standards in treatments and national guidelines or are topics in modern translational research protocols involving molecular biology for e.g., "patient centered individualized treatment". In this context we also describe the paths we had to tread in order to realize our new goals, which at the end were highly beneficial for the patients from many points of view. This description is also important for students and young researchers who, with an actual view on our recent developments, might want to know how medical progress was achieved.

Adjuvant Chemotherapy of Locally Advanced Colon Cancer: Final Results of a Randomized Trial Comparing 5-Fluorouracil and Folinic Acid with Folfiri.

BACKGROUND: There is still the need to optimize adjuvant treatment of colon cancer (CC). Standard adjuvant chemotherapy using 5-fluorouracil (FU) and folinic acid (FA) was compared with a combination including irinotecan (Folfiri). The aim of the present report was to analyze overall survival (OS) after long-term follow-up, to summarize final recurrence rates and toxicity data, and to identify possible clinical and pathological factors associated with prognosis. METHODS: Patients (CC stage IIb and III) were randomized to a 6-month treatment with FUFA or Folfiri. The trial was closed after 275 of 588 planned patients, 269 of which were included in the intention-to-treat analysis. RESULTS: 133 and 136 patients received FUFA and Folfiri, respectively. Adjuvant therapy was not completed for 16 FUFA (12.0%) and 44 Folfiri (32.4%) patients. Toxicities grade III and IV were observed in 17 (12.8%) patients treated with FUFA and in 50 (36.8%) patients treated with Folfiri. Recurrences occurred in 46 of 133 (34.6%) and in 47 of 136 (34.6%) patients who received FUFA and Folfiri, respectively. 5-year OS rates were 69.9% (95% confidence interval (CI): 61.2-77.1) for FUFA and 72.7% (95% CI: 63.9-79.8) for Folfiri. OS was associated with tumor grading (1 & 2 vs. 3), tumor sub-stage (II vs. IIIa vs. IIIb vs. IIIc), and tumor location (left vs. right colon). CONCLUSION: Folfiri cannot be generally recommended for adjuvant chemotherapy of CC. Besides tumor grading and sub-staging, prognosis of CC may depend on tumor location. Left-sided tumors had a significantly better prognosis irrespective of treatment.

Changes in blood glucose concentration are associated with relatively rapid changes in circulating fructosamine concentrations in cats.

The aim of the study was to determine the time required for plasma fructosamine concentration to increase after the onset of hyperglycaemia and decrease after resolution of hyperglycaemia. Healthy cats (n=14) were infused to maintain either moderate hyperglycaemia (n=5) (actual mean glucose 17 mmol/l) or marked hyperglycaemia (n=9) (actual 29 mmol/l) for 42 days. Fructosamine exceeded the upper limit of the reference range (331 micromol/l) after 3-5 days of marked hyperglycaemia, took 20 days to plateau and, after cessation of infusion, took 5 days to return to baseline. Fructosamine concentration for moderate hyperglycaemia took longer to exceed the reference range (7 days, range 4-14 days), and fewer days to plateau (8 days) and return to baseline (1 day). In cats with moderate hyperglycaemia, fructosamine concentration mostly fluctuated under the upper limit of the reference range. The range of fructosamine concentrations associated with a given glucose concentration was wide. The critical difference for fructosamine was 33 micromol/l.

Experience from an optional dissection course in a clinically-orientated concept to complement system-based anatomy in a reformed curriculum.

Profound anatomical knowledge is the basis for modern demands in medicine and surgery, but many countries worldwide including Australia and New Zealand have discontinued offering dissection courses to medical and dental students during the past decades. This educational project done in Australia aimed at enhancing basic and advanced anatomy teaching by engaging a sub-group of second-year undergraduate students of a compulsory prosection- and model-based anatomy course (n = 54/170) in an optional multimodal course, which should easily articulate with a vertical curriculum. With topographical cadaver dissections as core, peer student-teams prepared and peer-assessed anatomy lectures based on clinical topics, which were rated highly by the peers and teachers. Anatomical knowledge was tested by quizzes and a multiple-choice examination. Individual dissection skills were self- and teacher-assessed. A final course grade was assigned based on these assessments. The grades in the system-based compulsory course achieved by the attendees of the paralleling dissection course were compared with their peers attending other optional courses. After beginning of the semester, the students in the dissection course performed similar, significantly (P < 0.005) improved during the semester (78.5% vs. 69.9%, 70.1% vs. 64.1%), but in the integrated (including anatomy, biochemistry, physiology) final examination at the end of the year only tended to higher scores. As assessed through interviews and a voluntary questionnaire, all students of the optional dissection course liked these activities, which enhanced their learning experience. Thus, this concept elegantly integrates anatomical dissection with modern teaching demands and is feasible for implementation in modernized curricula. Anat Sci Educ 11: 32-43. © 2017 American Association of Anatomists.

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.

Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.

Minimum Volume Discussion in the Treatment of Colon and Rectal Cancer: A Review of the Current Status and Relevance of Surgeon and Hospital Volume regarding Result Quality and the Impact on Health Economics.

BACKGROUND: To answer the question whether minimum caseloads need to be stipulated in the German S3 (or any other) guidelines for colorectal cancer, we analyzed the current representative literature. The question is important regarding medical quality as well as health economics and policy. METHODS: A literature research was conducted in PubMed for papers concerning 'colon cancer' (CC), 'rectal cancer' (RC), and 'colorectal cancer' (CRC), with 'results', 'quality', and 'mortality' between the years 2000 and 2016 being relevant factors. We graded the recommendations as 'pro', 'maybe', or 'contra' in terms of a significant correlation between hospital volume (HV) or surgeon volume (SV) and treatment quality. We also listed the recommended numbers suggested for HV or SV as minimum caseloads and calculated and discussed the socio-economic impact of setting minimum caseloads for CRC. RESULTS: The correlations of caseloads of hospitals or surgeons turned out to be highly controversial concerning the influence of HV or SV on short- and long-term surgical treatment quality of CRC. Specialized statisticians made the point that the reports in the literature might not use the optimal biometrical analytical/reporting methods. A Dutch analysis showed that if a decision towards minimum caseloads, e.g. >50 for CRC resections, would be made, this would exclude a lot of hospitals with proven good treatment quality and include hospitals with a treatment quality below average. Our economic analysis envisioned that a yearly loss of EUR <830,000 might ensue for hospitals with volumes <50 per year. CONCLUSIONS: Caseload (HV, SV) definitely is an inconsistent surrogate parameter for treatment quality in the surgery of CC, RC, or CRC. If used at all, the lowest tolerable numbers but the highest demands for structural, process and result quality in the surgical/interdisciplinary treatment of CC and RC must be imposed and independently controlled. Hospitals fulfilling these demands should be medically and socio-economically preferred concerning the treatment of CC and RC patients.

Endocrine and Local IGF-I in the Bony Fish Immune System.

A role for GH and IGF-I in the modulation of the immune system has been under discussion for decades. Generally, GH is considered a stimulator of innate immune parameters in mammals and teleost fish. The stimulatory effects in humans as well as in bony fish often appear to be correlated with elevated endocrine IGF-I (liver-derived), which has also been shown to be suppressed during infection in some studies. Nevertheless, data are still fragmentary. Some studies point to an important role of GH and IGF-I particularly during immune organ development and constitution. Even less is known about the potential relevance of local (autocrine/paracrine) IGF-I within adult and developing immune organs, and the distinct localization of IGF-I in immune cells and tissues of mammals and fish has not been systematically defined. Thus far, IGF-I has been localized in different mammalian immune cell types, particularly macrophages and granulocytes, and in supporting cells, but not in T-lymphocytes. In the present study, we detected IGF-I in phagocytic cells isolated from rainbow trout head kidney and, in contrast to some findings in mammals, in T-cells of a channel catfish cell line. Thus, although numerous analogies among mammals and teleosts exist not only for the GH/IGF-system, but also for the immune system, there are differences that should be further investigated. For instance, it is unclear whether the primarily reported role of GH/IGF-I in the innate immune response is due to the lack of studies focusing on the adaptive immune system, or whether it truly preferentially concerns innate immune parameters. Infectious challenges in combination with GH/IGF-I manipulations are another important topic that has not been sufficiently addressed to date, particularly with respect to developmental and environmental influences on fish growth and health.

Calorimetric dissection of thermal unfolding of OspA, a predominantly beta-sheet protein containing a single-layer beta-sheet.

Outer surface protein A (OspA) from Borrelia burgdorferi is a predominantly beta-sheet protein comprised of beta-strands beta1-beta21 and a short C-terminal alpha-helix. It contains two globular domains (N and C-terminal domains) and a unique single-layer beta-sheet (central beta-sheet) that connects the two domains. OspA contains an unusually large number of charged amino acid residues. To understand the mechanism of stabilization of this unique beta-sheet protein, thorough thermodynamic investigations of OspA and its truncated mutant lacking a part of the C-terminal domain were conducted using calorimetry and circular dichroism. The stability of OspA was found to be sensitive to pH and salt concentration. The heat capacity curve clearly consisted of two components, and all the thermodynamic parameters were obtained for each step. The thermodynamic parameters associated with the two transitions are consistent with a previously proposed model, in which the first transition corresponds to the unfolding of the C-terminal domain and the last two beta-strands of the central beta-sheet, and the second transition corresponds to that of the N-terminal domain and the first beta-strand of the central beta-sheet in the second peak. The ratio of calorimetric and van't Hoff enthalpies indicates that the first peak includes another thermodynamic intermediate state. Large heat capacity changes were observed for both transitions, indicative of large changes in the exposure of hydrophobic surfaces associated with the transitions. This observation demonstrates that hydrophobic parts are buried efficiently in the native structure in spite of the low content of hydrophobic residues in OspA. By decomposing the enthalpy, entropy, and Gibbs free energy into contributions from different interactions, we found that the enthalpy changes for hydrogen bonding and polar interactions are exceptionally large, indicating that OspA maintains its stability by making full use of its unique beta-sheet and high content of polar residues. These thermodynamic analyses demonstrated that it is possible to maintain protein tertiary structure by making effective use of an unusual amino acid composition.

Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression levels: predictors for survival in colorectal cancer patients receiving adjuvant 5-fluorouracil.

PURPOSE: Despite adjuvant 5-fluorouracil (5-FU) therapy, approximately 30% of patients with International Union against Cancer stage II and III colorectal cancer develop recurrence. In this study, we determined the prognostic value of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression in colorectal cancer patients treated with adjuvant 5-FU. EXPERIMENTAL DESIGN: A real-time reverse transcription-PCR technique for quantitation of relative gene expression from paraffin-embedded specimen was established first. In a second step, archival paraffin-embedded primary tumor tissue of 309 patients who participated in adjuvant colorectal cancer trials was analyzed for TS and DPD mRNA expression. RESULTS: TS mRNA expression determined by real-time reverse transcription-PCR correlated with TS protein levels determined by TS immunoblot and immunohistochemistry in cultured colon cancer cell lines and paraffin-embedded primary tumor tissue. TS mRNA levels in fresh-frozen tissues also correlated with TS mRNA levels in corresponding paraffin sections. Among the patients receiving adjuvant 5-FU therapy, those with high TS survived longer than those with low TS, and in each TS subgroup, the ones with low DPD survived longer than the ones with high DPD levels. Multiple Cox regression analysis showed that besides tumor stage (P = 0.010), only the combination of TS and DPD expression turned out to be an independent prognostic factor for survival (P = 0.030). CONCLUSIONS: This suggests that TS and DPD quantitation may be helpful to evaluate prognosis of patients receiving adjuvant 5-FU and that patients with high TS and low DPD may benefit from adjuvant 5-FU chemotherapy.