Toward a Molecular Classification of Colorectal Cancer: The Role of Microsatellite Instability Status

Microsatellite instability (MSI) is the molecular hallmark of DNA mismatch repair deficiency. Since its initial description in colorectal cancer (CRC) in 1993 and its association with Lynch syndrome, the most common inherited cancer predisposition world-wide, accumulating evidence suggests that MSI status may also be of concrete prognostic and predictive value in the management of sporadic CRC. This mini review aims at providing a concise survey of the molecular basis and the multifaceted role(s) of MSI status in today’s clinical practice

Towards generating a new supernova equation of state: A systematic analysis of cold hybrid stars

The hadron-quark phase transition in core-collapse supernovae (CCSNe) has the potential to trigger explosions in otherwise nonexploding models. However, those hybrid supernova equations of state (EOS) shown to trigger an explosion do not support the observational 2 M$_\odot$ neutron star maximum mass constraint. In this work, we analyze cold hybrid stars by the means of a systematic parameter scan for the phase transition properties, with the aim to develop a new hybrid supernova EOS. The hadronic phase is described with the state-of-the-art supernova EOS HS(DD2), and quark matter by an EOS with a constant speed of sound (CSS) of $c_{QM}^2=1/3$. We find promising cases which meet the 2 M$_\odot$ criterion and are interesting for CCSN explosions. We show that the very simple CSS EOS is transferable into the well-known thermodynamic bag model, important for future application in CCSN simulations. In the second part, the occurrence of reconfinement and multiple phase transitions is discussed. In the last part, the influence of hyperons in our parameter scan is studied. Including hyperons no change in the general behavior is found, except for overall lower maximum masses. In both cases (with and without hyperons) we find that quark matter with $c_{QM}^2=1/3$ can increase the maximum mass only if reconfinement is suppressed or if quark matter is absolutely stable.Comment: 14 pages, 11 figures, v2: matches published versio

A Systematic Analysis of Hybrid Stars Using a Hadronic Equation of State Suitable for Core-Collapse Supernovae

Our long-term goal is to develop a new supernova equation of state that meets the observational 2 M⊙ neutron star constraint and that includes quark matter. In this work, we perform a parameter scan to systematically investigate the hadron-quark phase transition in cold neutron stars using the state-of-the-art supernova equation of state HS(DD2) for the hadronic phase. We find neutron star configurations with maximum masses above 2 M⊙ and even above the maximum mass of HS(DD2). Our results show good agreement with other parameter scans

Recurrent desmoids determine outcome in patients with Gardner syndrome: a cohort study of three generations of an APC mutation-positive family across 30years

Purpose: Screening of Gardner syndrome (GS) patients is tailored towards prevention of colorectal cancer (CRC). However, many patients suffer from desmoid tumors, which are challenging to treat due to invasive growth and local recurrence. The aims of our study were to determine the effectiveness of screening in GS and analyze outcome of desmoid tumors by treatment modality. Methods: This was a cohort study of a family of 105 descendants with GS. All family members who agreed were screened by endoscopy, and colorectal resection was performed upon pending malignancy. Resectable desmoids were excised, whereas large tumors were treated by a combination of brachytherapy (BT) and radiotherapy (RT). Main outcome measures were the incidence of CRC and overall and disease-specific mortality (ClinicalTrial.gov ID NCT01286662). Results: Thirty-seven of 105 family members have GS. Preventive colorectal resections were performed in 16 patients (15%), with one death due to gastric cancer. In four patients who denied screening endoscopy, invasive tumors of the colon (three patients) and stomach developed. Of 33 desmoid tumors, 10 (30%) were located in the mesentery, 17 (52%) in the abdominal wall, and 6 (18%) in extra-abdominal sites. Excision of 12 desmoids was performed in eight patients. Four desmoids were treated by BT and RT and showed full or partial remission. Conclusions: Provided adequate screening, good long-term control of colorectal tumors is achievable. However, desmoid tumors determine survival and quality of life in many patients. Our data suggest good local control using a combination of brachytherapy/radiotherapy in large desmoids unsuitable for surgical resectio

New aspects of the QCD phase transition in proto-neutron stars and core-collapse supernovae

The QCD phase transition from hadronic to deconfined quark matter is found to be a so-called "entropic" phase transition, characterized, e.g., by a negative slope of the phase transition line in the pressure-temperature phase diagram. In a first part of the present proceedings it is discussed that entropic phase transitions lead to unusual thermal properties of the equation of state (EoS). For example one finds a loss of pressure (a "softening") of the proto-neutron star EoS with increasing entropy. This can lead to a novel, hot third family of compact stars, which exists only in the early proto-neutron star phase. Such a hot third family can trigger explosions of core-collapse supernovae. However, so far this special explosion mechanism was found to be working only for EoSs which are not compatible with the 2 M⊙ constraint for the neutron star maximum mass. In a second part of the proceeding it is discussed which quark matter parameters could be favorable for this explosion mechanism, and have sufficiently high maximum masses at the same time

Concordant colon tumors in monozygotic twins previously treated for prostate cancer

This report describes the quasi-simultaneous occurrence of colon cancers in monozygotic twin brothers (age 63years) who had undergone androgen deprivation therapy for prostate cancers 4years earlier. Concordance among male twins for both of these cancers has never been reported. Although the family history suggested possible genetic predispositions to both cancers, the twins have no evidence of the genetic alterations associated with hereditary colorectal tumors. We explore the possibility that colorectal tumorigenesis in these twins was fuelled by a combination of genetic and iatrogenic factors, in particular the androgen deprivation therapy used to treat their prostate cancer

Familial colorectal cancer: eleven years of data from a registry program in Switzerland

Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n=134, 57%) or MMR-deficient (n=101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumor

Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e. the earlier age at diagnosis of CRC in successive generations. Performing nonparametric distribution-free statistical analyses, we investigated 55 parent-child pairs who had been diagnosed with CRC and who came from 21 Swiss HNPCC families with characterised MMR germline mutation (15 in MLH1 and 6 in MSH2). The overall median age at diagnosis was 43years, with an interquartile range (IQR) of 14 and incidence ages ranging from 18 to 62years. Descendants of HNPCC patients (median age at diagnosis 39years, IQR=12) were found to be diagnosed with CRC significantly earlier than their parents (47years, IQR=10), with the median of the paired age difference amounting to 8years (IQR=15; P<0.0001). Birth cohort effects could be excluded, since the same, statistically significant, age difference was also observed in the oldest offspring birth cohort (birth year <1916; P=0.01). Genetic anticipation appeared to be more pronounced when the disease allele was transmitted through the father than through the mother (median age difference 11 vs. 4years, respectively; both P<0.01). If confirmed in larger, ideally prospective studies, these results may have important implications for genetic counselling and clinical management of HNPCC familie

Muscular involvement assessed by MRI correlates to motor function measurement values in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a progressive skeletal muscle dystrophy characterized by ptosis, dysphagia, and upper and lower extremity weakness. We examined eight genetically confirmed OPMD patients to detect a MRI pattern and correlate muscle involvement, with validated clinical evaluation methods. Physical assessment was performed using the Motor Function Measurement (MFM) scale. We imaged the lower extremities on a 1.5T scanner. Fatty replacement was graded on a 4-point visual scale. We found prominent affection of the adductor and hamstring muscles in the thigh, and soleus and gastrocnemius muscles in the lower leg. The MFM assessment showed relative mild clinical impairment, mostly affecting standing and transfers, while distal motor capacity was hardly affected. We observed a high (negative) correlation between the validated clinical scores and our visual imaging scores suggesting that quantitative and more objective muscle MRI might serve as outcome measure for clinical trials in muscular dystrophie