Exosomal ROR1 in peritoneal fluid identifies peritoneal disseminated PDAC and is associated with poor survival.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters. Methods: Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed. Results: PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482). Conclusion: With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.

Onset and progression of postmortem histological changes in the central nervous system of RccHan™: WIST rats.

Death initiates a cascade of physiological and biochemical alterations in organs and tissues, resulting in microscopic changes that challenge the histopathological evaluation. Moreover, the brain is particularly susceptible to artifacts owing to its unique composition and its location within the cranial vault. The aim of this study was to compile and illustrate the microscopic changes in the central nervous system (CNS) of rats subjected to delayed postmortem fixation. It also scrutinizes the influence of exsanguination and cooling methods on the initiation and progression of these alterations. Twenty-four Wistar Han outbred rats (RccHan™: WIST) were sacrificed and stored either at room temperature (18-22°C) or under refrigeration (2-4°C). Necropsies were conducted at different time points postmortem (i.e., 0.5 h, 1 h, 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, 7 days and 14 days). Brain sections underwent simultaneous digital evaluation by 14 pathologists until a consensus was reached on terminology, key findings, and intensity levels. Microscopic observations varied among cell types. Glial cells were similarly affected throughout the CNS and showed pericellular halo, chromatin condensation and nuclear shrinkage. Neurons showed two types of postmortem changes as most of them showed progressive shrinkage, cytoplasmic dissolution and karyorrhexis whereas others acquired a dark-neuron-like appearance. Neuronal changes showed marked differences among neuroanatomical locations. Additional postmortem changes encompassed: granulation and microcavitation in neuropil and white matter; retraction spaces; detachment of ependyma, choroid plexus, and leptomeninges. Severity of findings after 48 h at room temperature was higher than after seven days under refrigeration and similar to or slightly lower than after 14 days under refrigeration. No clear differences were observed related to the sex or weight of the animals or their exsanguination status. This work elucidates the onset and progression of autolytic changes in the brains of Wistar Han rats, offering insights to accurately identify and enhance the histopathological evaluation.

Reproduction toxicity study with the synthetic amorphous silica SYLOID® AL-1 FP, HDK® N20, LUDOX® P T-40 F and SYLOID® MX 107 in the earthworm species Eisenia fetida.

Ecotoxicology studies were performed in the earthworm Eisenia fetida with four different synthetic amorphous silica (SAS) (SYLOID® AL-1 FP, SYLOID® MX 107, LUDOX® P T-40 F, and HDK® N20) mixed into artificial soil to determine a NOEC/LOEC for effects on reproduction (56 days after application), mortality and biomass development (28 days after application) using a standardized artificial soil with 10% peat. The LC50 for test-item effects on adult mortality, and an EC10 and EC50 for reproduction were also determined. Furthermore, earthworms underwent histopathology evaluation, and the amount of silica in different organs from these organisms was evaluated using EDX (Energy Dispersive X-ray Spectroscopy). Histopathology revealed no findings in any organ of the earthworms, except for desiccated dissepiments in evaluated decedents at extremely high SAS doses. To measure SAS uptake into the organs, a fully quantitative method for silica was established and validated using standards containing known concentrations of silica to ensure the accuracy of the analyses undertaken. Results from EDX analysis demonstrated the negligible presence of silicon within the brain ganglia and gonads of adult earthworms comparable to controls. Therefore, any deposition of the test items within these two organs was excluded. In contrast, traces of silicon higher than in controls were found in the intestinal lumina of the earthworms due to ingestion of SAS with soil and feed, but not in other organs.

Eosinophilic globules (syn. hyaline inclusions) and protein crystalloids in the nasal mucosa of rats treated with synthetic amorphous silica, an unspecific chitinase-like-protein-positive background lesion.

In a 13-week inhalation toxicity study with three recovery periods (3, 6, and 12 months), Crl: WI rats were allocated to nine groups, each containing 25 animals per sex. Eight groups were treated daily by inhalation with the test items at concentrations of 0.5, 1.0, 2.5, or 5.0 mg/m3 (SAS 1 groups 2, 3, 4, or 5, respectively; SAS 2 groups 6, 7, 8, or 9, respectively). Controls (group 1) were treated with air only. In nasal cavities, the major lesions consisted of increased eosinophilic globules and chitinase-3-like-protein-positive crystalloids* in the nasal mucosa, mainly in nasal cavity levels 2-4 up to week 26 of recovery without any further injury in olfactory mucosa, mainly in SAS 1-treated animals. Eosinophilic globules in the rodent nasal cavity are common and increase with age; they represent a particular finding of the rodent nasal mucosa. The relevance of chitinase-3-like protein (Ym1 + Ym2) expression in the rodent nasal mucosa is unknown but is normal in control animals. Both findings developed without any indicator for inflammatory processes. The increase of these unspecific background findings is considered an indicator of minor irritative effects. Due to the clear lack of nasal tissue injury or concurrent changes (degeneration, necrosis, inflammatory infiltrate, dysplasia, and/or neoplasia) following repeated inhalation exposure to SAS, it is deemed that the eosinophilic globules (hyaline inclusions) combined with the formation of eosinophilic protein crystalloids in this study represent an adaptive response.

Tissue response following implantation with the posterior dynamic distraction device (PDDD) in adolescent idiopathic scoliosis (AIS).

PURPOSE: The PDDD is a ratchet-based, unidirectional expandable rod to treat adolescent idiopathic scoliosis (AIS), primarily by correcting scoliotic deformity without full spinal fusion. We hypothesized that the device will be fully tolerated by the host and, if aseptic screw loosening occurs, it will be unrelated to wear particle formation. METHODS: This study comprised tissue samples from seven patients from a prospective study (NCT04296903) to assess the PDDD's safety and benefits, reoperated due to complications. Host response was assessed from histological slides (four levels/implant) in accordance with GLP and ISO10993-6:2016. The elementary chemical composition of wear particles present in tissue sections was quantified by energy dispersive X-ray spectroscopy (EDX). RESULTS: Host reaction was minor, characterized by low levels of diverse inflammatory cells, mild fibrosis, occasional small necrotic foci, neovascularization, hemorrhage, and, rarely, small bone fragments. Twenty-four of 28 tissue sections displayed varying degrees of wear particles (black discoloration), and most sections (17) were scored as 1 (< 25% of the sample). The discoloration observed corresponded to black-appearing, fine granular pigment. EDX analysis confirmed particles were composed of titanium, aluminum, and vanadium. Twenty-six of 28 samples were scored zero for necrosis and 2/28 were scored 1. Eleven samples were scored zero for fibrosis, 12 as 1, and five as 2. No aseptic screw loosening occurred. CONCLUSION: The PDDD induced minimal host reaction with little or no degeneration, inflammation or fibrosis. No changes present could be expected to promote device failure. The PDDD implant for treating AIS is well-tolerated and locally safe.

Survival outcome following surgical versus non-surgical treatment of colorectal lung metastasis-a retrospective cohort study.

PURPOSE: The optimal management of colorectal lung metastases (CRLM) is still controversial. The aim of this study was to compare surgical and non-surgical treatment for CRLM regarding the prognostic outcome. METHODS: This retrospective single-center cohort study included 418 patients, who were treated from January 2000 to December 2018 at a German University Hospital due to their colorectal carcinoma and had synchronous or metachronous lung metastases. Patients were stratified according the treatment of the CRLM into two groups: surgical resection of CRLM versus no surgical resection of CRLM. The survival from the time of diagnosis of lung metastasis was compared between the groups. RESULTS: Two- and 5-year overall survival (OS) from the time of diagnosis of lung metastasis was 78.2% and 54.6%, respectively, in our cohort. Patients undergoing pulmonary metastasectomy showed a significantly better 2- and 5-year survival compared to patients with non-surgical treatment (2-year OS: 98.1% vs. 67.9%; 5-year OS: 81.2% vs. 28.8%; p < 0.001). Multivariate Cox regression revealed the surgical treatment (HR 4.51 (95% CI = 2.33-8.75, p < 0.001) and the absence of other metastases (HR 1.79 (95% CI = 1.05-3.04), p = 0.032) as independent prognostic factors in patients with CRLM. CONCLUSION: Our data suggest that patients with CRLM, who qualify for surgery, benefit from surgical treatment. Randomized controlled trials are needed to confirm our findings. CLINICAL TRIAL REGISTRY NUMBER: The work has been retrospectively registrated at the German Clinical Trial Registry (DRKS00032938).

Enhanced study design for acute inhalation studies with hydrophobic surface-treated particles to determine toxicological effects including suffocation.

High concentrations of low-density particles may cause effects in acute inhalation toxicity studies which can be easily underestimated or misinterpreted following strictly the OECD TG 436, i.e., limited parameters as mortality and gross lesions will be evaluated only. Seven particle types (synthetic amorphous silica (SAS) HMDZ-SAS, silica gel, pyrogenic SAS, and precipitated SAS, calcium carbonate, aluminum oxide pyrogenic alumina, organic red pigment) were chosen at the highest technically feasible concentration of approximately 500 mg/m3 for acute inhalation studies with an expanded endpoint setup. Therefore additional parameters and a thorough histopathological evaluation of an extensive set of organs, including the respiratory tract emphasizing the nasal cavities were added. Six Crl:WI rats per study were exposed for four hours from which three animals were sacrificed after 24 hours and three animals after 14 days. HMDZ-SAS caused early death in all animals due to blockage of the nasal passages caused by its hydrophobicity. For all other Si-containing compounds, histology revealed minor inflammatory and reactive lesions in lungs after 24 hours that were still present after 14 days, except in silica gel-treated animals. After 14 days, for pyrogenic SAS, precipitated SAS, and pyrogenic alumina, granulomas formed in the BALT and lung-associated lymph nodes. In contrast, the calcium carbonate induced almost no findings, and the red pigment (also tested for the additional dose of 1000 mg/m3) stuck partially to the nasal mucosa without causing pathological damage and partly entered the lungs without showing any adverse effects. The results of the present study highlight the advantage of improving the rather simple study design of acute inhalation studies by implementing an extended study design.

Comment on Balwierz et al. Potential Carcinogens in Makeup Cosmetics. Int. J. Environ. Res. Public Health 2023, 20, 4780.

The article by Balwierz et al [...].

Near complete remission of an inoperable pancreatic acinar cell carcinoma after BRAF-/MEK-inhibitor treatment-A case report and review of the literature.

INTRODUCTION: Pancreatic acinar cell carcinomas are rare malignant neoplasms. High-quality evidence about the best treatment strategy is lacking. We present the case of a 52-year-old male with a BRAFV600E -mutated PACC who experienced a complete remission after chemotherapy with BRAF-/MEK-inhibitors. CASE: The patient presented with upper abdomen pain, night sweat, and weight loss. CT scan showed a pancreatic tumor extending from the pancreas head to body. Histological workup identified an acinar cell carcinoma. As the tumor was inoperable, chemotherapy with FOFIRNIOX was initiated and initially showed a slight regression of disease. The regimen had to be discontinued due to severe side effects. Molecular analysis identified a BRAFV600E mutation, so the patient was started on BRAF- and MEK-inhibitors (dabrafenib/trametinib). After 16 months, CT scans showed a near complete remission with a markedly improved overall health. DISCUSSION: Studies suggest that up to one-fourth of PACCs carry a BRAF mutation and might therefore be susceptible to a BRAF-/MEK-inhibitor therapy. This offers a new therapeutic pathway to treat this rare but malignant neoplasm.

NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. METHODS: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. RESULTS: We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1ß and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1ß. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1ß in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. CONCLUSIONS: In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.

Regenerative and progressing lesions in lungs and lung-associated lymph nodes from fourteen 90-day inhalation studies with chemically different particulate materials.

Rat lungs and lung-associated lymph nodes from 14 inhalation studies with chemically different particulate materials were histopathologically re-evaluated, and the bronchoalveolar lavage fluid (BALF) data and lung burden analyses were compared. All investigated substances caused similar lesions. For most substances, 1 mg/m3 of respirable particulate matter was established as the borderline for adverse morphological changes after the 90-day exposure period, confirmed by the increase in polymorphonuclear neutrophils in BALF. Possible reversibility was demonstrated when recovery groups are included in the study especially allowing the differentiation between regeneration or progressing of inflammatory changes during the recovery period. It was concluded, that the major driver of toxicity is not an intrinsic chemical property of the particle but a particle effect. Concerning classification for specific target organ toxicant (STOT) repeated exposure (RE), this paper highlights that merely comparing the lowest concentration, at which adverse effects were observed, with the Classification Labelling and Packaging (CLP) regulation (EC) no. 1272/2008 guidance values is inappropriate and might lead to a STOT classification under CLP for a large part of the substances discussed in this paper, on the basis of typically mild to moderate findings in rat lung and lung-associated lymph nodes on day 1 after exposure. An in-depth evaluation of the pathologic findings is required and an expert judgement has to be included in the decision on classification and labeling, evaluating the type and severity of effects and comparing these with the classification criteria.

Is pulmonary inflammation a valid predictor of particle induced lung pathology? The case of amorphous and crystalline silicas.

Although inflammation is a normal and beneficial response, it is also a key event in the pathology of many chronic diseases, including pulmonary and systemic particle-induced disease. In addition, inflammation is now considered as the key response in standard settings for inhaled particles and a critical endpoint in OECD-based sub-acute/ chronic animal inhalation testing protocols. In this paper, we discuss that whilst the role of inflammation in lung disease is undeniable, it is when inflammation deviates from normal parameters that adversity occurs. We introduce the importance of the time course and in particular, the reversibility of inflammation in the progression towards tissue remodelling and neoplastic changes as commonly seen in rat inhalation studies. For this purpose, we used chronic inhalation studies with synthetic amorphous silicas (SAS) and reactive crystalline silica (RCS) as a source of data to describe the time-course of inflammation towards and beyond adversity. Whilst amorphous silicas induce an acute but reversible inflammatory response, only RCS induces a persistent, progressive response after cessation of exposure, resulting in fibrosis and carcinogenicity in rodents and humans. This suggests that the use of inflammation as a fixed endpoint at the cessation of exposure may not be a reliable predictor of particle-induced lung pathology. We therefore suggest extending the current OECD testing guidelines with a recovery period, that allows inflammation to resolve or progress into altered structure and function, such as fibrosis.

A contemporary assessment of total neoadjuvant therapy (TNT) protocols for locally advanced rectal cancer: adoption and expert perspectives at German Cancer Society (DKG)-certified colorectal cancer centers.

PURPOSE: The treatment paradigm for locally advanced rectal cancer (LARC) is shifting toward the total neoadjuvant therapy (TNT) concept, which administered systemic chemotherapy in the neoadjuvant setting, either before or after chemoradiotherapy (CRT) or short-course radiotherapy (SCRT). First results have shown higher pathologic complete response (pCR) rates and a favorable impact on disease-free survival (DFS). Our study aimed to evaluate the current clinical practice and expert opinion regarding TNT for locally advanced rectal cancer across DKG (German Cancer Society)-certified colorectal cancer centers. METHODS: A comprehensive online questionnaire, constituted of 14 TNT-focused queries targeting patients with locally advanced rectal cancer, was conducted among DKG-certified colorectal cancer centers registered within the database of the Addz (Arbeitsgemeinschaft Deutscher Darmzentren) between December 2022 and January 2023. RESULTS: A significant majority (68%) indicated that they treated between 0 and 10 patients using a TNT protocol. Only a third (36%) of these centers participated in patient enrollment for a TNT study. Despite this, 84% of centers reported treating patients in a manner analogous to a TNT study, with the RAPIDO regimen being the most prevalent approach, employed by 60% of the respondents. The decision to adopt a TNT approach was primarily influenced by factors, such as the lower third of the rectum (93% of centers), cT4 stage (86% of centers), and a positive circumferential resection margin (80% of centers). Regarding concerns, 65% of the survey respondents expressed no reservations about the TNT concept, while 35% had concerns. In particular, there appears to be disagreement and uncertainty in regard to a clinical complete response and the "Watch and Wait" approach. While some centers adopt the watch-and-wait approach (42%), others only utilize it when extirpation is otherwise necessary (39%), and a portion still proceeds with surgery as initially planned (19%). The survey also addressed unmet needs, which were elaborated in the free-text responses. Overall, there was high interest in participating in planned observational studies. CONCLUSIONS: This study presents an overview of current clinical practice and unmet needs within DKG-certified German colorectal cancer centers. It is noteworthy that total neoadjuvant therapy (TNT) is predominantly performed outside of clinical trials. Moreover, across the centers, there is significant heterogeneity in handling clinical complete response and adopting the "watch and wait" approach. Further research is needed to establish standardization in the care of locally advanced rectal cancer.

Issues in the inhalation toxicity testing and hazard assessment for low density particulate materials such as synthetic amorphous silica (SAS).

Inhalation toxicity testing of particulate materials is mandated for classification. According to CLP, particulate materials should be tested as marketed and many particulate materials are marketed as non-respirable particles. However, OECD TG 413 requires exposure to particle sizes that are respirable and reach the alveoli. The requirement for exposure of rats to respirable particles is thus in contrast to CLP and requires the application of high shear forces. The exposure to artificially small particles causes a number of issues that hamper the interpretation of the results of the testing. These issues are aerosol altering in the exposure system, assessment of the adversity of the inflammatory lung responses, inclusion of recovery groups, and extrapolation of the results to humans exposed under occupational condition. In addition, effects of many particulate materials after testing according to OECD 413 are not intrinsic properties, but a general reaction of the lung to the deposited material, show very similar NOAECs for chemical diverse materials, and often are completely reversible.

Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association.

In the current era of precision oncology, it is widely acknowledged that CRC is a heterogeneous disease entity. Tumor location (right- or left-sided colon cancer or rectal cancer) is a crucial factor in determining disease progression as well as prognosis and influences disease management. In the last decade, numerous works have reported that the microbiome is an important element of CRC carcinogenesis, progression and therapy response. Owing to the heterogeneous nature of microbiomes, the findings of these studies were inconsistent. The majority of the studies combined colon cancer (CC) and rectal cancer (RC) samples as CRC for analysis. Furthermore, the small intestine, as the major site for immune surveillance in the gut, is understudied compared to the colon. Thus, the CRC heterogeneity puzzle is far from being solved, and more research is necessary for prospective trials that separately investigate CC and RC. Our prospective study aimed to map the colon cancer landscape using 16S rRNA amplicon sequencing in biopsy samples from the terminal ileum, healthy colon tissue, healthy rectal tissue and tumor tissue as well as in preoperative and postoperative stool samples of 41 patients. While fecal samples provide a good approximation of the average gut microbiome composition, mucosal biopsies allow for detecting subtle variations in local microbial communities. In particular, the small bowel microbiome has remained poorly characterized, mainly because of sampling difficulties. Our analysis revealed the following: (i) right- and left-sided colon cancers harbor distinct and diverse microbiomes, (ii) the tumor microbiome leads to a more consistent cancer-defined microbiome between locations and reveals a tumor microbiome-ileal microbiome association, (iii) the stool only partly reflects the microbiome landscape in patients with CC, and (iv) mechanical bowel preparation and perioperative antibiotics together with surgery result in major changes in the stool microbiome, characterized by a significant increase in the abundance of potentially pathogenic bacteria, such as Enterococcus. Collectively, our results provide new and valuable insights into the complex microbiome landscape in patients with colon cancer.

A review of horses sent to slaughter for human consumption: impact of horsemeat consumption, residual banned drugs, and public health risks.

Nearly all of the American horses exported to Mexico and Canada are slaughtered for human consumption, and their meat is either exported around the world or consumed locally. Previous work showed that 18 Thoroughbred racehorses purchased by rescues that would have otherwise been sold for export for the sole purpose of slaughter to produce meat for human consumption were administered phenylbutazone. We report the number of American horses exported to Canada and Mexico from 2016 to 2021, the presence of contaminated horsemeat from Canadian slaughterhouses, and the human use and idiosyncratic effects of veterinary phenylbutazone and side effects of clenbuterol, 2 of the drugs that were found in contaminated Canadian horsemeat. The number of live American horses exported to Canada declined precipitously from 2016 to 2017, and a second decline occurred in 2020. All food-producing animals are under strict regulatory control to prevent animals administered banned drugs to enter the food chain. A major principle of this program is zero tolerance for banned drugs and testing for compliance. No regulatory process is in place to remove horses administered banned drugs such as phenylbutazone. The efficacy lasts for more than 24 hours as a result of the irreversible binding to cyclooxygenase, slow elimination, and long elimination half-life of its metabolite oxyphenbutazone. High or frequent doses of phenylbutazone result in disproportionately increased plasma concentrations, which result in the residual presence in tissues. It is this fact that underlies the ban of this drug in food-producing animals. No human clinical surveillance program is in place to monitor individuals on the possible short- and long-term consequences of banned drugs in contaminated horsemeat. If the United States is unable to put in place a regulatory program to remove horses administered banned drugs as exists for all food-producing animals, the exportation of American horses across both borders for the sole purpose of slaughter for human consumption must end.

Proposal of a T3 Subclassification for Colon Carcinoma.

The TNM classification system is one of the most important factors determining prognosis for cancer patients. In colorectal cancer, the T category reflects the depth of tumor invasion. T3 is defined by a tumor that invades through the muscularis propria into pericolorectal tissues. The data of 1047 patients with complete mesocolic excision were analyzed. The depth of invasion beyond the outer border of the muscularis propria into the subserosa or into nonperitonealized pericolic tissue was measured and categorized in 655 pT3 patients: pT3a (≤1 mm), pT3b,c (>1−15 mm) and pT3d (>15 mm). The prognosis of these categories was compared. Five-year distant metastasis increased significantly from pT3a (5.7%) over pT3b,c (17.7%) to pT3d (37.2%; p = 0.001). There was no difference between pT2 (5.3%) and pT3a or between pT3d and pT4a (42.1%) or pT4b (33.7%). The 5-year disease-free survival decreased significantly from pT3a (77.4%) over pT3b,c (65.4%) to pT3d (50.1%; p = 0.015). No significant difference was found between pT2 (80.5%) and pT3a or between pT3d and pT4a (43.9%; p = 0.296) or pT4b (53.4%). The prognostic inhomogeneity in pT3 colon carcinoma has been demonstrated. A three-level subdivision of T3 for colon carcinoma in the TNM system into T3a (≤1 mm), T3b (>1−15 mm), and T3c (>15 mm) is recommended.