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Simple Summary Pancreatic cancer (PDAC) is a highly malignant disease with low survival rates. Due to its close proximity to the insulin producing pancreatic islets, PDAC should be exposed to comparatively higher concentrations of the growth promoting hormone insulin. We wanted to know if PDAC might take advantage of this circumstance. Therefore we cross examined the insulin receptor’s (IR) role in PDAC and precursor lesions and put it into context with the expression of the insulin-like growth factor 1 receptor (IGF1R). Our study of 160 PDAC patient samples showed that IR overexpression is already present at the precursor level. IR overexpression in PDAC was associated with adverse clinical features. The IGF1R was found to play a different role than formerly assigned. We hypothesize that the close proximity to the pancreatic islets is exploited by PDAC up to the point of the islets’ ultimate destruction by local cancer growth. Abstract Background: The proximity of pancreatic cancer (PDAC) to the physiological source of the growth promoting hormone insulin might be exploited by this highly malignant cancer entity. We investigated if (I) PDACs express the insulin receptor (IR) in cancer cells and cancer vasculature, (II) if IR correlates with clinicopathological patient characteristics, including survival, and hence is involved in PDAC biology, (III) if IR is already expressed in precursor lesions, if (IV) the IGF1 receptor (IGF1R) is associated with clinicopathological patient characteristics and survival and (V) is linked to IR expression. Methods: 160 PDAC samples were examined for IR and IGF1R expression by immunohistochemistry. A modified HistoScore was correlated with clinicopathological characteristics and survival. Results: IR overexpression was already observed in pancreatic intraepithelial neoplasia. Furthermore, it was more frequently observed in advanced disease and associated with distant metastasis, UICC stage, lymphatic invasion and an increased lymph node ratio, but without impacting survival in the end. IGF1R expression was not associated with clinicopathological parameters or survival, in contrast to former paradigms. Conclusions: We hypothesize that the close proximity to the pancreatic islets might be advantageous for cancer growth at first, but it experiences self-limitation due to surgical removal or local destruction following accelerated cancer growth.

Background Metabolic reprogramming in gastric cancer (GC) involves not only an alteration of glucose metabolism, but also of insulin receptor (IR) expression. We investigated if (1) GCs express the IR in cancer cells (CC-IR) and vasculature (VIR), (2) IR expression is clinically relevant and may be a novel target of GC treatment. Methods 467 primary GCs were studied by immunohistochemistry using an IR-specific antibody. CD31-immunostaining ensured the presence of representative intratumoral microvasculature. VIR, and membranous and cytoplasmic CC-IR (mCC-IR, cCC-IR) were evaluated using a modified HistoScore (HScore) and subsequently dichotomized into low or high IR expressions. The IR status was correlated with clinico-pathological patient characteristics, including survival and HER2 status. Results VIR, mCC-IR, and cCC-IR (HScore > 0) were found in 97.0%, 87.6%, and 95.7% of all GCs. After dichotomization of the HScores, 50.7, 48.8, and 50.3% were classified as VIR-high, mCC-IR-high, and cCC-IR-high, respectively. IR was associated with the Laurén phenotype, tumor localization, local tumor growth, vascular invasion, perineural invasion, tumor budding, mucin phenotype, UICC stage, worse survival, and the HER2 status. On multivariate analysis, VIR status was an independent prognosticator of overall (p = 0.010) and tumor-specific (p = 0.006) patient survival. Conclusions VIR and CC-IR expressions are frequent in GC, biologically significant and even correlate with the HER2 status, opening avenues for novel putative therapeutic interventions in GC.

Background The insulin-like growth factor 1 receptor (IGF1R) is suspected to be involved in colorectal carcinogenesis and has been associated with worse survival in colorectal cancer (CRC). We hypothesized that the alleged suspect might be in truth beyond any suspicion. We investigated if the expression of the IGF1R in CRC correlates with (1) clinicopathological patient characteristics, including survival, and hence is involved in colon cancer biology; (2) the expression of the IGF1R in CRC is linked to the expression of the insulin receptor (IR). Methods We evaluated 4497 CRC samples from 1499 patients for the expression of IGF1R in tumor cells by immunohistochemistry. Cytoplasmic (cCC-IGF1R) and membranous (mCC-IGF1R) immunostaining was evaluated by employing a modified HistoScore (HScore), which was dichotomized into low or high IGF1R expressions. The IGF1R status was correlated with clinicopathological patient characteristics, survival and the IR expression status. Results cCC-IGF1R and mCC-IGF1R (HScore> 0) were found in 85.4 and 60.8% of all CRCs. After dichotomization of the HScores, 54.9 and 48.6% were classified as cCC-IGF1R-high and mCC-IGF1R-high, respectively. IGF1R was associated with tumor localization, local tumor growth, lymphatic vessel invasion, grading, mismatch repair protein expression status and IR-expression. We found no significant association with overall or tumor-specific survival, with a tendency for an even improved overall survival for cCC-IGF1R. Conclusions IGF1R expression is frequent and biologically relevant in CRC, but does not correlate with patient survival. The IGF1R might be beyond suspicion in CRC after all.

Tumor associated neutrophils (TANs) and cytotoxic T cells (CTLs) are part of the tumor microenvironment of gastric cancer (GC). We explored their tumor biological significance in neoadjuvantly/perioperatively treated GC. Immunostaining was performed on whole tissue sections of 173 GCs, using antibodies directed against myeloperoxidase (MPO) and CD8. Stained specimens were digitalized, and the densities of TANs and CTLs were assessed separately in the mucosa, tumor surface, tumor center, invasion front, and tumor scar. The densities were correlated with clinicopathological patient characteristics. Compared with a historical cohort of 449 treatment naive GCs, the TAN density in the invasion front was significantly lower in neoadjuvantly/perioperatively treated GCs. TAN density in the tumor center and invasion front correlated with tumor regression. TAN density also correlated with CTL density in the tumor center and invasion front. A high density of CTL in the tumor center correlated with an improved overall survival and tumor specific survival. We show that neoadjuvant/perioperative (radio-) chemotherapy impacts on the immune microenvironment of GC, while also depending on sex. The density of TANs in neoadjuvantly/perioperatively treated GCs differed from findings made in a treatment naive GC cohort.

Aims In this study, we aimed to independently evaluate the utility and prognostic value of tumour budding (TB) according to the International Tumour Budding Consensus Conference (ITBCC) criteria in a large and a well-characterised European gastric cancer (GC) cohort. Methods and results In 456 consecutive, surgically treated GCs, TB was assessed according to the ITBCC criteria and scored as Bd0 (no buds), Bd1 (one to four buds), Bd2 (five to nine buds) or Bd3 (≥10 buds). Cases with TB present were divided into low- (Bd1/Bd2) and high-budding (Bd3) groups. The TB score was analysed in relation to the clinicopathological parameters, overall survival (OS) and tumour-specific survival (TSS); 115 (25.2%) cases had no, 104 (22.8%) had low and 237 (52.0%) had high TB. The TB score correlated significantly with sex, Lauren phenotype, pT-, pN- and M categories, histological grade, R status; and lymph node ratio, lymphatic invasion, perineural invasion and HER2-, MET- and MSI status. In both total and intestinal-type early invasive GC (n = 57 and n = 41, respectively), significant associations between the presence and extent of TB and presence of lymph node metastasis were detected. Significant differences in OS and TSS between the TB groups were found; however, TB did not retain significance in multivariate models. Conclusions Our data show that the ITBCC criteria can be applied to GC. The data correlated significantly with the diverse clinicopathological characteristics, including patient outcome, and can help to standardise diagnostics and research into special histological features of malignant tumours in general and GC in particular.

// Steffen M. Heckl 1 , Marie Pellinghaus 1 , Sandra Kruger 2 , Clara Bosselmann 1 , Franziska Wilhelm 2 , Hans-Michael Behrens 2 , Stefan Schreiber 1 and Christoph Rocken 2 1 Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany 2 Department of Pathology, Christian-Albrechts-University, Kiel, Germany Correspondence to: Steffen M. Heckl, email: Steffen.Heckl@uksh.de Keywords: colorectal cancer; insulin receptor; cancer risk factor; cancer prognosis; cancer therapeutic target Received: May 15, 2018 Accepted: December 10, 2018 Published: December 25, 2018 ABSTRACT Background: Metabolic reprogramming in cancer encompasses the insulin receptor (IR) as a player of energy homeostasis and proliferation. We aimed to characterize vascular (VIR) and epithelial (EIR) IR expression in CRC and correlate it with clinico-pathological parameters and survival. Methods: 1580 primary CRCs were explored by immunohistochemistry for evaluation of VIR and EIR. Subgroup analyses included in situ hybridization for IR isoform A (IR-A) and DNA mismatch repair protein immunohistochemistry. Clinico-pathological and survival parameters were studied. Results: High VIR was evident in 63.5% of all CRC samples and was associated with T-stage ( P = 0.005). EIR was present in 72.2% and was associated with lower T-stages ( P = 0.006) and UICC-stages ( P < 0.001). EIR negativity was associated with increased metastasis ( P = 0.028), nodal spread ( P < 0.001), lymphatic invasion ( P = 0.008) and a decreased tumor-specific ( P = 0.011) and overall survival ( P = 0.007; 95%–C.I.: 44.5–84.1). EIR negativity in UICC-stage II was associated with a significantly worse tumor-specific ( P = 0.045) and overall ( P = 0.043) survival. IR-A was expressed in CRC vessels and cells. Conclusions: We demonstrate VIR to be frequent in CRC and characterize EIR negativity as an important prognostic risk factor. The association between EIR negativity and worse survival in UICC-stage II should be prospectively evaluated for an application in therapeutic algorithms.