Pancreatic Lymph Node Metastasis Research Articles

Splenectomy reduces lung metastases and tumoral and metastatic niche inflammation.

The immune microenvironment plays a crucial role in supporting tumor growth and metastasis. Tumor-associated macrophages (TAMs) and neutrophils (TANs) are essential components of this microenvironment and affect tumor growth and progression in almost all solid neoplasms. Furthermore, TAMs, TANs and tumor-infiltrating dendritic cells (TIDCs) are found to infiltrate specific distant organs to prepare them as a site for metastatic cell seeding, forming the pre-metastatic niche. The spleen was identified as a major reservoir and source of circulating and tumor infiltrating immune cells. However, discrepancies about its role in supporting tumor growth exist. Thus, here we investigated the role of splenectomy in primary tumor and metastatic growth, and in the formation of an inflammatory niche. In a murine 4T1 and E0771 breast and Panc02 pancreatic cancer model, our results show that while splenectomy reduces the number of infiltrating TAMs, TANs and TIDCs within primary tumors, it does not affect its growth. In line, fewer TAMs, TANs and TIDCs accumulate in the metastatic microenvironment after splenectomy. Interestingly though, this affected metastatic growth depending on the metastatic route/site. The number of hematogenous breast cancer lung metastases was reduced after splenectomy but no effect was observed in breast or pancreatic lymph node metastases. Moreover, we observed that the immune composition of the pre-metastatic niche in lungs of breast cancer bearing mice was altered, and that this could cause the reduction of metastases. Altogether, our results highlight that splenectomy affects the immune microenvironment not only of primary tumors but also of pre-metastatic and metastatic sites.

Fotemustine-related leukoencephalopathy

A 66-year-old woman with an 11-year history of melanoma initially treated by surgery, reaching stage IV at age 60 (with cervical and later also pancreatic lymph node metastases), received 9 cycles of 800 mg/m dacarbazine (given every 3 weeks, started at age 63) and 4 cycles of 3 mg/kg ipilimumab (a monoclonal antibody treatment, given every 3 weeks, started at age 64). Three months after the end of ipilimumab treatment, brain CT was normal (Fig. 1). Five months after the end of ipilimumab treatment, fotemustine (an alkylating antineoplastic agent) induction phase treatment was started, followed by 100 mg/m fotemustine every 3 weeks). Ten months after the start of fotemustine treatment, the patient developed mental slowing, cognitive deficit, and tetrapyramidal syndrome. CT and MRI showed dramatic, strictly supratentorial, symmetrical, leukoencephalopathy on FLAIR sequences in absence of gadolinium-enhancement on T1-weighted imaging, together with severe generalised subcortical brain atrophy (Fig. 1). At that time, fotemustine treatment was stopped. Lumbar puncture was performed, and repeated twice during the following 3 months. CSF analysis was strictly normal including PCR for JC virus. The patient refused brain biopsy. The patient worsened progressively, became bedridden, and died 6 months after onset of neurological deficit. The patient’s family refused autopsy. Differential diagnoses in our patient included brain lymphoma, progressive multifocal leukoencephalopathy, and toxic leukoencephalopathy. Symmetrical MRI abnormalities, the respect of deep grey nuclei, the absence of gadolinium-enhancement, and normal CSF analysis made lymphoma diagnosis in our patient unlikely. Absence of repeated PCR for JC virus and the very symmetrical MRI changes were against a diagnosis of progressive multifocal leukoencephalopathy. Toxic leukoencephalopathy has been reported in a large group of drugs including alkylating antineoplastic agents such as cyclophosphamide, carmustine, and busulfan, but not in fotemustine [1, 2]. Strictly toxic leukoencencephalopathy (i.e. non-JC-virus-related) has never been reported in dacarbazine, ipilimumab or other monoclonal antibody drugs. Although delayed toxic leukoencephalopathy due to dacarbazine or ipilimumab, lymphoma, and progressive multifocal leukoencephalopathy could not be ruled out completely (especially in the absence of histological examination), fotemustine-related toxic leukoencephalopathy seemed to be most probably the cause of leukoencephalopathy in our case, since fotemustine was the most recently administered drug preceding onset of neurological deficit and MRI abnormalities. D. Renard (&) C. Campello Department of Neurology, CHU Nimes, Hopital Caremeau, Place du Pr Debre, Nimes Cedex 4 30029, France e-mail: dimitrirenard@hotmail.com

Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma

Background:Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma.Methods:The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours.Results:Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis.Conclusion:The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.

Assessing Tumor Progression Factors by Somatic Gene Transfer into a Mouse Model: Bcl-xL Promotes Islet Tumor Cell Invasion

Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP) drives expression of both the SV40 T antigen (RIP-Tag) and the receptor for subgroup A avian leukosis virus (RIP-tva), are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by ∼14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad) or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and invasion, as evaluated using two-chamber transwell assays. In addition, myosin Va was identified as a novel Bcl-xL-interacting protein that might mediate the effects of Bcl-xL on tumor cell migration and invasion.