Calciphylaxis following kidney transplantation: a case report

Introduction: Calciphylaxis occurring after kidney transplantation is rare and rarely reported. It results in chronic non-healing wounds and is associated with a poor prognosis and is often fatal. We present a case of proximal lower limb calciphylaxis that occurred early after kidney transplantation. The patient had no classic associated risk factors. He had previously had a total parathyroidectomy but had normal serum calcium-phosphate product and parathyroid hormone levels. The clinical outcome of this case was favorable and highlights some fundamental issues relating to management. Case prsentation: A 70-year-old British Caucasian man with end-stage renal failure secondary to IgA nephropathy presented six months post kidney transplantation with cutaneous calciphylaxis lesions involving the medial aspect of the thigh bilaterally. Conclusion: To the best of our knowledge, this is the first reported case of rapid onset cutaneous calciphylaxis occurring soon after kidney transplantation that was associated with a favorable outcome. Cutaneous calciphylaxis lesions should be promptly managed with meticulous wound care, antimicrobial therapy and the correction of calcium-phosphate product where indicated

Evaluation of serum and tissue levels of VAP-1 in colorectal cancer

BACKGROUND: The endothelial adhesion molecule, vascular adhesion protein-1 (VAP-1, AOC3) promotes lymphocyte recruitment to tumours, although the contribution that VAP-1 makes to lymphocyte recruitment in human colorectal cancer (CRC) is unknown. VAP-1 exists in circulating soluble form (sVAP-1). A previous study demonstrated elevated sVAP-1 levels in CRC patients. The aim of this study was to confirm this finding and study the differences in tissue VAP-1 expression between CRC and healthy tissues. METHODS: sVAP-1 levels were measured in the serum of 31 patients with CRC and 31 age- and sex-matched controls. Tissue VAP-1 levels were measured by immunohistochemistry, quantitative real-time PCR and Western blotting. RESULTS: The mean sVAP-1 level ± SD was significantly lower in the CRC group compared with the control group (399 ± 138 ng/ml versus 510 ± 142 ng/ml, P = 0.003). Tissue VAP-1 protein and mRNA levels were significantly lower in CRC compared with normal colon tissue. VAP-1 immunostaining was practically absent from CRC. CONCLUSIONS: VAP-1 is downregulated in human CRC and although the molecular basis of this down regulation is not yet known, we suggest it may be part of a mechanism used by the tumour to prevent the recruitment of anti-tumour immune cells. Our data contradicts the findings of others with regard sVAP-1 levels in patients with CRC. Possible reasons for this are discussed

Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study

Background: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding: Cancer Research UK

Oligometastatic deposits of prostate cancer found within the sigmoid pericolic fat that was resected for colonic adenocarcinoma: a case report.

BACKGROUND Prostate cancer may rarely metastasize to the colon and colonic lymph nodes, and local treatment of oligometastatic deposits may improve oncological outcomes. Immunohistochemical stains are used to determine the most likely source of metastatic deposits when they are seen within surgical specimens. The aim of this case report is to illustrate how such techniques were used to identify unexpected prostatic metastases within the pericolic fat of a sigmoid colon resection specimen following elective curative surgery for colorectal cancer. To our knowledge, this is the first report of complete excision of oligometastatic deposits of prostate cancer found incidentally within the specimen of another cancer. CASE REPORT An 89-year-old Caucasian man underwent sigmoid colectomy for an obstructing colorectal cancer in the sigmoid colon with some mesenteric lymphadenopathy. He had previously received radical radiotherapy for prostate cancer 10 years earlier. When the specimen was examined by the histopathologist, it was noted that the pericolic fat adjacent to the colorectal adenocarcinoma contained some metastatic deposits. Positive immunohistochemical staining for prostate-specific antigen and prostate-specific acid phosphatase with negative staining for CDX2 and CK20 revealed these to be prostatic metastases rather than colonic. Since these were completely excised, and there were no other metastases, this represented a serendipitous, curative excision of oligometastatic deposits of an additional cancer to the one that was being treated. CONCLUSIONS This case illustrates how immunohistochemical staining may be used to distinguish the source of metastatic deposits based on the likelihood of primary tumor from a careful and thorough patient history

Diffuse intestinal angiomatosis as a possible paraneoplastic manifestation of small cell lung cancer: a case of small bowel angiomatosis

Vascular malformations are rare, incompletely understood and heterogeneous in presentation and clinical course. They are known to be associated with a number of benign syndromes, commonly presenting in childhood. Angiomatosis is a form of vascular malformation, hardly documented in the English literature, and has only rarely been described in the small bowel. We present a case of a middle-aged female who developed small bowel obstruction secondary to diffuse small bowel angiomatosis and subsequently developed aggressive multifocal small cell lung cancer 2 months later. Her condition rapidly deteriorated with multiple metastases and she passed away 4 months later secondary to brain metastases and diffuse disease. Small cell lung cancer is well known for its association with paraneoplastic syndromes and has been reported to cause a rise in vascular endothelial growth factor. We postulate that in this case angiomatosis presented as a paraneoplastic syndrome associated with small cell lung cancer

TGF-β orchestrates the phenotype and function of monocytic myeloid-derived suppressor cells in colorectal cancer

BACKGROUND: Monocytic myeloid-derived suppressor cells (M-MDSCs) are significantly expanded in the blood of colorectal cancer (CRC) patients. However, their presence and underlying mechanisms in the tumour microenvironment of CRC have not been examined in detail. METHODS: Tumour tissues and peripheral blood from CRC patients were analysed for the presence of M-MDSCs. The mechanisms of suppression were analysed by blocking pathways by which MDSCs abrogate T cell proliferation. Co-culture of CRC cells with monocytes were performed with and without cytokine blocking antibodies to determine the mechanism by which CRC cells polarise monocytes. Multi-spectral IHC was used to demonstrate the intra-tumoral location of M-MDSCs. RESULTS: Tumour tissues and blood of CRC patients contain M-MDSCs which inhibit T cell proliferation. Whilst inhibition of arginase and nitric oxide synthase 2 fail to rescue T cell proliferation, blockade of IL-10 released by these HLA-DR(−) cells abrogates the suppresivity of M-MDSCs. Tumour conditioned media (TCM) significantly reduces HLA-DR expression, increases IL-10 release from monocytes and causes them to become suppressive. TGF-β is highly expressed in the TCM and accumulates in the plasma. TGF-β reduces HLA-DR expression and drives monocyte immunosuppressivity. The invasive margin of CRC is enriched in CD14(+) HLA-DR(−) cells in close proximity to T cells. CONCLUSIONS: Our study demonstrates the cross-talk between CRC cells, M-MDSCs and T cells. Characterisation of CRC M-MDSCs point to therapeutic avenues to target these cells in addition to TGF-β blockade. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-021-03081-5

Evaluation of serum lysyl oxidase as a blood test for colorectal cancer

AIMS: Lysyl oxidase (LOX) expression is elevated in colorectal cancer (CRC) tissue and associated with disease progression. A blood test may form a more acceptable diagnostic test for CRC although LOX has not previously been measured in the serum. We therefore sought to determine the clinical usefulness of a serum LOX test for CRC in a symptomatic population. METHODS: Adult patients referred to a hospital colorectal clinic with bowel symptoms completed a questionnaire and provided a blood sample for serum LOX measurement. Associations between presenting symptoms, serum LOX concentrations and outcomes of investigations were tested by univariate and multivariate analyses to determine if serum LOX was clinically useful in the prediction of CRC. LOX expression in CRC and adjacent colon biopsies was evaluated by ELISA and immunohistochemistry. RESULTS: ThirtyJone cases of colorectal cancer and 16 high-risk polyps were identified from a total of 962 participants. There was no association between serum LOX concentration and the presence of CRC, high-risk polyps or cancers at any site. LOX expression was significantly increased in CRC tissue compared to adjacent colon. CONCLUSION: Despite overexpression of LOX in CRC tissue, elevated serum levels could not be demonstrated. Serum LOX measurement is therefore not a clinically useful test for CRC

Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.

Early stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apc mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)-targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations