A Histological and Clinical Study of MatriDerm® Use in Burn Reconstruction.

Dermal substitutes are well established in the reconstructive ladder. MatriDerm® (Dr. Otto Suwelack Skin & Health Care AG, Billerbeck, Germany) is a single-layer dermal substitute composed of a bovine collagen (type I, III, and V) and elastin hydrolysate, that allows for immediate split-thickness skin grafting (SSG). The aim of this study was to histologically characterize the integration of MatriDerm® when used during burns surgery reconstruction. Eight subjects with nine burn scars and one acute burn wound underwent reconstruction with MatriDerm® and an immediate SSG. MatriDerm® integration and skin graft take were assessed with serial biopsies performed at weeks 1, 2, 3, and 4 and months 2, 3, 6, 9, and 12. Biopsies were assessed with standard special stains and immunohistochemistry, and representative slides were imaged with a transmission electron microscope. Patient satisfaction and clinical scar outcome were assessed with the Vancouver Scar Scale and a patient questionnaire. Histological analysis showed similar stages of wound healing as shown in other dermal templates but on a different timescale. There is early evidence of vascularization and an inflammatory infiltrate in the first 2 weeks. MatriDerm® is resorbed earlier than other dermal substitutes, with evidence of resorption at week 3, to be completely replaced by a neodermis at 2 months. The use of MatriDerm® in reconstruction with immediate skin grafting is supported histologically with early evidence of vascularization to support an epidermal autograft. Future histological studies may help further characterize the ideal dermal substitute.

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.

TGF-ß 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-ß is highly expressed in the TCM and accumulates in the plasma. TGF-ß 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-ß blockade.

A Case of Giant Proliferative Periocular Pyogenic Granuloma.

Pyogenic granuloma (PG) is a common vascular anomaly affecting the skin with occasional involvement of mucosa. Ophthalmic surgeons typically encounter these lesions as solitary, bright red, rapidly growing papules following surgery or trauma to the conjunctiva, e.g. chalazion, strabismus, or enucleation surgery. We present a rare and novel case of a disfiguring proliferative & eruptive giant pyogenic granuloma involving both mucosal and non-mucosal tissue of the ocular adnexa in the absence of any previous surgery, trauma, or medical history in a previously fit and well 43-year-old male. We demonstrate the histological features of the lesion following successful management with surgical excision & primary closure. The authors advocate surgery as the gold standard for managing such proliferative lesions ensuring low recurrence rates and histological confirmation for a lesion whose differential diagnoses include malignant eyelid lesions such as keratoacanthoma and squamous cell carcinoma.

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 Apcmin/+ 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.

Metastatic melanoma vs lymphoma. Using a sentinel lymph node biopsy a diagnostic tool.

Sentinel lymph node biopsy (SLNB) is a prognostic tool used in cases of melanoma with a stage IB or greater and the absence of clinical lymphadenopathy. A positive SLNB historically indicated a need for regional lymph node clearance. However, cases of clinical lymphadenopathy in the presence of primary melanoma negates the use of SLNB and rather the British Association of Dermatologists advocate a primary block dissection of regional lymphatic tissue [NICE UK. Melanoma: assessment and management. NICE Guideline NG 14. 2015]. The following describes the case of a patient with an original stage II melanoma and a concurrent diagnosis of B cell lymphoma associated with widespread lymphadenopathy. Our multi-disciplinary team believe the use of SLNB is a more informative investigation compared with ultrasonograpphy and fine needle aspiration for such cases. In cases of clinical uncertainty due to a dual diagnosis of lymphoma, cytology would not provide nodal morphology or histological architecture, required for lymphoma grade and subtype.

Whole Genome Methylation Analysis of Nondysplastic Barrett Esophagus that Progresses to Invasive Cancer.

OBJECTIVE: To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. BACKGROUND: Identifying patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma remains a challenge. Previous studies have demonstrated the potential utility of epigenetic markers for identifying this group. METHODS: A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with nondysplastic Barrett esophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing. RESULTS: In all, 12 patients with "progressive" versus 12 with "nonprogressive" nondysplastic Barrett esophagus were analyzed via methylation array. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adenocarcinoma or remain static. Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P = 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma. There were no differences in copy number between the 2 groups, but a global trend towards hypomethylation in the progressor group was observed. CONCLUSION: Hypomethylation of OR3A4 has the ability to risk stratify the patient with nondysplastic Barrett esophagus and may form the basis of a future surveillance program.

Large Bowel Obstruction, a Delayed Complication of Severe Gallstone Pancreatitis.

Colonic complications are rare after acute pancreatitis but are associated with a high mortality. Possible complications include mechanical obstruction, ischaemic necrosis, haemorrhage, and fistula. We report a case of large bowel obstruction in a 31-year-old postpartum female, secondary to severe gallstone pancreatitis. The patient required emergency laparotomy and segmental bowel resection, as well as cholecystectomy. Presentation of obstruction occurs during the acute episode or can be delayed for several weeks. The most common site is the splenic flexure owing to its proximity to the pancreas. Initial management may be conservative, stenting, or surgical. CT is an acceptable baseline investigation in all cases of new onset bowel obstruction. Although bowel obstruction is a rare complication of pancreatitis, clinicians should be aware of it due to its high mortality. Obstruction can occur after a significant delay following the resolution of pancreatitis. Those patients with evidence of colonic involvement on pancreatic imaging warrant further large bowel evaluation. Bowel resection may be required electively or acutely. Colonic stenting has an increasing role in the management of large bowel obstruction but is a modality of treatment that needs further evaluation in this setting.

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.

MALDI profiles of proteins and lipids for the rapid characterisation of upper GI-tract cancers.

AIM: To identify a reliable MALDI 'cancer fingerprint' to aid in the rapid detection and characterisation of malignant upper GI-tract disease from endoscopic biopsies. METHODS: A total of 183 tissue biopsies were collected from 126 patients with or without oesophago-gastric malignancy and proteins and lipids separated by methanol/chloroform extraction. Peak intensities in the lipid and protein MALDI spectra from five types of samples (normal oesophageal mucosa from controls, normal oesophageal mucosa from patients with oesophageal adenocarcinoma, nondysplastic Barrett's oesophagus, oesophageal adenocarcinoma, normal gastric mucosa and gastric adenocarcinoma) were compared using non-parametric statistical tests and ROC analyses. RESULTS: Normal oesophageal and gastric tissue generated distinct MALDI spectra characterised by higher levels of calgranulins in oesophageal tissue. MALDI spectra of polypeptides and lipids discriminated between oesophageal adenocarcinoma and Barrett's and normal oesophagus, and between gastric cancer and normal stomach. Many down-regulations were unique to each cancer type whilst some up-regulations, most notably increased HNPs 1-3, were common. CONCLUSIONS: MALDI spectra of small tissue biopsies generated with this straightforward method can be used to rapidly detect numerous cancer-associated biochemical changes. These can be used to identify upper GI-tract cancers regardless of tumour location.

Role of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of solid pancreatic and peripancreatic lesions: is onsite cytopathology necessary?

OBJECTIVES: The reported median diagnostic yield from endoscopic ultrasound (EUS) fine-needle aspiration (FNA) cytology is 78% (range 39-93%). The aim of this study is to describe a single-centre experience in the diagnostic work-up of solid pancreatic and peripancreatic masses without the benefit of an onsite cytopathologist. METHODS: In a consecutive series of 429 EUS examinations performed over a 12-month period by a single operator, 108 were on non-cystic pancreatic or biliary lesions. Data were collected prospectively and the accuracy of FNA was assessed retrospectively using either surgery or repeat imaging as the benchmark in the presence or absence of malignancy. RESULTS: Of the 108 FNAs, 102 (94%) were diagnostic, four were falsely negative (FN) and two were atypical and considered equivocal. There were 78 pancreatic lesions, of which 65 were true positives (TP), 11 true negatives (TN) and two FN, giving an overall accuracy of 97% (76/78). Of nine periampullary lesions, two were TP, six were TN and one was FN, giving an overall accuracy of 89% (8/9). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of EUS-FNA for pancreatic and periampullary lesions combined were 96%, 100%, 100% [95% confidence interval (CI) 95-100%], 85% (95% CI 62-97%) and 97%, respectively. There were 21 bile duct lesions, of which 10 were TP, eight TN, two atypical and one FN, giving an overall accuracy of 86% (18/21). The sensitivity, specificity, PPV, NPV and accuracy of EUS-FNA for biliary lesions were 91%, 100%, 100% (95% CI 69-100%), 91% (95% CI 59-100%) and 95%, respectively. CONCLUSIONS: The diagnostic accuracy of EUS-FNA for pancreatic lesions in our series was 97% and the PPV for the three subgroups of lesion type was 100%; these figures are comparable with the best rates reported in the literature, despite the absence of onsite cytopathology. These rates are potentially a direct result of high-volume practice, dedicated endosonography and cytopathology. These results show that it is possible to achieve high rates of accuracy in places where logistical issues make it impossible to maintain a cytopathologist in the endoscopy suite. In addition, our results contribute to the limited, collective global experience on the effectiveness of EUS-FNA in periampullary and biliary lesions.

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 PRESENTATION: 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.

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.

Cutaneous presentation of aleukemic monoblastic leukemia cutis - a case report and review of literature with focus on immunohistochemistry.

Aleukemic monoblastic leukemia cutis is a rare cutaneous manifestation of a systemic hematological disorder associated with dermal infiltration of monoblasts preceding bone marrow or peripheral blood involvement. We report a case of a 75-year-old woman who presented with an erythematous maculopapular rash, which was clinically diagnosed as viral exanthema. Microscopy of the skin biopsy showed features of monoblastic leukemia. Her general physical condition rapidly deteriorated and she died 4 weeks later. We present this case to alert dermatologists of innocuous erythematous skin lesions clinically resembling a viral exanthema, which, in rare instances, may be a presenting feature of an aleukemic monoblastic leukemia cutis. This entity poses problems for dermatopathologists even on immunohistochemistry as monoblasts are negative for hemopoietic precursor cell antigens like CD34, Terminal deoxynncleotidy1 transferase (TdT) and CD117.

Morphologic changes in the endometrium associated with the use of the mirena coil: a retrospective study of 106 cases.

This study outlines the histologic changes seen in 106 endometrial specimens after use of the Mirena coil (levonorgestrel) and compares these changes with previous studies. The variables assessed include nature of the endometrial glands, metaplastic glandular changes, nuclear atypia, hobnail change, and endometrial hyperplasia. Stromal changes include pseudodecidualization, mucinous change, ulceration, and infiltration by granulocytes, neutrophils, and plasma cells, and stromal hyaline nodules, a feature not described previously. Additional changes include superficial micropapillary change, infarcted decidua, dystrophic calcification, hemosiderophages, polypoid indentations, cervical microglandular hyperplasia and endocervical pseudodecidualization. These variables are compared with a similar previous study. Significant differences in the incidence of glandular metaplasia, dystrophic calcification, plasma cell infiltrates, hemosiderophages, and presence of nuclear atypia are noted. With increased use of the Mirena coil, histopathologists need to be aware of the characteristic and constant endometrial changes due to progestogenic and mechanical effects, despite a wide variation in the duration of usage.