Areas Of Chronic Inflammation Research Articles

Abstract 4075: Targeting attenuated IL-18 to PD-1: A next generation checkpoint inhibitor with enhanced anti-tumor activity

Abstract PD-1 antagonists have shown strong clinical proof of concept, but the development of next-generation versions that can target tumors that weakly respond and/or acquire drug resistance is a critical medical need. Lymphocytes, including T cells and NK cells, upregulate PD-1 and other immunoregulatory receptors in response to neoantigens. Such immunoregulation is important for maintaining the persistence of immune responses in a controllable manner so that immune pathology does not overwhelm the host. In addition to microbial proteins, neoantigens are often expressed by tumor cells. These 'tumor antigens' are derived from mutated genes or proteins not presented during T cell education. As such, many established tumors contain areas of chronic inflammation, including a subset of PD-1+ T cells that can be 'de-immuno-regulated' by anti-PD-1 antagonist antibodies, thus enhancing anti-tumor activity. IL-18 is a cytokine that delivers a 'danger' signal to NK cells and T cell subsets that express the IL-18 receptor complex (RC) and increases their capacity to kill, induces proliferation, diminishes terminal exhaustion, and sustains survival. Importantly, IL-18RC is expressed on progenitor exhausted T cells, the population of T cells in solid tumors that is most active and responds to anti-PD-1, but not terminal exhausted T cells. The latter have been shown to be non-responsive to PD-1 antagonism. Thus, we engineered an anti-PD-1-IL-18 antibody to enhance anti-tumor immune responses. Such a therapeutic requires two key characteristics: resistance to inhibition by IL-18BP, IL-18's natural antagonist, and PD-1-dependent cis-restricted binding to the IL18RC on PD-1+ cells to reduce trans-based systemic toxicity. We have engineered an IL-18BP-resistant mutant of IL-18 and generated variants with different degrees of attenuation for PD-1-dependent cis targeting. Attenuation was achieved by sterically hindering the capacity of IL-18 to bind the IL-18RC while maintaining cis activity without a requirement for proteolytic activation. We identified a variant of IL-18 that is 10,000-fold attenuated and, when fused to an anti-PD-1 antibody, mediated (1) PD-1-dependent cis activity in vitro equivalent to ~5x that of anti-PD-1 alone and (2) tumor shrinkage in mouse tumor models, including an ~80% frequency of complete responses. Due to the high degree of IL-18 attenuation, we were able to dose mice without toxicity to levels at which full PD-1 antagonism is maintained. To our knowledge, this anti-PD-1-IL-18 variant is the first PD-1 targeted cytokine capable of activating PD-1+ T cells via the cytokine’s receptor and fully antagonizing PD-1 as a single agent. Thus, targeting a highly attenuated variant of IL-18 that retains strong cis activity to PD-1 holds promise as a clinical candidate for the treatment of cancer indications that respond weakly to anti-PD-1 and/or are associated with acquired resistance. Citation Format: Xueyuan Zhou, Jeffrey Takimoto, Sunny Yoon, Nikhita Khanna, Brian Rabinovich. Targeting attenuated IL-18 to PD-1: A next generation checkpoint inhibitor with enhanced anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4075.

Comparative assessment of clinical efficacy of different methods of medical rehabilitation in patients with rhinosinusitis polyposa

The article presents the results of a comparative assessment of the effectiveness of the course application of therapeutic physical factors (alternating magnetic field and low-intensity laser radiation) in complex medical rehabilitation of patients with moderate and severe rhinosinusitis polyposa with uncontrolled course. It was shown that the use of genetically engineered biological therapy (GEBT) with dupilumab contributed to the positive dynamics of the clinical parameters of sinonasal polyposis. Complementing GEBT with the course application of an alternating magnetic field was accompanied by an increase in the regression of the main clinical manifestations of rhinosinusitis polyposa. The maximum corrective activity was noted in the group with the complex use of therapeutic physical factors — an alternating magnetic field and low-intensity laser radiation against the background of GEBT. The growth is based on the ability of the complex use of physiotherapeutic factors to cause the development of synergistic phenomena through the use of corrective effects of different modality, having different mechanisms of action. The physical factors under consideration are able to improve hemo- and microcirculation in the area of chronic inflammation, exhibit anti-inflammatory, analgesic, and trophic-stimulating effects, which, together with the inactivation of the main pro-inflammatory interleukins of type 2 inflammation, enhances the sanogenetic potential that determines the duration of remission. Taking into account the chronic relapsing nature of the rhinosinusitis polyposa course, it is planned to conduct prolonged studies covering a follow-up period of 1.5–2 years.

35007 An unusual clinical presentation of a squamous cell carcinoma mimicking mycetoma

Mycetoma is a chronic granulomatous infection of subcutaneous tissue caused by bacteria or fungi. It is endemic to tropical areas and leads to tissue swelling, ulcerated nodules, and draining sinus tracts. We present the case of a patient with an atypical squamous cell carcinoma (SCC), whose clinical presentation was consistent with mycetoma. Our patient is a 39-year-old Guatemalan male without past medical history who presented with a 20-year history of nonresolving swollen and ulcerated lesions on his left buttock. Upon examination, he had a large, edematous, and indurated mass with multiple circular ulcers and sinus tracts draining yellowish, malodorous discharge. Punch biopsies were performed for histology and tissue cultures. Tissue cultures for bacteria, atypical mycobacteria, nocardia, actinomyces, and fungi only grew polymicrobial bacterial organisms for which he was treated with antibiotics and had minimal improvement. Unexpectedly, histology revealed a well-differentiated SCC, and a left inguinal lymph node biopsy was positive for SCC. A wide excision was performed and hematology/oncology and surgery departments are currently following the patient for further management. This case demonstrates the importance of including SCC in the differential diagnosis when there is clinical suspicion of a long-standing infectious process such as mycetoma, especially when dealing with areas of chronic inflammation. The development of SCC has long been associated with non-healing wound ulcers. Even when solely an infectious process is suspected, clinicians should perform biopsies for both tissue cultures and histopathology to ensure prompt diagnosis, since malignancies such as SCC have the potential to masquerade as an infection.

Necrobiosis lipoidica: a rare clinical and pathomorphological case

According to modern scientific researches, necrobiosis lipoidica (NL) is a disease characterized by focal disorganization and lipid collagen dystrophy. It is believed that the basis of skin changes in this dermatosis is diabetic microangiopathy that is accompanied by sclerosis and obliteration of blood vessels, which leads to necrobiosis with subsequent deposition of lipids in the dermis. This pathology is registered relatively rarely, in 1 % of patients with diabetes mellitus (DM) on average. The combination of NL with DM, according to the literature data, ranges from 25 to 70%; more often (in 40–60 % of cases) DM is preceded by NL, and in 10–25 % of cases they occur simultaneously. In addition, in 10–50 % of cases NL is diagnosed in people without concomitant diabetes. The variability of clinical, epidemiological features and the relatively low prevalence of this pathology is often the cause for misdiagnosis or late diagnosis. The described clinical case is typical in terms of the epidemiological data: sex, age, presence of DM. At the same time, it is rare in terms of the clinical picture: it is not classically diabetic by localization (symmetrical areas of the legs are typical), by appearance of necrobiosis areas — granulomatous type of necrobiosis in the form of granuloma annulare, by histological structure — area of chronic perivascular lymphoplasmocytic inflammation with the involvement of single giant cells, which required additional clinical and anamnestic data for an objective report of the pathologist. Biopsy in this case was used as a differential diagnosis between granuloma annulare and necrobiotic necrogranuloma. In addition, this method of diagnosis has played an additional therapeutic role. This case may have demonstrated the activation of the cellular and humoral immune response in the area of chronic inflammation in response to a mechanical damage and the resolution of inflammation with complete tissue repair.

S2312 Acute Gastrointestinal Bleeding Due to a Duodenal Hamartomatous Polyp: A Case Report

Introduction: The small bowel accounts for less than 4% of tumors involving the gastrointestinal (GI) tract. Benign small bowel lesions could be mucosal or submucosal. Polypoid mucosal lesions include Brunner’s glands hyperplasia, nodular lymphoid hyperplasia, adenomas, and hamartomas with 20% arising in the duodenum. Submucosal tumors include lipomas, leiomyomas, lymphangiomas and neurofibromas. We report a case of a large duodenal hamartomatous polyp causing significant occult GI bleeding, requiring blood transfusion and urgent endoscopic intervention. Case Description/Methods: A 65-year-old African American male with a history of colon cancer and right hemicolectomy, atrial fibrillation, end stage renal disease, and chronic anticoagulation with apixaban was admitted for generalized weakness and found to have a hemoglobin (Hgb) of 5.5 g/dL without report of overt GI bleeding. The patient was diagnosed with a large duodenal polyp three years prior with biopsy showing adenoma and Brunner’s gland hyperplasia. He had been referred to a tertiary center for endoscopic removal of the polyp, which was deferred due to his multiple major co-morbidities. After resuscitation and transfusion of two units of packed red blood cells, an esophagogastroduodenoscopy (EGD) was performed which showed the presence of the pedunculated polyp in the second portion of duodenum, measuring 2.5 cm in size with active oozing. The rest of the EGD was normal. Using a polyloop and injection of 2cc of 1:10,000 epinephrine into the peduncle, the polyp was resected using a snare and endocut. The final histological diagnosis of the polyp was hamartomatous polyp with features of Peutz-Jeghers polyp and areas of chronic inflammation. After resection of the duodenal polyp, the patient's Hgb returned to normal limits at follow up. Discussion: GI bleeding due to a duodenal polyp is very rare. As a result, there is limited data on the management of duodenal polyps regarding surveillance and resection. As demonstrated in this case, the polyp was initially not resected due to absence of symptoms and major comorbidities, but the patient later presented with significant bleeding requiring urgent endoscopic intervention. The case highlights the necessity of careful evaluation and resection of duodenal polyps > 1cm before they become symptomatic as in this case of acute GI bleeding.Figure 1.: Acute gastrointestinal bleeding due to a 2.5 cm pedunculated polyp, pathology consistent with hamartoma, within the second portion of the duodenum with active oozing of blood.

Abstract 5667: Biomarkers associated with tertiary lymphoid structures are elevated in lung and bladder cancer patients who respond to durvalumab treatment

Abstract Introduction: Tertiary lymphoid structures are ectopic formations arising in areas of chronic inflammation, including cancers. TLS formation detected in tumors is thought to be associated with favorable prognosis, and markers of TLS formation and activity are currently being elucidated. The objective of this study was to determine the association between genes associated with TLS formation and outcomes in lung and bladder cancer patients treated with durvalumab (D). Methods: Previously published TLS-associated genes and gene signatures (Fridman et al., 2019) were assessed in baseline tumor biopsy RNA sequencing data from D-treated (monotherapy) non-small cell lung (NSCLC, n = 97) and bladder (BLCA, n = 62) cancer patients from a nonrandomized phase Ib/II clinical trial (1108/NCT01693562), as well as in lung adenocarcinoma (LUAD, n = 594), squamous cell carcinoma (LUSC, n = 551) and bladder cancer (BLCA, n = 433) cohorts from TCGA. Kaplan-Meier analysis was performed to determine associations between TLS-related signature expression at baseline and overall survival (OS) in D-treated patients, as well as in LUAD, LUSC, and BLCA patients from TCGA to determine prognostic significance of these signatures. TLS-related signatures were also compared in D-treated responders and non-responders via ANOVA. Results: Higher levels of CXCL13 transcript in D-treated patients was associated with better median OS (20.2 vs. 6.5 months in CXCL13-high vs. low patients respectively, p = 0.01). CXCL13 expression was not significantly associated with survival in either LUAD or LUSC TCGA patients. Elevated expression of TLS-related chemokine and T-follicular helper cell (Tfh) signatures were also linked to better OS in D-treated patients (p < 0.05) compared to lung cancer patients in TCGA. These signatures were significantly elevated in D-treated responders compared to patients with progressive disease (fold-change > 1.5, p < 0.05). In D-treated BLCA patients, elevated chemokine and Tfh signatures were associated with better OS (median OS not reached in signature-high patients, p < 0.05). Both signatures were not associated with OS in BLCA patients from TCGA. In BLCA D-treated complete responders (n = 4), all TLS-related markers were significantly elevated compared to patients with progressive disease. Elevated levels of CXCL13 transcript and either PDL1 protein or interferon-γ gene signature levels tracked with better OS in D-treated patients. Assessment of TLS structures via immunohistochemistry in the same patients is currently being explored. Conclusions: TLS-related genes were elevated at baseline in D-treated NSCLC and BLCA patients with better response and OS. Modulation of these signatures was predictive of IO response, as they were not associated with survival in treatment naïve patients in TCGA. These results enhance understanding of mechanisms driving increased immunogenicity in IO-responsive patients. Citation Format: Sriram Sridhar, Christopher M. Morehouse, Yashaswi Shreshta, Marlon Rebelatto, Ikbel Achour, Ioannis Kagiampakis, Ezogelin Oflazoglu, Katie Streicher. Biomarkers associated with tertiary lymphoid structures are elevated in lung and bladder cancer patients who respond to durvalumab treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5667.

Сравнительный гистологический анализ лоскутов крайней плоти и слизистой щеки для лечения проксимальных форм гипоспадии у детей

Buccal mucosa and preputial skin grafts are used for staged urethroplasty in proximal forms of hypospadias in children. Aim of our study was to carry out a comparative histological analysis of preputial skin and buccal mucosa. s and materials: Histological analysis of urethral tissue samples from 10 patients with proximal forms of hypospadias was conducted. All patients were treated with staged Brackas technique using free grafts at the Russian Childrens Clinical Hospital from 2013 to 2016. Patients were divided into two groups. In Group I (n=5), preputial skin graft was used for urethroplasty, while in Group II (n=5) buccal mucosa was taken. A histological study of both materials with comparison to a native urethra was performed. In Group I, the histological analysis showed keratinizing multilayered squamous epithelium, large number of dilated sweat and sebaceous glands with signs of inflammation, and hair follicles. In Group II, histological analysis revealed the presence of the typical structure for mucosal tissue, including multilayered flat non-keratinizing epithelium, as well as full absence of sweat, sebaceous glands, and hair follicles. comparative histological analysis of neourethra has shown the absence of sweat and sebaceous glands, hair follicles, and areas of chronic inflammation in buccal mucosa vs preputial skin, showing that buccal mucosa is more similar to native urethra. Therefore, buccal mucosa is favored as the material for urethroplasty.

Abstract 514: DUOX2-related H2O2 production contributes to pro-inflammatory cytokine-related DNA damage and tumor cell growth in models of pancreatic ductal adenocarcinoma

Abstract Chronic inflammation is an important risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). Dual oxidase 2 (DUOX2), one of the seven NADPH oxidase (NOX) family members, by generating extracellular H2O2, is intimately involved in both host defense and chronic inflammation in the gastrointestinal tract. Previously, we demonstrated that short (24 h) exposures of several human pancreatic cancer cell lines to pro-inflammatory cytokines (IFN-γ, IL-4/IL-13, IL-17A) can effectively enhance expression of DUOX2 and its maturation factor DUOXA2. To better mimic chronic inflammation in vivo, a panel of human PDAC cell lines was exposed to the TH2 cytokine IL-4 (50ng/ml) for longer times (7 days); and the effect of cytokine treatment on Stat6 activation and DUOX2 mRNA and protein expression was explored. In BxPC-3 and AsPC-1 cell lines, prolonged IL-4 stimulation results in a sustained activation of Stat6, dramatic induction of DUOX2 mRNA and protein expression, a 3-5-fold increase in extracellular H2O2 production compared to solvent-treated cells, and–most importantly–a robust DNA double strand break (DSB) response indicated by elevated levels of γH2AX. In marked contrast, for two JAK-Stat6 signaling defective PDAC lines, PANC-1 and CFPAC-1, no enhancement of DUOX2 expression with concomitant DSBs was observed under the same conditions. Moreover, when the anti-inflammatory drug dexamethasone (Dex) was co-administered with IL-4 (for 48h), cytokine-related DUOX2 induction and DNA damage in BxPC-3 and AsPC-1 cells was significantly diminished. Furthermore, in the KPC GEMM of PDAC, RT-PCR and immunohistochemistry revealed that DUOX2 mRNA and protein expression in pancreatic tumor tissues were significantly increased compared to adjacent normal tissues and were associated with areas of chronic inflammation. Finally, xenografts established with BxPC-3 cell clones in which DUOX2 mRNA was silenced by stable expression of DUOX2-specific shRNAs demonstrated severely delayed growth in vivo compared to clones stably expressing scrambled shRNAs. These studies, coupled with our previous data demonstrating elevated DUOX protein expression in pancreatitis, pancreatic intra-epithelial neoplasia (PanIN), and frank pancreatic cancers in humans, suggest that ROS- derived from cytokine-mediated DUOX2 up-regulation may initiate and promote pancreatic cancer progression through ROS-induced DNA damage. Citation Format: Yongzhong Wu, Jiamo Lu, Smitha Antony, Jennifer L. Meitzler, Agnes Juhasz, Guojian Jiang, Iris Dahan, James H. Doroshow. DUOX2-related H2O2 production contributes to pro-inflammatory cytokine-related DNA damage and tumor cell growth in models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 514.

Sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma of the head and neck.

To describe outcomes of a single institution experience with sentinel lymph node biopsy (SLNB) for high-risk cutaneous squamous cell carcinoma of the head and neck. Retrospective case series. Chart review was performed for patients who presented with clinically node negative cutaneous squamous cell carcinoma of the head and neck between December 2007 and May 2018. Patients who met high-risk criteria underwent SLNB and excision, with or without adjuvant therapy. Patients who underwent prior neck dissection were excluded. The main outcomes were SLNB result, lymph node spread, recurrence-free survival, disease-specific survival, and overall survival. Eighty-three patients underwent successful SLNB, and one patient underwent selective neck dissection for intraoperatively identified occult lymph node metastasis. Five patients (6%) had a sentinel node positive for tumor, of whom 4/5 received further treatment (neck dissection, radiation, and/or systemic therapy) with no further recurrence at the time of last follow-up. SLNB had a negative predictive value of 95% to 100%. Recurrent tumor at presentation, tumor arising from an area of chronic inflammation, and immunosuppression were significantly associated with increased risk of subsequent recurrence, with a mean follow-up of 19.9 months. SLNB can be used to identify regional lymph node metastases in cutaneous squamous cell carcinoma of the head and neck with a high negative predictive value (95%-100%). Factors associated with recurrence were tumor being locally recurrent at presentation, arising from an area of chronic inflammation, and immunosuppression. 4 Laryngoscope, 130:108-114, 2020.

Influence of chronic inflammation on Bcl-2 and PCNA expression in prostate needle biopsy specimens.

The association between inflammation and cancer has been established in certain forms of human malignancies; however, its role in prostate cancer remains unclear. The present study investigates a possible association between chronic inflammation and the development of epithelial neoplasia in the prostate. Needle biopsy specimens were obtained from patients with serum prostate-specific antigen levels >4 ng/ml, evaluated for morphological findings, and immunostained for Bcl-2 and proliferating cell nuclear antigen (PCNA). Bcl-2 is a survival protein that appears to lie at a nodal point in pathways involved in cell survival, carcinogenesis, and development of therapeutic resistance in certain cancer types. Similarly, PCNA is a critical protein for DNA replication, repair of DNA damage, chromatin structure maintenance, chromosome segregation and cell-cycle progression. The association between these two proteins was examined in prostate tissues with and without chronic inflammation, as well as tissues with and without evidence of neoplastic changes. Of the 106 needle biopsies examined, 18% exhibited atrophy with inflammation. Proliferative inflammatory atrophy/post-atrophic hyperplasia were observed in 42%, high-grade prostatic intraepithelial neoplasia (HGPIN) in 8%, prostatic adenocarcinoma in 11%, and 2% had atypical acinar proliferation suspicious for malignancy. A total of 36 specimens were stained for Bcl-2 and PCNA. Bcl-2 was expressed widely in inflammatory and epithelial tissue; however, more intense expression was observed in the areas of chronic inflammation, predominantly in infiltrating immune cells. The highest proliferation index was observed in the epithelia of HGPIN and cancer. An inverse correlation between the expression of Bcl-2 and the expression of PCNA was observed in the epithelium. The areas of chronic inflammation were associated with increased Bcl-2 expression, whereas the highly proliferative epithelium minimally expressed Bcl-2. These results suggest that Bcl-2 alters the phenotype of particular epithelial cells with a gain in neoplastic characteristics, leading to a likely precursor that may later progress into HGPIN and cancer.

Abstract 492: Chronic inflammation contributes to neoplastic progression in prostate tissue: a needle biopsy study

Abstract The relationship between inflammation and prostate cancer has not been established, although chronic inflammation has frequently been identified in prostate biopsies, radical prostatectomy and benign prostatic hyperplasia specimens. In the peripheral zone of the prostate, sometimes adjacent to foci of high-grade PIN and cancer, certain morphologic changes are often identified, which may represent active and terminal phases of chronic inflammation. These changes are designated as proliferative inflammatory atrophy (PIA) and post atrophic hyperplasia (PAH), and their morphology is well documented. In our previous studies, we have identified chronic inflammation as a putative contributor to neoplastic progression in prostate epithelial cells, and hypothesized that its adverse effects were related to an increase in Bcl2, a survival protein involved in cell survival and carcinogenesis. We hypothesize that changes in the stromal microenvironment, characterized by infiltration of immune cells, with generation of reactive oxygen species, can induce oxidative stress in the surrounding proliferating epithelium and cause permanent genomic alterations. In the present study, we focused on several key proteins involved in the inflammatory process, COX2 and iNOS; cell survival, Bcl2 and GSTPπ; and evaluated immunohistochemical expression of alpha-methylacyl coenzyme A racemase (AMACR) and basal cell-specific markers 34βE12 and/or p63 to evaluate possible neoplastic alterations in epithelial cells in an inflammatory environment. We evaluated 16 prostate core needle biopsy specimens that exhibited the presence of chronic inflammation as well as PIA and PAH lesions along with immunohistochemical staining for various markers was performed in each set of biopsies. The integrity of the basal layer was maintained in the area of chronic inflammation with high expression of p63 in 72% of these cells. Approximately 68% of luminal cells expressed high to moderate levels of iNOS and COX-2, whereas 55% of these cells express modest levels of GSTP1 and Bcl2. Interestingly, prostatic glands near the areas of chronic inflammation in the PIA lesions exhibit high AMACR expression in luminal cells and weak to patchy p63 expression in basal cells, which was associated with increased expression of the inflammatory markers COX2 and iNOS, as well as loss in pro-survival signal GSTP1 and Bcl2 in the adjacent luminal cells. These neoplastic alterations were observed in 6/16 (38%) of the needle biopsy specimens. Our findings suggest that basal cells undergo alterations in a setting of chronic inflammation. This is important because basal cells are considered to be progenitor cells capable of differentiating into secretory luminal cells, but under the influence of chronic inflammation, they may instead transform into the neoplastic cells that characterize high grade prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Citation Format: Shardul C. Soni, Michael Glover, Qinghu Ren, Gregory T. MacLennan, Pingfu Fu, Sanjay Gupta. Chronic inflammation contributes to neoplastic progression in prostate tissue: a needle biopsy study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 492. doi:10.1158/1538-7445.AM2017-492

Feline Injection-Site Sarcoma.

Feline injection-site sarcoma (FISS) is an aggressive tumor believed to arise from the proliferation of fibroblasts and myofibroblasts in areas of chronic inflammation, particularly at sites of injection. Local recurrence is frequent after surgical excision. Gelatinases (MMP-2 and MMP-9) and their inhibitor (TIMP-2) are endopeptidases pivotal in extracellular matrix remodeling and therefore in tumor invasiveness. The aim of this study was to investigate the immunohistochemical expression of MMP-2, MMP-9, and TIMP-2 in FISS to assess their usefulness as prognostic factors. Size, soft tissue sarcoma (STS) grading system, depth of infiltration, surgical margins, and Ki-67 index were evaluated as additional prognostic markers. Twenty-four cases of primary FISS were classified according to clinical follow-up as nonrecurrent (NR, n = 14; 58.3%) and recurrent (R, n = 10; 41.7%). MMP-2, MMP-9, and TIMP-2 were variably expressed in the FISS examined, confirming their role in tumor invasiveness, yet they did not show significant differences between the R and NR groups. These results could be due to different tumor stages or to the multiple activities of these enzymes, not limited to ECM remodeling. The immunohistochemical expression of these enzymes considered alone does not seem to be useful as a prognostic marker. STS grading system, depth of infiltration, surgical margins, and Ki-67 index did not relate to recurrence. Instead, the size of the tumor, measured after formalin fixation, with an optimal cutoff of 3.75 cm (accuracy = 86%; P < .05), and the mitotic count, with an optimal cutoff of 20 mitoses/10 HPF (accuracy = 80%; P < .05), could be evaluated as useful prognostic markers.

Discal Cyst: a Rare Cause of Neurologic Compression in the Young Adult

Introduction: discal cysts are rare pathology. Its clinical presentation can be mistaken for disc hernia- tion, with back pain, radiculopathy and neurological defi cit. It is more common in male patients in their fourth life decade. Because they are rare, there is no consensus about the treatment. A great variety of procedures, from medication for the pain to endoscopic or microdiscectomy excision, have been described. Objetive: Describe a case of discal cyst on the l4-l5 level with compression of l5 right nerve root treated successfully with a minimal invasive procedure. Study design: Case report. Methods: Review medical records, pertinent images, interview with the patient and surgical team, intra- operative and histopathological fi ndings. The surgical technique used was minimally invasive. Results: Magnetic resonance imaging (MRI) demonstrated a cystic lesion imaging at the level of the L4-L5 disc. The cystic mass displaced the thecal sac dorsally compressed the L5 transversing root. The patient was submitted to a minimally invasive microendoscopic technique using a tubular retractor. He recovered completely after the procedure, presenting absence of leg pain and went back to his regular activities 3 weeks after the surgery. Histopathological examination of the cyst revealed thick fi brous connective tissue interspersed with areas of chronic infl ammation. Conclusion: Discal cysts are rare intraspinal lesions. They can trigger severe neurological symptoms, and should be differentiated from other forms of epidural cysts and tumors. There are many treatment options that can be chosen from but no consensus. We used a treatment that was less invasive than the ones described in the literature.

OMIP‐034: Comprehensive immune phenotyping of human peripheral leukocytes by mass cytometry for monitoring immunomodulatory therapies

Keywords: mass cytometry; panel design; mass-response characteristic; human blood leukocytes; immune phenotyping; immune monitoring; autoimmunity; rheumatism; systemic lupus erythematosus (SLE); biomarker and clinical trial

A Case of Squamous Cell Carcinoma of Skin Subsequent to Subcutaneous Foreign Body

Squamous cell carcinoma (SCC) of the skin is one of the most common non melanoma skin cancers (NMSC), along with basal cell carcinoma (BCC). Besides ultraviolet radiation, the role of exposure to industrial agents, ionizing radiation and areas of chronic inflammation is associated with the development of SCC. SCC may also be associated with foreign bodies. We report a rare case of cutaneous SCC in an elderly Kashmiri female, developing subsequent to subcutaneous non metallic foreign body, which was successfully excised with negative margins, and transposition flap closure. DOI: http://dx.doi.org/10.3126/njdvl.v12i1.10604 Nepal Journal of Dermatology, Venereology &amp; Leprology Vol.12(1) 2014 pp.53-55

Editorial: "Cancer Immunotherapy: Lights and Shadows".

Editorial: "Cancer Immunotherapy: Lights and Shadows".

ANXA1Ac2-26 peptide reduces ID1 expression in cervical carcinoma cultures

Cervical cancer is the second most frequent cancer in women worldwide and is associated with genetic alterations, infection with human papilloma virus (HPV), angiogenesis and inflammatory processes. The idea that inflammation is involved in tumorigenesis is supported by the frequent appearance of cancer in areas of chronic inflammation. On the other hand, the inflammatory response is controlled by the action of anti-inflammatory mediators, among these mediators, annexin A1 (ANXA1), a 37kDa protein was detected as a modulator of inflammatory processes and is expressed by tumor cells.The study was carried out on the epithelial cancer cell line (SiHa) treated with the peptide of annexin A1 (ANXA1Ac2-26). We combined subtraction hybridization approach, Ingenuity Systems software and quantitative PCR, in order to evaluate gene expression influenced by ANXA1.We observed that ANXA1Ac2-26 inhibited proliferation in SiHa cells after 72h. In these cells, 55 genes exhibited changes in expression levels in response to peptide treatment. Six genes were selected and the expression results of 5 up-regulated genes (TPT1, LDHA, NCOA3, HIF1A, RAB13) and one down-regulated gene (ID1) were research by real time quantitative PCR. Four more genes (BMP4, BMPR1B, SMAD1 and SMAD4) of the ID1 pathway were investigated and only one (BMPR1B) shows the same down regulation.The data indicate the involvement of ANXA1Ac2-26 in the altered expression of genes involved in tumorigenic processes, which could potentially be applied as a therapeutic indicator of cervical cancer.

Localized, sustained presentation of VEGF-C in mouse dermis alters the local immune microenvironment (IRC5P.628)

Abstract Lymphangiogenesis is induced in areas of chronic inflammation, including in both autoimmunity (associated with immunoreactivity) and in many solid tumors (associated with metastases and immunosuppression). We asked whether and how local VEGF-C-driven lymphangiogenesis alone could affect adaptive immunity to a model antigen. To this end, we designed a hydrogel system for sustained local delivery of the lymphangiogenic protein VEGF-C. These proteins were engineered to express a peptide tag which are covalently crosslinkable onto the hydrogel matrix, and are thus better retained by the hydrogels. Following implantation into healthy mice, local delivery of VEGF-C increased lymphangiogenesis at the implant site as well as at the draining lymph nodes compared to empty hydrogel controls. This promoted increased local expression of CCL21, similar to observations in lymphangiogenic tumors, and associated with increased recruitment of CCR7+ cells, most notably CD4 T cells expressing markers of naïve or memory phenotypes. To further examine the immunological relevance of these observations on antigen-specific T cell populations, hydrogels delivering both VEGF-C and the model antigen OVA were implanted into healthy mice which had previously received an adoptive transfer of OT-II T cells. These hydrogels also recruited CD4 T cells expressing markers of naïve and memory phenotypes. Our studies suggest a role for lymphangiogenesis in the recruitment of immune cells during inflammation.

High-Risk Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and its incidence has increased in recent decades. Most cSCCs are successfully treated by surgery, but local and distant metastases develop in approximately 5% of cases; this proportion is higher in certain forms of cSCC with high-risk factors, namely: tumor size >2cm, depth >2mm, Clark level ≥IV, perineural invasion, lymphovascular invasion, poor differentiation, certain histologic subtypes (desmoplastic or adenosquamous carcinoma, invasive Bowen disease, or a cSCC arising in areas of chronic inflammation), immunosuppression, human papillomavirus infection, high-risk anatomic location (pinna of the ear, labial mucosa), expression of certain tumor genes, and inadequate tumor resection. The latest TNM (tumor, lymph node, metastasis) classification of cSCC published by the American Joint Committee on Cancer (AJCC) in the seventh edition of its Cancer Staging Manual now incorporates several of these risk factors to improve disease staging. We review all the factors currently considered to be markers of poor prognosis in cSCC and analyze the new AJCC classification and the different treatment options for high-risk cSCC.

Carcinoma epidermoide cutáneo de alto riesgo

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and its incidence has increased in recent decades. Most cSCCs are successfully treated by surgery, but local and distant metastases develop in approximately 5% of cases; this proportion is higher in certain forms of cSCC with high-risk factors, namely: tumor size >2cm, depth >2mm, Clark level ≥IV, perineural invasion, lymphovascular invasion, poor differentiation, certain histologic subtypes (desmoplastic or adenosquamous carcinoma, invasive Bowen disease, or a cSCC arising in areas of chronic inflammation), immunosuppression, human papillomavirus infection, high-risk anatomic location (pinna of the ear, labial mucosa), expression of certain tumor genes, and inadequate tumor resection. The latest TNM (tumor, lymph node, metastasis) classification of cSCC published by the American Joint Committee on Cancer (AJCC) in the seventh edition of its Cancer Staging Manual now incorporates several of these risk factors to improve disease staging. We review all the factors currently considered to be markers of poor prognosis in cSCC and analyze the new AJCC classification and the different treatment options for high-risk cSCC.