From In Silico Simulation between TGF-ß Receptors and Quercetin to Clinical Insight of a Medical Device Containing Allium cepa: Its Efficacy and Tolerability on Post-Surgical Scars.

(1) Objective: Keloid and hypertrophic scars are a challenge in clinical management, causing functional and psychological discomfort. These pathological scars are caused by a proliferation of dermal tissue following skin injury. The TGF-ß/Smad signal pathway in the fibroblasts and myofibroblasts is involved in the scarring process of skin fibrosis. Today, multiple therapeutic strategies that target the TGF-ß/Smad signal pathway are evaluated to attenuate aberrant skin scars that are sometimes difficult to manage. We performed a head-to-head, randomized controlled trial evaluating the appearance of the post-surgical scars of 64 subjects after two times daily topical application to compare the effect of a class I pullulan-based medical device containing Allium cepa extract 5% and hyaluronic acid 5% gel versus a class I medical device silicone gel on new post-surgical wounds. (2) Methods: Objective scar assessment using the Vancouver Scar Scale (VSS), POSAS, and other scales were performed after 4, 8, and 12 weeks of treatment and statistical analyses were performed. The trial was registered in clinicalTrials.gov ( NCT05412745). In parallel, molecular docking simulations have been performed to investigate the role of Allium cepa in TGF-ß/Smad signal pathway. (3) Results: We showed that VSS, POSAS scale, itching, and redness reduced significantly at week 4 and 8 in the subjects using devices containing Allium cepa and HA. No statistically significant differences in evaluated scores were noted at 12 weeks of treatment. Safety was also evaluated by gathering adverse events related to the application of the gel. Subject compliance and safety with the assigned gel were similar between the two study groups. Molecular docking simulations have shown how Allium cepa could inhibit fibroblasts proliferation and contraction via TGF-ß/Smad signal pathway. (4) Conclusions: The topical application of a pullulan-based medical device containing Allium cepa and HA showed a clear reduction in the local inflammation, which might lead to a reduced probability of developing hypertrophic scars or keloids.

Epithelial-to-Mesenchymal Transition Gene Signature in Circulating Melanoma Cells: Biological and Clinical Relevance.

The most promising method for monitoring patients with minimal morbidity is the detection of circulating melanoma cells (CMCs). We have shown that CD45-CD146+ABCB5+ CMCs identify a rare primitive stem/mesenchymal CMCs population associated with disease progression. The epithelial-to-mesenchymal transition (EMT) confers cancer cells a hybrid epithelial/mesenchymal phenotype promoting metastatization. Thus, we investigated the potential clinical value of the EMT gene signature of these primitive CMCs. A reliable quantitative real-time polymerase chain reaction (qRT-PCR) protocol was settled up using tumor cell lines RNA dilutions. Afterwards, immune-magnetically isolated CMCs from advanced melanoma patients, at onset and at the first checkpoint (following immune or targeted therapy), were tested for the level of EMT hallmarks and EMT transcription factor genes. Despite the small cohort of patients, we obtained promising results. Indeed, we observed a deep gene rewiring of the EMT investigated genes: in particular we found that the EMT gene signature of isolated CMCs correlated with patients' clinical outcomes. In conclusion, We established a reliable qRT-PCR protocol with high sensitivity and specificity to characterize the gene expression of isolated CMCs. To our knowledge, this is the first evidence demonstrating the impact of immune or targeted therapies on EMT hallmark gene expressions in CMCs from advanced melanoma patients.

Impact of HLA Class I Antigen, Killer Inhibitory Receptor, and FCGR3A Genotypes on Breast Cancer Susceptibility and Tumor Stage.

BACKGROUND: The identification in breast cancer (BC) of novel genetic biomarkers regulating natural killer (NK) cell function, including the HLA, KIR, and CD16A (FCGR3A), may be still a challenge. OBJECTIVE: We aimed to evaluate whether the combined effect of these polymorphisms has an impact on BC susceptibility and progression. METHODS: 47 BC Italian patients and healthy individuals (39 females and 66 males/females) were genotyped by Sanger sequencing (HLA-C exon 2-4 and FCGR3A-158V/F, 48L/R/H) and PCR-SSP typing (KIR genes). RESULTS: HLA-C gene allele analysis showed the group C1, with HLA-C*07:02:01 allele, to be significantly associated with tumor progression (16.7% vs. 4.0%, p=0.04, OR=4.867), and instead, group C2, with HLA-C*05:01:01, was protective against disease susceptibility (0.0% vs. 7.2%, p=0.019, OR=0.087). In addition, we highlighted a significant reduction of the KIR2DS4ins in BC patients (pcorr.=0.022) and an increased combined presence of KIR2DL1 and KIR2DS1 genes in advanced BC patients compared to earlier stages (66.7% vs. 19.2%, p=0.002). The concurrent lack of KIR2DL2 and KIR2DS4 genes in the presence of HLA-C2 alleles was significantly associated with increased susceptibility to BC (p=0.012, OR=5.020) or with lymph node involvement (p=0.008, OR=6.375). Lastly, we identified different combinations of the FCGR3A-48/158 variants and KIR genes in BC patients compared to controls. CONCLUSION: Our findings suggest that in the development of BC probably exists a disorder of the NK innate immunity influenced by KIR/HLA-C gene content and FCGR3A-158 polymorphisms and that the combined analysis of these biomarkers might help predict genetic risk scores for tailored screening of BC patients in therapy.

Total neoadjuvant therapy for the treatment of locally advanced rectal cancer: a systematic minireview.

Colorectal carcinoma is the second leading cause of cancer-related deaths, and indeed, rectal cancer accounting for approximately one third of newly diagnosed patients. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. Distant recurrences are the major cause of mortality. Currently, Locally Advanced Rectal Cancer (LARC) patients undergo a combined treatment of chemotherapy and radiotherapy, followed by surgery. Eventually, more chemotherapy, namely adjuvant chemotherapy (aCT), may be necessary. Total Neoadjuvant Therapy (TNT) is an emerging approach aimed to reduce distant metastases and improve local control. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Published results were encouraging, but the heterogeneity of protocols in use, makes the comparison and interpretation of data rather complex. One of the major concerns regarding TNT administration is related to its effect on larger and more advanced cancers that might not undergo similar down-staging as smaller, early-stage tumors. This minireview, based on a systematic literature search of randomized clinical trials and meta-analysis, summarizes current knowledge on TNT. The aim was to confirm or refute whether or not current practice of TNT is based on relevant evidence, to establish the quality of that evidence, and to address any uncertainty or variation in practice that may be occurring. A tentative grouping of general study characteristics, clinical features and treatments characteristics has been undertaken to evaluate if the reported studies are sufficiently homogeneous in terms of subjects involved, interventions, and outcomes to provide a meaningful idea of which patients are more likely to gain from this treatment.

Synchronous liver and peritoneal metastases from colorectal cancer: Is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy combined with liver resection a feasible option?

Background: Traditionally, synchronous liver resection (LR), cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases have been contraindicated. Nowadays, clinical practice has promoted this aggressive treatment in selected cases. This study aimed to review surgical and survival results of an extensive surgical approach including CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) and LR. Methods: PubMed, EMBASE, and Web of Science databases were matched to find the available literature on this topic. The search period was limited to 10 years (January 2010-January 2021). A threshold of case series of 10 patients or more was applied. Results: In the search period, out of 114 studies found about liver and peritoneal metastases from colorectal cancer, we found 18 papers matching the inclusion criteria. Higher morbidity and mortality were reported for patients who underwent such an extensive surgical approach when compared with patients who underwent only cytoreductive surgery and HIPEC. Also, survival rates seem worse in the former than in the latter. Conclusion: The role of combined surgical strategy in patients with synchronous liver and peritoneal metastases from colorectal cancer remains controversial. Survival rates and morbidity and mortality seem not in favor of this option. A more accurate selection of patients and more restrictive surgical indications could perhaps help improve results in this subgroup of patients with limited curative options.

MCAM/MUC18/CD146 as a Multifaceted Warning Marker of Melanoma Progression in Liquid Biopsy.

Human malignant melanoma shows a high rate of mortality after metastasization, and its incidence is continuously rising worldwide. Several studies have suggested that MCAM/MUC18/CD146 plays an important role in the progression of this malignant disease. MCAM/MUC18/CD146 is a typical single-spanning transmembrane glycoprotein, existing as two membrane isoforms, long and short, and an additional soluble form, sCD146. We previously documented that molecular MCAM/MUC18/CD146 expression is strongly associated with disease progression. Recently, we showed that MCAM/MUC18/CD146 and ABCB5 can serve as melanoma-specific-targets in the selection of highly primitive circulating melanoma cells, and constitute putative proteins associated with disease spreading progression. Here, we analyzed CD146 molecular expression at onset or at disease recurrence in an enlarged melanoma case series. For some patients, we also performed the time courses of molecular monitoring. Moreover, we explored the role of soluble CD146 in different cohorts of melanoma patients at onset or disease progression, rather than in clinical remission, undergoing immune therapy or free from any clinical treatment. We showed that MCAM/MUC18/CD146 can be considered as: (1) a membrane antigen suitable for identification and enrichment in melanoma liquid biopsy; (2) a highly effective molecular "warning" marker for minimal residual disease monitoring; and (3) a soluble protein index of inflammation and putative response to therapeutic treatments.

Complete mesocolic excision and central vascular ligation in colorectal cancer in the era of minimally invasive surgery.

Since the 19th century, appropriate lymphadenectomy has been considered a cornerstone of oncologic surgery and one of the most important prognostic factors. This approach can be applied to any surgery for gastrointestinal cancer. During surgery for colon and rectal cancer, an adequate portion of the mesentery is removed together with the segment of bowel affected by the disease. The adequate number of lymph nodes to be removed is standardized and reported by several guidelines. It is mandatory to determine the appropriate extent of lymphadenectomy and to balance its oncological benefits with the increased morbidity associated with its execution in cancer patients. Our review focuses on the concept of "complete mesenteric excision (CME) with central vascular ligation (CVL)," a radical lymphadenectomy for colorectal cancer that has gained increasing interest in recent years. The aim of this study was to evaluate the evolution of this approach over the years, its potential oncologic benefits and potential risks, and the improvements offered by laparoscopic techniques. Theoretical advantages of CME are improved local-relapse rates due to complete removal of the intact mesocolic fascia and improved distance recurrence rates due to ligation of vessels at their origin (CVL) which guarantees removal of a larger number of lymph nodes. The development and worldwide diffusion of laparoscopic techniques minimized postoperative trauma in oncologic surgery, providing the same oncologic results as open surgery. This has been widely applied to colorectal cancer surgery; however, CME entails a technical complexity that can limit its wide minimally-invasive application. This review analyzes results of these procedures in terms of oncological outcomes, technical feasibility and complexity, especially within the context of minimally invasive surgery.

Prehospital Hemorrhage Assessment Criteria: A Concise Review.

OBJECTIVE: Early assessment of the clinical status of trauma patients is crucial for guiding the treatment strategy, and it requires a rapid and systematic approach. The aim of this report is to critically review the assessment parameters currently used in the prehospital setting to quantify blood loss in trauma. DATA SOURCES: Studies regarding hemorrhagic shock in trauma were pooled from PubMed, EMBASE, and Cochrane databases using key words such as "hemorrhagic shock," "vital signs evaluation," "trauma," "blood loss," and "emergency medical service," alone or combined. STUDY SELECTION: Articles published since 2009 in English and Italian were considered eligible if containing data on assessment parameters in blood loss in adults. DATA EXTRACTION: Sixteen articles matching the inclusion criteria were considered in our study. DATA SYNTHESIS: Current prehospital assessment measures lack precise correlation with blood loss. CONCLUSIONS: Traditional assessment parameters such as heart rate, systolic blood pressure, shock index, and Glasgow Coma Scale score often lag in providing accurate blood loss assessment. The current literature supports the need for a noninvasive, continuously monitored assessment parameter to identify early shock in the prehospital setting.

Ultrasound-assisted investigation of photon triggered vaporization of poly(vinylalcohol) phase-change nanodroplets: A preliminary concept study with dosimetry perspective.

PURPOSE: We investigate the vaporization of phase-change ultrasound contrast agents using photon radiation for dosimetry perspectives in radiotherapy. METHODS: We studied superheated perfluorobutane nanodroplets with a crosslinked poly(vinylalcohol) shell. The nanodroplets' physico-chemical properties, and their acoustic transition have been assessed firstly. Then, poly(vinylalcohol)-perfluorobutane nanodroplets were dispersed in poly(acrylamide) hydrogel phantoms and exposed to a photon beam. We addressed the effect of several parameters influencing the nanodroplets radiation sensitivity (energy/delivered dose/dose rate/temperature). The nanodroplets-vaporization post-photon exposure was evaluated using ultrasound imaging at a low mechanical index. RESULTS: Poly(vinylalcohol)-perfluorobutane nanodroplets show a good colloidal stability over four weeks and remain highly stable at temperatures up to 78 °C. Nanodroplets acoustically-triggered phase transition leads to microbubbles with diameters <10 µm and an activation threshold of mechanical index = 0.4, at 7.5 MHz. A small number of vaporization events occur post-photon exposure (6MV/15MV), at doses between 2 and 10 Gy, leading to ultrasound contrast increase up to 60% at RT. The nanodroplets become efficiently sensitive to photons when heated to a temperature of 65 °C (while remaining below the superheat limit temperature) during irradiation. CONCLUSIONS: Nanodroplets' core is linked to the degree of superheat in the metastable state and plays a critical role in determining nanodroplet' stability and sensitivity to ionizing radiation, requiring higher or lower linear energy transfer vaporization thresholds. While poly(vinylalcohol)-perfluorobutane nanodroplets could be slightly activated by photons at ambient conditions, a good balance between the degree of superheat and stability will aim at optimizing the design of nanodroplets to reach high sensitivity to photons at physiological conditions.

Feasibility and outcomes of ERAS protocol in elective cT4 colorectal cancer patients: results from a single-center retrospective cohort study.

BACKGROUND: Programs of Enhanced Recovery After Surgery reduces morbidity and shorten recovery in patients undergoing colorectal resections for cancer. Patients presenting with more advanced disease such as T4 cancers are frequently excluded from undergoing ERAS programs due to the difficulty in applying established protocols. The primary aim of this investigation was to evaluate the possibility of applying a validated ERAS protocol in patients undergoing colorectal resection for T4 colon and rectal cancer and to evaluate the short-term outcome. METHODS: Single-center, retrospective cohort study. All patients with a clinical diagnosis of stage T4 colorectal cancer undergoing surgery between November 2016 and January 2020 were treated following the institutional fast track protocol without exclusion. Short-term postoperative outcomes were compared to those of a control group treated with conventional care and that underwent surgical resection for T4 colorectal cancer at the same institution from January 2010 to October 2016. Data from both groups were collected retrospectively from a prospectively maintained database. RESULTS: Eighty-two patients were diagnosed with T4 cancer, 49 patients were included in the ERAS cohort and 33 in the historical conventional care cohort. Both, the mean time of tolerance to solid food diet and postoperative length of stay were significantly shorter in the ERAS group than in the control group (3.14 ± 1.76 vs 4.8 ± 1.52; p < 0.0001 and 6.93 ± 3.76 vs 9.50 ± 4.83; p = 0.0084 respectively). No differences in perioperative complications were observed. CONCLUSIONS: Results from this cohort study from a single-center registry support the thesis that the adoption of the ERAS protocol is effective and applicable in patients with colorectal cancer clinically staged T4, reducing significantly their length of stay and time of tolerance to solid food diet, without affecting surgical postoperative outcomes.

Clinical care pathway program versus open-access system: a study on appropriateness, quality, and efficiency in the delivery of colonoscopy in the colorectal cancer.

Open-access colonoscopy (OAC), whereby the colonoscopy is performed without a prior office visit with a gastroenterologist, is affected by inappropriateness which leads to overprescription and reduced availability of the procedure in case of alarming symptoms. The clinical care pathway (CCP) is a healthcare management tool promoted by national health systems to organize work-up of various morbidities. Recently, we started a CCP dedicated to colorectal cancer (CRC), including a colonoscopy session for CRC diagnosis and prevention. We aimed to evaluate the appropriateness, the quality, and the efficiency in the delivery of colonoscopy with the open-access system and a CCP program in the CRC. Quality indicators for colonoscopy in subjects in the CCP were compared to referrals by general practitioners (OAC) or by non-gastroenterologist physicians (non-gastroenterologist physician colonoscopy, NGPC). Attendance rate to colonoscopy was greater in the CCP group and NGPC group than in the OAC group (99%, 99%, and 86%, respectively). Waiting time in the CCP group was shorter than in the OAC group (3.88 ± 2.27 vs. 32 ± 22.31 weeks, respectively). Appropriateness of colonoscopy prescription was better in the CCP group than in the OAC group (92 vs. 50%, respectively). OAC is affected by the lack of timeliness and low appropriateness of prescription. A CCP reduces the number of inappropriate colonoscopies, especially for post-polypectomy surveillance, and improves the delivery of colonoscopy in patients requiring a fast-track examination. The high rate of inappropriate OAC suggests that this modality of healthcare should be widely reviewed.

Perforated gastric cancer: a critical appraisal.

Gastric cancer perforation is a life-threatening condition that accounts for less than 5% of all gastric cancer patients and typically requires emergency surgery. However, preoperative diagnosis is difficult and management has a dual purpose: to treat peritonitis and to achieve a curative resection. The optimal surgical strategy is still unclear and prognosis remains poor. A search of the literature was performed using MEDLINE databases (Pubmed, EMBASE, Web of Science and Cochrane) using terms such as "perforated gastric cancer", "perforated gastric cancer and surgery", "perforated gastric tumour" and "gastric cancer perforated". Case reports, other reviews, non-english written papers and papers written before 2010 were excluded. Eight articles published between 2010 and 2020 matched the inclusion criteria for this review. Perforated gastric cancer was more prevalent in elderly males. Distal stomach was most frequently involved. Preoperative diagnosis was uncommon. Mortality rates ranged from 2 to 46%. Patients able to receive an R0 resection demonstrated better long-term survival compared with patients who had simple closure procedures. Laparoscopic procedure was mentioned only in one study. In an emergency situation, curative RO resection should always be offered in patients without multiple adverse factors. A surgical strategy using laparoscopic local repair as first step of surgery to resolve the peritonitis followed by a radical open or laparoscopic gastrectomy with lymphadenectomy could be considered. A balance between emergency and oncological needs should drive the surgical choice on a case by case basis.

Minimal Residual Disease in Melanoma:molecular characterization of in transit cutaneous metastases and Circulating Melanoma Cells recognizes an expression panel potentially related to disease progression.

Isolating circulating melanoma cells (CMCs) represents a powerful method to monitor minimal residual disease. We documented that MCAM/MUC18/CD146 expression is strongly associated with disease progression. ABCB5 is melanoma-stem antigen with self-renewal, proliferation, differentiation, tumorigenicity capabilities. These findings supported us to improve CMC detection, investigating MCAM/MUC18/CD146 and ABCB5 as enrichment targets in MM progression. Moreover, we decided to compare possible molecular diversity of these CMC fractions with metastatic tissue expression, collecting concomitantly cutaneous in transit metastases (CTM). We enriched CMCs from eight melanoma patients staged ≥pT1b AJCC, who developed CTMs at baseline or during follow up. We assessed a gene expression panel comprising ABCB5, the differentiation markers (Tyrosinase, MART1), angiogenic factors (VEGF, bFGF), the cell-cell adhesion molecules (MCAM/MUC18/CD146 5'-portion, Long, and Short isoforms, E-Cadherin, N-Cadherin, VE-Cadherin) and matrix-metallo-proteinases (MMP2 and MMP9) via high-sensitive RT-PCR. Preliminary findings defined three distinct sub-populations: "endothelial" CD45-CD146+CMCs, "stem" CD45-ABCB5+CMCs and a "hybrid- stem-endothelial"- CD45-MCAM+ABCB5+CMCs. The expression panel documented that - almost high expression found in CTMs - like in 73.5% of CMCs resulted positive for at least one transcript at baseline, showing gene-expression variability. Longitudinal monitoring documented shut-down of all gene-expressions in "endothelial"- and "hybrid stem-endothelial"-subsets, whilst persistency or acquisition of MCAM/MUC18/CD146, VE-CADH and MMPs was documented in disease-progression status.Conversely, a drastic expression shut-down was documented when patients achieved clinical remission. The "stem"- CMCs fraction" showed quite lower gene expression frequencies. MCAM/MUC18/CD146 and ABCB5 as melanoma-specific-targets are effective in the selection of highly primitive CMCs and highlights those putative genes associated with disease spreading progression.

Completely Isolated Enteric Duplication Cyst and Incidental Neuroendocrine Tumor of the Appendix: A Case Report.

BACKGROUND Completely isolated enteric duplication cysts (CIDCs) are rare malformations that can occur at any site in the gastrointestinal system. This report describes a woman with a CIDC and an incidental appendiceal neuroendocrine tumor (ANET). CASE REPORT A 26-year-old woman who presented with dysmenorrhea was assessed by ultrasound (US), which revealed a pelvic mass. Other imaging modalities, including magnetic resonance imaging (MRI), failed to clarify the origin of the mass. Intraoperative findings during diagnostic laparoscopy revealed an isolated, ovaloid mass with autonomous peristalsis and a short pedicle towards the root of the ileal mesentery. In addition, the appendix appeared enlarged with a hardened consistency. The mass was resected and an appendectomy performed laparoscopically. The pelvic mass was diagnosed as a CIDC and the appendix was incidentally found to contain a pT3Nx carcinoid tumor. Based on histological examination and guidelines of the European Neuroendocrine Tumor Network (ENET), the patient later underwent a laparoscopic right hemicolectomy. CONCLUSIONS CIDC in adulthood is very rare, especially when combined with an incidentally discovered pT3Nx appendiceal carcinoid tumor. Neither US nor MRI was able to provide a precise preoperative diagnosis. Diagnostic laparoscopy clarified the nature of the mass and revealed a lesion missed during the preoperative workup. Because of the diagnosis of ANET, the patient subsequently underwent a laparoscopic right hemicolectomy.

Stem-Mesenchymal Signature Cell Genes Detected in Heterogeneous Circulating Melanoma Cells Correlate With Disease Stage in Melanoma Patients.

During the process of metastasis, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. These cancer cells, defined circulating tumor cells (CTCs) spreading through the blood stream, may develop metastatic lesions or remain dormant. Some emerging clinical evidence supports that some tumor cells may possess metastatic properties already in the earlier stages of tumorigenesis. Because the initiation and progression of vertical growth in human melanoma is fundamental to the notion of tumor virulence and progression, we decided to immune-magnetic collect and molecularly characterize circulating melanoma cells (CMCs) from melanoma patients AJCC staged = pT1b (i.e., transition from radial to vertical phase). CMCs are phenotypically and molecularly heterogeneous, thus we performed a "home-made Liquid-Biopsy," by targeting the melanoma-associated-antigen, MCAM/MUC18/CD146, and/or the melanoma-initiating marker, ABCB5. We assessed a biomarker qualitative expression panel, contemplating the angiogenic-potential, melanoma-initiating and melanoma-differentiation drivers, cell-cell adhesion molecules, matrix-metallo-proteinases, which was performed on three enriched subpopulations from a total of 61 blood-samples from 21 melanoma patients. At first, a significant differential expression of the specific transcripts was documented between and within the CMC fractions enriched with MCAM-, ABCB5-, and both MCAM/ABCB5-coated beads, when analyzing two distinct groups: early AJCC- (stage I-II) and advanced- staged patients (stage II-IV). Moreover, in the early-AJCC staged-group, we could distinguish "endothelial," CD45-MCAM+ enriched-, "stem" S-CMCs, CD45-ABCB5+ enriched- and a third hybrid bi-phenotypic CD45-MCAM+/ABCB5+ enriched-fractions, due to three distinct gene-expression profiles. In particular, the endothelial-CMCs were characterized by positive expression of genes involved in migration and invasion, whilst the stem CMC-fraction only expressed stem and differentiation markers. The third subpopulation isolated based on concurrent MCAM and ABCB5 protein expression showed an invasive phenotype. All three distinct CMCs sub-populations, exhibited a primitive, "stem-mesenchymal" profile suggesting a highly aggressive and metastasizing phenotype. This study confirms the phenotypic and molecular heterogeneity observed in melanoma and highlights those putative genes involved in early melanoma spreading and disease progression.

Breast Cancer Is Associated with Increased HLA-DRB1*11:01 and HLA-DRB1*10:01 Allele Frequency in a Population of Patients from Central Italy.

The relationship between HLA-DRB1 allele polymorphism and breast cancer (BC) development is still unclear and needs further investigation. To address this issue, we analyzed HLA-DRB1 allele frequency (AF) by sequence-based typing (SBT) in 47 patients from central Italy with BC and 156 sex and age-matched healthy controls. Two hundred ninety-seven individuals from the same region were utilized as historical controls. Pearson's chi-square analysis with Yate's correction or Fisher's Exact test with Bonferroni's correction, as appropriate, were used to compare HLA-DRB1 AF differences in patients and controls. A total of 36 HLA-DRB1 alleles were identified. A detailed study showed that HLA-DRB1*11:01 and HLA-DRB1*10:01 alleles are significantly associated with increased BC risk. In particular, HLA-DRB1*11:01 AF was significantly higher in patients with BC than in healthy females and historical controls, even following Bonferroni's correction (stage I-II BC patients vs historical controls p<0.00; stage III-IV BC patients vs female healthy controls p=0.025 and historical controls p<0.00). The HLA-DRB1*10:01 allele was also positively associated with BC as evidenced by a significantly higher AF in patients with BC than in healthy controls (BC patients stage I-II vs historical controls corrected p =0.01). These results suggest that both HLA-DRB1*11:01 and HLA-DRB1*10:01 AF could represent interesting markers in patients at risk of developing BC.

Biological acellular pericardial mesh regulated tissue integration and remodeling in a rat model of breast prosthetic implantation.

The use of biological meshes has proven beneficial in surgical restriction and periprosthetic capsular contracture following breast prosthetic-reconstruction. Three different types (smooth, texturized, and polyurethane) of silicone round mini prostheses were implanted under rat skin with or without two different bovine acellular pericardial biological meshes (APMs, BioRipar, and Tutomesh). One hundred eighty-six female rats were divided into 12 groups, sacrificed after 3, 6, and 24 weeks and tissue samples investigated by histology and immunohistochemistry. Implantation of both APMs, with or without prostheses, reduced capsular α-SMA expression and CD3+ inflammatory cell infiltration, increasing capillary density and cell proliferation, with some differences. In particular, Tutomesh was associated with higher peri-APM CD3+ inflammation, prosthetic capsular dermal α-SMA expression and less CD31+ vessels and cell proliferation compared with BioRipar. None differences were observed in tissue integration and remodeling following the APM + prostheses implantation; the different prostheses did not influence tissue remodeling. The aim of our study was to investigate if/how the use of different APMs, with peculiar intrinsic characteristics, may influence tissue integration. The structure of APMs critically influenced tissue remodeling after implantation. Further studies are needed to develop new APMs able to optimize tissue integration and neoangiogenesis minimizing periprosthetic inflammation and fibrosis.