Cancer Immunology, Immunotherapy

Patterns of immune-cell infiltration in murine models of melanoma: roles of antigen and tissue site in creating inflamed tumors Abstract Immune-cell infiltration is associated with improved survival in melanoma. Human melanoma metastases may be grouped into immunotypes representing patterns of immune-cell infiltration: A (sparse), B (perivascular cuffing), and C (diffuse). Immunotypes have not been defined for murine melanomas, but may provide opportunities to understand mechanism-driving immunotype differences. We performed immunohistochemistry with immune-cell enumeration, immunotyping, and vascular density scoring in genetically engineered (Braf/Pten and Braf/Pten/β-catenin) and transplantable (B16-F1, B16-OVA, and B16-AAD) murine melanomas. The transplantable tumors were grown in subcutaneous (s.c.) or intraperitoneal (i.p.) locations. Braf/Pten and Braf/Pten/β-catenin tumors had low immune-cell densities, defining them as Immunotype A, as did B16-F1 tumors. B16-OVA (s.c. and i.p.) and B16-AAD s.c. tumors were Immunotype B, while B16-AAD i.p. tumors were primarily Immunotype C. Interestingly, the i.p. location was characterized by higher immune-cell counts in B16-OVA tumors, with counts that trended higher for B16-F1 and B16-AAD. The i.p. location was also characterized by higher vascularity in B16-F1 and B16-AAD tumors. These findings demonstrate that spontaneously mutated neoantigens in B16 melanomas were insufficient to induce robust intratumoral immune-cell infiltrates, but instead were Immunotype A tumors. The addition of model neoantigens (OVA or AAD) to B16 enhanced infiltration, but this most often resulted in Immunotype B. We find that tumor location may be an important element in enabling Immunotype C tumors. In aggregate, these data suggest important roles both for the antigen type and for the tumor location in defining immunotypes.

An HER2 DNA vaccine with evolution-selected amino acid substitutions reveals a fundamental principle for cancer vaccine formulation in HER2 transgenic mice Abstract Enhancement of endogenous immunity to tumor-associated self-antigens and neoantigens is the goal of preventive vaccination. Toward this goal, we compared the efficacy of the following HER2 DNA vaccine constructs: vaccines encoding wild-type HER2, hybrid HER2 vaccines consisting of human HER2 and rat Neu, HER2 vaccines with single residue substitutions and a novel human HER2 DNA vaccine, ph(es)E2TM. ph(es)E2TM was designed to contain five evolution-selected substitutions: M198V, Q398R, F425L, H473R and A622T that occur frequently in 12 primate HER2 sequences. These ph(es)E2TM substitutions score 0 to 1 in blocks substitutions matrix (BLOSUM), indicating minimal biochemical alterations. h(es)E2TM recombinant protein is recognized by a panel of anti-HER2 mAbs, demonstrating the preservation of HER2 protein structure. Compared to native human HER2, electrovaccination of HER2 transgenic mice with ph(es)E2TM induced a threefold increase in HER2-binding antibody (Ab) and elevated levels of IFNγ-producing T cells. ph(es)E2TM, but not pE2TM immune serum, recognized HER2 peptide p95 355LPESFDGDPASNTAP369, suggesting a broadening of epitope recognition induced by the minimally modified HER2 vaccine. ph(es)E2TM vaccination reduced tumor growth more effectively than wild-type HER2 or HER2 vaccines with more extensive modifications. The elevation of tumor immunity by ph(es)E2TM vaccination would create a favorable tumor microenvironment for neoantigen priming, further enhancing the protective immunity. The fundamental principle of exploiting evolution-selected amino acid substitutions is novel, effective and applicable to vaccine development in general.

Pembrolizumab as first-line treatment for metastatic uveal melanoma Abstract Background No standard treatment has been defined for metastatic uveal melanoma (mUM). Although clinical trials testing Nivolumab/Pembrolizumab for cutaneous melanoma did not include mUM, anti PD-1 agents are commonly used for this disease. Patients and methods In this prospective observational cohort single arm study, we investigated efficacy and safety of Pembrolizumab as first-line therapy for mUM. The efficacy was evaluated in terms of progression-free survival (PFS), response rate and overall survival (OS). Toxicity was also assessed. Results Seventeen patients were enrolled. A median of 8 cycles were administered (range 2–28). Two patients achieved partial response (11.7%), 6 a disease stabilization (35.3%), whereas 9 (53%) had a progression. No complete response was observed. PFS of the overall population was 3.8 months. PFS was 9.7 months for patients with an interval higher than 5 years from diagnosis of primary tumor to metastatic disease and 2.6 months for patients with an interval lower than 5 years [p = 0.039, HR 0.2865 (95% CI 0.0869–0.9443)]. Median OS was not reached. The two responding patients were still on treatment with Pembrolizumab at the time of data analysis. Survival was 12.8 months for patients with clinical benefit, while OS for progressive patients was 3.1 months. PD-L1 expression and genomic abnormalities predictive of relapse after diagnosis of primary tumor were not associated with PFS. Toxicity was mild, without grade 3–4 side effects. Conclusions The efficacy of Pembrolizumab does not seem particularly different when compared to other agents for mUM, but responding patients had a remarkable disease control.

Impact of combination immunochemotherapies on progression of 4NQO-induced murine oral squamous cell carcinoma Abstract Advanced oral squamous cell carcinomas (OSCC) have limited therapeutic options. Although immune therapies are emerging as a potentially effective alternative or adjunct to chemotherapies, the therapeutic efficacy of combination immune chemotherapies has yet to be determined. Using a 4-nitroquinolone-N-oxide (4NQO) orthotopic model of OSCC in immunocompetent mice, we evaluated the therapeutic efficacy of single- and combined-agent treatment with a poly-epitope tumor peptide vaccine, cisplatin and/or an A2AR inhibitor, ZM241385. The monotherapies or their combinations resulted in a partial inhibition of tumor growth and, in some cases, a significant but transient upregulation of systemic anti-tumor CD8+ T cell responses. These responses eroded in the face of expanding immunoregulatory cell populations at later stages of tumor progression. Our findings support the need for the further development of combinatorial therapeutic approaches that could more effectively silence dominant immune inhibitory pathways operating in OSCC and provide novel, more beneficial treatment options for this tumor.

First-in-human phase 1 dose-escalating trial of G305 in patients with advanced solid tumors expressing NY-ESO-1 Abstract Human tumor cells express antigens that serve as targets for the host cellular immune system. This phase 1 dose-escalating study was conducted to assess safety and tolerability of G305, a recombinant NY-ESO-1 protein vaccine mixed with glucopyranosyl lipid A (GLA), a synthetic TLR4 agonist adjuvant, in a stable emulsion (SE). Twelve patients with solid tumors expressing NY-ESO-1 were treated using a 3 + 3 design. The NY-ESO-1 dose was fixed at 250 µg, while GLA-SE was increased from 2 to 10 µg. Safety, immunogenicity, and clinical responses were assessed prior to, during, and at the end of therapy. G305 was safe and immunogenic at all doses. All related AEs were Grade 1 or 2, with injection site soreness as the most commonly reported event (100%). Overall, 75% of patients developed antibody response to NY-ESO-1, including six patients with increased antibody titer ( ≥ 4-fold rise) and three patients with seroconversion from negative (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of patients; 33.3% were new responses and 1 was boosted ( ≥ 2-fold rise). Following treatment, 8 of 12 patients had stable disease for 3 months or more; at the end of 1 year, three patients had stable disease and nine patients were alive. G305 is a potent immunotherapeutic agent that can stimulate NY-ESO-1-specific antibody and T-cell responses. The vaccine was safe at all doses of GLA-SE (2–10 µg) and showed potential clinical benefit in this population of patients.

PLAC1: biology and potential application in cancer immunotherapy Abstract The emergence of immunotherapy has revolutionized medical oncology with unprecedented advances in cancer treatment over the past two decades. However, a major obstacle in cancer immunotherapy is identifying appropriate tumor-specific antigens to make targeted therapy achievable with fewer normal cells being impaired. The similarity between placentation and tumor development and growth has inspired many investigators to discover antigens for effective immunotherapy of cancers. Placenta-specific 1 (PLAC1) is one of the recently discovered placental antigens with limited normal tissue expression and fundamental roles in placental function and development. There is a growing body of evidence showing that PLAC1 is frequently activated in a wide variety of cancer types and promotes cancer progression. Based on the restricted expression of PLAC1 in testis, placenta and a wide variety of cancers, we have designated this molecule with new terminology, cancer–testis–placenta (CTP) antigen, a feature that PLAC1 shares with many other cancer testis antigens. Recent reports from our lab provide compelling evidence on the preferential expression of PLAC1 in prostate cancer and its potential utility in prostate cancer immunotherapy. PLAC1 may be regarded as a potential CTP antigen for targeted cancer immunotherapy based on the available data on its promoting function in cancer development and also its expression in cancers of different histological origin. In this review, we will summarize current data on PLAC1 with emphasis on its association with cancer development and immunotherapy.

Checkpoint blockade immunotherapy enhances the frequency and effector function of murine tumor-infiltrating T cells but does not alter TCRβ diversity Abstract Checkpoint blockade immunotherapy is now a first-line treatment option for patients with melanoma. Despite achieving objective responses in about half of patients, the exact immune mechanisms elicited and those required for therapeutic success have not been clearly identified. Insight into these mechanisms is key for improving outcomes in a broader range of cancer patients. We used a murine melanoma model to track responses by different subsets of tumor-infiltrating lymphocytes (TIL) during checkpoint blockade immunotherapy. Tumors from treated mice had increased frequencies of both CD4+ and CD8+ T cells, which also showed evidence of functional reinvigoration and elevated effector cytokine production after immunotherapy. We predicted that increased T cell numbers and function within tumors reflected either infiltration by new T cells or clonal expansion by a few high-affinity tumor-reactive T cells. To address this, we compared TIL diversity before and after immunotherapy by sequencing the complementarity determining region 3 (CDR3) of all T cell receptor beta (TCRβ) genes. While checkpoint blockade effectively slowed tumor progression and increased T cell frequencies, the diversity of intratumoral T cells remained stable. This was true when analyzing total T cells and when focusing on smaller subsets of effector CD4+ and CD8+ TIL as well as regulatory T cells. Our study suggests that checkpoint blockade immunotherapy does not broaden the T cell repertoire within murine melanoma tumors, but rather expands existing T cell populations and enhances effector capabilities.

Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases Abstract Background PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment. Methods We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy. Results 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged. Conclusions The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.

Clinicopathological implications of TIM3 + tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients Abstract Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan–Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.

Novel circulating tumor cell-based blood test for the assessment of PD-L1 protein expression in treatment-naïve, newly diagnosed patients with non-small cell lung cancer Abstract We evaluated the analytical and clinical performance of a novel circulating tumor cell (CTC)-based blood test for determination of programmed death ligand 1 (PD-L1) protein expression status in real time in treatment-naïve non-small cell lung cancer (NSCLC) patients. CTCs were detected in 86% of patients with NSCLC (I–IV) at the time of diagnosis, with a 67% PD-L1 positivity rate (≥ 1 PDL + CTC). Among 33 NSCLC patients with PD-L1 results available via both tissue immunohistochemistry (IHC) and CTC assays, 78.9% were positive according to both methods. The CTC test identified an additional ten cases that were positive for PD-L1 expression but that tested negative via IHC analysis. Detection of higher PD-L1 expression on CTCs compared to that in the corresponding tissue was concordant with data obtained using other platforms in previously treated patients. The concordance in PD-L1 expression between tissue and CTCs was approximately 57%, which is higher than that reported by others. In summary, evaluation of PD-L1 protein expression status on CTCs isolated from NSCLC patients is feasible. PD-L1 expression status on CTCs can be determined serially during the disease course, thus overcoming the myriad challenges associated with tissue analysis.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pharmacal Research

Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives Abstract Engineering T cells with a chimeric antigen receptor (CAR) that reprograms their antigen selectivity and signaling has recently emerged as one of the most promising therapeutic approaches for treating cancers. For example, two CD19-specific CAR T cell (CAR-T) therapies have shown remarkable responses in patients with relapsed/refractory B-cell cancers, and were approved by the US Food and Drug Administration in 2017. This initial clinical success has spurred an explosion of interests in this novel therapy from both academia and industry, and results from basic and clinical research have enabled the rapid evolution of the CAR-T field. In this review, we describe the basic structure of the CAR and discuss how each of its domains affect the efficacy and safety of CAR-T therapies. In addition, we discuss some of the novel concepts and other considerations that are essential for ensuring the future success of CAR-T therapy.

Natural killer cells as a promising therapeutic target for cancer immunotherapy Abstract Natural killer (NK) cells are innate lymphoid cells that provide early protection against cancer development via their selectivity to kill abnormal cells undergoing cellular transformation without the need for prior stimulation. Given the correlation between NK cell dysfunction and cancer prognosis, restoration of endogenous NK cells in the tumor microenvironment or adoptive transfer of NK cells with improved function holds great promise in cancer treatment. Furthermore, MHC-unrestricted tumor lysis by NK cells complements the MHC-restricted killing of tumor cells by cytotoxic T cells, thus positioning NK cells as an alternative or complementary therapeutic target for cancers that are refractory to T cell-based therapy. Although previous therapeutic strategies have focused on the manipulation of NK cell inhibitory receptors, recent advances in our understanding of NK cell activation have provided additional promising strategies to enhance NK cell reactivity against cancer. These approaches include targeting immunosuppressive mechanisms in the tumor microenvironment, such as immune checkpoint receptors, and further enhancing NK cell activation via modulation of intracellular checkpoint molecules or incorporation of tumor-directed chimeric antigen receptors. Thus, an in-depth understanding of NK cell activation will facilitate the optimal design of therapeutic strategies against refractory cancers, possibly in rational and synergistic combination with other therapies.

Phosphatidylserine receptor-targeting therapies for the treatment of cancer Abstract Asymmetric distribution of phospholipids across the plasma membrane is a unique characteristic of eukaryotic cells. Phosphatidylcholine and sphingomyelin are exposed in the outer leaflet, and phosphatidylserine (PS) is predominantly located in the inner leaflet. Redistribution of PS to the cell surface can be observed in several physiological conditions, such as apoptosis and platelet activation, or in pathological conditions, such as the release of microvesicles/exosomes from tumor tissues. PS binding to the phosphatidylserine receptor (PSR) on immune cells initiates immunosuppressive pathways that can lead to immune evasion by cancer cells. Conversely, PSR activation of cancer cells plays an important role in their survival, proliferation and metastasis. Herein, we briefly summarize both recent advances in our understanding of the pathological roles of PS and its receptor in cancer biology, as well as relevant pharmacological approaches.

Natural compound inducers of immunogenic cell death Abstract Accumulating evidence shows that the anti-cancer potential of the immune response that can be activated by modulation of the immunogenicity of dying cancer cells. This regulated cell death process is called immunogenic cell death (ICD) and constitutes a new innovating anti-cancer strategy with immune-modulatory potential thanks to the release of damage-associated molecular patterns (DAMPs). Some conventional clinically-used chemotherapeutic drugs, as well as preclinically-investigated compounds of natural origins such as anthracyclines, microtubule-destabilizing agents, cardiac glycosides or hypericin derivatives, possess such an immune-stimulatory function by triggering ICD. Here, we discuss the effects of ICD inducers on the release of DAMPs and the activation of corresponding signaling pathways triggering immune recognition. We will discuss potential strategies allowing to overcome resistance mechanisms associated with this treatment approach as well as co-treatment strategies to overcome the immunosuppressive microenvironment. We will highlight the potential role of metronomic immune modulation as well as targeted delivery of ICD-inducing compounds with nanoparticles or liposomal formulations to improving the immunogenicity of ICD inducers aiming at long-term clinical benefits.

Roles of NKT cells in cancer immunotherapy Abstract Cancer immunotherapy has emerged as an effective therapeutic strategy to treat cancer. Among diverse immune populations, invariant natural killer T (iNKT) cells have shown potent antitumor activity by linking innate and adaptive immune systems. Upon activation by lipid antigens on CD1d molecules, iNKT cells rapidly produce various cytokines and trigger antitumor immunity directly or indirectly by activating other antitumor immune cells. Administration of a representative iNKT cell ligand alpha-galactosylceramide (α-GalCer) or α-GalCer-pulsed APCs effectively stimulates iNKT cells and thereby induces antitumor effects. In this review, we will introduce the biology and importance of NKT cells in antitumor immunity. Previous studies have demonstrated that iNKT cells not only activate various immune cells but also reinvigorate exhausted immune cells in the tumor microenvironment. Furthermore, we will summarize the major clinical trials utilizing iNKT-based immunotherapies.

T helper 17 (Th17) cells and interleukin-17 (IL-17) in cancer Abstract Th17 cells are a specialized subset of CD4+ T cells that are essential in driving inflammation during autoimmune disease and infection through a signature cytokine IL-17. Th17 cells have been found in various human cancers. The function of these cells in cancers is highly context-dependent; both tumor-promoting and tumor-suppressing activity have been reported. IL-17 and IL-22, Th17-derived cytokines, influence the tumor microenvironment by directly promoting transformed cell properties and neighboring stromal cell activity. These cytokines are also involved in regulation of the immune system by modulating the activities of myeloid cells and T cells. These findings suggest that Th17 cells and their cytokines are a key mediator of cancer development, representing a potential target for cancer therapy. Herein, I review recent preclinical studies on the function of Th17 cells and IL-17 in cancer and discuss possible therapeutic approaches to harness Th17 cells for cancer immunotherapy.

Role of myeloid-derived suppressor cells in immune checkpoint inhibitor therapy in cancer Abstract Over the past decade, immune checkpoint inhibitor (ICI) therapy has demonstrated improved therapeutic efficacy in a wide range of cancers. However, the benefits are restricted to a small population of patients. Therefore, studies on understanding the mechanisms resistant to ICI therapy and for finding predictive biomarkers for ICI therapy are being actively conducted. Recent studies have demonstrated that myeloid-derived suppressor cells (MDSC) inhibit ICI therapy by various mechanisms, and that the response to ICI therapy can be improved by blocking MDSC activity. Moreover, low level of MDSC in patients with cancer has been shown to be correlated with their good prognosis after ICI treatment, thereby suggesting MDSC as a predictive biomarker in this regard. This review focuses on the roles of MDSC in ICI therapy and their relevant applications.

Immunological and clinical implications of immune checkpoint blockade in human cancer Abstract Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 therapy are now FDA-approved treatment options for different cancer types. However, the therapeutic efficacy of ICIs varies substantially among cancer types and patients, and only a limited proportion of cancer patients benefit clinically from ICIs. To improve the therapeutic efficacy of cancer treatments involving ICI, the mechanisms of response to ICIs and the heterogeneous pattern of immune checkpoint receptor expression need to be better understood. Here, we review recent studies on ICIs in human cancer, providing the necessary basis for the rational design of immunotherapy and for appropriate patient selection.

Transendothelial migration (TEM) of in vitro generated dendritic cell vaccine in cancer immunotherapy Abstract Many efforts have been made to improve the efficacy of dendritic cell (DC) vaccines in DC-based cancer immunotherapy. One of these efforts is to deliver a DC vaccine more efficiently to the regional lymph nodes (rLNs) to induce stronger anti-tumor immunity. Together with chemotaxis, transendothelial migration (TEM) is believed to be a critical and indispensable step for DC vaccine migration to the rLNs after administration. However, the mechanism underlying the in vitro-generated DC TEM in DC-based cancer immunotherapy has been largely unknown. Currently, junctional adhesion molecules (JAMs) were found to play an important role in the TEM of in vitro generated DC vaccines. This paper reviews the TEM of DC vaccines and TEM-associated JAM molecules.

Realgar transforming solution-induced differentiation of NB4 cell by the degradation of PML/RARα partially through the ubiquitin–proteasome pathway Abstract PML/retinoic acid receptor alpha (RARα), as a hallmark of acute promyeloid leukemia (APL), is directly related to the outcome of clinical APL remedy. It is reported that arsenicals can effectively degrade PML/RARα, such as arsenic trioxide and realgar. However, the high toxicity or insolubility have hampered their clinical applications. Realgar transforming solution (RTS) was produced from realgar by bioleaching process in our lab. Previous studies demonstrated that RTS had a significant anti-cancer ability on chronic myeloid leukemia through oncoprotein degradation. The capacity of RTS on treating APL is what is focused on in this study. The results showed that RTS had a noticeable sensitivity in NB4 cell, and RTS remarkably down-regulated PML/RARα expression and induced cell differentiation. Further, RTS could accumulate PML/RARα into the nuclear bodies and then execute degradation, which could be reversed by proteasome inhibitor MG132. The results also exhibited that the reduction of RTS-induced PML/RARα expression accompanied by the elevation of ubiquitin and SUMO-1 protein expression. Finally, PML and SUMO-1 had been demonstrated to be co-localized after RTS treatment by immunofluorescence co-localization assay and immunoprecipitation assay. In conclusion, these results suggested that RTS-induced cell differentiation may attribute to the PML/RARα degradation partially through the ubiquitin–proteasome pathway.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Urogynecology

Commentary on 'Defecatory dysfunction and other clinical variables are predictors of pessary discontinuation'

Commentary on: Sacral neuromodulation treating chronic pelvic pain: a meta-analysis and systematic review of the literature

Letter to the editor: The negative predictive value of preoperative urodynamics for stress urinary incontinence following prolapse surgery

Commentary on: Effects of mesh-related complications in vaginal surgery on quality of life

Laparoscopic management of a large urethral leiomyoma Abstract Introduction and hypothesis A 42-year-old female presented with a 12-cm mass bulging the anterior vaginal wall and causing urgency urinary incontinence and bulk symptoms. Methods Imaging showed a tumor originating from the dorsal and cranial part of the urethra and developing in the vesicouterine space and vesicovaginal septum, dislocating the bladder ventrally and the uterus cranial-dorsally. Results Tranvaginal biopsy showed a benign leiomyoma. A laparoscopic approach with development of the vesicouterine space permitted a safe partial morcellation of the myoma. After the bladder and vaginal wall had been completely freed, further caudal dissection was conducted with isolation of the distal cranio-dorsal portion of the urethra. The dissection plane with the vaginal wall was developed up to the caudal margin of the urethral myoma almost corresponding to the vulvar plane, and total excision of the lesion was performed. Conclusion Laparoscopic management of urethral leiomyomas that develop into the vesicouterine space and vesicovaginal septum is feasible and safe also for very large lesions.

Laparoscopic bilateral cervicosacropexy: introduction to a new tunneling technique Abstract Introduction and hypothesis To elevate and suspend the apical end of the vagina, the uterosacral ligaments (USL) were replaced by polyvinylidene fluoride (PVDF) structures. These PVDF structures were placed in the peritoneal folds of the USL at the pelvic wall to mimic the lateral and backward tension and to avoid rectal obstruction. A special tunneling device was used, which allowed the semi-circular placement of the structure without destroying the peritoneum. Methods A 59-year-old woman with mixed urinary incontinence and apical prolapse (pelvic organ prolapse quantification system, POP-Q, stage 2) of the uterus underwent laparoscopic bilateral USL replacement. USLs were replaced by PVDF structures by performing the cervicosacropexy (CESA) technique using a semi-circular tunneling device. Results Apical support was restored (POP-Q stage 0), and the patient was continent thereafter. The tunneling device was pulled through the peritoneal folds of the USLs toward the cervix. The new USL structures were brought to their physiological position. The new technique did not lead to any complications and did not cause any side effects during 1-year follow-up. Conclusions Restoration of apical prolapse and urinary continence was achieved by bilateral USL replacement using a semi-circular tunneling device that was inserted through the lateral abdominal trocar incision.

Effects of wearing supportive underwear versus pelvic floor muscle training or no treatment in women with symptoms of stress urinary incontinence: an assessor-blinded randomized control trial Abstract Introduction and hypothesis In our previous single-arm pilot study, we reported that ready-made supportive underwear (shaper) was effective in elevating the bladder neck and reducing urinary incontinence (UI) symptoms. The aim of this study was to determine the effects of wearing a shaper compared with pelvic floor muscle training (PFMT) at home using a training compact disc with music, or no treatment, in an assessor-blinded randomized control trial, on reducing UI symptoms. Methods Participants aged 30–59 years with symptoms of stress urinary incontinence were randomly assigned to three groups: the shaper group, PFMT group, and no treatment group. The UI episodes/week and the Japanese version of the International Consultation on Incontinence Questionnaire Short-Form were compared between the baseline and the 6th or 12th week of the intervention period. Results Eighty-nine women who completed the 12-week intervention period were analyzed. After the 12-week intervention period, the improvement rate in UI symptoms (ratio of the case number in which the UI episodes/week decreased at least 50% from the baseline) was 73.3% (22/30 women) in the shaper group, 74.2% (23/31 women) in the PFMT group, and 25.0% (7/28 women) in the no treatment group. The improvement rate in UI symptoms in the shaper and PFMT groups was significantly higher than that in the no treatment group (both P < 0.001). Conclusions Wearing supportive underwear (shaper) was almost as effective as PFMT at home in reducing UI symptoms.

Perioperative adverse events in women undergoing concurrent urogynecologic and gynecologic oncology surgeries for suspected malignancy Abstract Introduction and hypothesis This study's objectives were to compare the incidence of adverse events after concurrent urogynecologic and gynecologic oncology surgery to gynecologic oncology surgery alone and to describe the frequency of modification in planned urogynecologic procedures. The authors hypothesized there would be no difference in major complications. Methods This was a retrospective matched cohort study of women who underwent concurrent surgery at a large tertiary care center between January 2004 and June 2017. Cohorts were matched by surgeon, surgery route, date, and final pathologic diagnosis. Perioperative data and postoperative adverse events classified by Clavien-Dindo grade were compared. Results One hundred and eight patients underwent concurrent surgeries, with 216 matched cohorts. Concurrent-case patients were more likely to be older, postmenopausal, have greater vaginal parity, have had preoperative chemotherapy, and have preoperative cardiac or pulmonary disease. There were no differences in intraoperative complications or Dindo grade ≥ 3 adverse events between groups, but there were more grade 2 adverse events in the concurrent cohort (44 vs 19%, p < 0.0001) including postoperative urinary tract infection (UTI) (26 vs 7%, p < 0.0001). Concurrent surgery remained associated with a higher incidence of grade ≥ 2 events on multivariate analysis [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.5–4.2, p = 0.0004). Discharge with a urinary catheter was more frequent after concurrent cases (35 vs 2%, p < 0.0001). Planned urogynecologic procedures were modified in 10% (n = 11) of cases. Conclusions Concurrent surgeries have an increased incidence of minor but not serious perioperative adverse events. One in ten planned urogynecologic procedures is either modified or abandoned during combined surgeries.

Interventions to reduce morbidity from vault hematoma following vaginal hysterectomy: a systematic review and meta-analysis Abstract Introduction and hypothesis A frequent complication following vaginal hysterectomy is the formation of vaginal vault hematoma. The objective of our systematic review was to assess the impact of various interventions in reducing the incidence of vault hematoma or postoperative febrile morbidity following vaginal hysterectomy. Methods We carried out a systematic search of Cochrane, MEDLINE, Embase, CINAHL, HTA database, PROSPERO, meta-Register of Controlled Trials (mRCT), PubMed, CENTRAL, Google Scholar, conference abstracts, and a hand search of journals from inception until September 2018. Our search strategy included interventions in women undergoing vaginal hysterectomy with modified vault closure with inclusion of peritoneal edges, vaginal vault drainage, or vaginal packing to reduce the incidence of clinically significant vault hematomas. Two independent reviewers (SR and AD) extracted data using a structured proforma. Meta-analysis was carried out using RevMan 5.3 software. Results We identified two studies on modified vaginal vault closure incorporating peritoneal edges that reported a significant reduction in vault hematoma incidence. Meta-analysis of two randomized trials on vaginal drains showed no difference in postoperative febrile morbidity secondary to vault hematoma [risk ratio (RR) 0.8, 95% confidence intervals (CI) 0.43–1.50]. Similar results were seen on meta-analysis of four randomized trials on the use of vaginal packing (RR 0.8, 95% CI 0.43–1.50). Conclusions Inclusion of peritoneal edges in vaginal vault closure may reduce the incidence of vault hematoma. The routine use of vaginal vault drainage and/or packing has not shown to reduce vault hematoma incidence or postoperative febrile morbidity. We recommend a change of practice to include peritoneal edges in vault closure based on the evidence available in our systematic review.

Reintegration needs of young women following genitourinary fistula surgery in Uganda Abstract Introduction and hypothesis Genitourinary fistulas (usually arising following prolonged obstructed labor) are particularly devastating for women in low-income counties. Surgical repair is often difficult and delayed. While much attention has been devoted to technical surgical issues, the challenges of returning to normal personal, family, and community life after surgical treatment have received less scrutiny from researchers. We surveyed young Ugandan women recovering from genitourinary fistula surgery to assess their social reintegration needs following surgery. Methods A cross-sectional survey of 61 young women aged 14–24 years was carried out 6 months postoperatively. Interviews were carried out in local languages using a standardized, interviewer-administered, semistructured questionnaire. Data were entered using EpiData and analyzed using SPSS. Results Ongoing reintegration needs fell into interrelated medical, economic, and psychosocial domains. Although >90% of fistulas were closed successfully, more than half of women had medical comorbidities requiring ongoing treatment. Physical limitations, such as foot drop and pelvic muscle dysfunction impacted their ability to work and resume their marital relationships. Anxieties about living arrangements, income, physical strength, future fertility, spouse/partner fidelity and support, and possible economic exploitation were common. Sexual dysfunction after surgery—including dyspareunia, loss of libido, fear of intercourse, and anxieties about the outcome of future pregnancies—negatively impacted women's relationships and self-esteem. Conclusions Young women recovering from genitourinary fistula surgery require individualized assessment of their social reintegration needs. Postoperative social reintegration services must be strengthened to do this effectively.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cardiology

Renal Artery Stenosis and Congestive Heart Failure: What Do We Really Know? Abstract Purpose of Review Congestive heart failure (CHF) is a major cause of morbidity, mortality, and health care expenditure. Although the role of renal artery stenosis (RAS) in CHF has been known, there are a number of areas of uncertainty. Recent Findings The prevalence of RAS in subjects with CHF varies from 15 to 54% depending on the cohort studied and the diagnostic modality used to identify RAS. In subjects with CHF, the presence of RAS is associated with worse renal function and a higher risk for mortality during long-term follow-up. Summary There are many unanswered questions regarding the role of RAS in subjects with CHF. This review highlights those questions and helps to set the research agenda in this area.

Strategies for Minimizing Occupational Radiation Exposure in Cardiac Imaging Abstract Purpose of Review Radiation safety has been at the center of interest of both researchers and healthcare institutions. This review will summarize and shed light on the various techniques adapted to reduce staff exposure to ionizing radiation (IR) in the field of cardiac imaging. Recent Findings In the last years, with the advance of awareness and the development of new technologies, there have been several tools and techniques adapted. The breakthrough of several technologies to lower radiation dose and shorten the duration of diagnostic tests associated with IR, the use of protection devices by staff members, and mostly the awareness of exposure to IR are the hallmark of these advances. Using all these measures has led to a significant decrease in staff exposure to IR. Summary Reducing staff exposure to meet the "As Low As Reasonably Achievable" principle is feasible. This review introduces the most important strategies applied in cardiac imaging.

Pluripotent Stem Cell-Derived Cardiomyocyte Transplantation for Heart Disease Treatment Abstract Purpose of Review Cardiovascular disease is the leading cause of mortality worldwide. Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) have great potential to treat heart disease, owing to their capacity of engraftment and remuscularization in the host heart after transplantation. In the current review, we provide an overview of PSC-CMs for clinical transplantation. Recent Findings Studies have shown that PSC-CMs can survive, engraft, and form gap junctions after transplantation, with functional benefit. Engrafted PSC-CMs matured gradually in host hearts. Only in a large animal model, transient ventricular arrhythmias were detected, mainly because of the ectopic pacing from the grafted PSC-CMs. Although intense immunosuppression is unavoidable in xenotransplantation, immunosuppression remains necessary for MHC-matched allogenic non-human primate PSC-CMs transplantation. Summary This review offers insights on how PSC-CMs contribute to functional benefit after transplantation to injured non-human primate hearts. We believe that PSC-CM transplantation represents a potentially novel treatment for ischemic heart diseases, provided that several technological and biological limitations can be overcome.

Effect of SGLT2 Inhibitors on the Sympathetic Nervous System and Blood Pressure Abstract Purpose of the Review Hyperactivity of sympathetic nervous system (SNS) plays a role in the development of arterial hypertension and heart failure, two co-morbidities frequently associated with type 2 diabetes (T2DM). This review aims at analyzing the effects of sodium-glucose cotransporter type 2 inhibitors (SGLT2is) on blood pressure and more especially on SNS activity in patients with T2DM. Recent Findings By enhancing glucosuria, natriuresis, and osmotic diuresis, SGLT2is improve glucose control, promote weight loss, lower arterial blood pressure, and reduce the risk of major cardiovascular events and hospitalization for heart failure. No rise of heart rate is detected despite reductions in blood pressure and plasma volume, which may suggest a dampening of SNS activity. Indeed, increasing experimental and clinical data demonstrated a reduction in SNS activity, including in key target organs such as the heart and the kidneys. Summary Of potential major interest, a better understanding of the mechanisms linking SGLT2 and SNS deserves further investigation.

Emerging Role of Coronary Computed Tomography Angiography in Lipid-Lowering Therapy: a Bridge to Image-Guided Personalized Medicine Abstract Purpose of Review To summarize the current status of coronary computed tomography angiography (CTA) in the assessment of coronary plaques and discuss the ability of serial coronary CTA to quantitatively measure changes in the plaque burden in response to lipid-lowering therapy. Recent Findings Recent advances in coronary CTA have allowed identification of high-risk coronary features in acute coronary syndrome and measurement of changes in the coronary plaque burden with good reproducibility. Statin therapy may delay plaque progression and change some plaque features. However, the clinical relevance of quantitative changes in coronary plaques and the optimal methods to reduce the plaque burden remain unclear. Summary Despite guideline-directed lipid-lowering therapy, adverse events still occur in substantial numbers of patients receiving statins. Coronary CTA is noninvasive and has high diagnostic performance in patients with coronary artery disease, making change in the plaque burden an applicable biomarker for individualized assessment of future risk.

New Insights in the Control of Low-Density Lipoprotein Cholesterol to Prevent Cardiovascular Disease Abstract Purpose of Review Low-density lipoprotein cholesterol (LDL-C) is one major cause of cardiovascular disease (CVD). In this review, we discuss current developments in the understanding of LDL-C as lifelong risk factor, treatment targets, and emerging approaches to reduce cardiovascular risk by lowering LDL-C. Recent Findings Recent evidence underscores the importance of LDL-C lowering in CVD prevention by mechanisms that increase the hepatic clearance of apolipoprotein B-containing lipoproteins from the plasma. Mendelian randomization studies provided evidence on both safety and efficacy of lower LDL-C in the long term. For young individuals, metrics other than 10-year CVD risk are required. Despite this evidence, LDL-C treatment target attainment is poor. Novel approaches are therefore needed. These include individualized strategies and new LDL-C-lowering pharmaceuticals. Summary Early, long-term treatment with LDL-C-lowering therapies has the potential to markedly reduce CVD incidence and progression. Future research should aim to identify patient characteristics that enable physicians to tailor therapy to each individual patient.

Genetics, Dyslipidemia, and Cardiovascular Disease: New Insights Abstract Purpose of Review The cardiovascular (CV) risk related to lipid disorders is well established and is based on a robust body of evidence from well-designed randomized clinical trials, as well as prospective observational studies. In the last two decades, significant advances have been made in understanding the genetic basis of dyslipidemias. The present review is intended as a comprehensive discussion of current knowledge about the genetics and pathophysiology of disorders that predispose to dyslipidemia. We also focus on issues related to statins and the proprotein convertase subtilisin/kexin type 9 (PCSK9) and some of its polymorphisms, as well as new cholesterol-lowering medications, including PCSK9 inhibitors. Recent Finding Cholesterol is essential for the proper functioning of several body systems. However, dyslipidemia—especially elevated low-density lipoprotein (LDL-c) and triglyceride levels, as well as reduced lipoprotein lipase activity—is associated with an increased risk of coronary artery disease (CAD). High-density lipoprotein (HDL-c), however, seems to play a role as a risk marker rather than as a causal factor of the disease, as suggested by Mendelian randomization studies. Several polymorphisms in the lipoprotein lipase locus have been described and are associated with variations in the activity of this enzyme, producing high concentrations of triglycerides and increased risk of CAD. Summary Dyslipidemia, especially increased LDL-c and triglyceride levels, continues to play a significant role in CV risk. The combination of genetic testing and counseling is important in the management of patients with dyslipidemia of genetic etiology. Strategies focused on primary prevention can offer an opportunity to reduce CV events.

Time Is a Precious Commodity: 2018 OPTN Policy Change and the Potential to Lower Heart Transplant Waitlist Time in the Sickest Patients Abstract Purpose of Review Heart transplantation is the gold standard therapy for end-stage heart failure; however, the donor pool is limited, making this a scarce resource that must be allocated to the sickest patients in an efficient, fair, and equitable manner. The allocation policies have been constantly revised over the years to refine the process. We will explore the new heart allocation system, OPTN-Policy 6, as well as, review why these changes were necessary. Recent Findings Over the past decade, the number of active heart transplant candidates nearly doubled, with a dramatic increase in the number of status 1A and 1B (high priority) candidates. Candidates have also faced increased waitlist times with geographic variances. The allocation policy changes will attempt to alleviate these problems as well as adapt to advances in technology. Summary The new allocation policy is designed to adapt to the present day reality of expanded mechanical support use, increased candidate acuity, increasing waiting times, and geographical disparities in transplant rates. Though the implementation of the new allocation policy will require some change in practice, the transplant community, as knowledge is gained, is accustomed to change and refinement in practice, in an effort to improve outcomes for patients with end-stage heart failure.

Left Atrial Occlusion Device Implantation: the Role of the Echocardiographer Abstract Purpose of Review Atrial fibrillation is the most common arrhythmia worldwide and is a major risk factor for embolic stroke. For patients with atrial fibrillation who are unable to tolerate systemic anticoagulation, left atrial appendage (LAA) occlusion has been shown to mitigate stroke risk. In this article, we describe the vital role of the echocardiographer in intraprocedural guidance of percutaneous LAA occlusion procedures as well as in the pre- and post-procedure assessment of these patients. Recent Findings A few percutaneously delivered devices for LAA exclusion from the systemic circulation are available in contemporary practice. These devices employ an either exclusive endocardial LAA occlusion approach, such as the Watchman (Boston Scientific, Maple Grove, MN) and Amulet (St. Jude Medical, Minneapolis, MN), or both an endocardial and pericardial (epicardial) approach such as the Lariat procedure (SentreHEART, Palo Alto, CA). Summary Two- and three-dimension transesophageal echocardiography is critical for patient selection, procedure planning, procedural guidance, and ensuring satisfactory immediate as well as long-term LAA occlusion/exclusion efficacy. This review will provide an overview of the role of the echocardiographer in all aspects of LAA occlusion/exclusion procedures for the most commonly used commercially available devices in current practice.

Aortic Regurgitation Abstract Purpose of Review Aortic regurgitation (AR) is a common form of valvular disease which is characterized by reflux of blood from the aorta into the left ventricle (LV) during diastole. AR results from various etiologies, affecting the aortic valve cusps or the aortic root. The clinical presentation of patients with AR depends on the severity of the regurgitation and differs whether AR develops acutely or if it progresses over a prolonged period, allowing the cardiac chambers to adapt. Echocardiography is the primary method to determine the etiology of AR and to define its severity. We review the current data regarding the diagnosis and treatment of AR. Recent Findings No single parameter is sufficient to determine AR severity; thus, an integrative, multi-parametric approach is required. Echocardiography is key for imaging the aortic valve morphology and flow as well as aortic root and ascending aorta. Determining LV ejection fraction and dimensions is essential for patient management and optimizing timing for intervention. Three-dimensional (3D) echocardiography is useful in the evaluation of AR etiology and severity. The use of Trasncatheter aortic valve replacement (TAVR) has emerged as an alternative to surgery in patients at high operative risk. Summary The diagnosis and management of AR requires a comprehensive approach and routine clinical and echocardiographic follow-up. Surgical or percutaneous therapy is indicated when symptoms develop and in those who have LV dysfunction or LV dilation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Learning & Behavior

Mental imagery in animals: Learning, memory, and decision-making in the face of missing information Abstract When we open our eyes, we see a world filled with objects and events. Yet, due to occlusion of some objects by others, we only have partial perceptual access to the events that transpire around us. I discuss the body of research on mental imagery in animals. I first cover prior studies of mental rotation in pigeons and imagery using working memory procedures first developed for human studies. Next, I discuss the seminal work on a type of learning called mediated conditioning in rats. I then provide more in-depth coverage of work from my lab suggesting that rats can use imagery to fill in missing details of the world that are expected but hidden from perception. We have found that rats make use of an active expectation (i.e., an image) of a hidden visual event. I describe the behavioral and neurobiological studies investigating the use of a mental image, its theoretical basis, and its connections to current human cognitive neuroscience research on episodic memory, imagination, and mental simulations. Collectively, the reviewed literature provides insight into the mechanisms that mediate the flexible use of an image during ambiguous situations. I position this work in the broader scientific and philosophical context surrounding the concept of mental imagery in human and nonhuman animals.

A fish eye view of the mirror test Summary Reactions to a recent study suggesting that cleaner wrasse can pass the mirror self-recognition test (Kohda et al. in PLOS Biology, 17(2), e3000021, 2019) reveal more about scientists' biases than about self-awareness. Scientists should base conclusions about species' abilities based on the corpus of data on that species rather than on a single test or preconceived expectations based on phylogeny alone.

Searching images and the meaning of alarm calls Summary The snake alarm call of Japanese tits prompts nesting adults to search for and mob the reptile until it is driven away. From playback experiments, Suzuki (2018) has inferred that the call provides an associative cue, evoking a searching image of the salient visual features of the predator—a novel approach to exploring visual attention and vocal communication in the wild.

Sometimes a stick might just be a stick Abstract Suzuki (Proceedings of the Natural Academy of Sciences, 115, 1541-1545, 2018) conducted elegant field experiments examining referential communication in Japanese tits. Bond (Learning & Behavior, in press, 2019) explains some key considerations and future experimentation that should be conducted to solidify these conclusions. An important takeaway from both Suzuki and Bond is that scientists can, and should, both be excited for new, interesting scientific discoveries, and also view such findings with a critical, but collegial, eye for more parsimonious explanations and the manipulations required to test such explanations.

Imagery in wild birds: Retrieval of visual information from referential alarm calls Abstract Japanese tits (Parus minor) produce specific alarm calls when they encounter a predatory snake. A recent field experiment showed that receiver tits became visually perceptive to an object resembling a snake when hearing these calls. However, the tits did not respond to the same object when hearing other call types or when the object was dissimilar to a snake. These findings provide the first experimental evidence for the retrieval of a visual search image from specific alarm calls, offering a novel approach for investigating the cognitive mechanisms underlying referential communication in wild animals.

Tools of engagement: Information seeking in chimpanzees Summary Two widely studied and impressive cognitive feats in nonhuman animals, metacognition and tool use, both require the cognitive tools of monitoring and controlling knowledge states and adaptive actions toward desirable outcomes. In a recent study, Perdue, Evans, and Beran (PLoS ONE, 13(4), e0193229, 2018) found that some chimpanzees used tools to selectively acquire information and make inferences, indicating metacognitive awareness and appropriate use of tools depending on the content of those knowledge states.

Parallel overinterpretation of behavior of apes and corvids Summary The report by Kabadayi and Osvath (Science, 357(6347), 202–204, 2017) does not demonstrate planning in ravens. The behavior of corvids and apes is fascinating and will be best appreciated through well-designed experiments that explicitly test alternative explanations and that are interpreted without unjustified anthropomorphic embellishment.

Facilitation and retardation of flavor preference conditioning following prior exposure to the flavor conditioned stimulus Abstract In two experiments, rats received pairings of an almond flavor (Experiments 1 and 2B) or a vanilla flavor (Experiment 2A) with sucrose. In each experiment, half of the rats received prior exposure to the flavor and half were exposed to water. Conditioned preference was then assessed through two-bottle, flavor versus water, choice tests. Latent inhibition (indicated by a weaker preference in pre-exposed subjects) was observed in the experiment using the vanilla flavor. However, facilitation (a stronger preference in pre-exposed subjects) instead of latent inhibition was evident with the almond flavor, both across acquisition trials and in the final choice test. These results indicate that, unlike most other paradigms of Pavlovian conditioning, conditioned stimulus pre-exposure in flavor preference learning may either facilitate or retard the acquisition (or the expression) of a conditioned flavor preference. We explore the proposal that the critical difference between the flavors lies in their hedonic values, with facilitation being more likely in a flavor that is initially disliked.

The role of context in animal memory Abstract Past research has shown that testing memory in the same context in which the memory was encoded leads to improved retention relative to testing memory in a new context. Context-dependent memory is directly related to the extent to which the encoding context can be reproduced. An experiment with pigeons is reported in which the context was a colored house-light that completely enveloped the learning and testing contexts. Under this condition, perfect retention of a visual discrimination that reversed at midsession was shown. Beyond reactivation of memory, new research with pigeons suggests that context provides access to different working and reference memory systems. Finally, experiments are reported that suggest context may selectively access information about features from the different dimensions of place, color, and time.

Associative structure of conditioned inhibition produced by inhibitory perceptual learning treatment Abstract Exposure to a set of complex stimuli yields an enhanced ability to discriminate between these stimuli. In previous experimental studies, two distinguishable stimuli, X and A, were each repeatedly paired with a common Stimulus B to create compound Stimuli XB and AB. Prior evidence suggests that unique Features X and A form mutually inhibitory associations. This was evidenced by pairing Feature A with a biologically relevant stimulus (i.e., an unconditioned stimulus [US]) and observing that Stimulus X alone later serves to inhibit anticipatory behaviors for that US. These observations may reflect the mutually inhibitory nature of the two Features X and A. However, by assessing the influence of X on behavior that anticipates the US rather than Feature A, these experiments tested inhibition only indirectly. In the present experiments, a more direct measure of inhibition is proposed and tested with rats. We found evidence of retardation and negative summation of associations between unique Features X and A in their capacity to serve as competing cues during overshadowing treatments. Stimulus X was less susceptible to overshadowing by A (which is indicative of retardation of the establishment of an X–A within-compound association) and was able to suppress overshadowing by A of another stimulus (Y) when X was presented with Y at test (which is indicative of negative summation of the representation of A by X). Thus, XB/AB trials were seen to establish an inhibitory relationship between X and A.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Hernia

Mesh fixation in open IPOM procedure with tackers or sutures? A randomized clinical trial with preliminary results Abstract Purpose In open intra-peritoneal onlay mesh (IPOM) hernia repair, mesh fixation can be done by tacks, sutures or fibrin glue. There are randomized controlled trials (RCTs) on laparoscopic IPOM procedure, but no RCT so far has examined mesh fixation techniques in open IPOM repair. Methods In a single-center RCT, 48 patients undergoing open IPOM repair of an abdominal wall hernia were included. After randomization, surgery was performed in a standardized fashion. Hernia size, extent of mesh fixation, and duration of surgery were documented. The primary endpoint was postoperative pain intensity. Secondary endpoints were: complications, length of stay, quality of life, return to work, hernia recurrence. Follow-up was 1 year in all 48 patients. Results After using tacks, mean pain intensity was 16.9, which is slightly lower than after suture fixation (19.6, p = 0.20). The duration of surgery was about the same (83 vs. 85 min). When using tack fixation, significantly more fixation points were applied as compared to sutures (19 vs. 12; p = 0.02), although mesh size was similar. The complication rate was similar (tacks: 6/28 vs. sutures: 3/20). Cost of suture fixation was about 26 €, which is markedly lower than the 180 € associated with tacks. However, surgeons clearly preferred mesh fixation with tacks, because it is more comfortable especially in small hernias. Conclusions The present study failed to show an advantage of tacks over suture fixation and even there are more severe adverse events. Using tacks significantly increases the costs of hernia repair.

Individual mesh size for open anterior inguinal hernia repair: an anthropometric study in Turkish male patients Abstract Purpose To conduct a study to determine the measurements of the inguinal region in male patients with inguinal hernias to reveal the proper mesh size for each patient. Methods In this prospective study, the anthropometric measurements were obtained from 100 consecutive adult male patients with unilateral primary inguinal hernias. First, the distance between the pubic tubercle and the medial border of the deep inguinal ring was measured (x). Second, the distance between the inner edge of the inguinal ligament and the uppermost level of the internal oblique aponeurosis at the midpoint of the inguinal ligament corresponding to the Hesselbach triangle was measured (y). Individual mesh sizes were calculated according to the original recommendations for mesh overlap. Results The mean x value was 41.6 mm (22–55 mm), the mean y value was 45.2 mm (30–68 mm). The mean dimensions of the mesh were 126.6 mm × 65.2 mm. The largest mesh was 140 mm × 88 mm, and the smallest one was 107 mm × 62 mm. The mean mesh area was 8320 mm2. It was larger than the index mesh area recommended by the Lichtenstein Hernia Institute in 45 patients and smaller in 55 patients. Conclusions The intraoperative measurements for ideal mesh size in Lichtenstein repair of inguinal hernias may present somewhat different mesh dimensions in many patients. Individualization of mesh size may be of importance in surgical outcomes.

New, simple and reliable volumetric calculation technique in incisional hernias with loss of domain Abstract Introduction The management of hernias with loss of domain is a challenging problem. It has been shown that the volume of the incisional hernia/peritoneal volume ratio < 20% was a predictive factor for tension-free fascia closure, after pre-operative pneumoperitoneum preparation (Goni Moreno technique). In this study, we propose an easy, reliable and fast technique to perform volumetric calculation, by the surgeon alone. Materials and methods 3D slicer software (free open-source software) was used to calculate with precision the intra-peritoneal and intra-hernia volumes, and to create a 3D reconstruction of both volumes. The measurement technique is described step by step using detailed figures and videos. Results The method was used to calculate the volumes for five consecutive patients, managed between January 2018 and March 2019. All the five patients had a ratio greater than 20% and, therefore, received a PPP program. The effectiveness of the procedure is objectified by the increase of the intraabdominal volume and the reduction of the incisional hernia/peritoneal volume ratio. The feasibility of a tension-free fascia closure was confirmed for the five patients. Conclusion In addition to a standardized definition of "loss of domain", a standardized volumetric technique, easy to reproduce, needs to be adopted. Our method can be done by any surgeon with basic computer skills and radiological knowledge in an autonomous and a fast manner, thus helping to select the right technique for the right patient.

Study of mesh infection management following inguinal hernioplasty with an analysis of risk factors: a 10-year experience Abstract Purpose We present a review of our 10-year experience in managing patients with mesh infection following hernioplasty and analyze the occurrence of known predisposing factors. Methods We analyzed 392 cases of mesh infection treated at our center between 2007 and 2018 after a preoperative work-up. (Thirty-one patients underwent the primary hernia repair procedure at our hospital, whereas the others underwent the primary surgery at other local centers and were referred to our center.) The method of infected mesh removal (open or laparoscopic) was selected depending on the primary surgical approach. Open repair involved the excision of the mesh, infected tissue, and sinus (if present). The laparoscopic approach was used to identify the abscess, excise the mesh, and allow drainage into the preperitoneal space. Results The operative course in all patients was uneventful. A second surgery to extract the residual mesh around the pubic bone was performed in 7 patients. Hernia recurred in 29 patients after mesh removal. The discharge culture results were positive in 193 patients. Of these, Staphylococcus spp. was identified as the causative organism in 126 patients. Risk factors for mesh infection, including obesity, smoking, and diabetes, were identified in 182 (46.5%), 154 (39.3%), and 35 (8.9%) patients, respectively. Conclusions It is recommended the approach of mesh removal is tailored as per the primary hernioplasty method. We analyzed the occurrence of risk factors for mesh infection in this study, but further studies are needed to develop a predictive model that is both internally and externally validated to evaluate the probability of mesh infection.

Enhanced recovery after surgical repair of incisional hernias Abstract Aim Enhanced recovery programmes (ERPs) were developed to improve the patient's post-operative comfort and reduce post-operative morbidity after several types of major surgery including the incisional hernia repair. The aim of this review was to describe the features of ERPs in the setting for incisional hernia repair. Methods The literature review was conducted until March 2019, but retrieved very few papers (n = 4) on this topic. All studies were retrospective. Results Setting and comorbidities of incisional hernia patients are of such importance in many cases that prehabilitation (including tobacco use cessation, management of obesity, diabetes or malnutrition) should play a greater role compared with other specialties. The other peri-operative measures are similar to other specialties but their implementation was very heterogeneous in the published studies. Conclusions Like in other surgeries, ERPs were feasible and probably efficient to improve the post-operative course of incisional hernia patients. But the level of evidence remains low.

Contribution of heparin to recovery of incarcerated intestine in a rat incarcerated hernia model Abstract Purpose Inguinal hernias are the most common type of abdominal wall hernias. Although surgery is the only effective treatment for these hernias in adults, several problems associated with surgical treatment have been reported. If the hernia exits from a weak point of the abdominal wall, it can obstruct the bowel, thereby causing serious complications, including intestinal obstruction or strangulation. Through this study, we aimed to analyze the optimal incarceration induction time taken to cause some degree of necrosis from which recovery would be possible in a rat incarcerated abdominal wall hernia model and to determine the efficacy of heparin for expedite recovery from intestinal incarceration. Methods A rat incarcerated abdominal wall hernia model was constructed, intestinal activity and the incarceration induction time were determined based on the color of the intestine and HE staining of intestinal sections. Heparin and procaine were sprayed onto intestinal surfaces, and their effects on the recovery from intestinal incarceration were evaluated. Results Recovery from intestinal incarceration would be better if the incarceration induction time was maintained below 2.5 h in our rat model, and heparin was found to be superior to procaine in the expedite recovery from intestinal incarceration, particularly immediately after relieving such intestines. Conclusions The results of this study are significant for planning the treatment of incarcerated inguinal hernia. Further, heparin is superior to procaine in terms of expedite recovery from intestinal incarceration.

Safety of hernia repairs in the setting of surgical volunteerism missions

Comment to: A 12-year experience of using the Kugel procedure for adult inguinal hernias via the internal ring approach. Lin R, Lin X, Lu F et al. Hernia 2018;22:863–870

Editor's corner

Primary unilateral uncomplicated inguinal hernia repair, which is the procedure most frequently, performed in operating theatres the world over? Situation of Africa

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com