Safety and efficacy of the anti-PD1 immunotherapy with nivolumab in trichoblastic carcinomas.

Trichoblastic carcinoma is a rare malignant cutaneous adnexal tumor with a risk of local invasion and distant metastasis. As of today, there is no consensus for the treatment of locally advanced or metastatic trichoblastic carcinoma. "AcSé Nivolumab" is a multi-center Phase II basket clinical trial (NCT03012581) evaluating the safety and efficacy of nivolumab in several cohorts of rare, advanced cancers. Here we report the results of nivolumab in patients with trichoblastic carcinoma. Of the eleven patients enrolled in the study, five patients had been previously treated by sonic hedgehog inhibitors. The primary endpoint 12-week objective response rate was 9.1% (N = 1/11) with 1 partial response. Six patients who progressed under previous lines of treatment showed stable disease at 12 weeks, reflecting a good control of the disease with nivolumab. Furthermore, 54.5% of the patients (N = 6/11) had their disease under control at 6 months. The 1-year overall survival was 80%, and the median progression-free survival was 8.4 months (95%CI, 5.7 to NA). With 2 responders (2 complete responses), the best response rate to nivolumab at any time was 18.2% (95%CI, 2.3-51.8%). No new safety signals were identified, and adverse events observed herein were previously described and well known with nivolumab monotherapy. These results are promising, suggesting that nivolumab might be an option for patients with advanced trichoblastic carcinomas. Further studies on larger cohorts are necessary to confirm these results and define the role of nivolumab in the treatment of trichoblastic carcinomas.

Role of Epithelial-to-Mesenchymal Transition for the Generation of Circulating Tumors Cells and Cancer Cell Dissemination.

Tumor-related death is primarily caused by metastasis; consequently, understanding, preventing, and treating metastasis is essential to improving clinical outcomes. Metastasis is mainly governed by the dissemination of tumor cells in the systemic circulation: so-called circulating tumor cells (CTCs). CTCs typically arise from epithelial tumor cells that undergo epithelial-to-mesenchymal transition (EMT), resulting in the loss of cell-cell adhesions and polarity, and the reorganization of the cytoskeleton. Various oncogenic factors can induce EMT, among them the transforming growth factor (TGF)-ß, as well as Wnt and Notch signaling pathways. This entails the activation of numerous transcription factors, including ZEB, TWIST, and Snail proteins, acting as transcriptional repressors of epithelial markers, such as E-cadherin and inducers of mesenchymal markers such as vimentin. These genetic and phenotypic changes ultimately facilitate cancer cell migration. However, to successfully form distant metastases, CTCs must primarily withstand the hostile environment of circulation. This includes adaption to shear stress, avoiding being trapped by coagulation and surviving attacks of the immune system. Several applications of CTCs, from cancer diagnosis and screening to monitoring and even guided therapy, seek their way into clinical practice. This review describes the process leading to tumor metastasis, from the generation of CTCs in primary tumors to their dissemination into distant organs, as well as the importance of subtyping CTCs to improve personalized and targeted cancer therapy.

Nanoparticle-based immunotherapy of pancreatic cancer.

Pancreatic cancer (PC) has a complex and unique tumor microenvironment (TME). Due to the physical barrier formed by the desmoplastic stroma, the delivery of drugs to the tumor tissue is limited. The TME also contributes to resistance to various immunotherapies such as cancer vaccines, chimeric antigen receptor T cell therapy and immune checkpoint inhibitors. Overcoming and/or modulating the TME is therefore one of the greatest challenges in developing new therapeutic strategies for PC. Nanoparticles have been successfully used as drug carriers and delivery systems in cancer therapy. Recent experimental and engineering developments in nanotechnology have resulted in increased drug delivery and improved immunotherapy for PC. In this review we discuss and analyze the current nanoparticle-based immunotherapy approaches that are at the verge of clinical application. Particularly, we focus on nanoparticle-based delivery systems that improve the effectiveness of PC immunotherapy. We also highlight current clinical research that will help to develop new therapeutic strategies for PC and especially targeted immunotherapies based on immune checkpoint inhibitors.

Macrophage Differentiation and Polarization Regulate the Release of the Immune Checkpoint Protein V-Domain Ig Suppressor of T Cell Activation.

Recently, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) was identified as a negative immune checkpoint regulator (NCR) that is mainly expressed in hematopoietic cells. Preclinical studies have shown that VISTA blockade results in impeded tumor growth and improved survival. Nevertheless, little is known about the physiological role of VISTA expression in macrophages. This study focused on the differential expression of VISTA in human monocytes and macrophages in order to elucidate a putative role of VISTA regulation upon macrophage polarization and activation. We observed that human peripheral monocytes constitutively release soluble VISTA, which was regulated via matrix metalloproteinases. However, monocyte stimulation with cytokines that induce macrophage differentiation, such as granulocyte-macrophage colony-stimulating (GM-CSF) and macrophage colony-stimulating factor (M-CSF), substantially reduced soluble VISTA release. VISTA release was further affected by various pro- and anti-inflammatory stimuli that led to macrophage polarization, where activated M1 macrophages generally released more VISTA than M2 macrophages. Additionally, we observed that stimulation of activated macrophages with the toll-like receptor 4 ligand lipopolysaccharide (LPS) led to a further decrease of soluble VISTA release. Moreover, we found that soluble VISTA impairs T cell cytotoxic activity but did not induce their programmed death. Our results suggest that VISTA is constantly produced and released in the peripheral blood where it may contribute to peripheral tolerance.

Expression of the Immune Checkpoint Protein VISTA Is Differentially Regulated by the TGF-ß1 - Smad3 Signaling Pathway in Rapidly Proliferating Human Cells and T Lymphocytes.

Immune checkpoint proteins play crucial roles in human embryonic development but are also used by cancer cells to escape immune surveillance. These proteins and biochemical pathways associated with them form a complex machinery capable of blocking the ability of cytotoxic immune lymphoid cells to attack cancer cells and, ultimately, to fully suppress anti-tumor immunity. One of the more recently discovered immune checkpoint proteins is V-domain Ig-containing suppressor of T cell activation (VISTA), which plays a crucial role in anti-cancer immune evasion pathways. The biochemical mechanisms underlying regulation of VISTA expression remain unknown. Here, we report for the first time that VISTA expression is controlled by the transforming growth factor beta type 1 (TGF-ß)-Smad3 signaling pathway. However, in T lymphocytes, we found that VISTA expression was differentially regulated by TGF-ß depending on their immune profile. Taken together, our results demonstrate the differential biochemical control of VISTA expression in human T cells and various types of rapidly proliferating cells, including cancer cells, fetal cells and keratinocytes.

Reduction in ionizing radiation exposure during minimally invasive anterior plate osteosynthesis of distal radius fracture: Naive versus deliberate practice.

This study aimed to decrease surgeon exposure to ionizing radiation through a new learning technique, "deliberate practice", which consists in improving performance by setting goals with feedback. The hypothesis was that exposure to ionizing radiation during distal radius fracture surgery using the minimally invasive plate osteosynthesis (MIPO) technique decreased faster with "deliberate" practice than with "naïve" practice. Radiographic dosimetry was measured in the first 30 fractures operated on by MIPO by 6 surgeons. The first 3 surgeons operated "naively" (Group 1) and the next 3 according to the "deliberate" procedure (Group 2). Group 2 received weekly feedback (number of exposed hands, number of fluoroscopic views, exposure duration, and X-ray dose). An expert, using fluoroscopic images and surgical videos, provided suggestions for improvement. Mean number of exposed hands was 23.66 in Group 1 and 1.9 in Group 2. Mean number of fluoroscopic views was 78.31 and 35.0, respectively. Mean X-ray exposure time was 74.34 and 32.89 s, respectively. Mean dosimetry was 1.40 mGy (and 0.59 mGy, respectively. The hypothesis was thus confirmed: dosimetry decreased faster in Group 2 than in Group 1. Teaching this deliberate practice should be generalized, to decrease the growth phase and increase the plateau phase of the learning curve.

Efficacy of sonic hedgehog inhibitors rechallenge, after initial complete response in recurrent advanced basal cell carcinoma: a retrospective study from the CARADERM database.

BACKGROUND: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib. MATERIALS AND METHODS: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment. RESULTS: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months). CONCLUSION: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms.

Functional role of galectin-9 in directing human innate immune reactions to Gram-negative bacteria and T cell apoptosis.

Galectin-9 is a member of the galectin family of proteins, which were first identified to specifically bind to carbohydrates containing ß-galactosides. Galectin-9 is conserved through evolution and recent evidence demonstrated its involvement in innate immune reactions to bacterial infections as well as the suppression of cytotoxic immune responses of T and natural killer cells. However, the molecular mechanisms underlying such differential immunological functions of galectin-9 remain largely unknown. In this work we confirmed that soluble galectin-9 derived from macrophages binds to Gram-negative bacteria by interacting with lipopolysaccharide (LPS), which forms their cell wall. This opsonisation effect most likely interferes with the mobility of bacteria leading to their phagocytosis by innate immune cells. Galectin-9-dependent opsonisation also promotes the innate immune reactions of macrophages to these bacteria and significantly enhances the production of pro-inflammatory cytokines - interleukin (IL) 6, IL-1ß and tumour necrosis factor alpha (TNF-α). In contrast, galectin-9 did not bind peptidoglycan (PGN), which forms the cell wall of Gram-positive bacteria. Moreover, galectin-9 associated with cellular surfaces (studied in primary human embryonic cells) was not involved in the interaction with bacteria or bacterial colonisation. However, galectin-9 expressed on the surface of primary human embryonic cells, as well as soluble forms of galectin-9, were able to target T lymphocytes and caused apoptosis in T cells expressing granzyme B. Furthermore, "opsonisation" of T cells by galectin-9 led to the translocation of phosphatidylserine onto the cell surface and subsequent phagocytosis by macrophages through Tim-3, the receptor, which recognises both galectin-9 and phosphatidylserine as ligands.

Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial.

BACKGROUND: Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS: KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. RESULTS: Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. CONCLUSIONS: The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

Which adjuvant treatment for patients with BRAFV600-mutant cutaneous melanoma?

Treatment of patients with melanoma has considerably improved over the past decade and more recently with adjuvant therapies for patients with American Joint Committee on Cancer (AJCC) stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma, in order to prevent recurrence. In the adjuvant setting, two options are available to patients with BRAFV600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib). In the absence of comparative studies, it is difficult to determine which of these options is best. Our aim was to review published studies focusing on the management of patients with BRAFV600-mutant melanoma in the adjuvant setting. We also reviewed the main clinical trials of BRAF plus MEK inhibitors and immunotherapy in advanced (i.e. unresectable metastatic) BRAF-mutant melanoma in an attempt to identify results potentially affecting the management of patients on adjuvants. More adverse events are observed with targeted therapy, but all resolve rapidly upon drug discontinuation, whereas with immune checkpoint blockers some adverse events may persist. New therapeutic strategies are emerging, notably neoadjuvant therapies for stage III patients and adjuvant therapies for stage II patients; the place of the adjuvant strategy amidst all these options will soon be re-evaluated. The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings. This review will lead clinicians to a better understanding of the different adjuvant treatments available for patients with totally resected AJCC stage III and IV BRAFV600-mutant melanoma before considering subsequent treatment strategies.

Revision surgery for carpal tunnel syndrome: a retrospective study comparing the combination of Canaletto® and Dynavisc® gel versus Dynavisc® gel alone.

The aim of this study was to assess the value of using a Canaletto® implant in combination with a gel composed of carboxymethylcellulose and polyethylene oxide in the surgical treatment of recurrent carpal tunnel syndrome (CTS). The case series included 31 patients with 32 hands operated for the second time for recurrent (22 cases) or recalcitrant (9 cases) CTS by neurolysis. The average patient age was 62 years. Dynavisc® gel alone was applied around the median nerve in the first 16 cases (Group I). The Canaletto® implant combined with Dynavisc® gel was used in the last 16 cases (group II). With an average follow up of 8 months (for group I) and 11 months (for group II), the pre/postoperative variation in pain assessed with a visual analog scale was 1.38/10 (group I) and 2.04/10 (group II), the QuickDASH score was 20.1/100 (Group I) and 20.48/100 (Group II), grip strength was 8% (Group I) and 20% (Group II), sensory nerve conduction speed was 23.20 m/s (group I) and 15.51 m/s (group II) and distal motor latency was 1.55 m/s (group I) and 1.21 m/s (group II). Ten patients recovered from hypoesthesia in both groups, 6 patients in group I and 2 patients in group II regained good trophicity of their superficial thenar muscles. Two patients from group II had not improved clinically although their electromyography had become normal. One patient from group II suffered a postoperative infection that required removal of the Canaletto® implant. He subsequently improved slightly. Our study found that for recurrent or recalcitrant CTS, the combination of Dynavisc® anti-adhesion gel around the median nerve and a Canaletto implant® after neurolysis results in outcomes that are as good as Dynavisc® alone, with a significant improvement of the QuickDASH score without the Canaletto®. In conclusion, the use of Dynavisc® gel alone around the median nerve after neurolysis seems to be as effective as other techniques described in literature but less invasive or time-consuming, and not associated with donor site morbidity such as the flexor tendon sheath.