A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors.

BACKGROUND: Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. METHODS: In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). RESULTS: Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event. CONCLUSION: SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

Intratumoral administration of the immunologic adjuvant AS01B in combination with autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells plus ipilimumab and intravenous nivolumab in patients with refractory advanced melanoma.

BACKGROUND: Patients with advanced melanoma who progress after treatment with immune checkpoint-inhibitors (ICI) and BRAF-/MEK-inhibitors (if BRAF V600 mutated) have no remaining effective treatment options. The presence of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment correlates with pre-existing immune recognition and responsiveness to immune checkpoint blockade. The synthetic saponin-based immune adjuvant AS01B enhances adaptive immunity through the involvement of myDC. METHODS: In this first-in-human phase I clinical trial, patients with metastatic melanoma refractory to ICI and BRAF-/MEK inhibitors (when indicated) were recruited. Patients received an intravenous administration of low-dose nivolumab (10 mg, every 2 weeks) plus an intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01B (every 2 weeks). All myDC, isolated from blood, were injected on day 2 into the same metastatic lesion. Tumor biopsies and blood samples were collected at baseline and repeatedly on treatment. Multiplex immunohistochemistry (mIHC) was performed on biopsy sections to characterize and quantify the IT and peritumoral immune cell composition. RESULTS: Study treatment was feasible and well tolerated without the occurrence of unexpected adverse events in all eight patients. Four patients (50%) obtained a complete response (CR) in the injected lesions. Of these, two patients obtained an overall CR, and one patient a partial response. All responses are ongoing after more than 1 year of follow-up. One additional patient had a stable disease as best response. The disease control rate was 50%. Median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration, with a reduced mean distance between T cells and tumor cells. Peripheral blood immune cell composition did not significantly change during study treatment. CONCLUSIONS: Combining an intratumoral injection of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myDC with repeated IT administration of ipilimumab and AS01B and systemic low-dose nivolumab is safe, feasible with promising early results, worthy of further clinical investigation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03707808.

Expression of Hemangioblast Proteins in von Hippel-Lindau Disease Related Tumors.

Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome that targets a highly selective subset of organs causing specific types of tumors. The biological basis for this principle of organ selectivity and tumor specificity is not well understood. VHL-associated hemangioblastomas share similar molecular and morphological features with embryonic blood and vascular precursor cells. Therefore, we suggest that VHL hemangioblastomas are derived from developmentally arrested hemangioblastic lineage keeping their potential of further differentiation. Due to these common features, it is of major interest to investigate whether VHL-associated tumors other than hemangioblastoma also share these pathways and molecular features. The expression of hemangioblast proteins has not yet been assessed in other VHL-related tumors. To gain a better understanding of VHL tumorigenesis, the expression of hemangioblastic proteins in different VHL-associated tumors was investigated. The expression of embryonic hemangioblast proteins Brachyury and TAL1 (T-cell acute lymphocytic leukemia protein 1) was assessed by immunohistochemistry staining on 75 VHL-related tumors of 51 patients: 47 hemangioblastomas, 13 clear cell renal cell carcinomas, 8 pheochromocytomas, 5 pancreatic neuroendocrine tumors, and 2 extra-adrenal paragangliomas. Brachyury and TAL1 expression was, respectively, observed in 26% and 93% of cerebellar hemangioblastomas, 55% and 95% of spinal hemangioblastomas, 23% and 92% of clear cell renal cell carcinomas, 38% and 88% of pheochromocytomas, 60% and 100% of pancreatic neuroendocrine tumors, and 50% and 100% of paragangliomas. We concluded that the expression of hemangioblast proteins in different VHL-associated tumors indicates a common embryological origin of these lesions. This may also explain the specific topographic distribution of VHL-associated tumors.

Prognostic value of left ventricular global constructive work in patients with cardiac amyloidosis.

PURPOSE: The aim of the present study was to evaluate the role of ejection fraction (EF), left ventricular (LV) global longitudinal strain (LVGLS) and global constructive work (GCW) as prognostic variables in patients with cardiac amyloidosis (CA). METHODS: CA patients were retrospectively identified between 2015 and 2021 at a tertiary care hospital. Comprehensive clinical, biochemical, and imaging evaluation including two-dimensional (2D) echocardiography with myocardial work (MW) analysis was performed. A clinical combined endpoint was defined as all-cause mortality and heart failure readmission. RESULTS: 70 patients were followed for 16 (7-37) months and 37 (52.9%) reached the combined endpoint. Patient with versus without clinical events had a significantly lower LVEF (40.71% vs. 48.01%, p = 0.039), LVGLS (-9.26 vs. -11.32, p = 0.034) and GCW (1034.47mmHg% vs. 1424.86mmHg%, p = 0.011). Multivariable analysis showed that LVEF ( odds ratio (OR): 0.904; 95% confidence interval (CI): 0.839-0.973, p = 0.007), LVGLS ( OR: 0.620; 95% CI: 0.415-0.926, p = 0.020) and GCW ( OR: 0.995; 95% CI: 0.990-0.999, p = 0.016) were significant predictors of outcome, but the model including GCW had the best discriminative ability to predict the combined endpoint (C-index = 0.888). A GCW less than 1443mmHg% was able to predict the clinical endpoint with a sensitivity of 94% and a specificity of 64% (Area under the curve (AUC): 0.771 (95% CI: 0.581-0.961; p = 0.005)). CONCLUSION: In CA patients, GCW may be of additional prognostic value to LVEF and GLS in predicting heart failure hospitalization and all-cause mortality.

[Nodular lymphocyte predominant Hodgkin lymphoma (paragranuloma of Poppema) in children: Case report, review of the literature and treatment]. / Lymphome de Hodgkin nodulaire à prédominance lymphocytaire (paragranulome de Poppema) chez l'enfant : à propos d'un cas, revue de la littérature et traitement.

We present the case of a 12 year old child with a limp. The diagnostic work-up reveals splenomegaly, multifocal bone involvement and abdominal adenopathies. A biopsy of an intra-abdominal lesion shows a lymphoid mass with a nodular architecture composed of poorly defined nodules. We identify large cells with irregular, sometimes poly-lobulated nuclei with a particular immunohistochemical profile. Those "pop-corn" cells are positive for CD20, CD79a, pax-5 and bcl-6 and are negative for CD15, CD30, bcl-2, TdT, CD56 and EMA. There is a diffuse follicular helper T cell population that is located in between the tumour cells. The overall picture is indicative of a nodular lymphocyte predominant Hodgkin lymphoma. Advanced stage of this disease is rare in children and there is currently little data to guide optimal treatment. Because of a stage IV disease, the patient is treated with chemotherapy after which complete metabolic remission is observed. 3.5 years after the initial diagnosis, our patient relapses. He is treated with chemotherapy and an autologous peripheral blood stem cell transplantation. He remains in complete remission since then. This case illustrates the favorable prognosis of the disease even after relapse.

Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial.

BACKGROUND: Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces immunogenic cell death, thereby providing maturation signals and enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDCs, in order to reinvigorate the cancer-immunity cycle. METHODS: In this phase I trial, patients with advanced melanoma who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastases with T-VEC on day 1 followed by IT injection of CD1c (BDCA-1)+ myDCs +/- CD141 (BDCA-3)+ myDCs on day 2. T-VEC injections were repeated on day 21 and every 14 days thereafter. The number of IT administered CD1c (BDCA-1)+ myDCs was escalated from 0.5×106, to 1×106, to a maximum of 10×106 cells in three sequential cohorts. In cohort 4, all isolated CD1c (BDCA-1)+ / CD141 (BDCA-3)+ myDCs were used for IT injection. Primary objectives were safety and feasibility. Repetitive biopsies of treated lesions were performed. RESULTS: In total, 13 patients were enrolled (cohort 1 n=2; cohort 2 n=2; cohort 3 n=3; cohort 4 n=6). Patients received a median of 6 (range 3-8) T-VEC injections. The treatment was safe with most frequent adverse events being fatigue (n=11 (85%)), fever (n=8 (62%)), and chills/influenza-like symptoms (n=6 (46%)). Nine (69%) and four patients (31%), respectively, experienced pain or redness at the injection-site. Clinical responses were documented in injected and non-injected lesions. Two patients (cohort 3) who previously progressed on anti-PD-1 therapy (and one patient also on anti-CTLA-4 therapy) developed a durable, pathologically confirmed complete response that is ongoing at 33 and 35 months following initiation of study treatment. One additional patient treated (cohort 4) had an unconfirmed partial response as best response; two additional patients had a mixed response (with durable complete responses of some injected and non-injected lesions). On-treatment biopsies revealed a strong infiltration by inflammatory cells in regressing lesions. CONCLUSIONS: IT coinjection of autologous CD1c (BDCA-1)+ +/- CD141 (BDCA-3)+ myDCs with T-VEC is feasible, tolerable and resulted in encouraging early signs of antitumor activity in immune checkpoint inhibitor-refractory melanoma patients. TRIAL REGISTRATION NUMBER: NCT03747744.

Improved automated early detection of breast cancer based on high resolution 3D micro-CT microcalcification images.

BACKGROUND: The detection of suspicious microcalcifications on mammography represents one of the earliest signs of a malignant breast tumor. Assessing microcalcifications' characteristics based on their appearance on 2D breast imaging modalities is in many cases challenging for radiologists. The aims of this study were to: (a) analyse the association of shape and texture properties of breast microcalcifications (extracted by scanning breast tissue with a high resolution 3D scanner) with malignancy, (b) evaluate microcalcifications' potential to diagnose benign/malignant patients. METHODS: Biopsy samples of 94 female patients with suspicious microcalcifications detected during a mammography, were scanned using a micro-CT scanner at a resolution of 9 µm. Several preprocessing techniques were applied on 3504 extracted microcalcifications. A high amount of radiomic features were extracted in an attempt to capture differences among microcalcifications occurring in benign and malignant lesions. Machine learning algorithms were used to diagnose: (a) individual microcalcifications, (b) samples. For the samples, several methodologies to combine individual microcalcification results into sample results were evaluated. RESULTS: We could classify individual microcalcifications with 77.32% accuracy, 61.15% sensitivity and 89.76% specificity. At the sample level diagnosis, we achieved an accuracy of 84.04%, sensitivity of 86.27% and specificity of 81.39%. CONCLUSIONS: By studying microcalcifications' characteristics at a level of details beyond what is currently possible by using conventional breast imaging modalities, our classification results demonstrated a strong association between breast microcalcifications and malignancies. Microcalcification's texture features extracted in transform domains, have higher discriminating power to classify benign/malignant individual microcalcifications and samples compared to pure shape-features.

Does the Choice of Anaesthesia Affect Cancer? A Molecular Crosstalk between Theory and Practice.

In recent years, there has been an increasing scientific interest in the interaction between anaesthesia and cancer development. Retrospective studies show that the choice of anaesthetics may influence cancer outcome and cancer recurrence; however, these studies show contradictory results. Recently, some large randomized clinical trials have been completed, yet they show no significant effect of anaesthetics on cancer outcomes. In this scoping review, we compiled a body of in vivo and in vitro studies with the goal of evaluating the biological effects of anaesthetics on cancer cells in comparison to clinical effects as described in recent studies. It was found that sevoflurane, propofol, opioids and lidocaine are likely to display direct biological effects on cancer cells; however, significant effects are only found in studies with exposure to high concentrations of anaesthetics and/or during longer exposure times. When compared to clinical data, these differences in exposure and dose-effect relation, as well as tissue selectivity, population selection and unclear anaesthetic dosing protocols might explain the lack of outcome.

Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis.

Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung 'plugs'). GCTB displays a complex and difficult-to-understand cell biological behaviour because of its heterogenous morphology. Recently, a driver mutation in histone H3.3 was found. This mutation is highly conserved in GCTB but can also be detected in glioblastoma. Denosumab was recently introduced as an extra option of medical treatment next to traditional surgical and in rare cases, radiotherapy. Despite these new insights, many 'old' questions about the key features of GCTB remain unanswered, such as the presence of telomeric associations (TAs), the reactivation of hTERT, and its slight genomic instability. This review summarises the recent relevant literature of histone H3.3 in relation to the GCTB-specific G34W mutation and pays specific attention to the G34W mutation in relation to the development of TAs, genomic instability, and the characteristic morphology of GCTB. As pieces of an etiogenetic puzzle, this review tries fitting all these molecular features and the unique H3.3 G34W mutation together in GCTB.

Cell Cycle Regulatory Protein Expression in Multinucleated Giant Cells of Giant Cell Tumor of Bone: do They Proliferate?

Cells of the monocyte macrophage lineage form multinucleated giant cells (GCs) by fusion, which may express some cell cycle markers. By using a comprehensive marker set, here we looked for potential replication activities in GCs, and investigated whether these have diagnostic or clinical relevance in giant cell tumor of bone (GCTB). GC rich regions of 10 primary and 10 first recurrence GCTB cases were tested using immunohistochemistry in tissue microarrays. The nuclear positivity rate of the general proliferation marker, replication licensing, G1/S-phase, S/G2/M-phase, mitosis promoter, and cyclin dependent kinase (CDK) inhibitor reactions was analyzed in GCs. Concerning Ki67, moderate SP6 reaction was seen in many GC nuclei, while B56 and Mib1 positivity was rare, but the latter could be linked to more aggressive (p = 0.012) phenotype. Regular MCM6 reaction, as opposed to uncommon MCM2, suggested an initial DNA unwinding. Early replication course in GCs was also supported by widely detecting CDK4 and cyclin E, for the first time, and confirming cyclin D1 upregulation. However, post-G1-phase markers CDK2, cyclin A, geminin, topoisomerase-2a, aurora kinase A, and phospho-histone H3 were rare or missing. These were likely silenced by upregulated CDK inhibitors p15INK4b, p16INK4a, p27KIP1, p53 through its effector p21WAF1 and possibly cyclin G1, consistent with the prevention of DNA replication. In conclusion, the upregulation of known and several novel cell cycle progression markers detected here clearly verify early replication activities in GCs, which are controlled by cell cycle arresting CDK inhibitors at G1 phase, and support the functional maturation of GCs in GCTB.

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial.

BACKGROUND: Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30-39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated. METHODS: Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue. RESULTS: Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1-4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2-152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029). CONCLUSION: IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS. TRIAL REGISTRATION: NCT03233152.

Spreading Pattern and Tissue Response to Hyaluronic Acid Gel Injections in the Subcutis: Ultrasound Videos, Ultrasound Measurements, and Histology.

BACKGROUND: Despite the popularity of hyaluronic acid (HA) filler treatments, few publications focus on their effects on adipose tissue. OBJECTIVES: The authors assessed the deposition pattern in the subcutis of injected HA, the tissue response at short and intermediate term, and the effects of remodeling the filler by strong finger pressure immediately after the treatment. METHODS: Two brands, specifically developed by the industry for deep injection, were compared. The gels were injected subcutaneously in 5 candidates for abdominoplasty or breast reduction, in the area of excision, 6 to 98 days before surgery. Ultrasound measurements and films were compared with postoperative histological findings. Tissue response was scored semi-quantitatively. RESULTS: Real-time ultrasound showed a slightly different deposition pattern of the 2 brands. Histologically, both were present in large pools of the same magnitude and looked the same. Linear retrograde injection sometimes resulted in a globular deposit due to elastic recoil of septae. After remodeling and over time, HA deposits became difficult to detect by ultrasound. Firm remodeling of the tissue immediately after injection or time had no significant effect on filler spread or tissue response. Except for 1 zone of granuloma formation, tolerance for both fillers was good. CONCLUSIONS: HA deposition in adipose tissue occurs in much larger pools than in the dermis. Ultrasound examination is useful during and immediately after the injection but less reliable after filler remodeling or over time. Filler deposition can be less precise, and reshaping by finger pressure can have less effect than expected.

[Marginal zone lymphoma associated with Reed-Sternberg cells: A challenge for the pathologist]. / Lymphome de la zone marginale ganglionnaire associé à des cellules de Reed-Sternberg : un challenge pour le pathologiste.

We report the case of a 46-year-old male patient presenting with a Claude Bernard-Horner Syndrome. Clinical evaluation showed a clonal B-cell population, lambda restricted. PET-scan captured femoral and axillary lymph nodes. Therefore the diagnosis of a marginal zone lymphoma was posted for which an attitude of watchful waiting was suggested. Eighteen months later, the patient developed an inguinal adenopathy. This lymph node led to the diagnosis of a nodular sclerosing Hodgkin lymphoma. Initial treatment with ABVD showed a good response, but the patient relapsed after eight months. A second biopsy confirmed the diagnosis of a marginal zone lymphoma but also identified giant Reed-Sternberg cells, (CD15+, CD30+ and CD20+). The initial biopsy was revised. This last diagnosis of a nodal marginal zone lymphoma with presence of Reed-Sternberg cells is rarely described in the literature. Several scientific theories can be found. Some cases described a transformation of non-Hodgkin lymphoma that presented Reed-Sternberg cells, other cases mentioned a collision or composite tumor. An accidental finding of Reed-Sternberg cells can be seen by after an infectious disease such as EBV. The presence of only Reed-Sternberg cells in a non-Hodgkin lymphoma is not sufficient to make a diagnosis of collision tumor.

Targeting USP13-mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC), activating mutations in the epidermal growth factor receptor (EGFR) induce sensitivity to EGFR tyrosine kinase inhibitors. Despite impressive clinical responses, patients ultimately relapse as a reservoir of drug-tolerant cells persist, which ultimately leads to acquired resistance mechanisms. We performed an unbiased high-throughput siRNA screen to identify proteins that abrogate the response of EGFR-mutant NSCLC to EGFR-targeted therapy. The deubiquitinase USP13 was a top hit resulting from this screen. Targeting USP13 increases the sensitivity to EGFR inhibition with small molecules in vitro and in vivo. USP13 selectively stabilizes mutant EGFR in a peptidase-independent manner by counteracting the action of members of the Cbl family of E3 ubiquitin ligases. We conclude that USP13 is a strong mutant EGFR-specific cotarget that could improve the treatment efficacy of EGFR-targeted therapies.

Intratumoral Combinatorial Administration of CD1c (BDCA-1)+ Myeloid Dendritic Cells Plus Ipilimumab and Avelumab in Combination with Intravenous Low-Dose Nivolumab in Patients with Advanced Solid Tumors: A Phase IB Clinical Trial.

Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in re-licensing antitumor cytotoxic T lymphocytes. IT injection of the IgG1 monoclonal antibodies ipilimumab and avelumab may induce antibody-dependent cellular cytotoxicity, thereby enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1)+ myDCs. Patients with advanced solid tumors after standard care were eligible for IT injections of ≥1 lesion with ipilimumab (10 mg) and avelumab (40 mg) and intravenous (IV) nivolumab (10 mg) on day 1, followed by IT injection of autologous CD1c (BDCA-1)+ myDCs on day 2. IT/IV administration of ipilimumab, avelumab, and nivolumab was repeated bi-weekly. Primary objectives were safety and feasibility. Nine patients were treated with a median of 21 × 106 CD1c (BDCA-1)+ myDCs, and a median of 4 IT/IV administrations of ipilimumab, avelumab, and nivolumab. The treatment was safe with mainly injection-site reactions, but also immune-related pneumonitis (n = 2), colitis (n = 1), and bullous pemphigoid (n = 1). The best response was a durable partial response in a patient with stage IV melanoma who previously progressed on checkpoint inhibitors. Our combinatorial therapeutic approach, including IT injection of CD1c (BDCA-1)+ myDCs, is feasible and safe, and it resulted in encouraging signs of antitumor activity in patients with advanced solid tumors.

MR imaging-anatomical-histological evaluation of the abdominal muscles, aponeurosis, and adductor tendon insertions on the pubic symphysis: a cadaver study.

PURPOSE: To perform an MR(magnetic resonance) imaging, anatomical, and histological evaluation of the abdominal muscles and adductor tendon insertions. METHOD: Four fresh cadaveric pelvis specimens were imaged at 3 T with the following imaging parameters: TE (echo time)/TR (repetition time): 20, 4090, slice thickness: 2 mm, FOV: 270 × 90, matrix size: 512. Anatomical slices were obtained with a band saw and photographed. MR images and photographs were evaluated by an anatomist and radiologist. Selected 3 mm thick slices were placed in formalin and decalcified, cut, placed on large slides, and stained with hematoxylin eosin stain (HES). RESULTS: The main adductor tendon insertions are: the anterosuperior aspect of the pubic bone for the adductor longus, the anteroinferior aspect of the pubic bone - for the adductor brevis, and the inferior aspect of the pubic bone for the adductor magnus. On histology, the adductor longus tendon fibers inserted perpendicularly into the bone at a fibrocartilage enthesis and cross connected along the anterior pubic ligament into the controlateral tendon. The rectus abdominis-pyramidalis unit was covered by a thin anterior and posterior aponeurosis. The posterior aponeurosis inserted into the superior aspect of the anterior pubic ligament, whereas the anterior aponeurosis fused distally with the adductor longus tendons. CONCLUSION: Our findings demonstrate the insertions of the adductor tendons, on the pubic ligament and pubic bone.Histologically, the adductor longus tendon fibers inserted perpendicularly into the bone through a fibrocartilage enthesis, and cross connected along the anterior pubic ligament into the contralateral tendon.

In situ cell cycle analysis in giant cell tumor of bone reveals patients with elevated risk of reduced progression-free survival.

OBJECTIVE: Giant cell tumor of bone (GCTB) is a frequently recurring locally aggressive osteolytic lesion, where pathological osteoclastogenesis and bone destruction are driven by neoplastic stromal cells. Here, we studied if cell cycle fractions within the mononuclear cell compartment of GCTB can predict its progression-free survival (PFS). METHODS: 154 cases (100 primaries and 54 recurrent) from 139 patients of 40 progression events, was studied using tissue microarrays. Ploidy and in situ cell cycle progression related proteins including Ki67 and those linked with replication licensing (mcm2), G1-phase (cyclin D1, Cdk4), and S-G2-M-phase (cyclin A; Cdk2) fractions; cell cycle control (p21waf1) and repression (geminin), were tested. The Prentice-Williams-Peterson (PWP) gap-time models with the Akaike information criterion (AIC) were used for PFS analysis. RESULTS: Cluster analysis showed good correlation between functionally related marker positive cell fractions indicating no major cell cycle arrested cell populations in GCTB. Increasing hazard of progression was statistically associated with the elevated post-G1/S-phase cell fractions. Univariate analysis revealed significant negative association of poly-/aneuploidy (p < 0.0001), and elevated cyclin A (p < 0.001), geminin (p = 0.015), mcm2 (p = 0.016), cyclin D1 (p = 0.022) and Ki67 (B56: p = 0.0543; and Mib1: p = 0.0564 -strong trend) positive cell fractions with PFS. The highest-ranked multivariate interaction model (AIC = 269.5) also included ploidy (HR 5.68, 95%CI: 2.62-12.31, p < 0.0001), mcm2 (p = 0.609), cyclin D1 (HR 1.89, 95%CI: 0.88-4.09, p = 0.105) and cyclin A (p < 0.0001). The first and second best prognostic models without interaction (AIC = 271.6) and the sensitivity analysis (AIC = 265.7) further confirmed the prognostic relevance of combining these markers. CONCLUSION: Ploidy and elevated replication licensing (mcm2), G1-phase (cyclin D1) and post-G1 phase (cyclin A) marker positive cell fractions, indicating enhanced cell cycle progression, can assist in identifying GCTB patients with increased risk for a reduced PFS.