Dendritic cell subsets and implications for cancer immunotherapy.

Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

Platelet-Rich Plasma Injections for the Treatment of Ankle Osteoarthritis.

BACKGROUND: Ankle osteoarthritis is debilitating and usually affects relatively young people, often as a result of previous ankle traumas, frequently occurring in sports. Platelet-rich plasma (PRP) injections for ankle osteoarthritis have shown no evidence of benefit over the course of 26 weeks. Previous studies on PRP for knee osteoarthritis showed that clinically significant improvements with PRP occurred between 6 to 12 months in the absence of initial benefit. No studies have evaluated the effect of PRP from 6 to 12 months in ankle osteoarthritis. PURPOSE: To assess the efficacy of PRP injections in ankle osteoarthritis over the course of 52 weeks. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In this 52-week follow-up trial, 100 patients with ankle osteoarthritis were randomized to a PRP group or placebo (saline) group. Patients received 2 intra-articular talocrural injections: at inclusion and after 6 weeks. Patient-reported outcome measures were used to assess pain, function, quality of life, and indirect costs over 52 weeks. RESULTS: Two patients (2%) were lost to follow-up. The adjusted between-group difference for the patient-reported American Orthopaedic Foot & Ankle Society score over 52 weeks was -2 points (95% CI, -5 to 2; P = .31) in favor of the placebo group. No significant between-group differences were observed for any of the secondary outcome measures. CONCLUSION: For patients with ankle osteoarthritis, PRP injections did not improve ankle symptoms and function over 52 weeks compared with placebo injections. REGISTRATION: NTR7261 (Netherlands Trial Register).

Don't Miss Me: Midfoot Sprains, A Point-of-Care Review.

Athletes practicing high-contact sports are exposed to an increased risk of midfoot injuries, namely midtarsal sprains. The complexity of reaching an accurate diagnosis is clearly depicted in the reported incidence of midtarsal sprains, ranging from 5% to 33% of ankle inversion injuries. Because the focus of the treating physician and physical therapist is on lateral stabilizing structures, midtarsal sprains are missed at initial evaluation in up to 41% of patients, with delayed treatment as a result.Detecting acute midtarsal sprains requires a high degree of clinical awareness. Radiologists must become familiar with the characteristic imaging findings of normal and pathologic midfoot anatomy to avoid adverse outcomes such as pain and instability. In this article we describe Chopart joint anatomy, mechanisms of midtarsal sprains, clinical importance, and key imaging findings with a focus on magnetic resonance imaging. A team effort is essential to provide optimal care for the injured athlete.

High Number of Medical Conditions Detected in Elite Athlete Periodic Health Evaluations, But Only Mild Consequences.

OBJECTIVE: To evaluate the number of medical conditions detected by periodic health evaluations (PHEs) in elite athletes, and their consequences for management and medical clearance. DESIGN: Retrospective design. PARTICIPANTS: Elite athletes of various sports in a high-performance program in The Netherlands, in the period between 2009 and 2020. INTERVENTIONS: The PHEs consisted of a questionnaire, general and musculoskeletal physical examination, laboratory blood test, electrocardiogram, pulmonary function testing, and (cardiopulmonary) exercise test. MAIN OUTCOME MEASURES: We extracted and analyzed the medical conditions that led to advice, clinical follow-up, further diagnostic investigation or treatment, and the medical clearance status of the athlete (clearance, temporarily no clearance, or permanently no clearance). RESULTS: We included 721 PHEs of 451 elite athletes. We found 1389 medical conditions that led to advice (n = 923, 66%), clinical follow-up (n = 124, 9%), further diagnostic investigation (n = 190, 14%), treatment (n = 132, 10%), or sports restriction (n = 20, 1%). Only 20 cases (3%) led to temporarily no medical clearance. After further investigation or treatment, no permanent sports restriction was imposed on any of the athletes. CONCLUSIONS: We found a high number of medical conditions detected with a PHE in elite athletes. However, the vast majority of detected conditions were mild, with consequences limited to preventive advice and follow-up. The yield of PHE to detect (potentially) severe pathological conditions seems low. Clinical relevance of PHE in elite athletes and potential future health benefits remain unclear.

Memory-like Differentiation Enhances NK Cell Responses to Melanoma.

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined. EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNγ and kill melanoma targets in vitro and in vivo using a xenograft model. RESULTS: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNγ production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D- and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells. CONCLUSIONS: Blood NK cells from allogeneic HD or patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials.

Professional football players at risk for non-acute groin injuries during the first half of the season: A prospective cohort study in The Netherlands.

OBJECTIVES: To study the incidence, diagnostics, treatment, anatomical region and return to play of non-acute groin injuries among professional footballers in the Netherlands. DESIGN: Prospective cohort study. METHODS: Medical staff members of all Dutch professional football clubs, recording prospectively injury occurrence of all professional footballers in their clubs, were asked to fill in an injury form about time-loss (⩾ 8 days) non-acute groin injury over the 2012-2013 season. RESULTS: A cohort of 410 players from 12 professional football clubs were included (response rate = 44%). The season incidence of non-acute groin injuries was nearly 7% (29 non-acute groin injuries). In 82% of all cases, the player suffered from non-acute groin injury in the first half of the season. The average time to return to play was 35 days, ranging from 8 to 84 days. The adductors were the most affected anatomical regions (82%), with the most frequent diagnosis being overuse of the adductors (36%), followed by adductor tendinopathy (18%). In addition to medical history and physical examination, ultrasound (50%) and MRI (32%) were the diagnostic methods most frequently mentioned. As well as physical therapy, treatment consisted mostly of manual therapy (96%) and dry needling (61%). CONCLUSIONS: A professional club with a squad of 25 players can expect on average two non-acute groin injuries per season with an average time-loss of 35 days. Players are more at risk in the first half of the season. In Dutch professional football, ultrasound is commonly used to diagnose non-acute groin injury, while manual therapy is the most commonly applied treatment.

The effect of concentrated bone marrow aspirate in operative treatment of fifth metatarsal stress fractures; a double-blind randomized controlled trial.

BACKGROUND: Fifth metatarsal (MT-V) stress fractures often exhibit delayed union and are high-risk fractures for non-union. Surgical treatment, currently considered as the gold standard, does not give optimal results, with a mean time to fracture union of 12-18 weeks. In recent studies, the use of bone marrow cells has been introduced to accelerate healing of fractures with union problems. The aim of this randomized trial is to determine if operative treatment of MT-V stress fractures with use of concentrated blood and bone marrow aspirate (cB + cBMA) is more effective than surgery alone. We hypothesize that using cB + cBMA in the operative treatment of MT-V stress fractures will lead to an earlier fracture union. METHODS/DESIGN: A prospective, double-blind, randomized controlled trial (RCT) will be conducted in an academic medical center in the Netherlands. Ethics approval is received. 50 patients will be randomized to either operative treatment with cB + cBMA, harvested from the iliac crest, or operative treatment without cB + cBMA but with a sham-treatment of the iliac crest. The fracture fixation is the same in both groups, as is the post-operative care.. Follow up will be one year. The primary outcome measure is time to union in weeks on X-ray. Secondary outcome measures are time to resumption of work and sports, functional outcomes (SF-36, FAOS, FAAM), complication rate, composition of osteoprogenitors in cB + cBMA and cost-effectiveness. Furthermore, a bone biopsy is taken from every stress fracture and analysed histologically to determine the stage of the stress fracture. The difference in primary endpoint between the two groups is analysed using student's t-test or equivalent. DISCUSSION: This trial will likely provide level-I evidence on the effectiveness of cB + cBMA in the operative treatment of MT-V stress fractures. TRIAL REGISTRATION: Netherlands Trial Register (reg.nr NTR4377 ).

Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: implications for immune-mediated cancer therapy.

One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs). This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK) from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naïve CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ) release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses.

A Study of Zoledronic Acid as Neo-Adjuvant, Perioperative Therapy in Patients with Resectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45+/Lin-/CD33+/CD11b+/CD15+), which infiltrate tumors and suppress anti-tumor immunity. We have previously demonstrated in a murine model of PDAC that zoledronic acid (ZA) depletes G-MDSC resulting in decreased tumor growth and improved survival. We report here the results of a phase 1 clinical trial (NCT00892242) using ZA as neo-adjuvant, perioperative therapy in patients with non-metastatic, resectable pancreatic adenocarcinoma. METHODS: Eligible PDAC patients received ZA (4mg) IV 2 weeks prior to surgery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from patients prior to treatment with ZA and 3 months after surgery for analysis of G-MDSC by flow cytometry. RESULTS: Twenty-three patients received pre-operative ZA with at least 6 months of follow-up Only 15 PDAC patients had non-metastatic PDAC, which was amenable to resection. ZA was well tolerated, and all adverse events were grade 1 or 2. The most common adverse events were fatigue, abdominal pain/discomfort, anorexia, and arthralgia. Of resected PDAC patients treated with ZA, 1- and 2-year overall survival (OS) was 85.7% and 33.3%, respectively, with a median OS of 18 months. This group had a 1- and 2-year progression-free survival (PFS) of 26.9% and 8.9%, respectively, with a median PFS of 12 months. The prevalence of G-MDSC was unchanged in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA. CONCLUSION: ZA is safe and well tolerated as neo-adjuvant, peri-operative therapy in PDAC patients. In this small study, we did not observe a difference in OS or PFS compared to historical controls. Also, there was no difference in the prevalence of G-MDSC in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.

Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis.

PURPOSE: To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (CCR2(+)/CD14(+)) as immunotherapeutic targets in the treatment of pancreatic cancer. EXPERIMENTAL DESIGN: Survival analysis was conducted to determine if the prevalence of preoperative blood monocytes correlates with survival in patients with pancreatic cancer following tumor resection. Inflammatory monocyte prevalence in the blood and bone marrow of patients with pancreatic cancer and controls was compared. The immunosuppressive properties of inflammatory monocytes and macrophages in the blood and tumors, respectively, of patients with pancreatic cancer were assessed. CCL2 expression by human pancreatic cancer tumors was compared with normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine pancreatic cancer. RESULTS: Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in patients with pancreatic cancer with resected tumors. Inflammatory monocytes are increased in the blood and decreased in the bone marrow of patients with pancreatic cancer compared with controls. An increased ratio of inflammatory monocytes in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human pancreatic cancer produces CCL2, and immunosuppressive CCR2(+) macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes inflammatory monocytes and macrophages from the primary tumor and premetastatic liver resulting in enhanced antitumor immunity, decreased tumor growth, and reduced metastasis. CONCLUSIONS: Inflammatory monocyte recruitment is critical to pancreatic cancer progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease.

An online survey of exercise-related headaches among cyclists.

BACKGROUND: Primary exertional headache (PEH) is a long-known phenomenon. Divergent prevalences of between 0.2 and 12.3% are reported among the general population. The aim of this study was to establish the prevalence among an athletic population. METHOD: A link to an online questionnaire was sent to all participants of a tough cycling event held in The Netherlands. RESULTS: Four thousand participants filled out the questionnaire. One thousand eight hundred and ten (45%) stated that they had suffered, at least once in their lives, from exercise-related headaches (EHs). Thirty-seven percent (668) of them had those headaches at least once a month and 10% (174) experienced a weekly occurrence. The rate of female cyclists with a history of EHs was 54%. With an increasing age, a decline of EHs was found. Five hundred eighty-one (37%) of the participants used medication for EHs. CONCLUSIONS: An estimation of the prevalence of PEHs among the studied population by comparison to the International Headache Society criteria resulted in a rate of 26%. The lower prevalence among older cyclists could be caused by avoidance of (high-intensity) exercise due to the burden that EH brings along. PEH appears to be quite common among an athletic population and merits further investigation.