Clinical outcome of robot-assisted residual mass resection in metastatic nonseminomatous germ cell tumor

Purpose: To evaluate the outcome of robot-assisted residual mass resection (RA-RMR) in nonseminomatous germ cell tumor (NSGCT) patients with residual tumor following chemotherapy. Patients and methods: Retrospective medical chart analysis of all patients with NSGCT undergoing RA-RMR at two tertiary referral centers between January 2007 and April 2019. Patients were considered for RA-RMR in case of a residual tumor between 10 and 50 mm at cross-sectional computed tomography (CT) imaging located ventrally or laterally from the aorta or vena cava, with normalized tumor markers following completion of chemotherapy, and no history of retroperitoneal surgery. Results: A total of 45 patients were included in the analysis. The Royal Marsden stage before chemotherapy was IIA in 13 (28.9%), IIB in 16 (35.6%), IIC in 3 (6.7%) and IV in 13 patients (28.9%). The median residual tumor size was 1.9 cm (interquartile range [IQR] 1.4–2.8; range 1.0–5.0). Five procedures (11.1%) were converted to an open procedure due to a vascular injury (n = 2), technical difficulty (n = 2) or tumor debris leakage (n = 1). A postoperative adverse event occurred in two patients (4.4%). Histopathology showed teratoma, necrosis and viable cancer in 29 (64.4%), 14 (31.1%), and two patients (4.4%), respectively. After a median follow-up of 41 months (IQR 22–70), one patient (2.2%) relapsed in the retroperitoneum. The one- and 2-year recurrence-free survival rate was 98%. Conclusion: RA-RMR is an appropriate treatment option in selected patients, potentially providing excellent cure rates with minimal morbidity. Long-term outcome data are needed to further support this strategy and determine inclusion and exclusion criteria

Additional surgical procedures and perioperative morbidity in post-chemotherapy retroperitoneal lymph node dissection for metastatic testicular cancer in two intermediate volume hospitals

Purpose: To evaluate the perioperative morbidity of PC-RPLND in two intermediate volume centers and to identify predictors of high morbidity. Methods: Retrospective analysis of 124 patients treated with open PC-RPLND at two tertiary referral centers between 2001 and 2018. Perioperative morbidity was determined by analyzing additional surgical procedures, intra-operative blood loss, and postoperative complications. Results: An additional procedure was necessary for 33 patients (26.6%). The risk was higher in patients with IGCCCG intermediate/poor prognosis (OR 3.56; 95% CI 1.33–9.52) and residual tumor size > 5 cm (OR 3.53; 95% CI 1.39–8.93). Blood loss was higher in patients with IGCCCG intermediate/poor prognosis (β = 0.177; p = 0.029), large residual tumor (β = 0.570; p < 0.001), an additional intervention (β = 0.342; p < 0.001) and teratoma on retroperitoneal histology (β = − 0.19; p = 0.014). Thirty-one patients had a postoperative complication Clavien-Dindo Grade ≥ 2 (25.0%). Complication risk was highest in patients undergoing an additional intervention (OR 3.46; 95% CI 1.03–11.60; p = 0.044). Conclusions: The rate of additional interventions in our series is comparable to what has been reported in high-volume centers. IGCCCG intermediate/poor prognosis patients with high-volume disease and patients undergoing an additional surgical procedure can be classified as high-risk patients

Dose-Dependent Effect of Platinum-Based Chemotherapy on the Risk of Metachronous Contralateral Testicular Cancer

PURPOSE: Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a contralateral TGCT (CTGCT). Although some studies suggest that prior treatment with platinum-based chemotherapy affects CTGCT risk, a relationship between CTGCT risk and platinum dose has not previously been assessed. We analyzed the association between the number of platinum-based chemotherapy cycles and CTGCT risk. PATIENTS AND METHODS: The risk of developing a metachronous CTGCT was evaluated in a nationwide cohort of 4,755 patients diagnosed with primary TGCT in the Netherlands between 1989 and 2007. Standardized incidence ratios were computed to compare CTGCT incidence with expected TGCT on the basis of TGCT incidence in the general population. The cumulative incidence of CTGCT was estimated in the presence of death as competing risk. The effect of treatment with platinum-based chemotherapy on CTGCT risk was assessed using multivariable Cox proportional hazards regression models. RESULTS: CTGCT was diagnosed in 136 patients (standardized incidence ratio, 14.6; 95% CI, 12.2 to 17.2). The cumulative incidence increased up to 20 years after primary diagnosis, reaching 3.4% (95% CI, 2.8% to 4.0%) after 20 years of follow up. The risk of developing a CTGCT decreased with age (hazard ratio [HR], 0.93; 95% CI, 0.90 to 0.96), was lower after nonseminomatous germ cell tumor (HR, 0.58; 95% CI, 0.35 to 0.96) and decreased with every additional cycle of chemotherapy (HRper cycle, 0.74; 95% CI, 0.64 to 0.85). CONCLUSION: Approximately one in every 30 survivors of TGCT will develop a CTGCT, with CTGCT incidence increasing up to 20 years after a primary TGCT. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with CTGCT risk

Extracellular vesicle-mediated protein delivery to the liver

Extracellular vesicles (EVs) are nanoscale particles that facilitate intercellular communication. They are regarded as a promising natural drug delivery system for transporting and delivering bioactive macromolecules to target cells. Recently, researchers have engineered EVs with FKBP12/FRB heterodimerization domains that interact with rapamycin to load and deliver exogenous proteins for both in vitro and in vivo applications. In this study, we examined the tissue distribution of EVs using near-infrared fluorescent imaging. We evaluated the effectiveness of EV-mediated delivery of Cre recombinase specifically to hepatocytes in the livers of Ai9 Cre-loxP reporter mice. Intravenous injection resulted in more efficient Cre protein delivery to the liver than intraperitoneal injections. Depleting liver-resident macrophages with clodronate-encapsulated liposome pre-treatment did not enhance EV-mediated Cre delivery to hepatocytes. Moreover, we demonstrated that multiple intravenous injections of Cre-EVs facilitated functional Cre delivery to hepatocytes. To the best of our knowledge, this is the first study to simultaneously investigate the tissue distribution of FKBP12/FRB-engineered EVs and their subsequent intracellular protein delivery in Ai9 Cre-loxP reporter mice. These insights can inform preclinical research and contribute to developing next-generation EV-based platforms for delivering therapeutic proteins or genome editing technologies targeting the liver

Massive expansion and cryopreservation of functional human induced pluripotent stem cell-derived cardiomyocytes

Since the discovery of human induced pluripotent stem cells (hiPSCs), numerous strategies have been established to efficiently derive cardiomyocytes from hiPSCs (hiPSC-CMs). Here, we describe a cost-effective strategy for the subsequent massive expansion (>250-fold) of high-purity hiPSC-CMs relying on two aspects: removal of cell-cell contacts and small-molecule inhibition with CHIR99021. The protocol maintains CM functionality, allows cryopreservation, and the cells can be used in downstream assays such as disease modeling, drug and toxicity screening, and cell therapy. For complete details on the use and execution of this protocol, please refer to Buikema (2020)

Disease activity in primary progressive multiple sclerosis: a systematic review and meta-analysis

BackgroundDisease activity in multiple sclerosis (MS) is defined as presence of relapses, gadolinium enhancing lesions and/or new or enlarging lesions on MRI. It is associated with efficacy of immunomodulating therapies (IMTs) in primary progressive MS (PPMS). However, a thorough review on disease activity in PPMS is lacking. In relapsing remitting MS, the prevalence of activity decreases in more contemporary cohorts. For PPMS, this is unknown.AimTo review disease activity in PPMS cohorts and identify its predictors.MethodsA systematic search in EMBASE, MEDLINE, Web of science Core Collection, COCHRANE CENTRAL register of trials, and GOOGLE SCHOLAR was performed. Keywords included PPMS, inflammation, and synonyms. We included original studies with predefined available data, extracted cohort characteristics and disease activity outcomes and performed meta-regression analyses.ResultsWe included 34 articles describing 7,109 people with PPMS (pwPPMS). The weighted estimated proportion of pwPPMS with overall disease activity was 26.8% (95% CI 20.6–34.0%). A lower age at inclusion predicted higher disease activity (OR 0.91, p = 0.031). Radiological activity (31.9%) was more frequent than relapses (9.2%), and was predicted by longer follow-up duration (OR 1.27, p = 0.033). Year of publication was not correlated with disease activity.ConclusionInflammatory disease activity is common in PPMS and has remained stable over the last decades. Age and follow-up duration predict disease activity, advocating prolonged monitoring of young pwPPMS to evaluate potential IMT benefits

Clinical outcome of post-chemotherapy retroperitoneal lymph node dissection in metastatic nonseminomatous germ cell tumour: A systematic review

Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is an important element of the management of patients with residual tumour after chemotherapy for disseminated nonseminomatous germ cell tumour (NSGCT). This is a challenging procedure and the outcome varies widely between institutions. There is much debate concerning the anatomical extent of the dissection and the literature is conflicting regarding the outcome of this procedure. In this systematic review we aim to summarise the literature on the relapse rate of PC-RPLND. We performed a search of the literature of the PubMed/MEDLINE and Embase databases, in accordance with the PRISMA guidelines. Studies reporting on the relapse rate of PC-RPLND in NSGCT patients with residual tumour were eligible for inclusion. We calculated the weighted average relapse rates of included studies and assessed the risk of bias using the Newcastle-Ottawa scale. A total of 33 studies, reporting on 2,379 patients undergoing open PC-RPLND (O-RPLND) and 463 patients undergoing minimally invasive PC-RPLND (MI-RPLND) were included. The weighted average relapse rates were 11.4% for O-RPLND, and 3.0% for MI-RPLND. The rates of retroperitoneal relapse were 4.6% and 1.7% after O-RPLND and MI-RPLND, respectively. For O-RPLND specifically, the average retroperitoneal relapse rate was 3.1% after modified dissection and 6.1% after bilateral dissection. We conclude that modified template dissection is oncologically safe in carefully selected patients. Minimally invasive procedures are feasible but long-term data on the oncological outcome are still lacking. PC-RPLND is a complex and challenging procedure, and patients should be treated at high-volume expert centres