Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial.

BACKGROUND: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma. METHODS: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 µM topotecan 200 µL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996. FINDINGS: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients. INTERPRETATION: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes. FUNDING: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Risk of Acquiring Perioperative COVID-19 During the Initial Pandemic Peak: A Retrospective Cohort Study.

OBJECTIVE: To determine the risk of acquiring perioperative COVID-19 infection in previously COVID-19 negative patients. SUMMARY OF BACKGROUND DATA: During the initial peak of the COVID-19 pandemic, there was significant concern of hospital acquired COVID-19 infections. Medical centers rapidly implemented systems to minimize perioperative transmission, including routine preoperative testing, patient isolation, and enhanced cleaning. METHODS: In this retrospective cohort study, medical records of all adult patients who underwent surgery at our quaternary, acute care hospital between March 15 and May 15, 2020 were reviewed. The risk of preoperatively negative patients developing symptomatic COVID-19 within 2-14 days postoperatively was determined. Surgical characteristics, outcomes, and complications were compared between those with and without acquired perioperative COVID-19 infection. RESULTS: Among 501 negative patients undergoing index surgeries, 9 (1.8%) developed symptomatic COVID-19 in the postoperative period; all occurred before implementation of routine preoperative testing [9/243, 3.7% vs 0/258, 0%, odds ratio (OR): 0.048, P = 0.036]. No patient who was polymerase-chain-reaction negative on the day of surgery (n = 170) developed postoperative infection. Perioperative infection was associated with preoperative diabetes (OR: 3.70, P = 0.042), cardiovascular disease (OR: 3.69, P = 0.043), angiotensin receptor blocker use (OR: 6.58, P = 0.004), and transplant surgery (OR: 11.00, P = 0.002), and multiple complications, readmission (OR: 5.50, P = 0.029) and death (OR: 12.81, P = 0.001). CONCLUSIONS: During the initial peak of the COVID-19 pandemic, there was minimal risk of acquiring symptomatic perioperative COVID-19 infection, especially after the implementation of routine preoperative testing. However, perioperative COVID-19 infection was associated with poor postoperative outcome.

SARS-COV-2 transmission rate is low when following a COVID+ patient in the operating room.

PURPOSE: Acquiring SARS-CoV-2 infection for uninfected patients undergoing surgical procedures following a COVID positive (COVID+) patient is of significant concern, both for patients seeking medical care in hospital settings and for management of surgical services during pandemic times. METHODS: Using data identifying all COVID+ surgical patients during the initial pandemic peak in New York City (March 15 to May 15, 2020), we analyzed the rate of postoperative symptomatic SARS-CoV-2 infection in COVID negative (COVID-) patients undergoing surgery in the same operating room within 48 h, thus determining nosocomial symptomatic infection rate attributable to COVID operating room exposure. RESULTS: Five COVID- patients directly followed a COVID+ patient, while 19 patients were exposed to COVID+ operating rooms within 24 h. By 48 h, 21 additional patients were exposed. No exposed patients acquired symptomatic SARS-CoV-2 infection postoperatively. CONCLUSION: With implementation of infection prevention and control procedures in the operating room under local pandemic conditions, our findings suggest that the risk of acquiring SARS-CoV-2 infection, when following a COVID+ patient in the same operating room, is very low.

Single-cell transcriptome analysis of lineage diversity in high-grade glioma.

BACKGROUND: Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). METHODS: We sampled the cellular milieu of HGGs by profiling dissociated human surgical specimens with a high-density microwell system for massively parallel single-cell RNA-Seq. We analyzed the resulting profiles to identify subpopulations of both HGG and microenvironmental cells and applied graph-based methods to infer structural features of the malignantly transformed populations. RESULTS: While HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors. CONCLUSIONS: These studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

Hamster Weight Patterns Predict the Intensity and Course of Schistosoma haematobium Infection.

Although Syrian golden hamsters are widely used as hosts for experimental infection by Schistosoma haematobium , surprisingly little is known about the course of infection and associated intensity (as defined by measures of parasite burden). As such, we sought to define inexpensive, simple, noninvasive, and accurate methods for assessing and predicting the severity of disease in S. haematobium -infected hamsters in order to prevent premature hamster sacrifice and unexpected morbidity and mortality. Through monitoring the weight and behavior of infected hamsters, we determined that the weight-loss patterns of infected hamsters are highly correlated with commonly used measures of the severity of infection (i.e., numbers of eggs passed in the stool, worm burdens, and total egg yields). In contrast, we found no significant correlation between hamster weight-loss patterns and egg yields from liver and intestinal tissues. Our findings suggest that a more complex relationship exists among worm burden, fecundity, and egg passage in the feces than previously appreciated. Regardless, our data may be useful for workers seeking to optimize harvests of S. haematobium eggs and worms from infected hamsters for downstream applications.