Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

"Empowering Us": A community-led survey of real-world perspectives of adults with type 1 diabetes using insulin pumps and continuous glucose monitoring to manage their glucose levels.

OBJECTIVE: To conduct an Australian community-led survey of adults with type 1 diabetes (T1D), identifying priorities for, and barriers to, optimal use of advanced glucose management technologies. RESEARCH DESIGN AND METHODS: A 30-question online survey of current or past users of insulin pump therapy (IPT), real-time continuous glucose monitoring (RT-CGM), or intermittently scanned CGM (isCGM) explored perceptions regarding device design, access, education, outcomes, and support. RESULTS: Between November 2021 and January 2022, surveys were completed by 3,380 participants (age [mean ± SD] 45 ± 16 years; 62% female; 20 ± 14 years diabetes), with 55%, 82%, and 55% reporting experience with IPT, RT-CGM, and isCGM, respectively. Overall, most considered diabetes technology '(extremely) important' for maintaining target glucose levels (98%) and reducing hypoglycaemia severity and frequency (93%). For most, technology contributed positively to emotional well-being (IPT 89%; RT-CGM 91%; isCGM 87%), which was associated with device effectiveness in maintaining glucose in range, comfort, and convenience. Barriers included affordability (IPT 68%; RT-CGM 81%; isCGM 69%) and insufficient information for informed choices about device suitability (IPT 39%; RT-CGM 41%; isCGM 36%). CONCLUSIONS: Technology is perceived by adults with T1D as important for managing glycaemia and emotional well-being. Modifiable barriers to use include affordability, and information regarding device suitability.

AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)-cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages.

The association of facility ownership with COVID-19 outbreaks in long-term care homes in British Columbia, Canada: a retrospective cohort study.

BACKGROUND: Long-term care (LTC) in Canada is delivered by a mix of government-, for-profit- and nonprofit-owned facilities that receive public funding to provide care, and were sites of major outbreaks during the early stages of the COVID-19 pandemic. We sought to assess whether facility ownership was associated with COVID-19 outbreaks among LTC facilities in British Columbia, Canada. METHODS: We conducted a retrospective observational study in which we linked LTC facility data, collected annually by the Office of the Seniors Advocate BC, with public health data on outbreaks. A facility outbreak was recorded when 1 or more residents tested positive for SARS-CoV-2 between Mar. 1, 2020, and Jan. 31, 2021. We used the Cox proportional hazards method to calculate the adjusted hazard ratio (HR) of the association between risk of COVID-19 outbreak and facility ownership, controlling for community incidence of COVID-19 and other facility characteristics. RESULTS: Overall, 94 outbreaks involved residents in 80 of 293 facilities. Compared with health authority-owned facilities, for-profit and nonprofit facilities had higher risks of COVID-19 outbreaks (adjusted HR 1.99, 95% confidence interval [CI] 1.12-3.52 and adjusted HR 1.84, 95% CI 1.00-3.36, respectively). The model adjusted for community incidence of infection (adjusted HR 1.12, 95% CI 1.07-1.17), total nursing hours per resident-day (adjusted HR 0.84, 95% CI 0.33-2.14), facility age (adjusted HR 1.01, 95% CI 1.00-1.02), number of facility beds (adjusted HR 1.20, 95% CI 1.12-1.30) and facilities with beds in shared rooms (adjusted HR 1.16, 95% CI 0.73-1.85). INTERPRETATION: Findings suggest that ownership of LTC facilities by health authorities in BC offered some protection against COVID-19 outbreaks. Further study is needed to unpack the underlying pathways behind this observed association.

Guidelines for selecting an appropriate currency in biodiversity offset transactions.

When designing biodiversity offset transactions, selecting the appropriate currency for measuring losses and gains to biodiversity is crucial. Poorly designed currencies reduce the likelihood that the proposed offset will sufficiently compensate for the development impact on the affected biota. We present a framework for identifying appropriate offset currencies for terrestrial biodiversity features, either vegetation communities or particular species. The guidelines were developed based on a review of issues and solutions presented in the existing literature, including government policies and guidance. We assert that while benchmark-based condition scores provide a suitable offset transaction currency for vegetation communities, this approach is also commonly applied to individual species based on the often-unproven assumption that vegetation quality is a proxy for the value of a site to that species. We argue that species are better served by species-specific currencies based on either species abundance, or the suitability and amount of the habitat available. For species where it is practical and meaningful to measure the abundance on site, an abundance-based currency using either directly observable or proxy indicators is the most representative measure of the net impact on the species. In other instances, such as when species are difficult to locate, or not reliably present on site, a currency based on the quality and amount of habitat is preferable. The habitat-quality component should be measured relative to its value for the species, with the most important attributes weighted accordingly. Ensuring the currency used in biodiversity offset transactions is practical to measure, and relevant to the species or vegetation community is an important step in minimising the net biodiversity losses from unavoidable impacts.

GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity.

Inhibitory myeloid cells and their cytokines play critical roles in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the development of toxicities and resistance following infusion. We have previously shown that neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF) prevents these toxicities and enhances CART cell functions by inhibiting myeloid cell activation. In this report, we study the direct impact of GM-CSF disruption during the production of CD19-directed CART cells on their effector functions, independent of GM-CSF modulation of myeloid cells. In this study, we show that antigen-specific activation of GM-CSFKO CART19 cells consistently displayed reduced early activation, enhanced proliferation, and improved anti-tumor activity in a xenograft model for relapsed B cell malignancies. Activated CART19 cells significantly upregulate GM-CSF receptors. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not the predominant mechanism of this activation phenotype. GM-CSFKO CART19 cell had reduced BH3 interacting-domain death agonist (Bid), suggesting an interaction between GM-CSF and intrinsic apoptosis pathways. In conclusion, our study demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CART cells directly ameliorates CART cell early activation and enhances anti-tumor activity in preclinical models.

Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography.

T cells genetically engineered to express chimeric antigen receptors (CAR) have shown unprecedented results in pivotal clinical trials for patients with B cell malignancies or multiple myeloma (MM). However, numerous obstacles limit the efficacy and prohibit the widespread use of CAR T cell therapies due to poor trafficking and infiltration into tumor sites as well as lack of persistence in vivo. Moreover, life-threatening toxicities, such as cytokine release syndrome or neurotoxicity, are major concerns. Efficient and sensitive imaging and tracking of CAR T cells enables the evaluation of T cell trafficking, expansion, and in vivo characterization and allows the development of strategies to overcome the current limitations of CAR T cell therapy. This paper describes the methodology for incorporating the sodium iodide symporter (NIS) in CAR T cells and for CAR T cell imaging using [18F]tetrafluoroborate-positron emission tomography ([18F]TFB-PET) in preclinical models. The methods described in this protocol can be applied to other CAR constructs and target genes in addition to the ones used for this study.

Challenges of chimeric antigen receptor T-cell therapy in chronic lymphocytic leukemia: lessons learned.

Development of chimeric antigen receptor T cell (CART) therapy has led to an unprecedented success against B-cell leukemia and lymphoma and resulted in U.S. Food and Drug Administration-approved treatment protocols. Despite the initial clinical response in B cell-related malignancies, high relapse rates suggest that much work is needed to uncover mechanisms of resistance. In chronic lymphocytic leukemia (CLL), the durable activity of CAR T-cells is limited, and CAR T-cell therapy success is lower than in other malignancies. T cells from these patients are vulnerable to a state of dysfunction because of stresses including chronic infection, rapid cell cycle on antigen recognition, immunosuppressive tumor microenvironment, and cancer-related treatments. T cells are also introduced to additional stresses when cultured ex vivo during the CAR T-cell manufacturing process. All these factors contribute to the limited regenerative capacity of T cells, which can lead to CAR T-cell treatment failure. In this article, we review the challenges of CAR T-cell therapy in patients with CLL and discuss potential strategies to overcome these challenges.

Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma.

Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

Development of a Clinically Relevant Reporter for Chimeric Antigen Receptor T-cell Expansion, Trafficking, and Toxicity.

Although chimeric antigen receptor T (CART)-cell therapy has been successful in treating certain hematologic malignancies, wider adoption of CART-cell therapy is limited because of minimal activity in solid tumors and development of life-threatening toxicities, including cytokine release syndrome (CRS). There is a lack of a robust, clinically relevant imaging platform to monitor in vivo expansion and trafficking to tumor sites. To address this, we utilized the sodium iodide symporter (NIS) as a platform to image and track CART cells. We engineered CD19-directed and B-cell maturation antigen (BCMA)-directed CART cells to express NIS (NIS+CART19 and NIS+BCMA-CART, respectively) and tested the sensitivity of 18F-TFB-PET to detect trafficking and expansion in systemic and localized tumor models and in a CART-cell toxicity model. NIS+CART19 and NIS+BCMA-CART cells were generated through dual transduction with two vectors and demonstrated exclusive 125I uptake in vitro. 18F-TFB-PET detected NIS+CART cells in vivo to a sensitivity level of 40,000 cells. 18F-TFB-PET confirmed NIS+BCMA-CART-cell trafficking to the tumor sites in localized and systemic tumor models. In a xenograft model for CART-cell toxicity, 18F-TFB-PET revealed significant systemic uptake, correlating with CART-cell in vivo expansion, cytokine production, and development of CRS-associated clinical symptoms. NIS provides a sensitive, clinically applicable platform for CART-cell imaging with PET scan. 18F-TFB-PET detected CART-cell trafficking to tumor sites and in vivo expansion, correlating with the development of clinical and laboratory markers of CRS. These studies demonstrate a noninvasive, clinically relevant method to assess CART-cell functions in vivo.

Resistance to CART cell therapy: lessons learned from the treatment of hematological malignancies.

Chimeric antigen receptor T (CART) cell immunotherapy has yielded significant clinical success in treating certain hematological malignancies. However, despite high initial response rates, most patients eventually relapse. Resistance to CART cell therapy can stem from tumor cell mutations, T cell defects, and tumor microenvironment (TME) immunosuppression. Tumor cells can downregulate target antigen expression to evade CART cell detection or mutate death receptor pathways to resist CART cell cytotoxicity. Patient T cells can be intrinsically defective, and CART cells often undergo exhaustion. The TME is abundant with immunosuppressive cells and factors which contribute to suboptimal CART cell activity. Collectively, issues originating in tumor cells, T cells, and the TME present significant hurdles to long-term remission after CART cell therapy. Various strategies to combat CART cell resistance have shown promise in preclinical studies and early clinical trials and are crucial to achieving durable responses.

Evaluation of an initiative to improve advance care planning for a home-based primary care service.

BACKGROUND: Advance care planning (ACP) is a process that enables individuals to describe, in advance, the kind of health care they would want in the future. There is evidence that ACP reduces hospital-based interventions, especially at the end of life. ACP for frail older adults is especially important as this population is more likely to use hospital services but less likely to benefit from resource intensive care. Our study goal was to evaluate whether an approach to ACP developed for frail older adults, known as the Palliative and Therapeutic Harmonization or PATH, demonstrated an improvement in ACP. METHODS: The PATH approach was adapted to a primary care service for homebound older adults in Vancouver, Canada. This retrospective chart review collected surrogate measures related to ACP from 200 randomly selected patients enrolled in the service at baseline (prior to June 22, 2017), and 114 consecutive patients admitted to the program after implementation of the PATH ACP initiative (October 1, 2017 to May 1, 2018). We compared the following surrogate markers of ACP before and after implementation of the PATH model, chart documentation of: frailty stage, substitute decision-maker, resuscitation decision, and hospitalization decision. A composite ACP documentation score that ascribed one point for each of the above four measures (range 0 to 4) was also compared. For those with documented resuscitation and hospitalization decisions, the study examined patient/ substitute decision-maker expressed preferences for do-not-resuscitate and do-not-hospitalize, before and after implementation. RESULTS: We found the following changes in ACP-related documentation before and after implementation: frailty stage (27.0% versus 74.6%, p < .0001); substitute decision-maker (63.5% versus 71.9%, p = 0.128); resuscitation decision documented (79.5% versus 67.5%, p = 0.018); and hospitalization decision documented (61.5% versus 100.0%, p < .0001); mean (standard deviation) composite ACP documentation score (2.32 (1.16) versus 3.14 (1.11), p < .0001). The adjusted odds ratios (95% confidence intervals) for an expressed preference of do-not-resuscitate and do-not-hospitalize after implementation were 0.87 (0.35, 2.15) and 3.14 (1.78, 5.55), respectively. CONCLUSIONS: Results suggest partial success in implementing the PATH approach to ACP in home-based primary care. Key contextual enablers and barriers are important considerations for successful implementation.

Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia.

Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1+ CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.

Advance Care Planning and Decision-Making in a Home-Based Primary Care Service in a Canadian Urban Centre.

BACKGROUND: Advance care planning (ACP) is a process that enables individuals to describe, in advance, the kind of health care they would want in the future, and has been shown to reduce hospital-based interventions at the end of life. Our goal was to describe the current state of ACP in a home-based primary care program for frail homebound older people in Vancouver, Canada. We did this by identifying four key elements that should be essential to ACP in this program: frailty stage, documentation of substitute decision-makers, and decision-making with regard to both resuscitation (i.e., do not resuscitate (DNR)) and hospitalization (i.e., do not hospitalize (DNH)). While these elements are an important part of the ACP process, they are often excluded from common practice. METHODS: This was a cross-sectional, observational study of data abstracted from 200 randomly selected patient electronic medical records between July 1 and September 30, 2017. We describe the association between demographic characteristics, comorbidities, and four key elements of ACP documentation and decision-making as documented in the clinical record using bivariate comparison, a logistic regression model and multiple logistic regression analysis. RESULTS: In 73% (n=146) of the patient records, there was no explicit documentation of frailty stage. Sixty-four per cent had documentation of a substitute decision-maker. Of those who had their preferences documented, 90.6% (n=144/159) indicated a preference for DNR, and 23.6% (n=29/123) indicated a preference for DNH. In multiple regression modeling, a diagnosis of dementia and older age were associated with documentation of a DNR preference, adjusted odds ratio (AOR) = 4.79 (95% CI 1.37, 16.71) and AOR = 1.14 (95% CI 1.05, 1.24), respectively. Older age, male sex, and English identified as the main language spoken were associated with a DNH preference. AOR = 1.17 (95% CI 1.06, 1.28), AOR = 4.19 (95% CI 1.41, 12.42), and AOR = 3.42 (95% CI 1.14, 10.20), respectively. CONCLUSIONS: Clinician documentation of some elements of ACP, such as identification of a substitute decision-maker and resuscitation status, have been widely adopted, while other elements that should be considered essential components of ACP, such as frailty staging and preferences around hospitalization, are infrequent and provide an opportunity for practice improvement initiatives. The significant association between language and ACP decisions suggests an important role for supporting cross-cultural fluency in the ACP process.

Using CRISPR/Cas9 to Knock Out GM-CSF in CAR-T Cells.

Chimeric antigen receptor T (CAR-T) cell therapy is a cutting edge and potentially revolutionary new treatment option for cancer. However, there are significant limitations to its widespread use in the treatment of cancer. These limitations include the development of unique toxicities such as cytokine release syndrome (CRS) and neurotoxicity (NT) and limited expansion, effector functions, and anti-tumor activity in solid tumors. One strategy to enhance CAR-T efficacy and/or control toxicities of CAR-T cells is to edit the genome of the CAR-T cells themselves during CAR-T cell manufacturing. Here, we describe the use of CRISPR/Cas9 gene editing in CAR-T cells via transduction with a lentiviral construct containing a guide RNA to granulocyte macrophage colony-stimulating factor (GM-CSF) and Cas9. As an example, we describe CRISPR/Cas9 mediated knockout of GM-CSF. We have shown that these GM-CSFk/o CAR-T cells effectively produce less GM-CSF while maintaining critical T cell function and result in enhanced anti-tumor activity in vivo compared to wild type CAR-T cells.

GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts.

Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell-associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF-deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

A before-after study of hospital use in two frail populations receiving different home-based services over the same time in Vancouver, Canada.

BACKGROUND: As individuals age, they are more likely to experience increasing frailty and more frequent use of hospital services. First, we explored whether initiating home-based primary care in a frail homebound cohort, influenced hospital use. Second, we explored whether initiating regular home care support for personal care with usual primary care, in a second somewhat less frail cohort, influenced hospital use. METHODS: This was a before-after retrospective cohort study of two frail populations in Vancouver, Canada using administrative data to assess the influence of two different services started in two different cohorts over the same time period. The participants were 246 recipients of integrated home-based primary care and 492 recipients of home care followed between July 1st, 2008 and June 30th, 2013 before and after starting their respective services. Individuals in each group were linked to their hospital emergency department visit and discharge abstract records. The main outcome measures were mean emergency department visit and hospital admission rates per 1000 patient days for 21 months before versus the period after receipt of services, and the adjusted incidence rate ratios (IRRs) on these outcomes post receipt of service. RESULTS: Before versus after starting integrated home-based primary care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 4.1 (3.8, 4.4) versus 3.7 (3.3, 4.1), and hospital admissions rates were 2.3 (2.1, 2.5) versus 2.2 (1.9, 2.5). Before versus after starting home care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 3.0 (2.8, 3.2) versus 4.0 (3.7, 4.3) visits and hospital admissions rates were 1.3 (1.2, 1.4) versus 1.9 (1.7, 2.1). Home-based primary care IRRs were 0.91 (0.72, 1.15) and 0.99 (0.76, 1.27) and home care IRRs were 1.34 (1.15, 1.56) and 1.46 (1.22, 1.74) for emergency department visits and hospital admissions respectively. CONCLUSIONS: After enrollment in integrated home-based primary care, emergency department visit and hospital admission rates stabilized. After starting home care with usual primary care, emergency department visit and hospital admission rates continued to rise.

Molecular Marker Study of Particulate Organic Matter in Southern Ontario Air.

To study the origins of airborne particulate organic matter in southern Ontario, molecular marker concentrations were studied at Hamilton, Simcoe, and York Gateway Tunnel, representing industrial, rural, and heavy traffic sites, respectively. Airborne particulate matter smaller than 10 µm in aerodynamic diameter was collected on quartz filters, and the collected samples were analyzed for total carbons, 5-6 ring PAHs, hopanes, n-alkanes (C20 to C34), and oxygenated aromatic compounds. Results showed that PAH concentrations at all three sites were highly correlated, indicating vehicular emissions as the major source. Meanwhile, in the scatter plots of α,ß-hopane and trisnorhopane, concentrations displayed different trends for Hamilton and Simcoe. The slopes of the linear regressions for Hamilton and the tunnel were statistically the same, while the slope for Simcoe was significantly different from those. Comparison with literature values revealed that the trend observed at Simcoe was explained by the influence from coal combustion. We also found that the majority of oxygenated aromatic compounds at both sites were in the similar level, possibly implying secondary products contained in the southern Ontario air. Regardless of some discrepancies, absolute principal component analysis applied to the datasets could reproduce those findings.

Post-Chemotherapy Robotic Retroperitoneal Lymph Node Dissection: Institutional Experience.

PURPOSE: There is little literature on robotic retroperitoneal lymph node dissection (RRPLND) in the difficult post-chemotherapy (PC) setting. We report on the outcome of RRPLND in patients with PC-residual masses. MATERIALS AND METHODS: Between 2011 and 2015, we performed 12 PC-RRPLND. Mean patient age was 37.8 years. Mean body mass index was 30.78. Nine (75%) patients had nonseminomatus germ cell tumor (NSGCT) and three (25%) patients had seminoma tumors. Cancer stage was III in six (50%), II-C in three (25%), II-B in two (16.7%), and II-A in one (8.03%). International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification in the NSGCT was good in six, intermediate in two, and poor in one, and was good in the three seminoma patients. RESULTS: The procedure was completed effectively in 11 (91.7%) patients. Mean operative time was 312 minutes. The mean estimated blood loss was 475 mL. Mean hospital stay was 3.2 days. Mean number of lymph node excised was 12. Six of the excised masses were ≥5 cm (N3), largest was 7.5 cm. Pathology showed teratoma in five (45.5%), benign/necrosis in five (45.5%), and viable germ cells in one (9%). Major complication (Clavien ≥3) occurred in one patient and minor (Clavien ≤2) in two. Antegrade ejaculation was preserved in eight patients and in one could not be assessed. At a median follow-up of 31 months, no infield or outfield relapses occurred. CONCLUSIONS: Robotic PC-retroperitoneal lymph node dissection (RPLND) is technically feasible and with acceptable morbidity. It is associated with low blood loss and short hospital stay. More research is needed to assess the long-term outcome and to compare standard open RPLND.