Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are indicated for metastatic urothelial cancer (mUC), but predictive and prognostic factors are lacking. We investigated clinical variables associated with ICI outcomes. METHODS: We performed a multicentre retrospective cohort study of 135 patients who received ICI for mUC, 2016-2021, at three Canadian centres. Clinical characteristics, body mass index (BMI), metastatic sites, neutrophil-to-lymphocyte ratio (NLR), response and survival were abstracted from chart review. RESULTS: We identified 135 patients and 62% had received ICI as a second-line or later treatment for mUC. A BMI ≥25 was significantly correlated to a higher overall response rate (ORR) (45.4% vs 16.3%, p value=0.020). Patients with BMI ≥30 experienced longer median overall survival (OS) of 24.8 vs 14.4 for 25≤BMI<30 and 8.5 months for BMI <25 (p value=0.012). The ORR was lower in the presence of bone metastases (16% vs 41%, p value=0.006) and liver metastases (16% vs 39%, p value=0.013). Metastatic lymph nodes were correlated with higher ORR (40% vs 20%, p value=0.032). The median OS for bone metastases was 7.3 versus 18 months (p value <0.001). Patients with liver metastases had a median OS of 8.6 versus 15 months (p value=0.006). No difference for lymph nodes metastases (13.5 vs 12.7 months, p value=0.175) was found. NLR ≥4 had worse OS (8.2 vs 17.7 months, p value=0.0001). In multivariate analysis, BMI ≥30, bone metastases, NLR ≥4, performance status ≥2 and line of ICI ≥2 were independent factors for OS. CONCLUSIONS: Our data identified BMI and bone metastases as novel clinical biomarkers that were independently associated with ICI outcomes in mUC. External and prospective validation are warranted.

Clinical diagnostic accuracy of respiratory failure in critically ill hematopoietic stem cell transplant patients.

RATIONALE: Acute respiratory failure (ARF) is a frequent complication following hematopoietic cell transplantation (HCT). We aimed to characterize the etiologies of ARF in patients who died in the intensive care unit following HCT based on autopsy findings. We then evaluated agreement between the clinical and pathologic diagnosis. METHODS: We performed a chart review of all HCT patients who died and underwent autopsy in our ICU between 2006-2016. We evaluated the presumed clinical diagnosis and confidence in the diagnosis by chart review, the pathologic diagnosis on autopsy, and whether the clinical-pathologic diagnoses were concordant. When there was discordance, we evaluated whether knowledge of the pathology could have changed management. RESULTS: Thirteen patients underwent autopsy after dying. Infection was the presumed cause in 11/13 cases. The clinical and pathologic diagnoses were concordant in 6/13(46%). In the seven discordant cases (all clinically diagnosed as infection), autopsy revealed two non-infectious inflammatory causes, one post-transplant lymphoproliferative disorder, and three non-bacterial infectious etiology. Pathologic findings may have changed management in 7/13(54%) cases. CONCLUSIONS: In a subset of HCT-recipients who died from respiratory failure, discordance was frequent between clinical and pathologic diagnoses. The risks and benefits of obtaining tissue to improve our diagnostic accuracy requires further evaluation.

Quality of patient-reported outcomes in oncology clinical trials using immune checkpoint inhibitors: A systematic review.

BACKGROUND: There are limited data regarding the quality of patient-reported outcome (PRO) data in immune checkpoint inhibitor (ICI) clinical trial publications. METHODS: A systematic search of citations from various databases was conducted to identify prospective clinical trials involving ICI in advanced tumors from 2003 to 2020. A 30-point score was adapted from the CONSORT PRO extension statement to assess adherence to CONSORT PRO reporting. Linear regression was used to identify factors associated with quality reporting. RESULTS: After the review of 8058 articles, 33 trials were included with ICIs as either monotherapy (91%) or part of a combination regimen (9%). The median score was 23.5 points (range 15-29). In the majority of cases (82%), PROs were reported in a separate publication from the original study. Most of the trials were conducted in the metastatic setting and predominantly in melanoma, lung, and renal cell carcinoma (RCC) (73%). Univariate analysis revealed that trials with greater than 250 patients were associated with a higher score. The score was more likely to be lower in disease sites other than melanoma, lung, and RCC and was higher in the KEYNOTE than in the CHECKMATE trial series. There was no significant correlation between the score and whether a trial met its primary end-point or if the trial improved or worsened the quality of life. In the multivariate analysis, the number of patients enrolled to the trial, disease site, and trial series remained significant. CONCLUSIONS: The quality of reporting of PROs in ICI phase II and III clinical trials is heterogeneous across various cancer sites. As PRO data are increasingly used to counsel patients and complement clinical decision making, innovative and collaborative efforts are required to improve the reporting of these essential data.

Primary cardiac sarcomas: A multi-national retrospective review.

BACKGROUND: Primary cardiac sarcoma (PCS) is a rare but often fatal disease. The current study aimed to analyze the impact of baseline demographics, local and systemic therapies in a contemporary cohort. METHODS: Clinical records of PCS across six institutions in three continents were reviewed. Kaplan-Meier method was used to estimate survival. Cox proportional hazard model was used to determine variables impacting progression-free survival (PFS) or overall survival (OS). RESULTS: Sixty-one patients with PCS (1996-2016) were identified. The median age at diagnosis was 46 (range 18-79); 36% (n = 22) presented with metastatic disease. The most common histology was angiosarcoma (n = 24, 39%). A total of 46 patients received surgery (75%) but only 5 (8%) patients achieved R0 resection. Multi-modality treatment to the primary tumor was given to 28 patients (46%; localized disease 23/39 (59%); metastatic disease 5/22 (23%)). The median OS for the entire cohort was 17.5 months (95% CI 9.5-20.6), with seven (11%) patients surviving longer than 36 months. On multi-variate analysis, age <65 (P = 0.01) was the only significant favorable prognostic factor. For first-line palliative chemotherapy, the median PFS was 4.4 months (95% CI 2.9-7.7 months). The best response for first-line chemotherapy was 32% (CR = 1, PR = 9). No significant improvement in OS was identified in patients presenting throughout the 20-year period of this review. CONCLUSION: Younger age at diagnosis was associated with improved outcome although the prognosis of PCS remains poor. Given the lack of improvement in survival, further dedicated research is required.

Outcomes of lung transplant candidates referred for co-management by palliative care: A retrospective case series.

BACKGROUND: Lung transplant candidates experience important symptoms, but they are rarely referred for palliative care consultation until they are deemed ineligible for transplant. Our lung transplant service has a high rate of palliative care referral for patients awaiting transplant. AIM: We reviewed the characteristics, interventions, and outcomes of lung transplant candidates referred for co-management by palliative care, to determine whether they safely received opioids and went on to transplantation. DESIGN AND PARTICIPANTS: Retrospective review of lung transplant candidates referred to our palliative care consultation service between January 2010 and May 2012. RESULTS: Of 308 lung transplant candidates, 64 (20.7%) were referred to palliative care. Most had interstitial lung disease and were referred for dyspnea and a rapidly deteriorating course. A total of 59 (92%) were prescribed opioids for dyspnea, 55/59 used the opioids more than once, and 38/59 were maintained on standing opioids. There were no episodes of clinically important opioid toxicity or respiratory depression, and there was a trend toward increased exertion during exercise sessions post-opioid versus pre-opioid (19.3 vs 17.0 kcal, respectively, p = 0.06). At last follow-up, 30 (47%) had been transplanted, 23 (36%) had died while on the wait-list, 9 (14%) had died after delisting, and 2 (3%) were still awaiting transplantation. Of the 30 patients who underwent lung transplantation, only 7 (23%) still required an opioid prescription 1 month post-discharge. CONCLUSION: In lung transplant candidates, palliative care and opioids in particular can be safely provided without compromising eligibility for transplantation. Palliative care should not be delayed until a patient is deemed ineligible for transplant.

Characteristics, interventions, and outcomes of lung transplant recipients co-managed with palliative care.

BACKGROUND: Lung transplantation (LT) recipients carry a high symptom burden. Palliative Care (PC) is a field of medicine focused on symptom control and psychosocial support, but transplant recipients are often referred to PC very late in the disease course, if at all. In our institution, the LT service has increasingly consulted PC to co-manage LT recipients with end-stage graft dysfunction or other terminal conditions. We present the characteristics, PC interventions used, and outcomes of these patients. METHODS: We conducted a single-center, retrospective, cohort study of LT recipients referred for PC consultation between January 2010 and May 2012. We collected patient demographics, timing and location of PC consultation, PC interventions, and patient outcomes. RESULTS: Twenty-four patients met the inclusion criteria. Sixteen (67%) had chronic allograft dysfunction. Reasons for referral were dyspnea (42%), end-of-life planning (42%), pain (29%), cough (4%), anxiety (4%), and depression (4%). Referral was made a median of 3.2 (range, 0.2 to 18) years from transplant and a median 14 days (range, 0 to 227 days) from death. Eighty-three percent of consultations occurred >48 hours from time of death. Ninety-two percent of patients were prescribed opioids over their course of treatment. Among the 12 (50%) who died in our center, 10 (83%) were receiving comfort medications. Eight patients (33%) initially requested full resuscitation at the time of PC consultation, but seven of these patients (or their surrogates) later agreed to a do not resuscitate (DNR) order; the eighth was still alive at last follow-up. No patient in this study received cardiopulmonary resuscitation (CPR) at the time of death. CONCLUSION: LT recipients referred for PC co-management typically receive comfort medications and avoid the aggressive end-of-life care usually reported for this population. The effect of PC interventions on patient quality of life requires further study.

The desirability of an Intensive Care Unit (ICU) clinician-led bereavement screening and support program for family members of ICU Decedents (ICU Bereave).

PURPOSE: Many bereaved family members (FMs) of intensive care unit decedents experience symptoms of complicated grief (CG) or social distress, but there is no standard screening or follow-up for these individuals. We determined the desirability and need for an intensive care unit-based bereavement screening and support program for these FMs. METHODS: We surveyed bereaved FMs to measure symptoms of CG, prolonged grief disorder, and social difficulties and the desire for support; and staff physicians and nurses at 2 teaching hospitals in Toronto, Canada, to determine comfort and interest in providing routine bereavement support. RESULTS: We could not contact 69% of FMs largely because of inaccuracies in the patient record. Of the 64 who were contacted, 32 (50%) agreed to be surveyed a mean (SD) of 7.4 (2.2) months after the loss of their relative. Among eligible staff, 57 (61%) of 94 completed the questionnaire. Nine (28%) FMs met subthreshold criteria for CG or prolonged grief disorder, and 7 (22%) met criteria for social distress. Only 10 (31%) had received professional support for emotional symptoms, and 2 (6%) received professional assistance for their social difficulties. Fifty-eight percent supported routine screening, and 68% wanted to receive (or receive more) support. Fifty-five percent of FMs expressed a strong willingness to meet with the medical team to review events surrounding the death of the patient, which was the type of support that the health care staff were most comfortable providing. Most staff (85%) reported providing emotional support at the time of death, but few provided any support afterwards. Fifty-six (98%) of 57 would be willing to support or participate in a formal bereavement screening and support program. Respondents cited the need for training and dedicated time to carry out such a program. CONCLUSIONS: An ICU-based bereavement screening and support program for FMs of ICU decedents is both needed and desirable, although there are important needs and barriers. Future studies should evaluate the effectiveness for such a program at improving outcomes among bereaved FMs.

Changes in end of life care 5 years after the introduction of a rapid response team: a multicentre retrospective study.

RATIONALE: Rapid response teams (RRTs) are intended to stabilize deteriorating patients on the ward, but recent studies suggest that RRTs may also improve end-of-life care (EOLC). We sought to study the effect of introducing an RRT on EOLC at our institutions, and compare the EOLC care received by patients who were consulted by the RRT with that of patients who were not consulted by the RRT. METHODS: Retrospective review of 450 consecutive deaths at 3 institutions. We compared demographic factors and EOLC received before (2005) and 5 years after (2010) the introduction of an RRT. We also compared these same factors for patients who died in 2010 with and without RRT consultation. RESULTS: There were no differences in the proportion of patients who had Patient/Family Conferences or orders to limit life support on the ward between 2005 and 2010. Although the RRT was consulted for 30% of patients eligible to be seen by the RRT, the RRT was involved in only 11.1% of Patient/Family Conferences that took place on the ward. The prevalence of palliative care consultation and orders for opioids as needed was higher in 2010 than 2005, but those seen by the RRT were less likely to receive a palliative care consultation (30.2% vs. 55.9%), spiritual care consultation (25.4% vs. 41.3%) or an order for sedatives as needed (44.4% vs. 65.0%) than those who were not seen by the RRT. There was no change in the proportion of patients admitted to the ICU in 2010 compared with 2005, and multivariable logistic regression showed that the year of death did not influence the likelihood of ICU admission based on any comorbid or demographic factors. CONCLUSIONS: The introduction of an RRT was not associated with significant improvements in EOLC at our institutions. However, almost 1/3 of dying patients were consulted by the RRT, suggesting that the RRT could play a role in facilitating improved EOLC for some inpatients.

Rapid response teams, do not resuscitate orders, and potential opportunities to improve end-of-life care: a multicentre retrospective study.

PURPOSE: Rapid response teams (RRTs) were created to stabilize acutely ill patients on the ward, but recent studies suggest that RRTs may improve end-of-life care (EOLC). To learn more about the role of the RRT in EOLC at our institutions, we conducted a retrospective review. METHODS: Retrospective review of 300 RRT consultations at 3 academic hospitals in Toronto, Canada. RESULTS: The typical consultation was for an elderly patient with chronic illness. More than 90% had a "full resuscitation" order at the time of consultation. One third were admitted to the intensive care unit within 48 hours of the RRT consultation, and 24.7% ultimately died. Twenty-seven (9.3%) had a patient/family conference on the ward within 48h of the RRT consultation, 24 (8.3%) of whom changed their resuscitation order as a result. Among those who changed their resuscitation order, fewer than 20% were referred to the palliative care or spiritual care service, or prescribed comfort medications as needed (pro re nata), within 48 h of the RRT consultation; 2 patients died without receiving any common EOLC orders, and 15 (63%) died before discharge. CONCLUSIONS: RRT consultation is an important milestone for many patients approaching EOL. RRTs frequently participate in EOL discussions and decision-making, but they may miss opportunities to facilitate EOLC.

Evidence for a common toolbox based on necrotrophy in a fungal lineage spanning necrotrophs, biotrophs, endophytes, host generalists and specialists.

The Sclerotiniaceae (Ascomycotina, Leotiomycetes) is a relatively recently evolved lineage of necrotrophic host generalists, and necrotrophic or biotrophic host specialists, some latent or symptomless. We hypothesized that they inherited a basic toolbox of genes for plant symbiosis from their common ancestor. Maintenance and evolutionary diversification of symbiosis could require selection on toolbox genes or on timing and magnitude of gene expression. The genes studied were chosen because their products have been previously investigated as pathogenicity factors in the Sclerotiniaceae. They encode proteins associated with cell wall degradation: acid protease 1 (acp1), aspartyl protease (asps), and polygalacturonases (pg1, pg3, pg5, pg6), and the oxalic acid (OA) pathway: a zinc finger transcription factor (pac1), and oxaloacetate acetylhydrolase (oah), catalyst in OA production, essential for full symptom production in Sclerotinia sclerotiorum. Site-specific likelihood analyses provided evidence for purifying selection in all 8 pathogenicity-related genes. Consistent with an evolutionary arms race model, positive selection was detected in 5 of 8 genes. Only generalists produced large, proliferating disease lesions on excised Arabidopsis thaliana leaves and oxalic acid by 72 hours in vitro. In planta expression of oah was 10-300 times greater among the necrotrophic host generalists than necrotrophic and biotrophic host specialists; pac1 was not differentially expressed. Ability to amplify 6/8 pathogenicity related genes and produce oxalic acid in all genera are consistent with the common toolbox hypothesis for this gene sample. That our data did not distinguish biotrophs from necrotrophs is consistent with 1) a common toolbox based on necrotrophy and 2) the most conservative interpretation of the 3-locus housekeeping gene phylogeny--a baseline of necrotrophy from which forms of biotrophy emerged at least twice. Early oah overexpression likely expands the host range of necrotrophic generalists in the Sclerotiniaceae, while specialists and biotrophs deploy oah, or other as-yet-unknown toolbox genes, differently.