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Background The efficacy of adjuvant chemotherapy with FEC-D (5-fluorouracil-epirubicin-cyclophosphamide followed by docetaxel) is superior to that with FCE-100 alone in women with early-stage breast cancer. As the use of FEC-D increased in clinical practice, health care providers anecdotally noted higher-than-expected toxicity rates and frequent early treatment discontinuations because of toxicity. In the present study, we compared the rates of serious adverse events in patients who received adjuvant FEC-D chemotherapy in routine clinical practice with the rates reported in the pacs-01 trial. Methods We retrospectively reviewed all patients prescribed adjuvant FEC-D for early-stage breast cancer at 4 regional cancer centres in Ontario. Information was collected from electronic and paper charts by a physician investigator from each centre. Data were analyzed using chi-square tests, independent samples t-tests, one-way analysis of variance, and univariate regression. Results The 671 electronic and paper patient records reviewed showed a median patient age of 52.2 years, 229 patients (34.1%) with N0 disease, 508 patients (75.7%) with estrogen or progesterone receptor- positive disease (or both), and 113 patients (26%) with her2/neu-overexpressing breast cancer. Febrile neutropenia occurred in 152 patients (22.7%), most frequently at cycle 4, coincident with the initiation of docetaxel [78/152 (51.3%)]. Primary prophylaxis with hematopoietic growth factor support was used in 235 patients (35%), and the rate of febrile neutropenia was significantly lower in those who received prophylaxis than in those who did not [15/235 (6.4%) vs. 137/436 (31.4%); p < 0.001; risk ratio: 0.20]. Conclusions In routine clinical practice, treatment with FEC-D is associated with a higher-than-expected rate of febrile neutropenia, in light of which, primary prophylaxis with growth factor should be considered, per international guidelines. Adoption based on clinical trial reports of new therapies into mainstream practice must be done carefully and with scrutiny. [ABSTRACT FROM AUTHOR]

There is a paucity of studies assessing the incidental finding of histoplasmosis in the explanted tissue from lung transplant recipients (LTRs). Thus, there are currently no recommendations for the management of Histoplasmosis in the explanted organ of LTRs. This study aims to describe our experience in the management of histopathologic evidence of Histoplasmosis, encountered unexpectedly in the explanted tissue of LTRs at the time of transplantation. We retrospectively identified LTRs at the Toronto program from 2010-2017, with histopathologic evidence of Histoplasma in the lung explanted tissue. Of 810 LTRs, 6 recipients had Histoplasmosis in the explanted organ (incidence 0.75%, clinical characteristics shown in Table 1. None of the 6 patients had a previously known diagnosis of Histoplasmosis. All of them lived in Ontario, Canada, and only one had traveled abroad in the past five years (to Florida, USA). All 6 patients had lung parenchyma and lymph node involvement in the histopathology findings, with necrotizing granulomas and fungal spores compatible with Histoplasmosis. All patients received antifungal pre-emptive therapy after transplant: 4 (67%) Itraconazole and 2 (33%) voriconazole for a mean duration of 4.8 months (IQR, 2.82-8.1 months). No patients in this group developed posttransplant Histoplasmosis (median follow up of 3.0 years [IQR 2.0-4.1 years]). The unexpected finding of histoplasmosis in the explanted tissue of LTRs was infrequent (0.75%) in this non-endemic area. None of the patients, all of whom received antifungal therapy, developed active Histoplasmosis post-transplant. [ABSTRACT FROM AUTHOR]

Importance: Little is known about the incidence and outcomes of Clostridioides difficile infection (CDI) in solid organ transplant (SOT) recipients., Objective: To estimate the CDI incidence and outcomes in SOT recipients., Design, Setting, and Participants: A population-based cohort study was conducted using administrative health care data for all Ontario, Canada, residents who received organ allografts from April 1, 2003, to December 31, 2017; March 31, 2020, was the end of the study period., Main Outcomes and Measures: The primary outcome was hospital admission with CDI diagnosis. The secondary outcomes included all-cause death, intensive care unit admission, acute kidney injury requiring dialysis, and fulminant CDI comprising any of the following: toxic megacolon, ileus, perforation, or colectomy. The association between short- vs long-term mortality (ie, death occurring within or after 90 days post-CDI) and the following variables was evaluated: age, sex, Deyo-Charlson Comorbidity Index, SOT type, early- vs late-onset CDI, fulminant CDI, intensive care unit admission, and acute kidney injury requiring acute dialysis., Results: Overall, 10 724 SOT recipients (6901 [64.4%] men; median age, 54 [IQR, 44-62] years) were eligible. Kidney transplant was the most common SOT type (6453 [60.2%]). The median follow-up time was 5.0 (IQR, 2.3-8.8) years, resulting in 61 987 person-years of follow-up. A total of 726 patients (6.8%) were hospitalized with CDI. The 1-year CDI incidence significantly increased in annual cohorts (ie, from 23.1; 95% CI, 12.8-41.8 per 1000 person-years in 2004 to 46.7; 95% CI, 35.0-62.3 per 1000 person-years in 2017; P = .001). Clostridioides difficile was associated with a 16.8% rate (n = 122) of 90-day mortality. In patients who underwent kidney transplant, CDI was typically late-onset (median interval, 2.2; IQR, 0.4-6.0 years) compared with recipients of other organs. Acute kidney injury requiring dialysis was significantly associated with short-term (adjusted odds ratio [aOR], 1.86; 95% CI, 1.07-3.26) and long-term (adjusted hazard ratio [aHR], 1.89; 95% CI, 1.29-2.78) mortality, and late-onset CDI was also significantly associated with a greater risk of short-term (aOR, 4.26; 95% CI, 2.51-7.22) and long-term (aHR, 2.49; 95% CI, 1.78-3.49) mortality., Conclusions and Relevance: In this study, increasing CDI trends in annual cohorts of SOT recipients were observed. Posttransplant CDI was associated with mortality, and late-onset CDI was associated with a greater risk of death than early-onset CDI. These findings suggest that preventive strategies should not be limited to the initial months following transplantation. Comprehensive therapeutic approaches targeting acute kidney injury risk factors in SOT recipients may reduce short- and long-term post-CDI mortality.

Background: Posttransplant lymphoproliferative disorder (PTLD) is a severe complication after kidney transplantation. This study examined the incidence, risk factors, clinical management, and outcomes of PTLD in a cohort of kidney transplant recipients., Design: This single-center cohort study included 1642 patients transplanted from January 1, 2000, to December 31, 2012, with follow-up until December 31, 2013. The incidence and risk factors for PTLD were examined using a Cox proportional hazards model. A Cox model was also used to assess the association of PTLD and graft outcomes., Results: Sixteen recipients developed PTLD over follow-up. The incidence rate was 0.18 (95% confidence interval [CI]: 0.11-0.29) cases per 100 person-years. Four were from Epstein-Barr virus (EBV) mismatched (D+/R-) transplants and 12 from EBV-positive recipients (R+). Recipients with D+/R- matches were at a significantly higher risk of developing PTLD than R+ (hazard ratio [HR]: 7.52 [95% CI: 2.42-23.32]). Fifteen cases had immunosuppression reduced, 11 cases were supplemented with rituximab or ganciclovir, 6 cases required chemotherapy or radiation, and 6 cases had tumors excised. By the end of follow-up, 6 patients went into remission, 5 returned to chronic dialysis, and 5 patients died. Patients with PTLD were significantly more likely to have total graft failure (return to chronic dialysis, preemptive retransplant, or death with graft function) than patients without PTLD (HR: 3.41 [95% CI: 1.72-6.78)., Discussion: Epstein-Barr virus mismatch continues to be a strong risk factor for developing PTLD after kidney transplantation. Recipients with PTLD have a poor prognosis, as the optimal management remains to be elucidated.

Background: Tuberculosis (TB) is a significant opportunistic infection in solid organ transplant recipients (SOTR). There are limited data on TB incidence in transplantation from low prevalence countries as well as on long-term TB-specific immune responses., Methods: We performed a single-center retrospective review of SOTR diagnosed with active TB between 2000 and 2015 and further contacted the available patients for a study of long-term T-cell responses using an interferon-gamma (IFN-γ) release assay and a flow cytometry-based assay., Results: We identified 31 SOTR with active TB for an incidence of 62 cases/100 000 patient-years. Nineteen (61.3%) of 31 patients were diagnosed within the first year after transplant. Nineteen (61.3%) were born in countries with high TB prevalence and disseminated disease occurred in 22.6%. No patient had been screened for latent TB infection pretransplant. The majority of patients received isoniazid and a rifamycin as part of multidrug regimen. In addition, 13 (44.8%) of 29 patients received quinolones. One-year mortality in this population was 19.4%. Eight patients were available for long-term immune responses. Of these, all had detectable IFN-γ response by IFN-γ release assay testing and 7 of 8 had detectable TB-specific T cells, primarily central and effector T-cell responses in the CD4 compartment and terminally differentiated T cells in the CD8 compartment., Conclusions: TB has high incidence in SOTR even in low-prevalence regions but especially targets patients who originated from TB-endemic countries. Long-term TB-specific T-cell responses were found in the majority of patients.

Background: Kidney transplant recipients (KTR) may be at increased risk for Clostridium difficile infections (CDI) but risk factors and outcomes in this population have not been well studied., Methods: An observational cohort study was conducted to determine the incidence, risk factors, and outcomes of CDI in KTR. A total of 1816 KTR transplanted between 2000 and 2013 at the Toronto General Hospital were included. Sixty-eight patients developed CDI. Controls were selected at a 4:1 ratio using risk-set sampling, and risk factors were explored using conditional logistic regression models. The impact of CDI on graft outcomes was evaluated using Cox proportional hazards models., Results: The incidence rate of CDI was 0.64 cases/100 person-years. Independent predictors of CDI included antibiotic use (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.35-6.15), increased duration of hospitalization posttransplant (OR, 1.04; 95% CI, 1.02-1.06]), receiving a deceased donor kidney (OR, 2.98; 95% CI, 1.47-6.05), and a history of biopsy-proven acute rejection (OR, 5.82; 95% CI, 2.22-15.26). In the Cox proportional hazards model, CDI was found to be an independent risk factor for the subsequent development of biopsy-proven acute rejection (hazard ratio, 2.18; 95% CI, 1.34-3.55)., Conclusions: Our results confirm that transplant-specific factors place KTR at a higher risk for CDI. Clostridium difficile infections may increase the risk of adverse outcomes, such as biopsy-proven acute rejection. These findings emphasize the importance of preventive strategies to reduce the morbidity associated with CDI in KTR.

Background: Reactivation of human herpesvirus (HHV)-6 and HHV-7 has been linked to various posttransplant adverse events through immunomodulatory effects. The potential utility of monitoring for HHV-6 and HHV-7 viremia remains unclear., Methods: In this clinical trial, 129 liver transplant recipients were randomized to be monitored in real-time for HHV-6 and HHV-7 viremia by polymerase chain reaction at regular intervals from 0 to 12 weeks after transplantation ("monitoring" group) or to undergo usual care ("no-monitoring" group). Therapeutic intervention for a positive polymerase chain reaction result included reduction in immunosuppression and preemptive antiviral therapy, at the discretion of the attending team. The primary outcome was a composite of adverse events indirectly attributable to viral reactivation (including opportunistic infection, graft rejection and severe hepatitis C virus recurrence)., Results: In the "monitoring" group, HHV-6 and HHV-7 viremia occurred in 23 of 64 patients (35.9%) and 21 of 64 patients (32.8%) patients, respectively. We found no cases of symptomatic HHV-6 and HHV-7 disease. Some therapeutic interventions were performed in 59.1% of viremic episodes. There were no differences in cumulative incidence of the primary outcome between the "monitoring" and "no-monitoring" groups at 1 year (58.7% vs. 52.3%; odds ratio, 0.77; 95% confidence interval, 0.38-1.55) or at 5 years after transplantation (79.0% vs. 70.3%; odds ratio, 0.63; 95% confidence interval, 0.28-1.42). However, we found a trend toward a lower incidence of graft rejection at year 1 in the "monitoring" group (30.2% vs. 44.6%; P=0.091)., Conclusion: In this first trial, no benefit could be demonstrated from routine monitoring of HHV-6 and HHV-7 viremia in graft or patient outcome after liver transplantation.

Background: CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play a role in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs., Methods: In a prospective study of 85 LTRs, expression of cytokines (tumor necrosis factor, interferon-γ, interleukin [IL]-6, IL-8, IL-15, IL-16, IL-17, CXCL10 [IP-10], and MCP-1 [CCL2]) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection ("Infect"; n=25), concomitant "Infect+ACR" (n=10), and "No Infect and No ACR" (n=154) were analyzed., Results: The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR compared with the "No Infect and No ACR" group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [P=0.001] and IL-16: 472.1 vs. 283.01 pg/mL [P=0.01]). However, in a linear mixed-effects model, significant association was found only between CXCL10 (IP-10) and ACR. A one-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (odds ratio, 1.4; 95% confidence interval, 1.12-1.84)., Conclusion: Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs, suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation.