Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice.

Primary Toxoplasma gondii infection is usually subclinical, but cervical lymphadenopathy or ocular disease can be present in some patients. Active infection is characterized by tachyzoites, while tissue cysts characterize latent disease. Infection in the fetus and in immunocompromised patients can cause devastating disease. The combination of pyrimethamine and sulfadiazine (pyr-sulf), targeting the active stage of the infection, is the current gold standard for treating toxoplasmosis, but failure rates remain significant. Although other regimens are available, including pyrimethamine in combination with clindamycin, atovaquone, clarithromycin, or azithromycin or monotherapy with trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone, none have been found to be superior to pyr-sulf, and no regimen is active against the latent stage of the infection. Furthermore, the efficacy of these regimens against ocular disease remains uncertain. In multiple studies, systematic screening for Toxoplasma infection during gestation, followed by treatment with spiramycin for acute maternal infections and with pyr-sulf for those with established fetal infection, has been shown to be effective at preventing vertical transmission and minimizing the severity of congenital toxoplasmosis (CT). Despite significant progress in treating human disease, there is a strong impetus to develop novel therapeutics for both the acute and latent forms of the infection. Here we present an overview of toxoplasmosis treatment in humans and in animal models. Additional research is needed to identify novel drugs by use of innovative high-throughput screening technologies and to improve experimental models to reflect human disease. Such advances will pave the way for lead candidates to be tested in thoroughly designed clinical trials in defined patient populations.

Unusual presentation of Q fever in a kidney-pancreas transplant recipient.

Q fever is uncommon in solid organ transplant (SOT) recipients. We describe a case of granulomatous lung disease as an unusual presentation of chronic Q fever in a kidney-pancreas transplant recipient.

Diagnosis and treatment of histoplasmosis in solid organ transplant patients.

PURPOSE OF REVIEW: Unlike immunocompetent hosts, solid organ transplant (SOT) recipients with posttransplant histoplasmosis (PTH) often present with disseminated disease and have an attributable mortality of approximately 10%. In this review, we discuss currently available diagnostic tests and treatment strategies in PTH. RECENT FINDINGS: None of the available tests have a 100% diagnostic accuracy. Histoplasma antigen assays are the most sensitive commercially available tests. However, crossreactivity of histoplasma antigen with aspergillus galactomannan and false positive histoplasma antigen tests because of rabbit antithymocyte globulin may cause difficulty in interpreting positive test results in transplant recipients. Molecular assays such as amplification and sequencing of 'panfungal' portions of the 28S ribosomal RNA from clinical specimens appear to be promising.Lipid formulations of amphotericin B and itraconazole are the drugs of choice in the treatment of PTH. Other extended spectrum azoles also appear to be effective, but, like itraconazole, problems with drug interactions and prolongation of the QTc interval (except for isavuconazole, which shortens the QTc interval) remain. Mycophenolate therapy is associated with severe disease and should be stopped during active disease and, if feasible, calcineurin inhibitors and steroids should be reduced. SUMMARY: A combination of various tests (culture, antigen tests, nucleic amplification tests, etc.) should be used to optimize diagnostic yield. The role of unbiased next generation sequencing for early diagnosis and newer azoles in the treatment needs to be further explored.

Toxoplasmosis in the non-orthotopic heart transplant recipient population, how common is it? Any indication for prophylaxis?

PURPOSE OF REVIEW: Unlike in orthotopic heart transplant (OHT) setting where toxoplasma prophylaxis is a standard practice in pretransplant toxoplasma seronegative recipients who have received donor hearts from seropositive donors (D+/R-), there is no consensus regarding prophylaxis in non-OHT recipients. RECENT FINDINGS: The incidence of toxoplasma disease in non-OHT recipients is less than 1% but its true burden is underestimated. Among 31 cases of toxoplasma disease reported from 2004 through 2017, renal and liver transplant recipients comprised of 90% of cases. A total of 94% of 18 recipients with known pretransplant serology were seronegative recipients (mostly D+/R-). Out of 16 recipients with adequate information, 10 (63%) and five (31%) were deemed to be donor derived and nondonor-derived primary toxoplasmosis respectively. Tissue invasive reactivation was uncommon. Almost all cases were described in patients not on prophylaxis at the time of presentation. Universal screening of donor/recipient toxoplasma serology for risk stratification is beneficial as illustrated by reports of fatal cases of toxoplasmosis due to unavailability of positive donor serology results. SUMMARY: Toxoplasma disease in non-OHT predominantly occurs in pretransplant seronegative recipients- mostly in D+/R- group and is rare in seropositive recipients. Posttransplant prophylaxis should be targeted against the high-risk D+/R- group and should be considered in seropositive recipients in whom unusually high immunosuppression is implemented. Toxoplasma serologies and PCR should be used in combination for the diagnosis of toxoplasmosis in non-OHT patients.

Histoplasmosis in transplant recipients.

Histoplasma capsulatum is a dimorphic fungus that most often causes asymptomatic infection in the immunocompetent population. In immunocompromised patients, including solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, however, it is likely to cause severe life-threatening infection. Post-transplant histoplasmosis (PTH) in SOT is uncommon with an incidence of ≤1% and is even rarer in HCT patients. The majority of PTH in SOT is diagnosed in the first 2 years following transplantation. Histoplasmosis may result from endogenous reactivation of latent infection, de novo post-transplant acquisition, and donor-derived infection. Disseminated infection is common. Fever is the most common symptom and clinical features are often nonspecific, but patients with disseminated infection may present with a septic picture. Other features, including pancytopenia and hepatosplenomegaly, may not be prominent early in the course of illness. Contemporary histoplasma antigen assays are the most sensitive tests but cross-reactivity with antigens of other fungi, including with Aspergillus galactomannan, is not uncommon. Treatment should be continued for at least a year. Histoplasma antigen levels have prognostic value and can be used to monitor the response to therapy. The attributable mortality is approximately 10%. Routine screening of donors and recipients is not currently recommended.

Leishmaniasis in solid organ and hematopoietic stem cell transplant recipients.

Leishmaniasis occurs in <1% of solid organ and hematopoietic stem cell transplant recipients in endemic countries in which transplants are performed. Visceral leishmaniasis (VL) makes up the bulk of reported cases. The onset generally occurs months after transplantation and the mode of acquisition is often impossible to determine, but de novo vector-borne infection and reactivation of inapparent infection are thought to be the principal means. The potential role of clinically inapparent donor infection is uncertain and screening is not currently recommended, nor is it recommended for recipients from endemic areas, some of whom may have detectable circulating protozoan nucleic acid. While transplant recipients with VL often present with the non-specific findings of fever and cytopenia, the additional presence of hepatosplenomegaly in patients from endemic areas should lead to a directed diagnostic evaluation with bone marrow examination and PCR testing of marrow and peripheral blood having a high yield. Management may often be complicated by the presence of concomitant infections. A lipid formulation of amphotericin B is the preferred treatment, especially for VL, but the relapse rate in transplant recipients is approximately 25%. PCR monitoring of blood for either secondary prophylaxis or preemptive therapy requires further study.

Significance of a Positive Toxoplasma Immunoglobulin M Test Result in the United States.

A positive Toxoplasma immunoglobulin M (IgM) result is often interpreted as a marker of an acute infection. However, IgM can persist for several years, and Toxoplasma commercial IgM diagnostic test kits can yield a number of false-positive results. For these reasons, a chronic Toxoplasma infection can be erroneously classified as an acute infection, resulting in serious adverse consequences, especially in pregnant women, leading to emotional distress and unnecessary interventions, including termination of pregnancy. Interpretation of Toxoplasma serology at a reference laboratory can help differentiate a recently acquired infection from a chronic infection. Serological test results for 451 patients with positive Toxoplasma IgM and IgG test results obtained at nonreference laboratories (NRLs) that were referred to Palo Alto Medical Foundation Toxoplasma Serology Laboratory (PAMF-TSL) to determine whether the patient was acutely or chronically infected were retrospectively reviewed. PAMF-TSL results established that of the 451 patients, 335 (74%) had a chronic infection, 100 (22%) had an acute infection, and 7 (2%) were not infected, and for 9 (2%), results were indeterminate. Positive Toxoplasma IgM and IgG test results obtained at NRLs cannot accurately distinguish between acute and chronic infections. To do so, testing at reference laboratories is required, as mandated in 1997 in a letter from the Food and Drug Administration (FDA) to clinicians and laboratories in the United States.

Toxoplasma prophylaxis in haematopoietic cell transplant recipients: a review of the literature and recommendations.

PURPOSE OF REVIEW: Toxoplasmosis in haematopoietic cell transplant (HCT) recipients is associated with high morbidity and mortality rates. Prophylaxis following HCT is recommended for high-risk pre-HCT toxoplasma-seropositive (pre-HCTSP) recipients. However, there is no agreement or consistency among programmes on whether to adopt prophylaxis or not, or if used, on the chosen antitoxoplasma prophylactic regimen. This review discusses the role of prophylaxis, and preemptive treatment, for toxoplasmosis in the setting of HCT. RECENT FINDINGS: Approximately two-thirds of toxoplasmosis cases following HCT are reported in allogeneic pre-HCTSP (allo pre-HCTSP) patients. This finding confirms a major role of reactivation of latent infection in the pathogenesis of toxoplasmosis in this patient population. Toxoplasma disease-related mortality in allo pre-HCTSP patients was reported at 62%, but it can be significantly decreased with early detection and treatment of toxoplasma infection. There are no randomized trials comparing the efficacy of different prophylactic agents to prevent toxoplasmosis after HCT. Several observational studies have demonstrated the efficacy of trimethoprim-sulfamethoxazole (TMP/SMX) in decreasing the incidence of toxoplasmosis following HCT. There is limited information regarding efficacy of other prophylactic agents. Preemptive treatment using routine blood PCR monitoring seems to be beneficial in detecting infection early and preventing disease in several observational studies and has been adopted for allo pre-HCTSP HCT patients when universal prophylaxis is not possible. SUMMARY: Universal prophylaxis with TMP/SMX in allo pre-HCTSP patients should be implemented by all transplant programmes. Preemptive treatment with routine blood PCR monitoring is an option if prophylaxis cannot be used.

Radiation therapy for cT1-2 carcinoma of the palatine tonsil diagnosed via a simple tonsillectomy: Dosimetry and patterns of care in the IMRT era.

OBJECTIVE: Small carcinomas of the palatine tonsil are often diagnosed via simple tonsillectomy, a maneuver with non-therapeutic intent. Herein, practice patterns for this unique situation are evaluated. PATIENTS AND METHODS: A retrospective review was performed across 10 facilities to identify patients with cT1-2 squamous carcinomas of the tonsil diagnosed by simple tonsillectomy between 2010 and 2018. Patients who received curative-intent intensity modulated radiotherapy (IMRT) without additional surgery were included. Target volumes were reviewed, and cumulative incidences of local failure and severe late dysphagia were calculated. RESULTS: From 638 oropharyngeal patients, 91 were diagnosed via simple tonsillectomy. Definitive IMRT with no additional surgery to the primary site was utilized in 57, and three with gross residual disease were excluded, leaving 54 for analysis. Margins were negative in 13%, close (<5 mm) in 13%, microscopically positive in 61%, and not reported in 13%. Doses typically delivered to gross disease (68-70.2 Gy in 33-35 fx or 66 Gy/30 fx) were prescribed to the tonsil bed in 37 (69%). Sixteen patients (29%) received doses from 60 to 66 Gy (≤2 Gy/fx) and one received 50 Gy (2 Gy/fx). No local failures were observed. One late oropharyngeal soft tissue ulcer occurred, treated conservatively (grade 2). At five years, the cumulative incidence of severe late dysphagia was 17.4% (95% CI 6.1-28.8%). CONCLUSION: Small tonsil carcinomas diagnosed by simple tonsillectomy represent a niche subset with favorable oncologic outcomes. Regardless, radiation oncologists tend to deliver full-dose to the tonsil bed. The necessity of this routine could be questioned in the modern era.

Volumetric Modulated Arc Therapy (VMAT) Craniospinal Irradiation (CSI) for Children and Adults: A Practical Guide for Implementation.

PURPOSE: Volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) has been shown to have significant dosimetric advantages compared to 3-dimensional conformal therapy but is a technically complex process. We sought to develop a guide for all aspects of the VMAT CSI process and report patient dosimetry results. METHODS AND MATERIALS: We initiated VMAT CSI in 2017 and have regularly revised our standard operating procedure for this process since then. Herein, we report a detailed template for the entire VMAT CSI process from initial patient setup and immobilization at time of computed tomography (CT) simulation to contouring and treatment planning, quality assurance, and therapy delivery. The records of 12 patients who were treated with VMAT CSI were also retrospectively reviewed. RESULTS: Patient age ranged from 2 to 59 years with 5 pediatric patients (age <18 years), 5 young adults (age 18-35 years), and 2 older adults (age >35 years). The majority of patients (67%) had medulloblastoma. CSI dose ranged from 21.6 to 36 Gy, with a median of 36 Gy. The median CSI planning target volume was 2383 cc with a median V95% of 99.8% and median 0.03 cc hotspot of 112.5%. The average V107% was 7.4% and the average conformality index was 1.01. CONCLUSIONS: VMAT CSI has potentially significant dosimetric and acute toxicity advantages compared to 3-dimensional conformal. However, proper procedures need to be in place throughout the process in order to be able to realize these potential advantages. We herein describe our detailed standard operating procedure for VMAT CSI. Recognizing the scarcity of proton beam centers in many areas, VMAT CSI represents a feasible treatment with more widespread availability.

Implementation, adherence, and results of systematic SARS-CoV-2 testing for asymptomatic patients treated at a tertiary care regional radiation oncology network.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus is a current pandemic. We initiated a program of systematic SARS-CoV-2 polymerase chain reaction (PCR) testing in all asymptomatic patients receiving radiotherapy (RT) at a large radiation oncology network in the Charlotte, NC metropolitan region and report adherence and results of the testing program. METHODS: Patients undergoing simulation for RT between May 18, 2020 and July 10, 2020 within the Levine Cancer Institute radiation oncology network who were asymptomatic for COVID-19 associated symptoms, without previous positive SARS-CoV-2 testing, and without recent high-risk contacts were included. PCR testing was performed on nasal cavity or nasopharyngeal swab samples. Testing was performed within 2 weeks of RT start (pre-RT) and at least every 4 weeks during RT for patients with prolonged RT courses (intra-RT). An automated task based process using the oncology electronic medical record (EMR) was developed specifically for this purpose. RESULTS: A total of 604 unique patients were included in the cohort. Details on testing workflow and implementation are described herein. Pre-RT PCR testing was performed in 573 (94.9%) patients, of which 4 (0.7%) were positive. The adherence rate to intra-RT testing overall was 91.6%. Four additional patients (0.7%) tested positive during their RT course, of whom 3 were tested due to symptom development and 1 was asymptomatic and identified via systematic testing. A total of 8 (1.3%) patients tested positive overall. There were no known cases of SARS-CoV-2 transmission from infected patients to clinic staff and/or other patients. CONCLUSIONS: We detailed the workflows used to implement systematic SARS-CoV-2 for asymptomatic patients at a large radiation oncology network. Adherence rates for pre-RT and intra-RT testing were high using this process. This information allowed for appropriate delay in initiating RT, minimizing the occurrence of RT treatment interruptions, and no known cases of transmission from infected patients to clinic staff and/or other patients.

The Association Between Radiation Therapy Dose and Overall Survival in Patients With Intracranial Infiltrative Low-Grade Glioma Treated With Concurrent and/or Adjuvant Chemotherapy.

PURPOSE: Previous trials have shown no benefit for radiation therapy (RT) dose escalation when RT is given as adjuvant monotherapy for infiltrative low-grade glioma (LGG). However, the current standard of care for high-risk LGG is RT with concurrent and/or adjuvant chemotherapy. The effect of RT dose escalation on overall survival (OS) in the setting of concurrent and/or adjuvant chemotherapy is not well established. METHODS AND MATERIALS: We used the National Cancer Database to select records for adult patients with intracranial grade 2 LGG diagnosed between 2004 and 2015. Patients must have received adjuvant external beam RT with concurrent and/or adjuvant chemotherapy. RT dose level was categorized as standard (45-54 Gy) or high (>54-65 Gy). Multivariable and propensity score matched analyses were used. RESULTS: The study cohort consisted of 1043 patients, of whom 644 (62%) received standard dose (median, 54 Gy) and 399 (38%) received high-dose RT (median, 60 Gy). RT dose level was not associated with OS (hazard ratio, 1.2; P = .1) in multivariable analysis. Propensity score matching yielded 380 matched pairs (n = 760). There was no difference in OS for high-dose versus standard-dose RT in the matched cohort (5-year OS 64% vs 69%; P = .14) or in the 2 prespecified subgroups of astrocytoma histology and 1p/19q noncodeleted. CONCLUSIONS: Adjuvant RT dose escalation above 54 Gy in the setting of concurrent and/or adjuvant chemotherapy was not associated with improved OS for patients with infiltrative LGG in this National Cancer Database retrospective study. This was also true for the subgroups with less chemotherapy-sensitive disease, including astrocytoma histology and 1p/19q noncodeleted, although these analyses were limited by small size. Methods to improve OS other than RT dose escalation in the setting of concurrent and/or adjuvant chemotherapy should be considered for patients with poor-prognosis LGG.

Preoperative Radiosurgery for Resected Brain Metastases: The PROPS-BM Multicenter Cohort Study.

PURPOSE: Preoperative radiosurgery (SRS) is a feasible alternative to postoperative SRS, with potential benefits in adverse radiation effect (ARE) and leptomeningeal disease (LMD) relapse. However, previous studies are limited by small patient numbers and single-institution designs. Our aim was to evaluate preoperative SRS outcomes and prognostic factors from a large multicenter cohort (Preoperative Radiosurgery for Brain Metastases [PROPS-BM]). METHODS AND MATERIALS: Patients with brain metastases (BM) from solid cancers who had at least 1 lesion treated with preoperative SRS and underwent a planned resection were included from 5 institutions. SRS to synchronous intact BM was allowed. Radiographic meningeal disease (MD) was categorized as either nodular or classical "sugarcoating" (cLMD). RESULTS: The cohort included 242 patients with 253 index lesions. Most patients (62.4%) had a single BM, 93.7% underwent gross total resection, and 98.8% were treated with a single fraction to a median dose of 15 Gray to a median gross tumor volume of 9.9 cc. Cavity local recurrence (LR) rates at 1 and 2 years were 15% and 17.9%, respectively. Subtotal resection (STR) was a strong independent predictor of LR (hazard ratio, 9.1; P < .001). One and 2-year rates of MD were 6.1% and 7.6% and of any grade ARE were 4.7% and 6.8% , respectively. The median overall survival (OS) duration was 16.9 months and the 2-year OS rate was 38.4%. The majority of MD was cLMD (13 of 19 patients with MD; 68.4%). Of 242 patients, 10 (4.1%) experienced grade ≥3 postoperative surgical complications. CONCLUSIONS: To our knowledge, this multicenter study represents the largest cohort treated with preoperative SRS. The favorable outcomes previously demonstrated in single-institution studies, particularly the low rates of MD and ARE, are confirmed in this expanded multicenter analysis, without evidence of an excessive postoperative surgical complication risk. STR, though infrequent, is associated with significantly worse cavity LR. A randomized trial between preoperative and postoperative SRS is warranted and is currently being designed.

The effect of adjuvant radiotherapy on overall survival in adults with intracranial ependymoma.

BACKGROUND: Adult intracranial ependymoma is rare, and the role for adjuvant radiotherapy (RT) is not well defined. METHODS: We used the National Cancer Database (NCDB) to select adults (age ≥ 22 years) with grade 2 to 3 intracranial ependymoma status postresection between 2004 and 2015 and treated with adjuvant RT vs observation. Four cohorts were generated: (1) all patients, (2) grade 2 only, (3) grade 2 status post-subtotal resection only, (4) and grade 3 only. The association between adjuvant RT use and overall survival (OS) was assessed using multivariate Cox and propensity score matched analyses. RESULTS: A total of 1787 patients were included in cohort 1, of which 856 patients (48%) received adjuvant RT and 931 (52%) were observed. Approximately two-thirds of tumors were supratentorial and 80% were grade 2. Cohorts 2, 3, and 4 included 1471, 345, and 316 patients, respectively. There was no significant association between adjuvant RT use and OS in multivariate or propensity score matched analysis in any of the cohorts. Older age, male sex, urban location, higher comorbidity score, earlier year of diagnosis, and grade 3 were associated with increased risk of death. CONCLUSIONS: This large NCDB study did not demonstrate a significant association between adjuvant RT use and OS for adults with intracranial ependymoma, including for patients with grade 2 ependymoma status post-subtotal resection. The conflicting results regarding the efficacy of adjuvant RT in this patient population highlight the need for high-quality studies to guide therapy recommendations in adult ependymoma.