Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.

Pathological perspectives in pilocytic astrocytomas: Extent of resection as the sole critical factor for recurrence-free survival, and the challenge of evaluating conclusions derived from limited data.

Introduction: Pilocytic astrocytoma (PA) is one of the most common primary intracranial neoplasms in childhood with an overall favorable prognosis. Despite decades of experience, there are still diagnostic and treatment challenges and unresolved issues regarding risk factors associated with recurrence, most often due to conclusions of publications with limited data. We analyzed 499 patients with PA diagnosed in a single institution over 30 years in order to provide answers to some of the unresolved issues. Materials and Methods: We identified pilocytic astrocytomas diagnosed at the University of California, San Francisco, between 1989 and 2019, confirmed the diagnoses using the WHO 2021 essential and desirable criteria, and performed a retrospective review of the demographic and clinical features of the patients and the radiological, pathologic and molecular features of the tumors. Results: Among the patients identified from pathology archives, 499 cases fulfilled the inclusion criteria. Median age at presentation was 12 years (range 3.5 months - 73 years) and the median follow-up was 78.5 months. Tumors were predominantly located in the posterior fossa (52.6%). There were six deaths, but there were confounding factors that prevented a clear association of death to tumor progression. Extent of resection was the only significant factor for recurrence-free survival. Recurrence-free survival time was 321.0 months for gross total resection, compared to 160.9 months for subtotal resection (log rank, p <0.001). Conclusion: Multivariate analysis was able to identify extent of resection as the only significant variable to influence recurrence-free survival. We did not find a statistically significant association between age, NF1 status, tumor location, molecular alterations, and outcome. Smaller series with apparently significant results may have suffered from limited sample size, limited variables, acceptance of univariate analysis findings as well as a larger p value for biological significance. PA still remains a predominantly surgical disease and every attempt should be made to achieve gross total resection since this appears to be the most reliable predictor of recurrence-free survival.

Cytomegalovirus reactivation in a critically ill patient: a case report.

BACKGROUND: The aim of this case report is to discuss diagnostic workup and clinical management of cytomegalovirus reactivation in a critically ill immunocompetent pediatric patient. CASE PRESENTATION: A 2-year-old white boy who had no medical history presented with respiratory distress and fever. His Pediatric Risk of Mortality and Pediatric Logistic Organ Dysfunction scores were 20 and 11, respectively. Our preliminary diagnosis was multiple organ dysfunction secondary to sepsis. Antibiotic treatment was started; he was intubated and artificially ventilated. Norepinephrine infusion was started. Hemophagocytic lymphohistiocytosis was diagnosed because our patient had elevated levels of serum ferritin, bicytopenia, splenomegaly, fever (> 38.5 °C), and hemophagocytosis shown in a bone marrow sample. Therapeutic plasma exchange and intravenously administered high-dose corticosteroid for hemophagocytic lymphohistiocytosis and continuous renal replacement treatment for acute renal failure were initiated. Following 5-day high-dose corticosteroid administration, therapeutic plasma exchange, and continuous renal replacement treatment, his clinical status and kidney and liver functions improved, and vasoactive requirement and ferritin levels decreased. He was extubated on the seventh day. On the tenth day of hospitalization he had a seizure and was diagnosed as having septic encephalopathy. His immune functions were found to be normal. Although his medical condition improved continuously, he had left spontaneous pneumothorax on the 21st day of admission as a complication of necrotizing pneumonia. Since pneumothorax persisted, left upper lobectomy surgery was performed on the 30th day of hospitalization. In the pathological examination of the excised lung tissue, features of cytomegalovirus infection were observed. Ganciclovir treatment was started. Serological tests indicated that our patient had cytomegalovirus reactivation. Antiviral treatment was stopped after 17 days, when cytomegalovirus deoxyribonucleic acid (DNA) polymerase chain reaction results became negative. He fully recovered and was discharged on the 50th day of admission. CONCLUSIONS: Cytomegalovirus reactivation in critically ill patients is a prevalent problem and shown to be associated with higher mortality and morbidity. In a case of serologic detection of cytomegalovirus reactivation without any clinical sign of infection, pre-emptive treatment could be considered with assessment of risks and benefits for each patient. Antiviral therapy is highly recommended for patients who have risk factors identified.