Evolution of germline TP53 variant classification in children with cancer.

Li-Fraumeni syndrome, caused by germline pathogenic variants in TP53, results in susceptibility to multiple cancers. Variants of uncertain significance (VUS) and reclassification of variants over time pose management concerns given improved survival with cancer surveillance for LFS patients. We describe the experience of TP53 variant reclassification at a pediatric cancer center. METHODS: We reviewed medical records (2010-2019) of 756 patients seen in Texas Children's Cancer Genetics Clinic. We noted initial TP53 classification and any reclassifications. We then classified TP53 variants following ClinGen TP53 variant curation expert panel recommendations using data from ClinVar, medical literature and IARC database. RESULTS: Of 234 patients tested for TP53, 27 (11.5%) reports contained pathogenic/likely pathogenic (P/LP) variants and 7 (3)% contained VUS. By January 2022, 4 of 6 unique VUS and 2 of 16 unique P/LP variants changed interpretations in ClinVar. Reinterpretation of these 4 VUS in ClinVar matched clinical decision at the time of initial report. Applying TP53 VCEP specifications classified 3 VUS to P/LP/benign, and one pathogenic variant to likely benign. CONCLUSIONS: Planned review of variant significance is essential, especially for patients with high probability of LFS.

In-vitro activity of cefepime and other broad-spectrum antimicrobials against several groups of gram-negative bacilli and Staphylococcus aureus.

The in vitro activity of cefepime was compared with that of amikacin, ceftazidime, imipenem, ciprofloxacin, and piperacillin-tazobactam by using the E-test against five groups of carefully selected organisms: Klebsiella pneumoniae (68 isololates), Pseudomonas aeruginosa (62), methicillin-susceptible Staphylococcus aureus (MSSA) (60), and two groups of Enterobacteriaceae (60 and 62 isolates, respectively). The bacteria were subdivided according to whether the infection was nosocomial or community-acquired, applying accepted and predefined criteria. These isolates were obtained from patients admitted to our medical center throughout 1998. We retrospectively compared antimicrobial susceptibilities of the study sample with those of the +/- 3000 bacterial strains isolated from blood stream infections since 1990: the study sample appeared to represent adequately the clinical databank. Presence of extended-spectrum beta-lactamase (ESBL) was determined in all groups of Enterobacteriaceae with the ESBL screening E-test strip. Of the 252 Gram-negative bacilli tested, 242 (96%) were susceptible to cefepime, whereas only 168 (67%) were susceptible to ceftazidime, 211 (84%) to amikacin, and 220 (87%) to piperacillin-tazobactam (p < 0.001). Imipenem was slightly superior to cefepime with only seven isolates resistant (3%), six of which were P. aeruginosa. Cefepime was more active against Enterobacteriaceae than ceftazidime (93% vs. 72%, p < 0.001). This superiority was most evident against nosocomial strains of K. pneumoniae, against which cefepime was > three times more active than ceftazidime. The high level of resistance seen in nosocomial isolates of K. pneumoniae is consistent with high rates of ESBL production (69%, compared with 15-26% in other Enterobacteriaceae). The MIC90 of cefepime to methicillin-sensitive S. aureus was 1.5 micrograms/mL, whereas that of ceftazidime was 4 micrograms/mL; the susceptibility rate of both was 100%. In conclusion, cefepime possesses in vitro potencies against MSSA and current clinical strains of Gram-negative bacilli, many of which harbor resistance to other antimicrobial agents. Hence, it seems very suitable for empiric coverage of serious nosocomial infections.

Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.