Impacts of the Inflation Reduction Act on the Economics of Clean Hydrogen and Synthetic Liquid Fuels.

The Inflation Reduction Act (IRA) in the United States provides unprecedented incentives for deploying low-carbon hydrogen and liquid fuels, among other low-greenhouse gas (GHG) emissions technologies. To better understand the prospective competitiveness of low-carbon or negative-carbon hydrogen and liquid fuels under the IRA in the early 2030s, we examined the impacts of the IRA provisions on the costs of producing hydrogen and synthetic liquid fuel made from natural gas, electricity, short-cycle biomass (agricultural residues), and corn-derived ethanol. We determined that, with IRA credits (45V or 45Q) but excluding the incentives provided by other national or state policies, hydrogen produced by electrolysis using carbon-free electricity (green H2) and by natural gas reforming with carbon capture and storage (CCS) (blue H2) is cost-competitive with the carbon-intensive benchmark gray H2, which is produced by steam methane reforming. Biomass-derived H2 with or without CCS is not cost-competitive under the current IRA provisions. However, if the IRA allowed biomass gasification with CCS to claim a 45V credit for carbon-neutral H2 and a 45Q credit for negative biogenic CO2 emissions, this pathway would be less costly than gray H2. The IRA credit for clean fuels (45Z), currently stipulated to end in 2027, would need to be extended or similar policy support would need to be provided by other national or state policies in order for clean synthetic liquid fuel to be cost-competitive with petroleum-derived liquid fuels. The levelized IRA subsidies per unit of CO2 mitigated for all of the hydrogen and synthetic liquid fuel production pathways, except for electricity-derived synthetic liquid fuel, range from $65-$384/t of CO2. These values are within or below the range of the U.S. federal government's estimates of the social cost of carbon (SCC) in the 2030-2040 time frame.

Emissions and energy impacts of the Inflation Reduction Act.

Economy-wide emissions drop 43 to 48% below 2005 levels by 2035 with accelerated clean energy deployment.

Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies.

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml-1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future.

The state of macro-energy systems research: Common critiques, current progress, and research priorities.

The growing field of macro-energy systems (MES) brings together the interdisciplinary community of researchers studying the equitable and low-carbon future of humanity's energy systems. As MES matures as a community of scholars, a coherent consensus about the key challenges and future directions of the field can be lacking. This paper is a response to this need. In this paper, we first discuss the primary critiques of model-based MES research that have emerged because MES was proposed as a way to unify related interdisciplinary research. We discuss these critiques and current efforts to address them by the coalescing MES community. We then outline future directions for growth motivated by these critiques. These research priorities include both best practices for the community and methodological improvements.

18F-FDG Uptake During Early Adjuvant Chemotherapy Predicts Histologic Response in Pediatric and Young Adult Patients with Osteosarcoma.

The purpose of this study was to determine the relationship of 18F-FDG uptake in the primary tumor at diagnosis, during therapy, and after therapy with a histologic response and event-free survival in pediatric and young adult patients with osteosarcoma (OS). Methods: Serial (baseline and 5 and 10 wk after start of therapy) 18F-FDG PET/CT imaging was performed in patients with newly diagnosed OS treated uniformly in a therapeutic trial at a single institution. Whole-body images were obtained approximately 1 h after injection of 18F-FDG. Logistic regression was used to study the association of tumor uptake and changes in SUVmax between 0, 5, and 10 wk for both clinical endpoints. Results: Thirty-four patients (17 males; median age, 12.2 y; age range, 6.8-19.1 y) underwent PET imaging; 25 (74%) had localized disease. Primary tumor locations included the femur (n = 17; 50%), tibia (n = 9; 26%), and humerus (n = 5; 15%). Logistic regression showed that SUVmax at 5 wk (P = 0.034) and 10 wk (P = 0.022) and percentage change from baseline at 10 wk (P = 0.021) were highly predictive of a histologic response. Using SUVmax of 4.04 at week 5, SUVmax of 3.15 at week 10, and 60% decrease from baseline at week 10 as cutoff values, we determined that the respective sensitivities were 0.93, 0.93, and 0.79 and that the respective specificities were 0.53, 0.71, and 0.76. Conclusion: SUVmax on routine images at 5 or 10 wk and percentage change in SUVmax from baseline to week 10 were metabolic predictors of a histologic response in OS. These findings may be useful in the early identification of patients who are responding poorly to therapy and may benefit from a change in treatment.

Pediatric cancer pathology review from a single institution: Neuropathology expert opinion is essential for accurate diagnosis of pediatric brain tumors.

BACKGROUND AND OBJECTIVES: Second pathology review has been reported to improve accuracy in oncologic diagnoses, including pediatric malignancies. We assessed the impact of second review on the diagnosis of pediatric malignancies at a tertiary care referral center in Beirut, Lebanon. METHODS: Pathology reports of patients treated at the Children's Cancer Institute in Lebanon were retrospectively reviewed for the period 2008-2016 and compared with same samples' diagnoses at St. Jude Children's Research Hospital. Diagnostic disagreements were divided into major, minor, and none based on their effect on diagnosis and/or patient management. RESULTS: Second review was requested for 171 cases, accounting for 19% of all cases during that period. Second opinion was mostly requested for brain tumors (62% of all brain tumor cases) and neuroblastoma for NMYC testing (65% of all neuroblastoma), while hematologic malignancies had the fewest referrals (3% of all hematologic cases). Major disagreements in second review occurred in 20 cases (12% of total), and minor disagreements in 21 cases (12% of total). The largest proportion of major disagreements (71%) occurred in pediatric brain tumors, and novel molecular tests contributed to the diagnosis in 55% of these cases. CONCLUSIONS: The availability of a specialized pediatric neuropathologist and a basic panel of relevant molecular testing are essential for appropriate diagnosis of pediatric brain tumors. Centers that do not have the available infrastructure in place can benefit greatly from second review referrals for this challenging subset of tumors.

Genomic landscape of paediatric adrenocortical tumours.

Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis.

Safety and diagnostic accuracy of tumor biopsies in children with cancer.

BACKGROUND: Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In the current study, the authors sought to evaluate the safety and accuracy of biopsies in children with cancer. METHODS: All biopsies performed in children at the study institution with a suspected or established diagnosis of cancer from 2003 through 2012 were reviewed retrospectively. Patient characteristics and disease-related and procedure-related factors were correlated with procedure-related complications and diagnostic accuracy using logistic regression analysis. RESULTS: A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 (7.7%) were associated with an adverse event, 35 (3.4%) of which were minor (grade 1-2) and 32 (3.1%) of which were major (grade 3-4) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The most common major adverse events were blood transfusion (>10 mL/kg; 24 cases) and infection requiring intravenous antibiotics (6 cases). Eleven deaths (1.4%) occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies (90.3%) provided definitive histologic diagnoses. Using multivariable analysis, biopsy site, preprocedure hematocrit level, and body mass index were found to be associated with the risk of postprocedural complications (P<.0001, P<.0001, and P =.0029, respectively). Excisional biopsy and biopsy site were found to be independently associated with obtaining a diagnostic result (P =.0002 and P =.0008, respectively). CONCLUSIONS: Tumor biopsies in children with cancer are associated with a low incidence of complications and a high rate of diagnostic accuracy. The predictive factors identified for adverse outcomes may aid in risk assessment and preprocedural counseling.

Subsequent malignant neoplasms in pediatric patients initially diagnosed with neuroblastoma.

BACKGROUND: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. METHODS: Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. RESULTS: Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. CONCLUSIONS: Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.

Histopathologic diagnosis of pediatric neoplasms: a review of international consultations.

CONTEXT: Correct histopathologic diagnosis is fundamental to defining proper treatment and improving outcomes in children with malignancies. The Department of Pathology at St. Jude Children's Research Hospital (SJCRH) has collaborated with SJCRH International Outreach Program partner sites to improve the accuracy of histopathologic diagnoses in countries with limited resources. Pathologists at SJCRH provide review and evaluation of cases that are considered difficult or complex. OBJECTIVES: To determine the quality of pathology diagnosis and to identify areas for improvement in our international partner sites, we retrospectively analyzed all the international cases that were submitted for review. A comparison of our data with selected reports of surgical pathology error rates published in the medical literature was performed. DESIGN: From January 2009 through December 2011, SJCRH received 763 cases submitted by international pathologists from 37 countries for histopathologic review and evaluation. Of 763 cases reviewed, 705 (92.4%) met the criteria for inclusion in this study. Rates of concordance between the submitted diagnoses and SJCRH reviewed diagnoses were analyzed. RESULTS: Overall concordance, minor disagreement, and major disagreement rates between submitted diagnoses and SJCRH reviewed diagnoses were 430 (61.0%), 98 (13.9%), and 177 (25.1%) of the cases, respectively. Major disagreement rates ranged from 13.7% to 37.1% among studied countries. CONCLUSIONS: The major disagreement rate between referring international sites and SJCRH was substantially higher than the major disagreement rate among US institutions. Lack of the availability of immunohistochemistry and the training of pathologists in the diagnosis of pediatric neoplasms may have contributed to the discrepancies.

Surgical treatment of pediatric desmoid tumors. A 12-year, single-center experience.

BACKGROUND: Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart. METHODS: A retrospective review identified 39 patients who underwent treatment of PDT at St. Jude Children's Research Hospital over a 12-year period. Clinicopathologic and treatment characteristics were analyzed to identify predictors of outcome. RESULT: A total of 39 patients were treated during the study period, with a total number of 67 resections. Median age was 12.2 years; 49 % of patients were male, and 51 % were female. Median tumor size was 9.8 cm. PDT most commonly arose in the extremities (40 %), thorax (23 %), head and neck (21 %), and trunk (16 %). Also, 18 % of resections had negative margins (R0), 48 % were microscopic positive (R1), and 30 % were macroscopic positive (R2). The 1- and 5-year recurrence-free survival (RFS) was 97.1 and 73.1 %, respectively. Factors associated with worse RFS were patient age >12 years (HR = 5.08, p = 0.038) and tumor size >5 cm (HR = 1.22, p = 0.0597). Margin status did not affect RFS. Selective use of radiation therapy appeared to improve RFS. CONCLUSIONS: Our study suggests that margin status alone at the time of extirpation is not a predictor of ultimate cure or likelihood of recurrence. Many patients received adjuvant therapy, with benefits suggested after analysis. For patients with PDT, surgical extirpation should not come at the expense of functional preservation, as overall survival is excellent.

Improving the histopathologic diagnosis of pediatric malignancies in a low-resource setting by combining focused training and telepathology strategies.

BACKGROUND: Accurate diagnosis is critical for optimal management of pediatric cancer. Pathologists with experience in pediatric oncology are in short supply in the developing world. Telepathology is increasingly used for consultations but its overall contribution to diagnostic accuracy is unknown. PROCEDURE: We developed a strategy to provide a focused training in pediatric cancer and telepathology support to pathologists in the developing world. After the training period, we compared trainee's diagnoses with those of an experienced pathologist. We next compared the effectiveness of static versus dynamic telepathology review in 127 cases. Results were compared by Fisher's exact test. RESULTS: The diagnoses of the trainee and the expert pathologist differed in only 6.5% of cases (95% CI, 1.2-20.0%). The overall concordance between the telepathology and original diagnoses was 90.6% (115/127; 95% CI, 84.1-94.6%). CONCLUSIONS: Brief, focused training in pediatric cancer histopathology can improve diagnostic accuracy. Dynamic and static telepathology analyses are equally effective for diagnostic review.

Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system.

PURPOSE: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). METHODS AND MATERIALS: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. RESULTS: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. CONCLUSIONS: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.

Dynamic contrast-enhanced magnetic resonance imaging as a prognostic factor in predicting event-free and overall survival in pediatric patients with osteosarcoma.

BACKGROUND: The objective of this study was to prospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as an early imaging indicator of tumor histologic response to preoperative chemotherapy and as a possible prognostic factor for event-free survival (EFS) and overall survival in pediatric patients with newly diagnosed, nonmetastatic osteosarcoma who were treated on a single, multi-institutional phase 2 trial. METHODS: Three serial DCE-MRI examinations at week 0 (before treatment), week 9, and week 12 (tumor resection) were performed in 69 patients with nonmetastatic osteosarcoma to monitor the response to preoperative chemotherapy. Four DCE-MRI kinetic parameters (the influx volume transfer constant [K(trans) ], the efflux rate constant [k(ep) ], the relative extravascular extracellular space [v(e) ], and the relative vascular plasma space [v(p) ]) and the corresponding differences (ΔK(trans) , Δk(ep) , Δv(e) , and Δv(p) ) of averaged kinetic parameters between the outer and inner halves of tumors were calculated to assess their associations with tumor histologic response, EFS, and overall survival. RESULTS: The parameters K(trans) , v(e) , v(p) , and k(ep) decreased significantly from week 0 to week 9 and week 12. The parameters K(trans) , v(p) , and Δk(ep) at week 9 were significantly different between responders and nonresponders (P = .046, P = .021, and P = .008, respectively). These 3 parameters were indicative of histologic response. The parameter Δv(e) at week 0 was a significant prognostic factor for both EFS (P = .02) and overall survival (P = .03). CONCLUSIONS: DCE-MRI was identified as a prognostic factor for EFS and overall survival before treatment on this trial and was indicative of a histologic response to neoadjuvant therapy. Further studies are needed to verify these findings with other treatment regimens and establish the potential role of DCE-MRI in the development of risk-adapted therapy for osteosarcoma.

Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial.

BACKGROUND: The standard treatment of osteosarcoma includes cisplatin and high-dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin-based regimens and caused less toxicity. To build on this experience, the authors conducted a multi-institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma. METHODS: Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration-time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m(2) daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m(2) daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m(2) daily ×2 days) combined with ifosfamide or carboplatin. RESULTS: A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5-year event-free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5-year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40). CONCLUSIONS: The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin-containing or HDMTX-containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX.

Childhood hemangiopericytoma: review of St Jude Children's Research Hospital.

BACKGROUND: Hemangiopericytoma (HPC) is a heterogeneous, highly vascularized malignant soft-tissue neoplasm with 2 different clinical presentations: adult-type and infantile-type HPC. Intracranial HPC represents a special subtype with a high proclivity toward recurrence and metastasis. METHODS: The authors have reviewed the clinical features, response to treatment, and outcomes of 17 patients with HPC treated at St Jude Children's Research Hospital from 1962 to 2009. RESULTS: At diagnosis, 11 patients were older than 1 year (subgroup A) and 6 patients were younger than 1 year (subgroup B). Subgroup A: median age at diagnosis 13.5 years, (range, 4 to 20 y). Primary sites were intracranial (n=5), thigh (n=3), calf (n=1), foot (n=1), and scalp (n=1). One patient who presented with a thigh HPC had metastatic disease at diagnosis, and 3 patients with head location had unresectable tumors. Two patients with thigh location experienced objective responses to chemotherapy. Six patients died of disease progression, 4 of them had an intracranial location. The remaining 5 children are alive at follow-up of 12 to 32 years. Subgroup B: median age at diagnosis 0.5 months (range, 0 to 3 mo). Primary sites were thigh (n=2), calf (n=1), perianal (n=1), forearm (n=1), and lung (n=1). Three patients with limb location had unresectable disease at diagnosis, 2 of them experienced excellent responses to neoadjuvant chemotherapy and 1 did not show any response to chemotherapy and a staged resection was performed. All 6 infants are alive without evidence of disease at follow-up of 2 to 27 years. CONCLUSIONS: Infantile HPC is characterized by a better clinical behavior than the adult type, which requires an aggressive multimodality therapy. Chemoresponsiveness and spontaneous regression have been reported in children younger than 1 year, suggesting that a more conservative surgical approach should be used. Intracranial HPC is considered as an aggressive tumor because of its propensity for recurrence and metastasis.

Characterization, treatment, and outcome of intracranial neoplasms in the first 120 days of life.

Little is known about brain tumors in early infancy. Investigators reviewed the records of 27 patients (12 boys and 15 girls) diagnosed within 120 days of birth. The median age was 66 days (range, 0-110 days) at diagnosis. All patients underwent surgery; 18 received adjuvant chemotherapy, and 3 received adjuvant chemotherapy and radiation therapy. The median follow-up was 2.1 years (range, 0.2-21.6 years). At last encounter, 15 patients were alive, and 11 had no evidence of disease. Ten patients died of progressive disease, and 2 died of treatment-related complications. All survivors experienced late effects, including endocrine, neurologic, and cognitive deficits. Of the 13 patients who completed neurocognitive assessments, 7 had an IQ score less than 70. Children in whom brain tumors arise during early infancy can be cured with conventional therapy; however, contemporary approaches can adversely affect long-term function, and families need to be aware of these effects when making therapeutic decisions.

Placental alkaline phosphatase in pediatric adrenocortical cancer.

The germline R337H mutation in the TP53 gene is considered to be responsible for the increased incidence of adrenocortical tumors (ACTs) in children from Brazil. High level production of hormones in ACTs (>95%) cause virilization alone (60%), Cushing syndrome (<5%), the mixed type (30%), or other rarer manifestations. ACT probably develops owing to events occurring during the final stages of intrauterine life based on the very common early onset of signs and symptoms shortly after birth. In this study, we determined by immunohistochemistry and enzyme assays whether placental alkaline phosphatase (PLAP) is expressed in pediatric ACTs. Immunohistochemical analysis revealed positive p53 expression in 88% of the tested ACTs (29 of 33). PLAP was detected at a slightly lower frequency based on immunohistochemical (17 of 33, 51%) and enzyme activity analyses (9 of 16, 56%). In conclusion, probably at a certain time point during adrenocortical development (end of gestation to early postnatal period), some fetal zone cells survive owing to defective apoptosis and develop into childhood ACT, maintaining some characteristics of the embryonal period, such as PLAP expression. Further studies of PLAP should investigate the functional role, if any, of PLAP in such tumors.

Cationic 1,2-Azaborine Adducts of Trimethylphosphine, Triphenylphosphine oxide, and Pyridine-N-oxide.

The first cationic 1,2-azaborine adducts of neutral phosphorous- and oxygen-based nucleophiles have been synthesized and characterized via spectroscopic and single crystal X-ray diffraction analysis.

Inherited germline TP53 mutation encodes a protein with an aberrant C-terminal motif in a case of pediatric adrenocortical tumor.

Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years. The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome. In fact, about two-thirds of children with ACT have a TP53 mutation. However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis. We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer. The lack of family history of cancer and previous information about the carcinogenic potential of the mutation led us to further characterize it. Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation. Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors.