DIAGNOSTIC VALUE OF BRONCHOALVEOLAR LAVAGE IN LEUKEMIC AND BONE MARROW TRANSPLANT PATIENTS: THE IMPACT OF ANTIMICROBIAL THERAPY

Background Pneumonia carries significant morbidity and mortality in leukemic and bone marrow transplant patient.  The development of pulmonary infiltrates in the setting of such immunocompromise raises concern for both infectious and non-infectious etiologies, some of which are potentially treatabl.  Performing bronchoscopy provides several different options for sampling the lower respiratory tract.  Among these, bronchoalveolar lavage (BAL) is especially effective at collecting samples from the alveoli and has been shown to be associated with less risk than transbonchial biops. We sought to examine the effect of antimicrobial treatment on BAL results in a large study population of leukemic and bone marrow transplant patients. Subjects and Methods This retrospective chart review was performed at a single academic cancer center.  A power analysis was performed to determine the appropriate sample size. The patients were selected from those who had undergone an inpatient bronchoscopy in reverse chronological order until 300 patients with either a hematopoietic stem cell transplant or hematologic malignancy were identified.  The exclusion criteria were age <18, a diagnosis of HIV or acquired immune deficiency syndrome (AIDS), or outpatient status.  Electronic medical records were reviewed and data extracted by a single investigator, CY.  Data including age, sex, cancer diagnosis, time from HSCT, leukocyte count, neutropenia in addition to medications were collected.  A normal white blood cell (WBC) count was considered 4,000-12,000/mm3.  Neutropenia was defined as an absolute neutrophil count (ANC) less than 500/mm3.  Medications including antibiotic duration and timing, antifungal use, immunosuppressant use or glucocorticoids were recorded. A positive BAL yield was defined as the culture identification of at least one organism known to be pathogenic in this patient population.  Candida species and coagulase negative staphylocci were considered colonizers The bronchoscopy technique and procedure was similar for each patient, utilizing a Fujinon 470S bronchoscope for every procedure The BAL specimens were collected without suction connected to the bronchoscope prior to a systematic airway survey.  The BAL was performed by instilling two 60cc aliquots of room temperature sterile 0.9% saline followed by slow manual aspiration. Correlates of a positive BAL yield and time on antibiotics were initially analyzed via a chi-square test, or a Fisher’s exact test if the expected count was less than 5.Statistical analyses were performed with Statistical Analysis Software Version 9.3. Results A total of 302 patient records were evaluated.  The age range was 18-85 with an average age of 53.5.  Thirty eight percent of the patients were female and 41.8% of the patients had undergone HSCT.  A minority of the patients required mechanical ventilation either at the time of BAL or within 48 hours. One hundred seven of the 297 patients had a positive BAL culture for an overall BAL yield of 36%.  Of the 37 patients on antibiotics for less than 24 hours, including all 4 patients who were not on any antibiotics, twenty-one (56.8%) had a positive BAL culture compared with eighty-five of the 259 (32.8%) patients who had been on antibiotics longer than 24 hours at the time the BAL specimen was obtained and had a positive cultur.  Forty-eight patients were not receiving chemotherapy or immunosupressants, 15 (31.3%) of whom had a positive BAL yield.  One hundred twenty-six patients were on chemotherapy and 32 (25.4%) had a positive BAL culture.  Forty-one patients were not on chemotherapy but were on immunosupressants and 14 (34.1%) had a positive BAL yield.  Eighty patients were on both chemotherapy and immunosupressants and 46 (57.5%) had a positive BAL cultur. There were 64 patients with a normal WBC count and 30 (46.9%) had a positive BAL culture.  Patients with an abnormal WBC or frank neutropenia were less likely to have a positive BAL yield with 39.8% and 27.7% positive yield, respectively. Patients who were on antibiotics for at least 24 hours were significantly less likely to have a positive BAL yield. There was no significant difference in overall distribution of pathogen type.  There was a non-significant trend toward a lower incidence of fungi in those on antibiotics for at least 24 hours.  Conclusion It is common clinical practice to perform BAL in leukemic and bone marrow transplant patients with unexplained new lung infiltrates.  This study supports the practice of obtaining a BAL specimen within 24 hours of antimicrobial therapy in leukemic and HSCT patients with unexplained new lung infiltrates, a population that is universally on antimicrobials at the time of BAL

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Combination high-dose interleukin-2 and nivolumab for programmed cell death-1 refractory metastatic melanoma: a case series

BackgroundTherapeutic options are needed for metastatic melanoma refractory to therapies directed against programmed cell death-1. High-dose interleukin-2 has the potential to overcome programmed cell death-1 resistance.Case presentationWe report three consecutive Caucasian patients, two female (60 and 55 years old) and one male (56 years old), refractory to anti-programmed cell death-1 therapy who were treated with concurrent nivolumab and standard-dosing bolus high-dose interleukin-2. We did not see any unexpected toxicities with overlapping treatments as compared with either high-dose interleukin-2 or nivolumab alone.ConclusionsThe tolerance and disease control observed among the three patients in this limited series support formal exploration of this combination

Controlling the uptake and regulating the release of nitric oxide in microporous solids

Representative compounds from three classes of microporous solids, namely metal-organic frameworks (MOFs), hybrid ultramicroporous materials (HUMs) and porous-organic polymers (POPs), were investigated for their nitric oxide gas uptake and release behavior. Low pressure sorption studies indicated strong chemisorption of NO on the free amine groups decorating the MOF UiO-66-NH2 when compared to its non-amine functionalized parent. The HUMs demonstrated reversible physisorption within the low pressure regime but interestingly in one case there was evidence for chemisorption following pressurization with NO at 10 bar. Significant release of chemisorbed NO from the UiO-66-NH2 and one of the HUMs was triggered by addition of acid to the medium, a pH change from 7.4 to 5.4 being sufficient to trigger NO release. An imidazole-based POP exhibited chemisorption of NO at high pressure wherein the ring basicity facilitated both NO uptake and spontaneous release upon contact with the aqueous release medium

A Multicenter, International Collaborative Study for AJCC-Staging of Retinoblastoma: Metastasis-Associated Mortality

Purpose: To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB). Design: International, multicenter, registry-based retrospective case series. Participants: A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Methods: Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied. Main Outcome Measures: Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the KaplaneMeier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait. Results: Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n ¼ 92) from diagnosis to metastasis was 9.50 months. The 5-year KaplaneMeier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97e99) for cT1b and cT2a, 96% (95% CI, 95e97) for cT2b, 89% (95% CI, 88e90) for cT3 tumors, and 45% (95% CI, 31e59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55e25.70; P < 0.001) and cT4 (HR, 48.55; 95% CI, 12.86e183.27; P < 0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease. Conclusions: Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.Fil: Tomar, Ankit Singh. The New York Eye Cancer Center; Estados UnidosFil: Finger, Paul T.. The New York Eye Cancer Center; Estados UnidosFil: Gallie, Brenda. The Eye Cancer Clinic, Princess Margaret Cancer Centre; CanadáFil: Mallipatna, Ashwin. Hospital for Sick Children; CanadáFil: Kivelä, Tero T.. Helsinki University Hospital; FinlandiaFil: Zhang, Chengyue. Beijing Children's Hospital; ChinaFil: Zhao, Junyang. Beijing Children's Hospital; ChinaFil: Wilson, Matthew W.. University of Tennessee; Estados UnidosFil: Kim, Jonathan. University of Southern California; Estados UnidosFil: Khetan, Vikas. Sankara Nethralaya; IndiaFil: Ganesan, Suganeswari. Sankara Nethralaya; IndiaFil: Yarovoy, Andrey. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yarovaya, Vera. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Kotova, Elena. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yousef, Yacoub A.. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. University of Helsinki; FinlandiaFil: Ushakova, Tatiana L.. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Yugay, Olga V.. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Polyakov, Vladimir G.. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Ramirez Ortiz, Marco A.. Hospital Infantil de México Federico Gómez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de México Federico Gómez; MéxicoFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. The Chinese University of Hong Kong; Hong KongFil: Lau, Winnie W.. The Chinese University of Hong Kong; Hong KongFil: Lam, Carol P.. The Chinese University of Hong Kong; Hong KongFil: Sharwood, Phillipa. University of Sydney; AustraliaFil: Moorthy, Sonia. KK Women's and Children's Hospital; SingapurFil: Long, Quah Boon. KK Women's and Children's Hospital; Singapu

Global Retinoblastoma Treatment Outcomes: Association with National Income Level

Purpose: To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels.Design: International, multicenter, registry-based retrospective case series.Participants: Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents.Methods: Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes.Main outcome measures: Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy).Results: Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P < 0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P < 0.001).Conclusions: This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage.Fil: Tomar, Ankit Singh. New York Eye Cancer Center; Estados UnidosFil: Finger, Paul T.. New York Eye Cancer Center; Estados UnidosFil: Gallie, Brenda. University of Toronto; CanadáFil: Kivelä, Tero T.. Helsinki University Hospital; Finlandia. University of Helsinki; FinlandiaFil: Mallipatna, Ashwin. University Of Toronto. Hospital For Sick Children; CanadáFil: Zhang, Chengyue. Beijing Children’s Hospital; ChinaFil: Zhao, Junyang. Beijing Children’s Hospital; ChinaFil: Wilson, Matthew W.. University of Tennessee; Estados UnidosFil: Brenna, Rachel C.. University of Tennessee; Estados UnidosFil: Burges, Michala. University of Tennessee; Estados UnidosFil: Kim, Jonathan. Keck Medical School of the University of Southern California; Estados UnidosFil: Khetan, Vikas. Sankara Nethralaya; IndiaFil: Ganesan, Suganeswari. Sankara Nethralaya; IndiaFil: Yarovoy, Andrey. The S. N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yarovaya, Vera. The S. N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Kotova, Elena. The S. N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yousef, Yacoub A.. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. Helsinki University Hospital; Finlandia. University of Helsinki; FinlandiaFil: Ushakova, Tatiana L.. N. N. Blokhin National Medical Research Center Oncology of Russian Federation; Alemania. Medical Academy of Postgraduate Education; AlemaniaFil: Yugay, Olga V.. N. N. Blokhin National Medical Research Center Oncology of Russian Federation; AlemaniaFil: Polyakov, Vladimir G.. N. N. Blokhin National Medical Research Center Oncology of Russian Federation; AlemaniaFil: Ramirez Ortiz, Marco A.. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. Chinese University Of Hong Kong; Hong KongFil: Lau, Winnie W.. Chinese University Of Hong Kong; Hong KongFil: Lam, Carol P.. Chinese University Of Hong Kong; Hong KongFil: Sharwood, Phillipa. University of Sydney; Australi

Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center.

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups