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Because of the COVID-19 pandemic, healthcare facilities have experienced pressure of increasing occupancy rates and more demanding Indoor Air Quality requirements in recent months. In this context, the efficient management of the HVAC system in these buildings has become a crucial topic to address. The retrofit project was the result of the joint effort of a digital solution provider, Enerbrain, and the Hospital’s energy services provider, Edison. By exploiting IoT and ICT technologies and cloud-based machine learning algorithms, the HVAC-related control features of the main heating and ventilation systems of the hospital have been upgraded with no major modifications to the existing setup. The implemented solution allows energy managers to remotely verify the real-time indoor comfort conditions and to control the upgraded systems, which, thanks to the machine learning adaptive algorithms, are now effectively meeting the required set-points through advanced optimization strategies. This paper presents the implementation of a retrofit measure applied to the HVAC Building Management System of a big public hospital in Lombardy and the energy savings achieved in the 2020-2021 heating season.

Molecular assessment of measurable residual disease (MRD) in NPM1-mutated AML patients is a powerful prognostic tool to identify the risk of relapse. There is limited data regarding MRD-guided decisions against alloSCT in elderly patients and FLT3-ITD co-mutation. We describe the outcome of NPM1-mutated AML patients in whom alloSCT was deferred based on ELN 2017 risk and MRD response. We report a relapse rate of 53% in this group, with a much higher incidence for older than 60 years patients than for younger patients (73% vs. 37%). When comparing outcomes of alloSCT in CR1 to intensive chemotherapy consolidation within each age group, patients over 60 years and patients with FLT3-ITD co-mutation had significantly lower RFS with intensive consolidation. Yet, in all subgroups, the lower RFS did not translate into OS difference, suggesting that relapsed NPM1 patients can often be salvaged and consequently achieve long-term remission. Our study supports the use of MRD response along with FLT3-ITD status in the decision to use post-remission therapy. We demonstrate that older patients and patients with FLT3-ITD-mutated AML have a high relapse rate but can be salvaged, leading to long-term survival., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Optical coherence tomography (OCT) representations in clinical practice are static and do not allow for a dynamic visualization and quantification of blood flow. This study aims to present a method to analyze retinal blood flow dynamics using time-resolved structural OCT., Methods: We developed novel imaging protocols to acquire video-rate time-resolved OCT B-scans (1024 × 496 pixels, 10 degrees field of view) at four different sensor integration times (integration time of 44.8 µs at a nominal A-scan rate of 20 kHz, 22.4 µs at 40 kHz, 11.2 µs at 85 kHz, and 7.24 µs at 125 kHz). The vessel centers were manually annotated for each B-scan and surrounding subvolumes were extracted. We used a velocity model based on signal-to-noise ratio (SNR) drops due to fringe washout to calculate blood flow velocity profiles in vessels within five optic disc diameters of the optic disc rim., Results: Time-resolved dynamic structural OCT revealed pulsatile SNR changes in the analyzed vessels and allowed the calculation of potential blood flow velocities at all integration times. Fringe washout was stronger in acquisitions with longer integration times; however, the ratio of the average SNR to the peak SNR inside the vessel was similar across all integration times., Conclusions: We demonstrated the feasibility of estimating blood flow profiles based on fringe washout analysis, showing pulsatile dynamics in vessels close to the optic nerve head using structural OCT. Time-resolved dynamic OCT has the potential to uncover valuable blood flow information in clinical settings.

Venetoclax, an oral BCL-2 inhibitor, has been widely incorporated in the treatment of acute myeloid leukaemia. The combination of hypomethylating agents and venetoclax is the current standard of care for elderly and patient's ineligible for aggressive therapies. However, venetoclax is being increasingly used with aggressive chemotherapy regimens both in the front line and in the relapse setting. Our growing experience and intensive research demonstrate that certain genetic abnormalities are associated with venetoclax sensitivity, while others with resistance, and that resistance can emerge during treatment leading to disease relapse. In the current review, we provide a summary of the known mechanisms of venetoclax cytotoxicity, both regarding the inhibition of BCL-2-mediated apoptosis and its effect on cell metabolism. We describe how these pathways are linked to venetoclax resistance and are associated with specific mutations. Finally, we provide the rationale for novel drug combinations in current and future clinical trials., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: High-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain., Methods: We analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes., Results: We found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m 2 increase in FA dose. We identified a threshold of 350 mg/m 2 /treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity., Conclusion: Our findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Quantitative PCR for specific mutation is being increasingly used in Acute Myeloid Leukemia (AML) to assess Measurable Residual Disease (MRD), allowing for more tailored clinical decisions. To date, standardized molecular MRD is limited to typical NPM1 mutations and core binding factor translocations, with clear prognostic and clinical implications. The monitoring of other identified mutations lacks standardization, limiting its use and incorporation in clinical trials. To overcome this problem, we designed a plasmid bearing both the sequence of the mutation of interest and the ABL reference gene. This allows the use of commercial standards for ABL to determine the MRD response in copy number. We provide technical aspects of this approach as well as our experience with 19 patients with atypical NPM1, RUNX1 and IDH1/2 mutations. In all cases, we demonstrate a correlation between response and copy number. We further demonstrate how copy number monitoring can modulate the clinical management. Taken together, we provide proof of concept of a novel yet simple tool, which allows in-house MRD monitoring for identified mutations, with ABL-based commercial standards. This approach would facilitate large multi-center studies assessing the clinical relevance of selected MRD monitoring.

Objectives: Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety., Methods: Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines., Results: ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity., Conclusions: Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The GALLIUM study showed a progression-free survival advantage of 7% in favor of obinutuzumab vs. rituximab-based immunochemotherapies as first-line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab-based therapy. This is a multicenter retrospective-cohort study including adult FL patients comparing the toxicity of first-line rituximab vs. obinutuzumab-based chemo-immunotherapies (R and O groups, respectively). We compared the best standard-of-care therapy used per time period, before and after obinutuzumab approval. The primary outcome was any infection during induction and 6 months post-induction. Secondary outcomes included rates of febrile neutropenia, severe and fatal infections, other adverse events, and all-cause mortality. Outcomes were compared between groups. A total of 156 patients were included in the analysis, 78 patients per group. Most patients received bendamustine (59%) or CHOP (31.4%) as adjacent chemotherapy. Half of the patients received growth-factor prophylaxis. Overall, 69 patients (44.2%) experienced infections, and a total of 106 infectious episodes were recorded. Patients in the R and O groups had similar rates of any infection (44.8% and 43.5%, p = 1), severe infections (43.3% vs. 47.8%, p = 0.844), febrile neutropenia (15% vs. 19.6%, p = 0.606), and treatment discontinuation, as well as similar types of infections. No covariate was associated with infection in multivariable analysis. No statistically significant difference was evident in adverse events of grades 3-5 (76.9% vs. 82%, p = 0.427). To conclude, in this largest real-life study of first-line treated FL patients comparing R- to O-based therapy, we did not observe any difference in toxicity during the induction and 6 months post-induction period., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Studies addressing coronavirus disease 2019 (COVID-19) in patients with hematological malignancies have reported mortality rates of up to 40%; however, included predominantly hospitalized patients., Methods: During the first year of the pandemic, we followed adult patients with hematological malignancies treated at a tertiary center in Jerusalem, Israel, who contracted COVID-19, with the aim of studying risk factors for adverse COVID-19-related outcomes. We used remote communication to track patients managed at home-isolation, and patient questioning to assess the source of COVID-19 infection, community versus nosocomial., Results: Our series included 183 patients, median age was 62.5 years, 72% had at least one comorbidity and 39% were receiving active antineoplastic treatment. Hospitalization, critical COVID-19, and mortality rates were 32%, 12.6%, and 9.8%, respectively, remarkably lower than previously reported. Age, multiple comorbidities, and active antineoplastic treatment were significantly associated with hospitalization due to COVID-19. Treatment with monoclonal antibodies was strongly associated with both hospitalization and critical COVID-19. In older (≥60) patients not receiving active antineoplastic treatment, mortality, and severe COVID-19 rates were comparable to those of the general Israeli population. We did not detect patients that contracted COVID-19 within the Hematology Division., Conclusion: These findings are relevant for the future management of patients with hematological malignancies in COVID-19-affected regions., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction and Objectives: Lenalidomide is considered a standard of care in multiple myeloma (MM) Some MM patients will develop delayed hypersensitivity to lenalidomide, which can lead to treatment discontinuation. Desensitization to lenalidomide can help these patients to complete treatment courses. Here, we aimed to review lenalidomide-treated MM patients who developed delayed hypersensitivity-induced rash and were treated with desensitization., Methods: A retrospective analysis of medical files of MM patients, who were desensitized to lenalidomide due to delayed hypersensitivity rash. Patients were treated between 2018 and 2022 at Hadassah Medical Center, Jerusalem, Israel., Results: Search of patients yielded 16 patients that underwent desensitization to lenalidomide within the study period. The desensitization protocol consisted of a slow, 3-week-long protocol with lenalidomide's target doses of 10, 15, and 25 mg/day. Of the 16 patients, 10 (62.5%) succeeded to complete the protocol and thus were able to complete lenalidomide treatment cycles. One patient with unsuccessful desensitization was subsequently treated with first-generation IMiD thalidomide, with no rash appearing. None of the patients that were treated with desensitization had severe immune-mediated or non-dermatological adverse reactions., Conclusions: Desensitization to lenalidomide is safe and effective. Discontinuation of lenalidomide in MM patients with delayed hypersensitivity and no contraindication to desensitization should be discouraged. Collaboration between hematologists and allergists is needed., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Therapeutic options in relapsed refractory (R/R) light-chain (AL) amyloidosis patients are limited. Given the encouraging results in t(11;14) multiple myeloma and the high prevalence of t(11;14) in AL amyloidosis, venetoclax is an attractive treatment option in this setting. We report here the results of a multi-center retrospective study on 26 R/R AL amyloidosis patients treated off-label with venetoclax. The median lines of therapy prior to venetoclax was 3.5 (range 1-7), and 88% of our cohort had t (11;14). Twenty-two patients (85%) were previously treated with daratumumab. The overall hematologic response rate was 88%, 35% achieved a CR, and 35% achieved VGPR. The median event-free survival was 25 months (m) (95% CI 9.7 m-not reached), and the median overall survival was 33 m (95% CI 25.9-39.2 m). Most of the patients in this cohort are in ongoing deep responses and continuing venetoclax therapy. The treatment was relatively safe. One patient died due to infection, and there were two grade 3 infections in our cohort. Tumor lysis syndrome (TLS) was not seen in any patient. Dose reductions were frequent but did not affect the efficacy. These promising results require confirmation in a randomized controlled trial.

Introduction: Invasive aspergillosis (IA) affects mainly patients with hematological malignancies, and early diagnosis is crucial for timely treatment. Most diagnoses are based on clinical and mycological criteria, mostly galactomannan (GM) test in serum or bronchoalveolar fluid, which is performed in case of clinical suspicion or as routine screening in patients at high risk who are not receiving anti-mold prophylaxis, for early detection of IA. The aim of this study was to assess in a real-world setting the efficacy of biweekly serum GM screening for the early detection of IA., Methods: A retrospective cohort that included 80 adult patients treated at the Hematology Department, Hadassah Medical Center, 2016-2020, with a diagnosis of IA. Clinical and laboratory data were collected from patients' medical files and the rate of GM-driven, GM-associated, and non-GM-associated IA was calculated., Results: There were 58 patients with IA. The rate of GM-driven diagnosis was 6.9%, GM-associated diagnosis was 43.1%, and non-GM-associated diagnosis was 56.9%. The GM test as a screening tool had led to IA diagnosis in only 0.2% of screened serums with a number needed to screen in order to find 1 patient with IA of 490., Conclusion: Clinical suspicion outweighs GM screening as a tool for early diagnosis of IA. Nevertheless, GM has an important role as a diagnostic tool for IA., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations.

Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Remission assessment in acute myeloid leukemia has evolved over the recent years with the advent of molecular and flow-based minimal residual disease determination. Nonetheless, early time point such as day 5 and day 14 (D14), still have prognostic and therapeutic implications. D14 refractory disease is regarded as a poor prognostic factor, however the therapeutic intervention is still under debate, with evidence suggesting a successful re-induction might offer similar long-term outcome as D14 aplasia. Others advocate the use of more intensive salvage protocols as a mean to overcome the negative prognostic effect. In the current study, we compare outcome of D14 refractory AML patients treated with either re-induction or salvage protocol. More importantly, we identify response characteristics that might suggest which patients will benefit from re-induction approach. Accurate identification of chemotherapy refractory patients might allow the early incorporation of non-chemotherapy based protocols in the future., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The lateral resolution of an optical coherence tomography (OCT) instrument was considered to be equal to the illumination spot size on the retina. To evaluate the potential lateral resolution of the Spectralis OCT, an instrument calculated to have a 14 µm resolution., Methods: The lateral point spread function (PSF) was evaluated using diamond abrasive powder 0 to 1 µm in diameter in silicone elastomer and a validated target with 800 nm FeO particles in urethane. The amplitude transfer function was calculated from human OCT images. Finally, resolution was measured using the 1951 USAF target., Results: Measurement of the lateral PSF from 1215 diamond particle images yielded a full-width half maximum (FWHM) to be 5.11 µm and for 732 FeO particles, 4.9 µm. From the amplitude transfer function, the FWHM of the diffraction limited PSF was calculated to be 5.0 µm. The USAF target imaging showed a lateral resolution of 4.6 µm., Conclusions: Although a calculation of the spot size of the illumination beam was reported in the past as the lateral resolution of the OCT instrument, the actual lateral resolution is better by a factor of at least 2.5 times. The clinically used A-scan spacing was derived from the calculated, and not the true resolution, and results in under sampling. This set of findings likely apply to all commercial clinical instruments., Translational Relevance: The scan density parameters of past and present commercial OCT instruments were based on earlier translational concepts, which now appear to have been incorrect.

Introduction: Mutated RUNX1 is considered a poor prognostic factor and usually is mutually exclusive with NPM1 mutations. Monitoring of molecular markers for minimal residual disease provides a powerful tool to assess remission and guide clinical decisions., Methods: Newly diagnosed RUNX1-mutated AML patients, designated to intensive chemotherapy-based treatment or nonintensive regimens, were monitored for mutated RUNX1 transcript levels by qPCR with patient-specific primers. Samples were obtained along the treatment course and follow-up., Results: A clear correlation was observed between mutated RUNX1 levels and response to treatment as observed by flow cytometry and STR-based assessment., Conclusion: We demonstrate the feasibility of RUNX1-based MRD to correlate with the clinicopathological status of leukemia. We further suggest how RUNX1 qPCR monitoring can influence clinical decision-making and contribute to improved personalized patient care., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease ( p  = 0.036) and mortality ( p  = 0.023), hypertension with severe/critical disease ( p  = 0.046) and hospitalization ( p  = 0.001), active haemato-oncological treatment with hospitalization ( p  = 0.009), and remdesivir treatment was associated with decreased mortality ( p  = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.

Purpose: Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL). Despite its aggressive course, PMBCL is considered curable. While in recent years dose-adjusted (DA) EPOCH-R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) has become widely endorsed as first-line therapy for newly-diagnosed PMBCL, the optimal treatment for this disease and the role of radiotherapy (RT) remains unclear. DA-EPOCH-R provides good clinical outcomes, albeit is associated with short- and long-term toxicity. To address this issue, the current retrospective bi-icenter analysis compared efficacy and toxicity of DA-EPOCH-R and a less toxic R-CHOP/R-ICE regimen used for the treatment of newly-diagnosed PMBCL., Patients and Methods: The study included all patients with a histologically confirmed PMBCL diagnosis treated with DA-EPOCH-R or R-CHOP/R-ICE between 01/2013-12/2020 at two tertiary medical centers. Patient demographic and clinical data were derived from institutional electronic medical records. The analysis included 56 patients: 31 received DA-EPOCH-R and 25 - R-CHOP/R-ICE., Results: At a median follow-up of 1.9 years (IQR 3.1 years), similar progression-free survival (2.1 versus 2.4 years; p = 0.7667), overall survival (2.5 versus 2.7 years; p = 0.8047) and complete response (80%) were observed in both groups. However, DA-EPOCH-R was associated with significantly longer hospitalization required for its administration (p < 0.001) and a trend for higher frequency of infections, stomatitis, thrombotic complications and febrile neutropenia-related hospitalizations., Conclusion: DA-EPOCH-R and R-CHOP/R-ICE provide similarly encouraging outcomes in newly-diagnosed PMBCL patients. R-CHOP/R-ICE is associated with lower toxicity and significantly reduced hospitalization. Our findings suggest that this regimen may be considered as an alternative to DA-EPOCH-R in this patient population., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Genomic discovery efforts in patients with cancer have been critical in identifying a recurrent theme of mutations in epigenetic modifiers. A number of novel and exciting basic biological findings have come from this work including the discovery of an enzymatic pathway for DNA cytosine demethylation, a link between cancer metabolism and epigenetics, and the critical importance of post-translational modifications at specific histone residues in malignant transformation. Identification of cancer cell dependency on a number of these mutations has quickly resulted in the development of therapies targeting several of these genetic alterations. This includes, the development of mutant-selective IDH1 and IDH2 inhibitors, DOT1L inhibitors for MLL rearranged leukemias, EZH2 inhibitors for several cancer types, and the development of bromodomain inhibitors for many cancer types--all of which are in early phase clinical trials. In many cases, however, specific genetic targets linked to malignant transformation following mutations in individual epigenetic modifiers are not yet known. In this review we present functional evidence of how alterations in frequently mutated epigenetic modifiers promote malignant transformation and how these alterations are being targeted for cancer therapeutics., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA mutations (p.E542K, p.E545K, p.A1046T, and p.H1047R) were detected in 7 of 55 patients, 4 of whom also had BRAF mutations. Mutant NRAS was present in peripheral blood CD14(+) cells, but not lymphoid cells, from an NRASQ61R mutant patient. Our results underscore the central role of RAS-RAF-MEK-ERK activation in ECD and identify an important role of activation of RAS-PI3K-AKT signaling in ECD. These results provide a rationale for targeting mutant RAS or PI3K/AKT/mTOR signaling in the subset of ECD patients with NRAS or PIK3CA mutations., (© 2014 by The American Society of Hematology.)

In this work absolute values of regional renal blood volume (rRBV) and flow (rRBF) are assessed by means of contrast-enhanced (CE) MRI using an intravascular superparamagnetic contrast agent. In an animal study, eight foxhounds underwent dynamic susceptibility-weighted MRI upon injection of contrast agent. Using principles of indicator dilution theory and deconvolution analysis, parametric images of rRBV, rRBF, and mean transit time (MTT) were computed. For comparison, whole-organ blood flow was determined invasively by means of an implanted flow probe, and the weight of the kidneys was evaluated postmortem. A mean rBV value of 28 ml/100 g was found in the renal cortex, with a corresponding mean rBF value of 524 ml/100 g/min and an average MTT of about 3.4 s. Although there was a systematic difference between the absolute blood flow values determined by MRI and the ultrasonic probe, a significant correlation (r(s) = 0.72, P < 0.05) was established. The influence of the arterial input function (AIF), T(1) relaxation effects, and repeated measurements on the precision of the perfusion quantitation is discussed., (Copyright 2003 Wiley-Liss, Inc.)

The interrelation between the morphologic degree of renal artery stenosis and changes in parenchymal perfusion is assessed using an intravascular contrast agent. In seven adult foxhounds, different degrees of renal artery stenosis were created with an inflatable clamp implanted around the renal artery. Dynamic susceptibility-weighted gradient-echo imaging was used to measure signal-time curves in the renal artery and the renal parenchyma during administration of 1.5 mg/kg BW of an intravascular ultrasmall particle iron oxide (USPIO) contrast agent. From the dynamic series, regional renal blood volume (rRBV), regional renal blood flow (rRBF), and mean transit time (MTT) were calculated. The morphologic degree of stenosis was measured in the steady state using a high-resolution 3D contrast-enhanced (CE) MR angiography (MRA) sequence (voxel size = 0.7 x 0.7 x 1 mm(3)). Five patients with renoparenchymal damage due to long-standing renal artery stenosis were evaluated. In the animal stenosis model, cortical perfusion remained unchanged for degrees of renal artery stenosis up to 80%. With degrees of stenoses > 80%, cortical perfusion dropped to 151 +/- 54 ml/100 g of tissue per minute as compared to a baseline of 513 +/- 76 ml/100 g/min. In the patients, a substantial difference in the cortical perfusion of more than 200 +/- 40 ml/100 g/min between the normal and the ischemic kidneys was found. The results show that quantitative renal perfusion measurements in combination with 3D-CE-MRA allow the functional significance of a renal artery stenosis to be determined in a single MR exam. Differentiation between renovascular and renoparenchymal disease thus becomes feasible., (Copyright 2003 Wiley-Liss, Inc.)

The angiotensin antagonist [Sar1-Ile8]angiotensin II was infused into the lateral ventricles of mature spontaneously hypertensive and normotensive Wistar-Kyoto rats. Infusions were maintained at rats of 1200 ng/h for 6 days, and blood pressure was measured daily in the unanesthetized state. Blood pressure reduction occurred promptly and only in the hypertensive animals. This antihypertensive effect persisted for several days after discontinuation of the infusion. In contrast, iv infusion of the angiotensin antagonist at comparable doses failed to alter blood pressure in any significant fashion. These data suggest that the brain isorenin system participates in the maintenance of hypertension in the spontaneously hypertensive rat.