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In 2008, the Veterans Health Administration (VHA) established a suicide high-risk flag (HRF) for patient records. To inform ongoing suicide prevention activities as part of operations and quality improvement work in the U.S. Department of Veterans Affairs, the authors evaluated suicide risk following HRF activations and inactivations.For annual cohorts of VHA users, HRF receipt and demographic and clinical care contexts in the 30 days before HRF activations were examined for 2014-2016 (N=7,450,831). Veterans were included if they had VHA inpatient or outpatient encounters during the index or previous year. Suicide rates in the 12 months after HRF activations and inactivations were assessed. Using multivariable Cox proportional hazards regression, the authors compared suicide risk following HRF activation and inactivation with veterans without HRFs, adjusted for age, gender, and race-ethnicity.HRF activation (N=47,015) was commonly preceded within 30 days by a documented suicide attempt (39.5%) or inpatient mental health admission (40.1%). Suicide risk was elevated in the 12 months after flag activation (crude suicide rate=682 per 100,000 person-years, adjusted hazard ratio [HR]=21.00, 95% confidence interval [CI]=18.55-23.72) compared with risk among VHA users without HRF activity. Risk after HRF inactivation (N=41,251) was also elevated (crude suicide rate=408 per 100,000 person-years, adjusted HR=12.43, 95% CI=10.57-14.63) compared with risk among VHA users without HRF activity.Suicide risk after HRF activation was substantially elevated and also high after HRF inactivation. Findings suggest the importance of comprehensive suicide risk mitigation and support recent VHA process enhancements to formalize inactivation criteria and support veterans after HRF inactivation.

Purpose Curative intended treatment is challenging in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and associated with a dismal prognosis for long-term survival. Despite novel treatment options, the majority of patients are treated with chemotherapy-based regimens. Although widely used, little data exist on the combination of fludarabine, cytarabine, granulocyte colony stimulating factor (FLAG) and mitoxantrone as salvage strategy for r/r AML. Materials and methods Sixty-six patients receiving Mito-FLAG for r/r AML treated at a German tertiary care center between 2009 and 2019 were analyzed with regard to response rates, survival and safety profile. Results Overall response rate was 75.8% with 56.1% of patients achieving complete remission (CR) and 19.7% partial remission (PR). After a median follow-up of 54 months, median overall survival (OS) was 13 months. Patients transitioned to allogeneic hematopoietic stem cell transplantation (alloHSCT) (75.8%) showed a significant improvement in OS with a median OS of 17 (95% CI 8.5–25.4) months vs 3 (95% CI 1.7–4.3) months (p Conclusion The Mito-FLAG salvage protocol represents an effective and feasible treatment regimen for r/r AML. Importantly, a high rate of transition to successful alloHSCT with the aim of long-term disease-free survival has been shown.

Patients with acute myeloid leukaemia (AML) have a five-year survival rate of 28·7%. Natural killer (NK)-cell have anti-leukaemic activity. Here, we report on a series of 13 patients with high-risk R/R AML, treated with repeated infusions of double-bright (CD56bright /CD16bright ) expanded NK cells at an academic centre in Brazil. NK cells from HLA-haploidentical donors were expanded using K562 feeder cells, modified to express membrane-bound interleukin-21. Patients received FLAG, after which cryopreserved NK cells were thawed and infused thrice weekly for six infusions in three dose cohorts (106 -107 cells/kg/infusion). Primary objectives were safety and feasibility. Secondary endpoints included overall response (OR) and complete response (CR) rates at 28-30 days after the first infusion. Patients received a median of five prior lines of therapy, seven with intermediate or adverse cytogenetics, three with concurrent central nervous system (CNS) leukaemia, and one with concurrent CNS mycetoma. No dose-limiting toxicities, infusion-related fever, or cytokine release syndrome were observed. An OR of 78·6% and CR of 50·0% were observed, including responses in three patients with CNS disease and clearance of a CNS mycetoma. Multiple infusions of expanded, cryopreserved NK cells were safely administered after intensive chemotherapy in high-risk patients with R/R AML and demonstrated encouraging outcomes.

PURPOSE Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. MATERIALS AND METHODS The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. RESULTS Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. CONCLUSION Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.

INTRODUCTION A Sysmex XN-series hematology analyzer (Sysmex), the next generation up from the Sysmex XE-series, can provide information regarding malaria infection in the form of a parasitic red blood cell (pRBC) flag. This study aimed to determine the usefulness of the pRBC flag for early detection and follow-up in patients infected with Plasmodium vivax. METHODS A total of 221 patients with fever for whom CBC and malaria microscopy had been requested were analyzed. Sixty-seven individuals were diagnosed with P vivax infection, and 154 were diagnosed with other febrile diseases. The sensitivity and specificity of the pRBC flag for malaria parasite detection and the relationship between parasite density and presence of the pRBC flag were determined. The concordance rate between malaria microscopy and pRBC flag in 147 follow-up cases was calculated. RESULTS The pRBC flag was detected in 56 of 67 malaria patients (sensitivity, 83.6%; specificity, 100%). The patients with the pRBC flag at initial diagnosis revealed significantly higher parasite density than the patients without the pRBC flag (P

We retrospectively compared the outcomes of 20 patients receiving Venetoclax + low-dose Cytarabine + Actinomycin D (ACTIVE) with 29 patients receiving FLAG-Ida as salvage therapy for relapsed or refractory AML (R/R AML) after alloSCT. The groups were statistically balanced according to age, performance status, cytogenetics, and previous treatment. The overall response rate (CR + CRp + MLFS) of ACTIVE was 75% (15/20) in comparison to 66% (19/29) in the FLAG-Ida group (p = 0.542). The cumulative CR + CRp rate was significantly higher in the ACTIVE group compared to FLAG-Ida (70% (14/20) vs. 34% (10/29), respectively, p = 0.02). All three patients failing previous Venetoclax therapy and five out of seven patients with previous FLAG-Ida exposure achieved a CR/CRp after ACTIVE induction. ACTIVE patients survived longer compared to FLAG-Ida patients (13.1 vs. 5.1 months, respectively, p = 0.032). The treatment-related mortality was 0% in the ACTIVE group and 34% (10/29) in the FLAG-Ida patients (p = 0.003). The cumulative incidence of relapse did not differ between the two treatment groups. ACTIVE appears to have comparable antileukemic activity and lower toxicity compared to FLAG-Ida resulting in improved survival. Patients with Venetoclax or FLAG-Ida exposure responded to ACTIVE.

Background FLAG ± Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), is a salvage chemotherapy regimen for relapsed or refractory (R/R) acute myeloid leukemia (AML), with complete remission (CR) rates historically ranging from 52% to 63%. We review the outcomes for patients with R/R AML treated with FLAG ± Ida at the University of California Davis Comprehensive Cancer Center. Patients and Methods Adult patients (≥ 18 years) with R/R AML who received FLAG or FLAG + Ida from January 1, 2012 to October 31, 2016 were identified via chart review. Outcomes evaluated were CR, CR with incomplete hematologic recovery (CRi), overall response rate, overall survival (OS), relapse-free survival, and adverse events. Results Forty-two patients were included. The median age was 52 years (range, 23-73 years), and 57% were male. Sixteen (38.1%) patients had relapsed disease, and 26 (61.9%) had refractory disease. Most (n = 35; 83.3%) patients had European LeukemiaNet intermediate-risk AML. Responses were CR in 20 (47.6%) and CRi in 6 (14.3%). The median OS was 10 months (range, 0.8-51 months), and the median relapse-free survival was 12 months (range, 1-51 months) for responders. The median OS for patients who achieved CR was not reached, and the estimated 48-month survival rate was 56%. The median OS after CRi or no response was 3.47 and 2.17 months, respectively. The median OS was not significantly different when censored for stem cell transplant following chemotherapy, nor with use/deferral of idarubicin. The most common adverse effects were pancytopenia and infection. Conclusion Patient outcomes after treatment with FLAG ± Ida for R/R AML remain similar to prior reports, confirming its role as a salvage regimen for these patients.

Background and objectives Our study sought to evaluate and compare different prediction scores for massive transfusion in-hospital packed red blood cell (PRBC) transfusions. Materials and methods Between January 2013 and December 2018, 1843 trauma patients were enrolled in the registry of a level-1 trauma centre. All prehospital and in-hospital variables needed to calculate the Shock Index and RED FLAG, Assessment of Blood Consumption (ABC) and Trauma Associated Severe Hemorrhage (TASH) scores were prospectively collected in the registry. The primary endpoint was the initiation of transfusion within the first hour of the patient's arrival at the hospital. Results A total of 1767 patients were included for analysis with a mean age of 43 years (±19) and a mean Injury Severity Score of 15 (±14). The in-hospital TASH score had the highest predictive performance overall (area under the curve [AUC] = 0.925, 95% confidence interval [CI] [0.904-0.946]), while the RED FLAG score (AUC = 0.881, 95% CI [0.854-0.908]) had the greatest prehospital predictive performance compared to the ABC score (AUC = 0.798, 95% CI [0.759-0.837]) and Shock Index (AUC = 0.795, 95% CI [0.752-0.837]). Using their standard thresholds, the RED FLAG score was the most efficient in predicting early transfusion (sensitivity: 87%, specificity: 76%, positive predictive value: 25%, negative predictive value: 99%, Youden index: 0.63). Conclusion The RED FLAG score appears to outperform both the ABC score and the Shock Index in predicting early in-hospital transfusion in trauma patients managed by pre-hospital teams. If adopted, this score could be used to give advance warning to trauma centres or even to initiate early transfusion during pre-hospital care.

Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm (

A dry tap obtained on bone marrow aspiration is considered a failure to aspirate marrow particles. However, it is often related to an underlying bone marrow pathology that hinders successful aspiration of hematopoietic cells. In this retrospective analysis, 2768 bone marrow aspirates and trephine biopsies were reviewed. Of these, 223 patients with bone marrow aspirations which yielded no marrow particles (dry tap) were included in the study. Patients in whom adequate trephine biopsy could not be obtained were excluded from the study. The final diagnosis was made by studying the trephine biopsy and correlating it with other ancillary investigations. Of the 2768 bone marrow aspirations studied, dry tap was seen in 223 (8.0%) patients. Of these, 209 (93.7%) patients had an underlying bone marrow pathology while 14 (6.3%) patients had dry tap due to faulty technique. Hematological malignancies were seen in 164 (73.5%) patients, benign hematological disorders in 33 (14.9%) patients while 4% patients had non-hematological disorders. Among hematological malignancies, leukemia (acute and chronic) was the commonest cause of a dry tap seen in 40.3% of the patients. Dry tap obtained on bone marrow aspiration should serve as a red flag for the hematologist rather than a failed procedure. In most cases, it indicates the possibility of underlying bone marrow pathology. Trephine biopsy should always be studied in such cases.

Irritable bowel syndrome (IBS) affects 10% to 15% of the population and often is difficult to treat with available pharmacologic agents. Dietary therapies for IBS are of particular interest because up to 90% of IBS patients exclude certain foods to improve their gastrointestinal symptoms. Among the available dietary interventions for IBS, the low FODMAP diet has the greatest evidence for efficacy. Although dietary therapies rapidly are becoming first-line treatment of IBS, gastroenterologists need to be aware of the negative effects of prescribing restrictive diets and red flag symptoms of maladaptive eating patterns.

Introduction Most Hirschsprung's disease (HD) are diagnosed in young children with increased risk (”red flag”). Older children (>6 months) require open rectal biopsy (ORB) with its own impact on risk and resources. We investigated if “red flag”, age, and sex used in combination could exclude HD. Materials and Methods “Red flags” are risk factors associated with HD, including neonatal bowel obstruction, genetic association, failure of passage of meconium in Results A total of 187 children underwent 84 suction rectal biopsies and 113 ORBs (n = 197 in total). Final histopathological diagnoses were non-HD (n = 154) and HD (n = 43). Total 78% of rectal biopsies were non-HD, of which 63% by ORB. Non-HD was associated with absence of “red flag” (49 vs. 16%*), increased age at biopsy (22 months vs. 28 days*), >6 months old (62 vs. 30%*), and female gender (54 vs. 16%*), compared with HD. In the absence of “red flag,” 7/82 (9%) had HD (negative predictive value = 91%). Logistic regression analysis found absent “red flag” predicted non-HD biopsy with odds ratio 4.77 (1.38, 16.47), corrected for age and sex. Conclusion Negative rectal biopsy rate for HD is very high. The majority required ORB. Although “red flag” and gender, but not age, have strong predictive values, it is inadequate for excluding HD. This study supports the need for alternative strategies in excluding HD.

Aim. To assess the efficacy, safety, and tolerance of gemtuzumab ozogamicin (GO) combined with FLAG/FLAG-Ida chemotherapy or azacitidine in patients with relapsed/refractory acute myeloblastic leukemia (AML) in clinical practice. Materials & Methods. The study included 32 patients (16 men and 16 women). The median age was 44 years (range 23-83 years). Among them there were 15 (46.8 %) patients with refractory and 17 (53.2 %) patients with relapsed AML. GO combined with FLAG/FLAG-Ida was administered to 15 (46.8 %) patients, whereas 17 (53.2 %) patients were treated with GO and azacitidine combination. Therapy safety was assessed according to CTCAE v. 5.0. Results. Overall response rate including complete remission (CR), CR MRD-, CR with incomplete hematologic recovery, and morphologic leukemia-free status was 59.4 % (19/32). Refractoriness was observed in 31.25 % (10/32) of patients. Early mortality was 9.4 % (3/32). Overall response was 64.7 % (11/17) in the azacitidine and 53.3 % (8/15) in the FLAG/FLAG-Ida groups. In 4 (80 %) out of 5 patients with prior to FLAG treatment refractoriness, the response was achieved after GO + azacitidine therapy. In 58.9 % (10/17) of patients who received GO + azacitidine therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be performed. The incidence of GO infusion complications in the tested groups did not significantly differ (p = 0.72) and was 46.7 % (7/15) (40 % with grade 1/2 and 6.7 % with grade 3) in the GO + FLAG/FLAG-Ida group and 35.3 % (6/17) (29.4 % with grade 1/2 and 5.9 % with grade 4) in the GO + azacitidine group. In the GO + FLAG/FLAG-Ida group 5 (33.3 %) patients experienced serious adverse events (SAE) of sepsis. In the GO + azacitidine group SAEs were reported in 6 (35.3 %) patients: 4 (66.6 %) with sepsis, 1 (16.7 %) with acute cardiovascular failure, and 1 (16.7 %) with acute respiratory failure. The median (range) duration was 23 (10-39) days for neutropenia grade 4, 24 (11-38) days for neutropenia grade 3, 21 (11-41) days for thrombocytopenia grade 4, 26 (16-45) days for thrombocytopenia grade 3, and 25 (22-45) days for thrombocytopenia grade 1/2. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy, however, no significant differences were identified. No cases of veno-occlusive liver disease were reported. Median overall survival (OS) for both groups (n = 32) was 31.4 months, median disease-free survival (n = 21) was 13.3 months. In the group of patients with effective treatment, the median OS was not reached. In non-responders, it was 18 months (р = 0.0442). Conclusion. GO combined with FLAG/FLAG-Ida chemotherapy or azacitidine proved effective in relapsed/refractory AML patients. Remission did not appear to be associated with ELN risk, gender, age, CD33 expression, number of prior therapy lines, or number of relapses. GO + azacitidine combination showed efficacy, safety, and good tolerance in patients with prior high-dose chemotherapy refractoriness as well as low ECOG performance status. That allowed for the subsequent allo-HSCT administration to these patients. There was no significant difference between the groups of patients in the incidence of hematologic, non-hematologic toxicity, and time to hematologic recovery. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy which is consistent with literature data. GO-based effective treatment in relapsed/refractory AML considerably improves OS: during 36 months of follow-up the median was not reached.

INTRODUCTION: Sysmex XN-9100™ (Sysmex, Kobe, Japan) system has an optional White Progenitor Cell (WPC) channel. While the White Differentiation (WDF) channel reports a combined flag for blasts/abnormal lymphocytes, WPC channel specifies flagging into a separate flag for each cell type or removes the flag entirely. Aim of this study was to evaluate the added value of this WPC channel in the detection of malignant samples. METHODS: Routine blood samples analyzed on Sysmex XE-5000 with flagging for either blasts, abnormal lymphocytes, or atypical lymphocytes (n = 630) were selected for testing on Sysmex XN-9100, resulting in a reflex WPC analysis in 420 samples. All samples were microscopically evaluated with DI-60 digital cell imaging analyzer. RESULTS: WPC reflex testing resulted in a suspect flag ("blasts" and/or "abnormal lymphocytes") in 334 samples, which was confirmed microscopically in 38% (128/334). In all true positive samples, WPC correctly classified the initial WDF flag in either "blasts" flag or "abnormal lymphocytes?" flag in 75%. Only 12% (50/420) of WDF "blasts/abnormal lymphocytes" positive samples became negative after WPC reflex testing. Subgroup analysis showed differences between the "pediatric" versus "adult" groups and the "hematological/chemotherapy" versus "nonhematological/nonchemotherapy" groups in specificity and smear reduction. CONCLUSION: Overall, WPC reflex testing showed good sensitivity (99%); however, the specificity remains poor (29%). Using reflex WPC to the WDF channel resulted in a 12% reduction of the smear review rate. Although the WPC channel offers different interesting advantages, additional topics and a specific workflow should be applied to optimize the use of this channel. ispartof: INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY vol:43 issue:2 pages:191-198 ispartof: location:England status: published

Sequential protocols combining salvage chemotherapy with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute myeloid leukemia (AML) have been studied more than a decade. Purpose of this retrospective analysis was to evaluate the anti-leukemic efficacy and toxicity of FLAG-IDA protocol (fludarabine, cytarabine, and idarubicin) followed by treosulfan-based conditioning for patients with active AML. From January 2014 to November 2019, a total of 29 active AML patients [median age, 64 years (range, 23–73)] were treated. All patients completed protocol regimen and were transplanted. Five patients (17%) had grade 3–4 toxicities; therefore, treosulfan was substituted with total body irradiation (TBI) non-myeloablative conditioning. Six (20%) patients died within 30 post-transplant days, all from infectious complications. Out of 23 evaluable patients on day 30, 22 (96%) achieved complete hematologic remission with full donor chimerism. Non-relapse mortality (NRM) rates at 1 and 3 years were 22% and 49%, respectively. Median overall survival (OS) was 12 (95% CI, 4–20) months. OS and disease-free survival were 50% and 46% at 1 year and 28% and 17% at 2 years, respectively. Age, gender, disease burden, number of previous lines, and comorbidity score did not predict survival. Sequential strategy combining FLAG-IDA and treosulfan may offer a salvage option for few selected patients with active AML; however, high NRM presents a major obstacle to treatment success. Future efforts should focus on reducing NRM by moderating regimen intensity and by better selection of patients.

Introduction Our goal was to evaluate if traffic-light driven personalized care for COVID-19 was associated with improved survival in acute hospital settings. Methods Discharge outcomes were evaluated before and after prospective implementation of a real-time dashboard with feedback to ward-based clinicians. Thromboembolism categories were “medium-risk” (D-dimer >1000 ng/mL or CRP >200 mg/L); “high-risk” (D-dimer >3000 ng/mL or CRP >250 mg/L) or “suspected” (D-dimer >5000 ng/mL). Cytokine storm risk was categorized by ferritin. Results 939/1039 COVID-19 positive patients (median age 67 years, 563/939 (60%) male) completed hospital encounters to death or discharge by 21st May 2020. Thromboembolism flag criteria were reached by 568/939 (60.5%), including 238/275 (86.6%) of the patients who died, and 330/664 (49.7%) of the patients who survived to discharge, p < 0.0001. Cytokine storm flag criteria were reached by 212 (22.6%) of admissions, including 80/275 (29.1%) of the patients who died, and 132/664 (19.9%) of the patients who survived, p < 0.0001. The maximum thromboembolism flag discriminated completed encounter mortality (no flag: 37/371 [9.97%] died; medium-risk: 68/239 [28.5%]; high-risk: 105/205 [51.2%]; and suspected thromboembolism: 65/124 [52.4%], p < 0.0001). Flag criteria were reached by 535 consecutive COVID-19 positive patients whose hospital encounter completed before traffic-light introduction: 173/535 (32.3% [95% confidence intervals 28.0, 36.0]) died. For the 200 consecutive admissions after implementation of real-time traffic light flags, 46/200 (23.0% [95% confidence intervals 17.1, 28.9]) died, p = 0.013. Adjusted for age and sex, the probability of death was 0.33 (95% confidence intervals 0.30, 0.37) before traffic light implementation, 0.22 (0.17, 0.27) after implementation, p < 0.001. In subgroup analyses, older patients, males, and patients with hypertension (p ≤ 0.01), and/or diabetes (p = 0.05) derived the greatest benefit from admission under the traffic light system. Conclusion Personalized early interventions were associated with a 33% reduction in early mortality. We suggest benefit predominantly resulted from early triggers to review/enhance anticoagulation management, without exposing lower-risk patients to potential risks of full anticoagulation therapy.

Aims. Giardia is sometimes missed by the pathologist, and we sought to determine how often this occurs at our institution—a large tertiary care center with a subspecialty gastrointestinal pathology service and what certain clinical and histologic clues can be used to flag cases with a higher likelihood of infection, targeting them for greater scrutiny. Methods and Results We identified a set of patients who tested positive for Giardia with a stool-based test, and who also received a small bowel biopsy at a similar time-point. These biopsies were retrospectively reviewed for Giardia, finding 8 positive cases. The organism was prospectively detected in 4 cases (50%) but overlooked in the remaining 4 cases (50%). Three of the 4 cases missed cases showed only rare organisms. The detected cases tended to more frequently have prominent lymphoid aggregates (3 detected cases, 0 overlooked cases) and intraepithelial lymphocytosis (3 detected cases, 0 overlooked cases). Certain clinical and histologic clues can be used to flag cases with a higher likelihood of infection. Specifically, we found abnormalities of the mucosa (active inflammation, intraepithelial lymphocytosis, villous expansion, prominent lymphoid aggregates) in each case, and 4 of 8 cases were from immunocompromised patients. Finally, 2 of 8 cases were terminal ileum biopsies. Conclusions Biopsies with a histologic abnormality or those from immunocompromised patients should receive greater attention. Routinely looking for Giardia at that terminal ileum is necessary.

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).

Reasons for delayed presentation in cancer are reported as patient or professional delays. Studies have examined patient demographic factors associated with presentation delay, but it is currently unknown why patients feel they delayed presenting. Questionnaire study of consecutive patients attending an urgent suspicion of cancer clinic at a tertiary referral centre in Glasgow over a 3-month period. 395 patients were included. 53 (13%) patients waited 0–7 days, 164 (41%) patients 1–4 weeks, 139 (35%) 1–12 months and 31 (8%) waited longer than 12 months, before presenting. 8 (3%) did not state length of time before presentation. 123 (31%) patients were not worried about their symptoms. 5 of the 13(38%) patients diagnosed with head and neck cancer, waited up to 12 months. 5 (38%) cancer patients delayed presentation because they were not worried about symptoms. Patients with head and neck cancer are not worried about their symptoms and delay their presentation, possibly contributing towards later stage diagnosis.

Acute myeloid leukemia (AML) is a biologically heterogeneous disease of the hematopoietic system characterized by clonal accumulation and expansion of immature myeloid cells in the bone marrow. Unfortunately, with current treatment strategies, only approximately 35–40% of patients at least 60 years and 5–15% of patients older than 60 years are cured of this disease [1]. Even with adaptation of cytogenetic and molecular risk-stratified therapies, 10–40% of patients do not achieve a complete remission (CR) after intensive induction therapy and are deemed to have primary refractory disease. Refractory disease is defined by the European LeukemiaNet (ELN) as the inability to attain CR or complete remission with incomplete hematologic recovery (CRi) after two courses of intensive induction treatment. Of note, this definition is not consistent throughout the literature [2]. Although some patients are able to achieve CR, greater than 50% of these patients subsequently experience disease relapse [3]. For patients who relapse, only a small fraction undergo successful salvage treatment with ability to attain a second CR [3]. Additionally, these patients are often not candidates for aggressive treatment (i.e. allogeneic stem cell transplant [alloHSCT]) given comorbid conditions and lack of suitable donors. Therefore, this leaves a large unmet clinical need for treatment of both relapsed and refractory (R/R) AML. Open in a separate window Box 1 no caption available

The aimof this study was to identify cytotoxic activity and to compare severity of cytotoxic activity of de-alcoholized alcohol-water extracts obtained from the leaves and roots of Sweet Flag (Acorus Calamus L.) on rat bone marrow cells in vitro. Rat bone marrow cells were isolated from the femoral diaphysis of the animals under cold temperatures. To obtain various concentrations of extract from the leaves (LEA) and roots REA, the initial extracts (concentration 1.0 g/mL) were immunologically titrated by rolling method. A quantitative assessment of cytotoxicity was made by testing plasma membrane damage in the Trypan Blue dye exclusion test. It was found that the cytotoxicity of a substance obtained from the roots of Sweet Flag (REA) depends on the dose and time of contact with rat bone marrow. REA has a cytotoxic effect at concentrations of 0.03-1.65 g/mL. When in contact with rat bone marrow cells for 15 minutes it causes an increase in the number of dead cells by 0.48–1.56×106per milliliter (p The substance obtained from the leaves of Sweet Flag (LEA) does not cause cell membrane destruction and does not have a significant effect on the viability of rat bone marrow cells in all studied concentrations

Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases. We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used. Forty-seven patients were included in the study; of these, 61% had a classical ‘distal demyelinating pattern’, 34.2% had a ‘CIDP-like pattern’, and the others had an ‘axonal pattern’. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination. Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a ‘red flag’ for the prompt initiation of rituximab to try to delay long-term disability.

Objective: The objective of this study was to determine whether patients with rhinitis medicamentosa (RM) have an increased odds of having an opioid use disorder (OUD) and which characteristics may predict this association. Methods: The authors conducted a retrospective case control study of patients 18 years and older who presented to the otolaryngology clinic at an academic medical center from January 2013 through December 2017. Cases, defined as patients who presented with excessive decongestant nasal spray usage based on history, were matched to control patients who presented with chronic rhinitis and did not report regular nasal decongestant usage. The charts were reviewed for patients that carried a problem of opioid abuse, identified using ICD-9 codes 304.XX or ICD-10 codes F11.XX. The primary outcome of this study was the odds of having an OUD. Secondary outcomes were assessed by summary statistics. Results: One hundred and thirty-one cases of RM were matched to 1871 controls of chronic rhinitis. Seven cases (5.3%) and 24 (1.3%) controls had a diagnosis of OUD, consistent with an odds ratio of 3.98 for opioid abuse in patients with RM (95% CI: 1.47-9.71). Oxymetazoline was used by 85.5% (n = 112) of patients with RM. Thirty-six patients (27.1%) with RM underwent nasal surgery following a diagnosis of RM, of which twenty patients (55.6%) were prescribed opioids following the procedure. Conclusions: RM is associated with increased odds of having an OUD.

Background Gas in the renal excretory system is described as a consequence of recent procedures but it can be a sign of severe conditions such as fistulas or infections; however, gas-containing renal stones are only rarely encountered. Purpose To describe the association of gas-containing renal stones and urinary tract infection. Material and Methods We performed a retrospective evaluation of the clinical and imaging findings in a series of six patients with gas-containing renal stones and compared our findings with those of patients with gas-containing renal stones reported in the literature. Urine and stone cultures were used as a diagnostic standard for urinary tract infection. Results Including the present series, there is a total of 21 patients with gas-containing renal stones in the literature. Based on clinical presentation, urinary tract infection could be suspected in 10 (57%) patients, while urine and/or stone cultures showed infection in 18 of 19 (95%) patients, with only one case with no bacterial growth in both (5%); in the remaining patient the information was not available. Conclusion Gas-containing renal stones are a rarely reported entity usually diagnosed with computed tomography. They are a radiological sign often associated with urinary tract infection that can also be encountered in patients with non-specific renal symptoms.

We present our experience on the use of fludarabine, cytarabine, granulocyte colony-stimulating factor in combination with Bortezomib. In total, 13 children with relapsed/refractory leukemia (acute lymphoblastic leukemia=9 and acute myeloid leukemia=4) were included from January 2018 to May 2019. Culture-positive sepsis and intensive care unit admission rates were 38% and 30%, respectively, with no postchemotherapy mortality in this cohort. Morphologic remission was documented in 92% and negative minimal residual disease was achieved in 61%, with 100% remission in those with acute myeloid leukemia. These results bear significant relevance in developing countries where multidrug-resistant sepsis is on the rise.

Introduction Dental infection can progress to life-threatening cervicofacial and deep space infections. Therefore, safe management requires early identification of serious infections in primary care with appropriate referral to secondary care. We have developed an acronym to aid assessment of the red flag clinical features for serious dental infection in primary care by general dental practitioners. Materials and methods Literature review and focus group discussions. Results We introduce the FATLIPS acronym for assessment of red flag features of dental infection: failed previous treatment(s), airway compromise, trismus, look (lower border mandible, orbit, oral, neck), immunosuppression, pyrexia, swallowing difficulties. Conclusion We propose the FATLIPS red flags acronym to help dentists assess the red flag features of dental infections in primary care., Key points The FATLIPS acronym aids assessment of red flag features for serious and severe dentofacial infection.The FATLIPS acronym is a simple aide-mémoire for use by dentists in primary care.The FATLIPS acronym can aid communication between dentists in primary and secondary care.

Background Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients. Findings We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients’ age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0–9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7–20.8, p p = 0.213). Conclusion Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.

Genetic alterations in the RUNX1 gene are associated with benign and malignant blood disorders, particularly of megakaryocyte and myeloid lineages. The role of RUNX1 in acute lymphoblastic leukemia (ALL) is less clear, particularly how germline genetic variation influences the predisposition to this type of leukemia. Sequencing 4,836 children with B-ALL and 1,354 cases of T-ALL, we identified 31 and 18 germline RUNX1 variants, respectively. RUNX1 variants in B-ALL consistently showed minimal damaging effects. By contrast, 6 T-ALL-related variants result in drastic loss of RUNX1 activity as a transcription activator in vitro. Ectopic expression of dominant-negative RUNX1 variants in human CD34+ cells repressed differentiation into erythroid, megakaryocytes, and T cells, while promoting myeloid cell development. Chromatin immunoprecipitation sequencing of T-ALL models showed distinctive patterns of RUNX1 binding by variant proteins. Further whole genome sequencing identified JAK3 mutation as the most frequent somatic genomic abnormality in T-ALL with germline RUNX1 variants. Co-introduction of RUNX1 variant and JAK3 mutation in hematopoietic stem and progenitor cells in mice gave rise to T-ALL with early T-cell precursor phenotype. Taken together, these results indicated that RUNX1 is an important predisposition gene for T-ALL and pointed to novel biology of RUNX1-mediated leukemogenesis in the lymphoid lineages.

The National Database of Nursing Quality Indicators (NDNQI, 2020) defines a patient fall as an unplanned descent to the floor with or without injury. A fall occurs in 30%-50% of hospitalized patients with cancer in the United States (Jatoi, 2017). According to the Joint Commission (2015), the average cost of each fall with injury in the United States was about $14,000 to the healthcare system, averaging about $50 billion annually (Kartiko et al., 2020). Fall-related injuries to patients can result in additional treatment, hospital admissions, prolonged hospital stays, delays in cancer treatment, immobility, pain, emotional distress, caregiver fatigue, and depression (Joint Commission, 2015). Patients with cancer are highly susceptible to falls because of the neurologic deficits caused by chemotherapy treatments, medications given to prevent side effects, allergic reactions to the chemotherapy medications, increasing age, cognitive status, disease site, and cancer- and treatment-related fatigue (Jatoi, 2017). The high financial costs to patients and healthcare providers, as well as the physical and mental impact on patients, led to this pilot project.

Introduction: Vitamin K antagonist therapy is safest and most effective with a high time within the therapeutic range (TTR). The TTR is difficult to calculate in the consultation room, therefore physicians need an easier-to-use tool to predict poor VKA control.We explored the prognostic value of subtherapeutic INRs on future TTR in two settings:(1) Clinical review setting, where a physician (bi) annually reviews a patient and uses the INRs since the last visit to predict the TTR up to the next visit;(2) Day-to-day INR management setting, where every new INR measurement prompts a new prediction over the next 90 days.Materials and methods: Retrospective cohort of 17,711 patients from a dedicated thrombosis service, using acenocoumarol (target range 2.0-3.0), with a "streak" defined as four consecutive INRs(1) Odds ratios of any streak in the last 180 days or 1 year on a TTR (2) Odds ratio of a current streak on a TTR Results and conclusions: Clinical review setting: The occurrence of any streak in the last 180 days or 1 year increased the odds of a TTR Day-to-day INR management setting: A current streak increases the odds of poor TTR over the next 90 days 3.58 (95% CI 2.64-4.87) fold.We conclude that a streak of four consecutive subtherapeutic INRs can aid physicians in flagging at-risk patients.

BackgroundPublic awareness of ‘red flag’ symptoms for head and neck cancer is low. There is a lack of evidence regarding patient concerns and expectations in consultations for cancer assessment.MethodThis prospective questionnaire study examined the symptoms, concerns and expectations of 250 consecutive patients attending an ‘urgent suspicion of cancer’ clinic at a tertiary referral centre.ResultsThe patients’ most frequent responses regarding their concerns were ‘no concerns’ (n = 72, 29 per cent); ‘all symptoms’ were a cause for concern (n = 65, 26 per cent) and ‘neck lump’ was a symptom causing concern (n = 37, 17 per cent). The expectations of patients attending clinic were that they would find out what was wrong with them, followed by having no expectations at all. Overall patient knowledge of red flag symptoms was lacking and their expectations were low.ConclusionPatients with non-cancer symptoms are frequently referred with suspected cancer. Patients with red flag symptoms are not aware of their significance and they have low expectations of healthcare.

OBJECTIVES: We investigated whether patients with chronic obstructive pulmonary disease could safely receive noninvasive ventilation outside of the ICU. DESIGN: Retrospective cohort study. SETTING: Twelve states with ICU utilization flag from the State Inpatient Database from 2014. PATIENTS: Patients greater than or equal to 18 years old with primary diagnosis of acute exacerbation of chronic obstructive pulmonary disease and secondary diagnosis of respiratory failure who received noninvasive ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Multilevel logistic regression models were used to obtain hospital-level ICU utilization rates. We risk-adjusted using both patient/hospital characteristics. The primary outcome was in-hospital mortality; secondary outcomes were invasive monitoring (arterial/central catheters), hospital length of stay, and cost. We examined 5,081 hospitalizations from 424 hospitals with ICU utilization ranging from 0.05 to 0.98. The overall median in-hospital mortality was 2.62% (interquartile range, 1.72–3.88%). ICU utilization was not significantly associated with in-hospital mortality (β = 0.01; p = 0.05) or length of stay (β = 0.18; p = 0.41), which was confirmed by Spearman correlation (ρ = 0.06; p = 0.20 and ρ = 0.02; p = 0.64, respectively). However, lower ICU utilization was associated with lower rates of invasive monitor placement by linear regression (β = 0.05; p < 0.001) and Spearman correlation (ρ = 0.28; p < 0.001). Lower ICU utilization was also associated with significantly lower cost by linear regression (β = 14.91; p = 0.02) but not by Spearman correlation (ρ = 0.09; p = 0.07). CONCLUSIONS: There is wide variability in the rate of ICU utilization for noninvasive ventilation across hospitals. Chronic obstructive pulmonary disease patients receiving noninvasive ventilation had similar in-hospital mortality across the ICU utilization spectrum but a lower rate of receiving invasive monitors and probably lower cost when treated in lower ICU-utilizing hospitals. Although the results suggest that noninvasive ventilation can be delivered safely out- side of the ICU, we advocate for hospital-specific risk assessment if a hospital were considering changing its noninvasive ventilation delivery policy. (Crit Care Med 2019; XX:00–00)

Gastric outlet obstruction is a common condition in which mechanical obstruction in the distal stomach, pylorus, or duodenum causes nausea, vomiting, abdominal pain, and early satiety. This article reviews the changing etiology of this disorder and advances in its treatment.

Cancer of unknown primary (CUP) denotes cancer cases where metastatic spread is histologically confirmed, but no respective primary tumor can be identified. The challenging diagnosis of CUP is further complicated in cases with previously identified malignancies or with dubious clonal relationship between metastatic sites due to ambiguous histology. Our study aims at elucidating clonal relationships by comparing the respective mutational spectra. Targeted next-generation sequencing (NGS) employing formalin-fixed and paraffin-embedded (FFPE) tumor tissue was performed on 174 consecutive CUP patients. Among these, 43/174 (24.7%) patients had a documented prior malignancy. Data on pairwise targeted NGS testing to address clonal relationships between the previous malignancy and the presumed CUP (n = 11) or between different CUP metastatic sites (n = 7) was available in 18 patients. NGS could clarify clonal relationships in 16/18 cases. Among the 11 CUP patients with antecedent malignancies, four cases were clonally independent of the previous malignancy but harbored deleterious germline mutations in BRCA/BAP1/ATM genes. Seven CUP cases were clonally related to the antecedent malignancy, changing the CUP diagnosis to relapse of the prior malignancy. In the seven CUP cases, with doubtfully related metastatic sites, NGS confirmed clonal relationship in five cases and was inconclusive in two. In conclusion, NGS proved an efficient tool to elucidate clonal relationships in clinically challenging CUP cases. Our study cautions against a premature diagnosis of CUP. Relapses of antecedent malignancies should be carefully considered. CUPs clonally independent from the antecedent malignancy should raise a red flag of a potential cancer-predisposing germline mutation.

BACKGROUND: Automated hematology analyzers often generate many flags which can provide important clues to the underlying hematological abnormality. Although pathologists are generally well versed in recognizing the importance of flags indicating potential leukemic blasts, their utility in hinting toward infectious etiology, especially during epidemics, is less well known. We analyzed any abnormal flags generated by a three-part automated hematology analyzer in serologically confirmed cases of dengue. MATERIALS AND METHODS: The study included 28 patients diagnosed with serologically confirmed dengue infection. The venous samples were run on ABX Miros-60 three-part hematology analyzer. The complete blood count data and any abnormal flags were noted and correlated with peripheral blood film findings in all patients. RESULTS: An abnormal white blood cell (WBC) flag was noted in all 28 patients, including two in whom all other hematological parameters were within normal limits. In 26 (93%) patients, M2G1G2 WBC flag was noted while the samples of the remaining two patients generated M2G1 and L1M2G1G2 WBC flags, respectively. CONCLUSION: An abnormal WBC flag, when correlated in appropriate clinical context, especially during a dengue outbreak, can aid in targeting the cohort of patients who will require immediate referral for serological confirmation.

Given the poor prognosis of patients with relapsed/refractory acute myeloid leukemia (AML), better therapy is needed. Fludarabine enhances the efficacy of Ara-C (cytarabine) by increasing intracellular Ara-C-triphosphate. The FLAG (fludarabine, high-dose Ara-C, supported with granulocyte colony-stimulating factor) regimen has been tested for use in AML patients by other investigators. In the phase II study reported here, we evaluated the efficacy and toxicity of FLAGM therapy (FLAG with mitoxantrone), further intensified by adding mitoxantrone, based on the results of a phase I study by our group. The major endpoints were complete remission (CR) rate and early death. From June 2004 to February 2008, 41 patients (median age 52 years; range 18-64 years) were enrolled. Thirty (73% 95% CI 58-84%) patients achieved CR, which met the primary endpoint; there was a single case of early death from pneumonia. Two-year overall survival was 39.4% (95% CI 25.2-55.6%). Of those who achieved CR, 27 underwent allogeneic stem cell transplantation (SCT), and 12 SCT recipients showed long-term survival. Grade 3/4 non-hematological adverse events included infection (59%), nausea/vomiting (15%), diarrhea (7%), and elevated liver enzymes (7%). In conclusion, FLAGM is an effective and safe salvage therapy for patients with relapsed/refractory AML, and facilitated SCT for a large proportion of patients.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML). Materials & Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18-70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28th day after the start of treatment. WT1 gene expression was evaluated on the 14th-16th day of treatment. Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14th-16th day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with < 10 % blast cells in BM (89.6 %; p = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; p = 0.03). Median DFS in patients with WT1 expression reduction to < 1 log on the 14th-16th day was 5 vs. 18 months in patients without WT1 expression reduction (p = 0.01). DFS varied in groups of patients with blast cell count < 10 % in BM on the 14th-16th day of treatment based on the level of WT1 expression reduction (p = 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, p = 0.02; median OS was 19 vs. 6.9 months, p = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, p = 0.039; median not reached vs. 10.2 months, p = 0.039). Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14th-16th day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Objective Diagnosis of AML requires additional procedures, including pathological examination, immunophenotyping, cytogenetic examination, and molecular diagnosis. The determination of the specific cytogenetic abnormality is important for the selection of appropriate treatment and prognostic analysis.The 2 most common mutations of the FLT3 gene are FLT3-ITD and FLT3-D835. Here, we will present FLT3-ITD positive AML cases admitted to our clinic between 2019-2021. Case report We have 5 cases of AML FLT3-ITD heterozygous. In all our cases, Midastaurin was given with 7+3 chemotherapy (CT) in the initial treatment. While 1 of our cases went into remission, the other 4 relapsed. All of the patients who relapsed were given FLAG CT, no remission was achieved and they were switched to ADE CT. Remission was achieved in 2 of 4 patients, 2 of them were refractory. One patient was given gilteritinib. HSCT was performed in 2 patients. While 2 of our patients are dead, 2 of them are in remission and 1 of our patients is still under treatment. Results FLT3 gene mutations are strongly associated with leukocytosis and poor prognosis in patients with AML(1-3). Patients with any of these mutations have a higher risk of recurrence and a lower survival rate3. All of our patients had leukocytosis at the time of diagnosis. Four of our patients relapsed and all of these patients were refractory to chemotherapy. Our patients who were refractory to treatment had a high mortality rate (50%) and a lower survival time (8-12 months). Conclusion FLT3 signaling inhibitors have been used both alone and in combination to improve clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy provides clinical response, its efficacy is usually temporary and resistance develops rapidly. Various combination therapies are used to enhance efficacy and prevent or overcome resistance. More studies are needed to evaluate its efficacy and explain the development of resistance.

OBJECTIVE This study aimed to explore the correlation of long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) expression with clinicopathological features and its predictive value for treatment response and survival profiles in refractory or relapsed acute myeloid leukemia (R/R AML) patients. METHODS Seventy three R/R AML patients who received cladribine combined with cytarabine and granulocyte colony-stimulating factor (G-CSF) (CLAG) or fludarabine combined with cytarabine and G-CSF (FLAG) based chemotherapy and 37 non-malignant controls were recruited. LncRNA TUG1 expression was detected in bone marrow sample obtained before treatment. Complete response (CR), partial response (PR), overall response rate (ORR) and overall survival (OS) were evaluated. RESULTS LncRNA TUG1 expression was upregulated in R/R AML patients compared to controls. It was also elevated in R/R AML patients with age ⩾ 60 years (vs. age < 60 years, P= 0.030) and in patients with secondary AML (vs. primary AML, P= 0.035). R/R AML patients with lncRNA TUG1 high expression achieved numerically lower CR (P= 0.053), decreased ORR (P= 0.028) and shorter OS (P< 0.001) than patients with lncRNA TUG1 low expression. Univariate logistic regression and COX's regression disclosed that lncRNA TUG1 high expression correlated with declined ORR, numerically decreased CR, and reduced OS. Furthermore, multivariate analyses verified that lncRNA TUG1 high expression was an independent predictive factor for decreased ORR and worse OS. CONCLUSIONS In conclusion, lncRNA TUG1 expression was elevated in R/R AML patients, and it might serve as a potential biomarker for poor prognosis in R/R AML patients treated with CLAG or FLAG based chemotherapy.

Background Outcomes of relapsed/refractory childhood acute leukemia remain poor. We analyzed the safety/efficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, with/without idarubicin (FLAG ± IDA) as salvage therapy compared with recent published results of novel therapies. Methods This retrospective study included children aged 1 to 15 years with relapsed/refractory acute leukemia who received FLAG ± IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded. Result Fifty patients were identified: 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG ± IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG ± IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% ± 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p = 0.001). Conclusion Despite a 68% complete remission rate using FLAG ± IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens.

Background Patients with acute myeloid leukemia (AML) treated with intensive chemotherapy may require re-induction based on the evaluation of day 14 bone marrow biopsy. Methods : A retrospective chart review was performed to evaluate adult patients with AML who received re-induction with fludarabine, high dose cytarabine and granulocyte colony stimulating factor (FLAG) regimen for residual disease (≥ 5% blasts by morphology) on day 14 bone marrow examination between September 2012 and July 2017 at our institution. Results We identified 27 patients who received FLAG therapy for treatment of residual disease on day 14 marrow examination following initial induction. The median age at diagnosis was 61 years and the majority of patients had poor risk AML. The overall response rate was 78% and 15 patients proceeded to allogeneic hematopoietic stem cell transplantation. Conclusion The regimen was well tolerated and is a viable re-induction option for patients with residual disease on a day 14 bone marrow.

During the COVID-19 pandemic an outbreak of chilblain lesions has been described worldwide. The relationship with SARS-CoV-2 infection is still debated. Emerging literature regarding this possible correlation focuses on two hypotheses: an endothelial infection or the result of an IFN type I-mediated immune response.

Otitis externa is an infection of the external auditory canal. It rarely results in facial palsy except in severe cases such as necrotizing otitis externa, which is a life-threatening invasive infection of the external auditory canal. Early recognition with prompt and appropriate treatment of necrotizing otitis externa is crucial to prevent more sinister complications. Here we report a case of an elderly gentleman who presented with otitis externa and developed facial palsy a month later. We identified possible problems that may have led to the complication so that such an occurrence can be prevented in the future.

Background Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. Materials and Methods We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. Results The median age was 68 years (range 21−77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. Conclusion The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.