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Abstract The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2−/−γc −/− MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the minimal deleted region (MDR) encoding the DLEU2/miR-15a/miR-16-1 cluster. This model provides an innovative and faster CLL system where monocyte differentiation and macrophage polarization are exacerbated, and T-cells are dysfunctional. MDR deletion inversely correlates with the levels of predicted target proteins including BCL2 and PD1/PD-L1 on murine CLL cells and immune cells. The inverse correlation of miR-15a/miR-16-1 with target proteins has been confirmed on patient-derived immune cells. Forced expression of miR-16-1 interferes with monocyte differentiation into tumor-associated macrophages, indicating that selected ncRNAs drive the protumor phenotype of non-malignant immune cells.

Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system involvement, termed neuropsychiatric SLE (NPSLE). Central nervous system (CNS) vasculitis is one of the neurological pathologies seen in CNS lupus. Patients with NPSLE typically present with nonspecific symptoms such as headache and cognitive impairment. Due to a lack of specific neuroradiological findings, diagnosis and management of such patients remain a big challenge. We report a 5-year-old girl who presented with fever and headache as the only neurological symptoms. Magnetic resonance imaging (MRI) of the brain showed focal grey and white matter lesions, suggestive of inflammatory or demyelinating ethology. Even though MR imaging findings may not be diagnostic of CNS lupus vasculitis, the study is routinely performed as a part of initial evaluation in patients with juvenile SLE showing neurological signs and symptoms.

Leukemic masses are a known complication in patients with hematologic malignancies. Here we present a case regarding a patient with recently diagnosed B-acute lymphoblastic leukemia (B-ALL) who presented with multiple sites of extramedullary involvement including an anterior mediastinal mass. This mass persisted despite multiple rounds of multiagent cytotoxic therapy. In this report, we summarize the literature regarding mediastinal masses in the setting of B-ALL and illustrate that such masses in patients with leukemias may have surprising etiology, separate from the primary disease.

Background: Accidental ingestion of foreign bodies in children is critical, as the inability to effectively communicate can potentially lead to devastating consequences. We aimed to determine the epidemiology of foreign body ingestion and variability according to age, gender, type, and location of foreign body, and describe its management. Aim and Objective: The aim was to study the various types of foreign body ingestions in children admitted to pediatric surgery and their management. Materials and Methods: A retrospective study was conducted from January 2020 to June 2022 on children under the age of 12 years with a confirmed diagnosis of foreign body ingestion. Patients were clinically and radiologically assessed, after which standard protocols were followed wherein patients were followed by either observation or emergent management. Emergent management included removal of the foreign body by either endoscopy or surgery. Comparisons among multiple age groups, gender, type of foreign body, location of foreign body, and their management were analyzed. Results: Out of 99 subjects in our study, there were 76 boys and 23 girls. The median age of presentation was 5 years. Most children were asymptomatic at presentation. The most frequently ingested foreign body was a coin in all age groups. The majority of the foreign bodies were suspected to be in the small bowel. The foreign bodies that had crossed the duodenojejunal flexure (n = 74, 74.7%) were managed conservatively with the observation of a variable period of a minimum of 24 h and a maximum of 48 h. 21 cases were managed by endoscopic removal, while three cases required surgical intervention. Conclusions: Overall, the most common gastrointestinal foreign body was a coin in all age groups. Button battery is the most worrisome foreign body; however, depending on its position, it can be managed conservatively. Upper GI foreign bodies can be safely removed endoscopically. Parental counseling is very important for the prevention of ingestion of foreign bodies.

Abstract Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate that was first evaluated in B-cell lymphomas but was subsequently shown to be highly effective in acute lymphoblastic leukemia (ALL). INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval in the United States in 2017. While the formal approval for INO is as monotherapy in relapsed/refractory ALL, subsequent studies with INO administered in combination with chemotherapy and/or blinatumomab both in the frontline and salvage settings have yielded promising results. In this review, we discuss the clinical development of INO in ALL, highlighting lessons learned from the initial clinical trials of INO, as well as the many ongoing studies that are seeking to expand the role of INO in ALL.

Abstract Background To determine the effectiveness of applying the Sydney Triage to Admission Risk Tool (START) in conjunction with senior early assessment in different Emergency Departments (EDs). Methods This multicentre implementation study, conducted in two metropolitan EDs, used a convenience sample of ED patients. Patients who were admitted, after presenting to both EDs, and were assessed using the existing senior ED clinician assessment, were included in the study. Patients in the intervention group were assessed with the assistance of START, while patients in the control group were assessed without the assistance of START. Outcomes measured were ED length of stay and proportion of patients correctly identified as an in-patient admission by START. Results A total of 773 patients were evaluated using the START tool at triage across both sites (Intervention group n = 355 and control group n = 418 patients). The proportion of patients meeting the 4-hour length of stay thresholds was similar between the intervention and control groups (30.1% vs. 28.2%; p = 0.62). The intervention group was associated with a reduced ED length of stay when compared to the control group (351 min, interquartile range (IQR) 221.0–565.0 min versus 383 min, IQR 229.25–580.0 min; p = 0.85). When stratified into admitted and discharged patients, similar results were seen. Conclusion In this extension of the START model of care implementation study in two metropolitan EDs, START, when used in conjunction with senior early assessment was associated with some reduced ED length of stay.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Not available.

Abstract Background Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax. Methods This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m2 IV on days 1–7, venetoclax at maximum dose of 200-400 mg orally on days 1–21 (AML cohort) or days 1–14 (MDS/CMML cohort) and pevonedistat 20 mg/m2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort. Findings Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61–86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3–4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance. Conclusions The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157).

Abstract Background Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. Methods Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. Results Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. Conclusion Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

Abstract Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65–70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.

Abstract Distributing cryptographic keys over public channels in a way that can provide information-theoretic security is the holy grail for secure communication. This can be achieved by exploiting quantum mechanical principles in so-called quantum key distribution (QKD). Continuous-variable (CV) QKD based on coherent states, in particular, is an attractive scheme for secure communication since it requires only standard telecommunication technology that can operate at room temperature. However, a recently discovered side-channel created in the process of state preparation leads to a leakage of information about the transmitted quantum state, opening a security loophole for eavesdroppers to compromise the security of the CVQKD system. Here, we present a CVQKD system without this modulation leakage vulnerability. Our implementation is based on a baseband modulation approach and uses an in-phase and quadrature (IQ) modulator for state preparation and radio frequency heterodyne detection together with carefully designed digital signal processing for state measurement. We consider practical aspects in the implementation and demonstrate the generation of a composable secret key secure against collective attacks. This work is a step towards protecting CVQKD systems against practical imperfections of physical devices and operational limitations without performance degradation.

Continuous-variable QKD protocols are usually easier to implement than discrete-variables ones, but their security analyses are less developed. Here, the authors propose and demonstrate in the lab a CVQKD protocol that can generate composable keys secure against collective attacks.

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

Background: Shoulder ultrasound is a well-established point-of-care diagnostic modality in orthopaedic and sports medicine. Despite offering measurements of high-quality morphology, this methodology has faced several challenges, including variability in ultrasound systems, operator dependency, and lack of reliable and objective quantitative measures to track disease progression and responses to therapeutic interventions. Computer-aided quantitative ultrasound algorithm (CAQUSA) is an emerging novelty that automates the detection of normal and abnormal structures. Although CAQUSA has been shown to improve detections and diagnoses of soft tissue lesions, the proof-of-concept of utilizing CAQUSA to measure subacromial space width and its encroachment to the rotator cuff tendon have not been tested to assist in clinical decision-making for subacromial pain syndrome.Objective: This study aimed to develop a CAQUSA that measured the acromiohumeral distance (AHD) and test the algorithm’s reliability and agreement with manual measurements in wheelchair users with spinal cord injury (SCI).Methods: 116 ultrasound video clips recorded from 10 manual wheelchair users with SCI were evaluated manually by an experienced examiner with expertise in AHD examination and by the CAQUSA, which was developed for bone segmentation with probability mapping. The reliability and agreement of the diagnostic performance between the examiner and the CAQUSA were calculated and compared in both groups of AHD measurements.Results: The CAQUSA achieved a satisfactory agreement between computer-aided (11.95 ± 2.29 mm) and manual (11.33 ± 2.48 mm) measurements. The intraclass correlation coefficient between the two measures was excellent (ICC = 0.95). The sensitivity was 0.2 mm, with 95% true positives and 5% false positives at the fixed threshold of CAQUSA.Conclusion: AHD measurements made by the clinical observer were similar to that of the CAQUSA for assessing the clinical metrics related to subacromial pain syndrome. However, the CAQUSA showed greater reliability in its unclear or misleading image analysis. Based on the findings of this proof-of-concept study, the CAQUSA has promise for clinical utilization and interchangeability to minimize examiner-dependent errors and potentially reduce the cost of care.

Abstract In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a clinical trial. Triplet therapy was associated with significantly higher rates of complete remission (CR) (67% versus 32%, P = 0.002), CR/CRi (93% versus 70%, P = 0.02), FLT3-PCR negativity (96% versus 54%, P 0.5 (40 versus 21 days, P = 0.15) and platelet > 50 K (29 versus 25 days, P = 0.6) among responders was numerically longer with triplets, but 60-day mortality was similar (7% v 10%). With a median follow-up of 24 months (median 12 months for triplet arm, and 63 months for doublet arm), patients receiving a triplet regimen had a longer median overall survival (not reached versus 9.5 months, P

A case of intussusception may be missed on initial presentation, if the physician is not vigilant or if non-specific symptoms are present. It may progress to prolapse per anus, if not attended to. We reported a case of intussusception, i.e. missed on the initial presentation by a local practitioner and progressed to prolapse per anus and perforation peritonitis. The patient was managed well and experienced an uneventful course.

Subarachnoid fat is an uncommon finding that has several etiologies. It is important to determine the etiology in order to plan appropriate treatment. We present a case report of an 80-year-old female brought to the emergency department after a fall with complaints of headache and pain in the sacral region. Computed tomography and magnetic resonance images of the head demonstrated fat in the subarachnoid space. Computed tomography and magnetic resonance images of the sacrum demonstrated a Tarlov cyst with a sacral fracture extending into the cyst, likely representing the origin of the fat in the subarachnoid space. This case demonstrates a rare etiology of fat in the subarachnoid space.

Abstract The secret key rate of a continuous-variable quantum key distribution (CV-QKD) system is limited by excess noise. A key issue typical to all modern CV-QKD systems implemented with a reference or pilot signal and an independent local oscillator is controlling the excess noise generated from the frequency and phase noise accrued by the transmitter and receiver. Therefore accurate phase estimation and compensation, so-called carrier recovery, is a critical subsystem of CV-QKD. Here, we explore the implementation of a machine learning framework based on Bayesian inference, namely an unscented Kalman filter (UKF), for estimation of phase noise and compare it to a standard reference method and a previously demonstrated machine learning method. Experimental results obtained over a 20-km fibre-optic link indicate that the UKF can ensure very low excess noise even at low pilot powers. The measurements exhibited low variance and high stability in excess noise over a wide range of pilot signal to noise ratios. This may enable CV-QKD systems with low hardware implementation complexity which can seamlessly work on diverse transmission lines.

Security analyses for trusted quantum random number generators usually consider only classical side-information. Here, the authors fill this gap by fully characterising the experimental apparatus of a homodyne-based QRNG, assuming that the vacuum fluctuations and noise are stationary and Gaussian.

Pancreas is an exceptionally rare location for desmoid tumors. There are very few case reports of pancreatic fibromatosis in the English radiology literature. We present a case of a 45-year-old male with a mixed solid and cystic desmoid tumor of the pancreas which was surgically resected and was followed by recurrence in the mesentery. This will be the first case report of pancreatic desmoid with documented recurrence of fibromatosis in the mesentery which was also surgically resected and confirmed on pathology. In this case report, we discuss this entity's radiological findings with pathology correlation, clinical findings and management along with literature review.

Ureteral complications after open aortoiliac reconstruction for aneurysmal and occlusive disease have been reported previously. However, ureteral complications from endovascular interventions for iliac artery disease are relatively rare. We describe a case of left ureteral stenosis resulting in hydroureteronephrosis after multiple endovascular interventions involving the left common and external iliac arteries. The intraoperative findings during robotic ureterolysis revealed significant peri-iliac fibrosis and scarring in the area of the iliac stents. This case illustrates that, although uncommon, ureteral stenosis may occur after iliac stenting owing to peristent fibrosis.

B-cell receptor (BCR) signaling pathway and Bcl-2 family prosurvival proteins, specifically Bcl-2 and Mcl-1, are functional in the pathobiology of chronic lymphocytic leukemia (CLL). A pivotal and apical molecule in the BCR pathway is Bruton’s tyrosine kinase (BTK). Together, BTK, Bcl-2, and Mcl-1 participate in the maintenance, migration, proliferation, and survival of CLL cells. Several ongoing and published clinical trials in CLL reported high rates of remission, namely, undetectable measurable residual disease (u-MRD) status with combined BTK inhibitor ibrutinib and Bcl-2 antagonist, venetoclax. While the majority of patients achieve complete remission with undetectable-measurable residual disease, at least one third of patients do not achieve this milestone. We hypothesized that cells persistent during ibrutinib and venetoclax therapy may be sensitive to combined venetoclax and Mcl-1 inhibitor, AMG-176. To test this hypothesis, we took peripheral blood samples at baseline, after Cycle 1 and Cycle 3 of ibrutinib monotherapy, after one week and 1 cycle of ibrutinib plus venetoclax therapy. These serial samples were tested for pharmacodynamic changes and treated in vitro with AMG-176 or in combination with venetoclax. Compared to C1D1 cells, residual cells during ibrutinib and venetoclax treatment were inherently resistant to endogenous cell death. Single agent exposure induced some apoptosis but combination of 100 nM venetoclax and 100 or 300 nM of AMG-176 resulted in 40–100% cell death in baseline samples. Cells obtained after four cycles of ibrutinib and one cycle of venetoclax, when treated with such concentration of venetoclax and AMG-176, showed 10–80% cell death. BCR signaling pathway, measured as autophosphorylation of BTK was inhibited throughout therapy in all post-therapy samples. Among four anti-apoptotic proteins, Mcl-1 and Bfl-1 decreased during therapy in most samples. Proapoptotic proteins decreased during therapy. Collectively, these data provide a rationale to test Mcl-1 antagonists alone or in combination in CLL during treatment with ibrutinib and venetoclax.

The involvement of the cervix as a site of relapse for hematologic malignancies is rare. We herein present a case of relapsed B-cell Acute Lymphoblastic Leukemia/Lymphoma (ALL) mimicking advanced cervical cancer. The patient is a 61-year-old female with history B-cell ALL and had multiple relapses confined to the bone marrow and had received several different chemotherapy regimens. She presented with lower abdominal pain after the end of her last cycle for which an MRI abdomen and pelvis was done and it showed the presence of an asymmetrical cervical mass. Further imaging included a PET-CT showing the presence of hypermetabolic cervical mass with left pelvic and retroperitoneal lymph node involvement. She underwent a biopsy of 3 distinct lesions in the cervix and vagina and a diagnosis of relapsed B-cell ALL was confirmed in two out of the three specimens. Keywords: Hematologic malignancy, Diagnosis - relapse, Cervical cancer

Abstract Background Patients with CML treated with TKI can have a life expectancy comparable to that of the general population. Due to the extended duration of TKI administration, treatment discontinuation has been increasingly sought. Methods Medical records of 100 patients with CML who were in MR4.5 and discontinued their TKI outside clinical trials were reviewed. Results After a median follow-up of 30 months (range, 5–112 months) after discontinuation, 35% and 17% lost MR4.5 and major molecular response (MMR), respectively. Only six patients lost MMR 12 months or more after discontinuation. Loss of MR4.5 was observed in 29% and 7% of patients with sustained MR4.5 duration of more than 2 and 6 years before discontinuation, respectively. By univariate analysis, there was a higher risk of loss of MR4.5 for patients who were treated for less than 87 months, received second or subsequent line TKI, never received interferon, or those with sustained MR4.5 for less than 6 years. By multivariate analysis, sustained MR4.5 for 6 years or more was the only significant predictor for durable response. Overall, 30% of patients who discontinued while in MR4.5 were retreated with 93% regaining MR4.5 at a median of 5 months. Conclusion These results demonstrate that under proper conditions, treatment discontinuation is feasible outside of clinical trial setting. MR4.5 duration of 6 years or more before discontinuation is associated with very low risk of loss of MR4.5.

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.

Importance: Coronavirus 2019 pandemic (COVID 19) is caused by the Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) virus. The pandemic is affecting the livelihood of millions of people all over the world. At the time of preparing this report, the pandemic has affected 1 827 284 patients, with 113 031 deaths in 185 countries as per Johns Hopkins University. With no proven treatment for the disease, prevention of the disease in the community and healthcare setting is need of the hour. Objective: To perform a comprehensive literature search for preventive measures and experimental treatment options. In this review, we have focused our discussion on the risk of disease transmission, supportive treatment, and possible treatment options based on available evidence. Evidence Review: We performed a literature search on google scholar, PubMed, and society guidelines for literature related to COVID 19 and previous coronavirus pandemics. We included data review articles, observational studies, and controlled trials to synthesize the treatment options for COVID 19. Findings: In this article, we have extensively reviewed and discussed recommendations from various world organizations for the public and healthcare workers. We have also discussed currently available experimental treatments since there is no proven treatment for COVID 19. The best method of dealing with the current outbreak is to reduce the community spread and thus “flatten the curve.” Although Hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir, and Azithromycin have been tried, passive immunity through convalescent serum and vaccine is still at an experimental stage. Patients with severe COVID 19 infections could be considered for this experimental treatment through various national randomized control trials, which may eventually lead to an evidence-based treatment strategy. Conclusions and Relevance: Awareness of currently available experimental treatment among healthcare providers and exploration of possible treatment options through evidence is need of the hour. We have discussed the most recently available literature and evidence behind experimental treatment in this article.

Mixed phenotype acute leukemia (MPAL) is a rare leukemia that presents both myeloid and lymphoid markers on blasts. Here the authors perform genomic analysis to show MPAL involves genetic and epigenetic heterogeneity and is genetically distinct from AML, B-ALL, and T-ALL.

Many enzymes, particularly in one single family, with highly conserved structures and folds exhibit rather distinct substrate specificities. The underlying mechanism remains elusive, the resolution of which is of great importance for biochemistry, biophysics, and bioengineering. Here, we performed a neutron scattering experiment and molecular dynamics (MD) simulations on two structurally similar CYP450 proteins; CYP101 primarily catalyzes one type of ligands, then CYP2C9 can catalyze a large range of substrates. We demonstrated that it is the high density of salt bridges in CYP101 that reduces its structural flexibility, which controls the ligand access channel and the fluctuation of the catalytic pocket, thus restricting its selection on substrates. Moreover, we performed MD simulations on 146 different kinds of CYP450 proteins, spanning distinct biological categories including Fungi, Archaea, Bacteria, Protista, Animalia, and Plantae, and found the above mechanism generally valid. We demonstrated that, by fine changes of chemistry (salt-bridge density), the CYP450 superfamily can vary the structural flexibility of its member proteins among different biological categories, and thus differentiate their substrate specificities to meet the specific biological needs. As this mechanism is well-controllable and easy to be implemented, we expect it to be generally applicable in future enzymatic engineering to develop proteins of desired substrate specificities.

Abstract We demonstrate the experimental feasibility of a Trojan-horse attack that remains nearly invisible to the single-photon detectors employed in practical quantum key distribution (QKD) systems, such as Clavis2 from ID Quantique. We perform a detailed numerical comparison of the attack performance against Scarani-Ac´ın-Ribordy-Gisin (SARG04) QKD protocol at 1924 nm versus that at 1536 nm. The attack strategy was proposed earlier but found to be unsuccessful at the latter wavelength, as reported in N. Jain et al., New J. Phys. 16, 123030 (2014). However at 1924 nm, we show experimentally that the noise response of the detectors to bright pulses is greatly reduced, and show by modeling that the same attack will succeed. The invisible nature of the attack poses a threat to the security of practical QKD if proper countermeasures are not adopted.

Abstract Prolonged treatment of tuberculosis (TB) often leads to poor compliance, default and relapse, converting primary TB patients into category II TB (Cat IITB) cases, many of whom may convert to multi-drug resistant TB (MDR-TB). We have evaluated the immunotherapeutic potential of Mycobacterium indicus pranii (MIP) as an adjunct to Anti-Tubercular Treatment (ATT) in Cat II pulmonary TB (PTB) patients in a prospective, randomized, double blind, placebo controlled, multicentric clinical trial. 890 sputum smear positive Cat II PTB patients were randomized to receive either six intra-dermal injections (2 + 4) of heat-killed MIP at a dose of 5 × 108 bacilli or placebo once in 2 weeks for 2 months. Sputum smear and culture examinations were performed at different time points. MIP was safe with no adverse effects. While sputum smear conversion did not show any statistically significant difference, significantly higher number of patients (67.1%) in the MIP group achieved sputum culture conversion at fourth week compared to the placebo (57%) group (p = 0.0002), suggesting a role of MIP in clearance of the bacilli. Since live bacteria are the major contributors for sustained incidence of TB, the potential of MIP in clearance of the bacilli has far reaching implications in controlling the spread of the disease.

Background: A female neonate with anorectal malformation (ARM) may have one, two, or three openings in the perineum. One opening represents cloaca while three openings usually suggest low ARM. Females with two openings in the perineum may be ARM without any fistula, rectovaginal fistula, or absent vagina. The association of ARM with multiple intestinal atresias and malrotation is rare. Case Presentation: We present here a case of a female neonate with two perineal openings, whose perineum was explored by a general surgeon without any radiological investigation and was later found to have a high ARM, multiple jejunal and ileal atresia with malrotation. Conclusion: ARM associated with small bowel atresia and malrotation are rarely described. Such cases require management in Pediatric surgery settings.