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Introduction: Flexible ureteroscopy (fURS) is the most common surgical procedure for treatment of urolithiasis. Various surgical disciplines and subspecialties have examined surgeon kinematics to improve assessment and generate measures of skill. Despite frequency of utilization, there is no undisputed method for evaluating fURS skills. Our pilot study utilized kinematic evaluations of fURS simulation to determine whether specific surgeon movements, techniques, and strategies correlate with measures of ureteroscopic (URS) efficiency. Methods: A motion capture system and standard video camera were employed to characterize surgeon movement variables. A URS simulation box was used by practicing urologists at various skill levels to perform a series of simple and complex URS movement tasks. Two tasks were chosen for this initial pilot analysis. Body kinematics, time to task completion, and URS movements were analyzed. Task efficiency was defined as quicker time to task completion and smaller ureteroscope end effector travel distance. A combined performance efficiency score (PES) was calculated using the root sum square of these two measures. Results: Twelve practicing urologists were enlisted. Average urologist age was 37 years with an average of 10.1 years of training; 50% were women, 50% were residents; and 33% had completed an Endourology fellowship. For the simple task, no kinematic data correlated with PES; for the complex task, participant head and torso movement correlated with PES ( r  = 0.60, p  = 0.04 for head; r  = 0.65, p  = 0.02 for torso), with decreased body movement associated with higher efficiency. Conclusion: Our findings suggest that movement economy measures are associated with efficient URS manipulation for complex tasks. Decreased head and torso movement were associated with higher efficiency, suggesting that excess body movement may signal extraneous or improper URS movements. Additional assessment of these variables, including analysis in a clinical setting, is warranted as this may serve as a basis for improvement in endoscopic training and evaluation.

Patients with lymphoma, especially those treated with anti-CD20 monoclonal antibodies, suffer high COVID-19-associated morbidity and mortality. The goal of this study was to assess the ability of lymphoma patients to generate a sufficient humoral response after two injections of BNT162b2 Pfizer vaccine and to identify factors influencing the response. Antibody titers were measured with the SARS-CoV-2 IgG II Quant (Abbott ) assay in blood samples drawn from lymphoma patients 4 2 weeks after the second dose of vaccine. The cutoff for a positive response was set at 50 AU/mL. Positive serological responses were observed in 51% of the 162 patients enrolled in this cross-sectional study. In a multivariate analysis, an interval of <12 months between the last anti-CD20 monoclonal antibody dose and the second vaccine dose (odds ratio=31.3 [95% confidence interval: 8.4-116.9], P<0.001) and presence of active lymphoma (odds ratio=4.2 (95% confidence interval: 2.1- 8.2), P=0.006) were identified as negative response predictors. The rate of seropositivity increased from 3% in patients vaccinated within 45 days after the last monoclonal antibody administration to 80% in patients vaccinated >1 year after this therapy. The latter percentage was equal to that of patients never exposed to monoclonal antibodies. In conclusion, lymphoma patients, especially those recently treated with anti- CD20 monoclonal antibodies, fail to develop sufficient humoral response to BNT162b2 vaccine. While a serological response is not the only predictor of immunity, its low level could make this population more vulnerable to COVID-19, which implies the need for a different vaccination schedule for such patients.

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.

The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies. We compared antibody binding and live virus neutralization of sera from naturally infected and Moderna-vaccinated individuals against two SARS-CoV-2 variants: B.1 containing the spike mutation D614G and the emerging B.1.351 variant containing additional spike mutations and deletions. Sera from acutely infected and convalescent COVID-19 patients exhibited a 3-fold reduction in binding antibody titers to the B.1.351 variant receptor-binding domain of the spike protein and a 3.5-fold reduction in neutralizing antibody titers against SARS-CoV-2 B.1.351 variant compared to the B.1 variant. Similar results were seen with sera from Moderna-vaccinated individuals. Despite reduced antibody titers against the B.1.351 variant, sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351, suggesting that protective humoral immunity may be retained against this variant., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease., (© 2020 Wiley Periodicals, Inc.)

Objective: To define static, dynamic, and cognitive fit and their interactions as they pertain to exosystems and to document open research needs in using these fit characteristics to inform exosystem design., Background: Initial exosystem sizing and fit evaluations are currently based on scalar anthropometric dimensions and subjective assessments. As fit depends on ongoing interactions related to task setting and user, attempts to tailor equipment have limitations when optimizing for this limited fit definition., Method: A targeted literature review was conducted to inform a conceptual framework defining three characteristics of exosystem fit: static, dynamic, and cognitive. Details are provided on the importance of differentiating fit characteristics for developing exosystems., Results: Static fit considers alignment between human and equipment and requires understanding anthropometric characteristics of target users and geometric equipment features. Dynamic fit assesses how the human and equipment move and interact with each other, with a focus on the relative alignment between the two systems. Cognitive fit considers the stages of human-information processing, including somatosensation, executive function, and motor selection. Human cognitive capabilities should remain available to process task- and stimulus-related information in the presence of an exosystem. Dynamic and cognitive fit are operationalized in a task-specific manner, while static fit can be considered for predefined postures., Conclusion: A deeper understanding of how an exosystem fits an individual is needed to ensure good human-system performance. Development of methods for evaluating different fit characteristics is necessary., Application: Methods are presented to inform exosystem evaluation across physical and cognitive characteristics.

Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 - inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) ( p  = .001) and overall survivals (OS) ( p  = .0007). The 1-year RFS and OS were 44.2% vs 88% and 71% vs 96% for chemotherapy and ASCT, respectively. The corresponding TRM was 4/40 (10.0%) and 0/26 (0%), with relapse rates of 70.0% and 19.2% ( p  = .0002). In multivariate analysis, ASCT was associated with superior OS and RFS. In conclusion, ASCT offers significantly superior RFS and OS in favorable-risk AML in first complete remission. These data support the recent resurgence of interest in ASCT for AML.

Background: Major advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening., Aim: In this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given "on demand" according to absolute neutrophil count (ANC)., Methods: Medical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985-2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC < 1.0 × 10 [9]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [9]/L., Results: The study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim "on demand" due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44)., Conclusions: Infectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician's discretion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo-immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single-arm, phase II trial to examine the efficacy and safety of lower-dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD-FCR) in elderly patients with previously untreated CLL. Forty patients received LD-FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression-free survival (PFS) was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment-related neutropenia occurred in 20 (47.6%) patients. During the entire study follow-up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non-neutropenic infections. In conclusion, LD-FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both "time and cost limited" and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high-risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard., (© 2019 John Wiley & Sons, Ltd.)

The authors wish to make the following revisions to this paper [...].

Background/aim: In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long follow-up., Patients and Methods: Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine., Results: Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5- and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To evaluate disease characteristics and long-term outcomes in patients requiring second-line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities., Method: A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second-line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second-line therapy. Overall and event-free survival was calculated from initiation of salvage treatment (OS2/EFS2)., Results: Median follow-up for the entire cohort was 67 and 37 months from second-line therapy. TTNT < 24 months was associated with shorter OS2 and EFS2 similar to those observed with primary refractory disease (OS2 19 and 23 months; EFS2 12 and 9 months for TTNT < 24 months and SD/PD, respectively). TTNT ≥ 24 months (71% chemotherapy-based second-line), had longer OS2 and EFS2 (48 and 20 months). Among the 13 patients receiving second-line therapy after discontinuing FCR due to toxicity EFS2 was 41 months (59 months from initiation of FCR)., Conclusion: With limitations of sample size and treatment heterogeneity, patients progressing <24 months following FCR have poor outcomes, similar to refractory patients, while longer remissions are indicative of a chemoimmunotherapy sensitive disease. Patients who discontinue FCR for toxicities may achieve excellent outcomes with subsequent treatment., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Inertial measurement units (IMUs) have been demonstrated to reliably measure human joint angles&mdash;an essential quantity in the study of biomechanics. However, most previous literature proposed IMU-based joint angle measurement systems that required manual alignment or prescribed calibration motions. This paper presents a simple, physically-intuitive method for IMU-based measurement of the knee flexion/extension angle in gait without requiring alignment or discrete calibration, based on computationally-efficient and easy-to-implement Principle Component Analysis (PCA). The method is compared against an optical motion capture knee flexion/extension angle modeled through OpenSim. The method is evaluated using both measured and simulated IMU data in an observational study ( n = 15) with an absolute root-mean-square-error (RMSE) of 9.24∘ and a zero-mean RMSE of 3.49∘. Variation in error across subjects was found, made emergent by the larger subject population than previous literature considers. Finally, the paper presents an explanatory model of RMSE on IMU mounting location. The observational data suggest that RMSE of the method is a function of thigh IMU perturbation and axis estimation quality. However, the effect size for these parameters is small in comparison to potential gains from improved IMU orientation estimations. Results also highlight the need to set relevant datums from which to interpret joint angles for both truth references and estimated data., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 × 10 3 cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 × 10 3 cells/μL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC ≤ 2 × 10 3 cells/μL at 6 m (5y OS 85% vs 48%, P = .004) and ALC ≤ 1.8 × 10 3 cells/μL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (≤4 × 10 3 cells/μL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted T reg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored., (Copyright © 2017 John Wiley & Sons, Ltd.)

Introduction: Stem cell transplantation is indicated in hematological malignancies as well as some solid tumors and congenital abnormalities. Autologous transplantation allows the administration of high dose chemotherapy without prolonged bone marrow aplasia. Allogeneic transplantation allows us to give the patient a new immune system that can locate and destroy remaining tumor cells. First attempts in patients began in 1939. Improved outcomes occurred after discovering the human leukocyte antigen system which allowed for matching the donor to the patient. Immunosuppression therapy to prevent graft versus host disease also improved the outcomes. Since the 1970's, more and more centers in North America and Europe opened stem cell transplantation programs. Today it is performed worldwide and on December 2012, the one million milestone transplant worldwide was achieved. The bone marrow transplantation program started at Rambam Health Care campus on September 1995. Since then 2000 transplantations were performed at Rambam. A third of these procedures were allogeneic and two thirds were autologous. In the last decade patient survival has improved significantly due to better supportive care and the use of reduced intensity conditioning relying on the graft versus tumor effect (GVT). New ways to reduce graft versus host disease (GVHD), while improving GVT effect are based on manipulating T cells in the graft and on genetically engineered T cell with enhanced antitumor cytotoxicity. In the future, allogeneic transplantation will become more complex, more individualized and more efficient.

Nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HSCT) is a rare phenomenon usually associated with graft-versus-host disease (GVHD). This systematic review of post-HSCT NS cases reported in the literature aimed to identify risk factors and unique features of the disease in this clinical setting. One hundred sixteen cases of post-HSCT NS published in the English literature between 1988 and 2015 were revealed and analyzed. The median onset of NS was 20.5 months (range, 3 to 174) post-HSCT. NS development was associated with acute or chronic GVHD in 87.2% of cases. Membranous nephropathy (MGN) was the most frequent pathology (65.5%), followed by minimal change disease (MCD) (19%). Complete remission of the NS was achieved in 63.5% of patients (59.1% of MGN cases and 81.3% of MCD cases; P = .15). Patients presenting with MCD recovered at a median of 1.75 months (range, 1 to 12) and with MGN a median of 7 months (range, 1 to 53) (P = .001). NS was treated with corticosteroids alone in 16.8% of patients and with a combination of corticosteroids and other immunosuppressive agents in 73.5% of patients. Univariate analysis failed to identify a single predictive factor of response to therapy. In conclusion, post-HSCT NS usually develops concomitant to GVHD and is associated with high rates of response to therapy. Although most patients were treated with a combination of immunosuppressive drugs, single-agent therapy with steroids may be sufficient in some cases., (Copyright © 2015 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤ 70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m(2) or 500 mg/m(2), and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome., (Copyright© Ferrata Storti Foundation.)

Unlabelled: BACKGROUND/ AIM: The prognostic significance of hyperleukocytosis in chronic lymphocytic leukemia (CLL) remains uncertain. The aim of the present study was to evaluate the clinical characteristics and outcome of patients with CLL and white blood count (WBC) >150×10(6)/l at the time of diagnosis., Patients and Methods: Using the database of the Israeli CLL Study Group, which includes 1,507 cases, we identified 41 patients diagnosed with WBC >150×10(6)/l and analyzed the survival in the group that was 62 months compared to 174 months in patients without hyperleukocytosis (p<0.001). However, multivariate analysis demonstrated that the WBC count had no predictive value in relation to survival time. While in the entire patient cohort advanced age and Binet stage, presence of thrombocytopenia and ZAP-70 expression were independently associated with poor prognosis, these parameters lost their prognostic value in patients with hyperleukocytosis., Conclusion: Although our results do not confirm that high initial levels of WBC are independently associated with shorter survival in CLL, the clinical course in these cases appears to be aggressive and conventional prognostic factors are not valid in this patient sub-group., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)